General Principles of Drug Therapy of Pregnant Women
The processes of evaluating potential adverse effects of various drugs in preclinical and clinical trials are described in Chapter 1. Unfortunately, these trials often do not provide sufficient information regarding safety in pregnant women or children. Individuals at the extremes of the age spectrum are particularly vulnerable to the toxic effects of drugs (see Chapter 4). The very young are susceptible due either to incomplete development of certain organs (e.g., the kidney) or the lack of expression of certain drug-metabolizing or transport proteins that play key pharmacokinetic roles (Kearns et al., 2003); the elderly are at increased risk due to age-related changes in body composition, organ function, and drug-metabolizing systems, all of which delay drug clearance (Mangoni and Jackson, 2003).
In pregnant women, the placenta provides a barrier for the transfer of certain drugs from the mother to the fetus (e.g., drug transporters expel toxic natural products and related drugs from the placenta, aromatase converts maternal androgen to estrogens); however, many compounds can freely cross the placental barrier and access the fetal circulation. The teratogenic effects of thalidomide on limb formation, alcohol on development of the CNS and cognition, and diethystilbestrol (DES) on genital development in males and females and on the subsequent development of vaginal and cervical carcinomas in female offspring are stark reminders of the dangers of fetal exposure to drugs. In the clinical setting, there is no direct method for determining fetal exposure to a drug. Drug concentration over time in the mother's systemic circulation is the major determinant of this exposure, but other contributing factors include the size, solubility, ionization, and protein binding of the drug; its active transport into and out of the placental circulation; and the rate of fetal clearance, which includes first-pass metabolism by the placenta.
Based on the relative paucity of human data on the teratogenic effects of drugs and the limited reliability of animal models, a fundamental tenet in treating pregnant women is to minimize, whenever possible, the exposure of mother and fetus to drugs; when necessary, one should preferentially use those drugs that have the best record of safety in pregnant women without adverse developmental effects on the fetus. Of equal importance, substances of abuse (e.g., cigarettes, alcohol, illegal drugs) should be avoided and, whenever possible, eliminated before conception. In addition, all pregnant women should take a multivitamin containing 400 μg of folic acid daily to diminish the incidence of neural tube defects. The greatest concern is during the period of organogenesis in the first trimester, when a number of the most vulnerable tissues are formed. Cancer chemotherapy drugs cannot be given with reasonable safety during the first trimester, but most cytotoxics may be administered without teratogenic effects and with maintenance of pregnancy in the third trimester (see Chapters 61, 62, 63).
Drugs that are used to promote fertility are a special case, since they, by nature of their use, will be present in the mother at the time of conception. Fortunately, available evidence largely supports the safety of fertility agents for fetal development, although there have been data suggesting increased risk with certain agents (e.g., neural tube defects and hypospadias associated with clomiphene; Elizur and Tulandi, 2008).
The FDA assigns different levels of risk to drugs for use in pregnant women, as listed in Table 66–5. Certain drugs are so toxic to the developing fetus that they must never be administered to a pregnant woman (category X); in some cases (e.g., thalidomide, retinoids), the potential for fetal harm is so great that multiple forms of effective contraception must be in place before the drug is initiated. For other drugs, the risk of adverse effects on the fetus may range from category A (drugs that have not been proven to have adverse effects on the fetus despite adequate investigation) to category C (drugs with risks that sometimes may be justified based on the severity of the underlying condition (e.g., hydralazine for pregnancy-induced hypertension, β adrenergic receptor agonists for premature labor; see "Pregnancy-Induced Hypertension/Pre-eclampsia" and "Tocolytic Therapy for Established Preterm Labor"). Unfortunately, the FDA listings may be overly simplistic or outdated for a given drug; for example, oral contraceptives are listed as category X, even though considerable data now indicate that birth defects are not increased in women taking oral contraceptives at the time of conception.
Table 66-5FDA Use-in-Pregnancy Ratings ||Download (.pdf) Table 66-5 FDA Use-in-Pregnancy Ratings
|Category A: Controlled studies show no risk. Adequate, well-controlled studies in pregnant women have failed to demonstrate a risk to the fetus in any trimester of pregnancy. |
|Category B: No evidence of risk in humans. Adequate, well-controlled studies in pregnant women have not shown an increased risk of fetal abnormalities despite adverse findings in animals, or, in the absence of adequate human studies, animal studies show no fetal risk. The chance of fetal harm is remote, but remains a possibility. |
|Category C: Risk cannot be ruled out. Adequate, well-controlled human studies are lacking, and animal studies have shown a risk to the fetus or are lacking as well. There is a chance of fetal harm if the drug is administered during pregnancy, but the potential benefits may outweigh the potential risk. |
|Category D: Positive evidence of risk. Studies in humans, or investigational or post-marketing data, have demonstrated fetal risk. Nevertheless, potential benefits from the use of the drug may outweigh the potential risk. For example, the drug may be acceptable if needed in a life-threatening situation or serious disease for which safer drugs cannot be used or are ineffective. |
|Category X: Contraindicated in pregnancy. Studies in animals or humans, or investigational or post-marketing reports, have demonstrated positive evidence of fetal abnormalities or risk that clearly outweighs any possible benefit to the patient. |
Nursing mothers constitute a second special situation with respect to potential adverse effects of drugs. Some drugs may interfere with milk production and/or secretion (e.g., estrogen-containing oral contraceptives) and thus should be avoided if possible in mothers who wish to breastfeed. Other drugs may be secreted into breast milk and expose the baby to potentially toxic levels during the vulnerable perinatal period (Ito and Lee, 2003). The amount of drug that is secreted in breast milk, like the amount that crosses the placenta, depends on drug characteristics such as size, ionization, protein binding, and pharmacokinetics of clearance. The American Academy of Pediatrics Committee on Drugs periodically reviews agents transferred into human milk and their effects on the infant or on lactation (Hale, 2005). Product information sheets that provide available information regarding the potential for adverse effects of specific drugs on breastfed infants should be consulted before prescribing medications to nursing mothers.
Hypertension affects up to 10% of pregnant women in the U.S.; with the increasing prevalence of hypertension in the general population and the tendency to delay childbearing, drug therapy for maternal hypertension likely will be given greater consideration in the future. A consensus panel has issued guidelines for the management of hypertension in pregnancy (National High Blood Pressure Education Program Working Group, 2000).
Hypertension that precedes pregnancy or manifests before 20 weeks of gestation is believed to overlap considerably in pathogenesis with essential hypertension. These patients appear to be at increased risk for gestational diabetes and need careful monitoring. In contrast, pregnancy-induced hypertension, or pre-eclampsia, generally presents after 20 weeks of gestation as a new-onset hypertension with proteinuria (>300 mg of urinary protein/24 hours); pre-eclampsia is thought to involve placenta-derived factors that affect vascular integrity and endothelial function in the mother, thus causing peripheral edema, renal and hepatic dysfunction, and in severe cases, seizures (Maynard et al., 2008). Chronic hypertension is an established risk factor for pre-eclampsia, but there is no conclusive evidence that antihypertensive therapy during pregnancy affects the incidence or outcome of pre-eclampsia in women with mild to moderate hypertension (Abalos et al., 2007). Nonetheless, the consensus panel recommended initiation of drug therapy in women with a diastolic blood pressure >105 mm Hg or a systolic blood pressure >160 mm Hg (National High Blood Pressure Education Program Working Group, 2000). If severe pre-eclampsia ensues, with marked hypertension and evidence of end-organ damage, then termination of the pregnancy by delivery of the baby is the treatment of choice, provided that the fetus is sufficiently mature to survive outside the uterus. If the baby is very preterm, then hospitalization and pharmacotherapy (expectant management) may be employed in an effort to permit further fetal maturation in utero.
Many pregnant women already carry the diagnosis of hypertension and are on drug therapy, which may be continued with careful monitoring, provided that blood pressure control is effective. In this setting, however, some drugs that commonly are used for hypertension in non-pregnant patients (e.g., angiotensin-converting enzyme inhibitors, angiotensin-receptor antagonists) should not be used due to unequivocal evidence of adverse fetal effects in animal models and humans (Podymow and August, 2008). Many experts will convert the patient to the centrally acting α adrenergic agonist α-methyldopa (aldomet) at an initial dose of 250 mg orally twice daily (FDA category B), which rarely is used for hypertension in non-pregnant patients. Other drugs with reasonable evidence of safety (category C) also may be used, including the combination α1-selective, β-nonselective adrenergic antagonist labetalol (trandate; 100 mg twice daily) and the Ca2+ channel blocker nifedipine (procardia xl, adalat cc; 30 mg once daily).
Similar considerations apply in previously normotensive women who develop pre-eclampsia; α-methyldopa again is a reasonable choice for outpatient management if the blood pressure exceeds the threshold for therapy. If severe pre-eclampsia or impending labor requires hospitalization, blood pressure can be controlled acutely with hydralazine (5 or 10 mg intravenously or intramuscularly, with repeated dosing at 20-minute intervals depending on blood pressure response) or labetalol (20 mg intravenously, with dose escalation to 40 mg at 10 minutes if blood pressure control is inadequate).
In addition to drugs for blood pressure control, women with severe pre-eclampsia or those who have central nervous system manifestations, such as headache, visual disturbance, or altered mental status, are treated as inpatients with magnesium sulfate, based on its documented efficacy in seizure prevention and lack of adverse effects on the mother or baby (Altman et al., 2002). Such treatment also should be considered for postpartum women with central nervous system manifestations, because ~20% of episodes of eclampsia occur in women who are more than 48 hours after delivery.
Prevention or Arrest of Preterm Labor
Scope of the Problem and Etiology. Preterm birth, defined as delivery before 37 weeks of gestation, occurs in >10% of pregnancies in the U.S. and is increasing in frequency; it is associated with significant complications, such as neonatal respiratory distress syndrome, pulmonary hypertension, and intracranial hemorrhage. Although incompletely understood, risk factors for preterm labor include multifetal gestation, premature rupture of the membranes, intrauterine infection, and placental insufficiency. The more premature the baby, the greater the risk of complications, prompting efforts to prevent or interrupt preterm labor.
The therapeutic objective in preterm labor is to delay delivery so that the mother can be transported to a regional facility specializing in the care of premature babies and supportive agents can be administered; such supportive treatments include glucocorticoids to stimulate fetal lung maturation (see Chapter 42) and antibiotics (e.g., erythromycin, ampicillin) to diminish the frequency of neonatal infection with group B β-hemolytic Streptococcus. Based on concerns over deleterious effects of antibiotic therapy, it is essential that antibiotics not be administered indiscriminately to all women thought to have preterm labor, but rather be reserved for those with premature rupture of the membranes and evidence of infection.
Prevention of Preterm Labor: Progesterone Therapy. Progesterone levels in some species diminish considerably in association with labor, whereas administration of progesterone inhibits the secretion of pro-inflammatory cytokines and delays cervical ripening. Thus, progesterone and its derivatives have long been advocated to diminish the onset of preterm labor in women at increased risk due to previous preterm delivery. Despite considerable controversy, recent randomized trials have revived interest in this approach. One drug used in this setting is 17α-hydroxyprogesterone at a dose of 250 mg administered weekly by intramuscular injection (Meis et al., 2003). Vaginal administration of progesterone (200 mg each night) also was used in one clinical trial with apparent efficacy (Fonseca et al., 2007). One clinical trial suggested that progesterone administration in this setting was associated with an increased incidence of gestational diabetes (Rebarber et al., 2007), and the role of progesterone prophylaxis during pregnancy remains to be established.
Tocolytic Therapy for Established Preterm Labor. Because preterm birth typically is heralded by the uterine contractions of labor, the inhibition of these contractions, or tocolysis, has been a focus of therapy (Simhan and Caritis, 2007). Although tocolytic agents delay delivery in ~80% of women, they neither prevent premature births nor improve adverse fetal outcomes such as respiratory distress syndrome. Thus, while widely employed, they should be viewed as temporizing agents, as described in "Prevention of Preterm Labor: Progesterone Therapy."
Specific tocolytic agents include β adrenergic receptor agonists, MgSO4, Ca2+ channel blockers, COX inhibitors, oxytocin-receptor antagonists, and nitric oxide donors. The mechanisms of action of these agents are illustrated in Figure 66–2.
Sites of action of tocolytic drugs in the uterine myometrium. The elevation of cellular Ca2+ promotes contraction via the Ca2+/calmodulin-dependent activation of myosin light chain kinase (MLCK). Relaxation is promoted by the elevation of cyclic nucleotides (cAMP and cGMP) and their activation of protein kinases, which cause phosphorylation/inactivation of MLCK. Pharmacological manipulations to reduce myometrial contraction include:
inhibiting Ca2+ entry (Ca2+ channel blockers, Mg2SO4)
reducing mobilization of intracellular Ca2+ by antagonizing GPCR-mediated activation of the Gq-PLC-IP3-Ca2+ pathway (with antagonists of the FP and OXT receptors) or reducing production of the FP agonist, PGF2α (with COX inhibitors)
enhancing relaxation by elevating cellular cyclic AMP (with β2 adrenergic agonists that activate Gs-AC) and cyclic GMP (with NO donors that stimulate soluble guanylyl cyclase)
sGC, soluble guanylyl cyclase; AC, adenylyl cyclase; FP, the PGF2α receptor; OXT, the oxytocin receptor; PLC, phospholipase C; COX, cyclooxygenase.
The β adrenergic receptor agonists relax the myometrium by activating the cyclic AMP-PKA signaling cascade that phosphorylates and inactivates myosin light-chain kinase, a key enzyme in uterine contraction. Ritodrine, a selective β2 agonist, was specifically developed as a uterine relaxant and remains the only tocolytic drug to have gained FDA approval; it was voluntarily withdrawn from the U.S. market. Terbutaline (brethine), which is FDA-approved for asthma, has been used off label for this purpose and can be administered orally, subcutaneously, or intravenously. Terbutaline may delay births, but only during the first 48 hours of treatment, and is associated with a number of adverse maternal effects, including tachycardia, hypotension, and pulmonary edema.
Similarly, Ca2+ channel blockers inhibit the influx of Ca2+ through depolarization-activated, voltage-sensitive Ca2+ channels in the plasma membrane, thereby preventing the activation of myosin light-chain kinase and the stimulation of uterine contraction. Nifedipine (procardia, adalat), the Ca2+ channel blocker used most commonly for this purpose, can be administered parenterally or orally. Relative to β2 adrenergic agonists, nifedipine is more likely to improve fetal outcomes and less likely to cause maternal side effects.
Based on the role of prostaglandins in uterine contraction, cyclooxygenase inhibitors (e.g., indomethacin) have been used to inhibit preterm labor, and some data suggest that they may reduce the number of preterm births. Because they also can inhibit platelet function and induce closure in utero of the ductus arteriosus, these inhibitors should not be employed in term pregnancies (or in pregnancies beyond 32 weeks of gestation, when the risk of severe complications of prematurity is relatively lower). Short courses of treatment (<72 hours) pose less risk for impaired circulation in the fetus.
Atosiban (tractocile), a nonapeptide analog of oxytocin, competitively inhibits the interaction of oxytocin with its membrane receptor on uterine cells and thereby decreases the frequency of uterine contractions. Although atosiban increased the number of women who remained undelivered for 48 hours and is widely used in Europe, it is not FDA-approved in the U.S.
Nitric oxide is a potent vasodilator and smooth muscle relaxant, and drugs such as nitroglycerin and other nitrates that increase its levels are used to treat myocardial ischemia (see Chapter 28). Both intravenous nitroglycerin and transdermal nitrate preparations have been evaluated in clinical trials to inhibit preterm labor. The major adverse effect is maternal hypotension.
Despite numerous clinical trials, the superiority of any one therapy has not been established, and none of the drugs has been shown definitively to improve fetal outcome. Thus, despite widespread and enthusiastic use by some centers, many experts do not endorse the routine use of tocolytic agents. Recent meta-analyses of published reports concluded that Ca2+ channel blockers and atosiban (not available in the U.S.) provided the best balance of successfully delayed delivery with lesser risks to the mother and baby (reviewed by Iams et al., 2008).
Labor induction is indicated when the perceived risk of continued pregnancy to the mother or fetus exceeds the risks of delivery or pharmacological induction. Such circumstances include premature rupture of the membranes, isoimmunization, fetal growth restriction, uteroplacental insufficiency (as in diabetes, pre-eclampsia, or eclampsia), and gestation beyond 42 weeks. Before inducing labor, it is essential to verify that the fetal lungs are sufficiently mature and to exclude potential contraindications (e.g., abnormal fetal position, evidence of fetal distress, placental abnormalities, or previous uterine surgery predisposing to uterine rupture).
Labor induction also is used increasingly in the absence of specific criteria listed above; such elective inductions may be predicated in part on matters of convenience for the mother or medical team. Collectively, induced or augmented labor now accounts for ~20% of all deliveries in the U.S., two-thirds of which are for nonmedical reasons.
Prostaglandins and Cervical Ripening. Prostaglandins play key roles in parturition (see Chapter 33). Thus, PGE1, PGE2, and PGF2a are used to facilitate labor by promoting ripening and dilation of the cervix. They can be administered either orally or via local administration (either vaginally or intracervically). The ability of certain prostaglandins to stimulate uterine contractions also makes them valuable agents in the therapy of postpartum hemorrhage (see "Prevention/Treatment of Postpartum Hemorrhage"). Although prostaglandins are widely employed for cervical ripening, their effectiveness versus that of oxytocin alone in diminishing the need for cesarean section in labor induction has not been definitively established.
Available preparations include dinoprostone (PGE2), which is FDA approved to facilitate cervical ripening. Dinoprostone is formulated as a gel for intracervical administration via syringe in a dose of 0.5 mg (prepidil) or as a vaginal insert (pessary) in a dose of 10 mg (cervidil); the latter is designed to release active PGE2 at a rate of 0.3 mg/hr for up to 12 hours and should be removed at the onset of labor or 12 hours after insertion. No more than three doses should be used in a 24-hour period. Dinoprostone should not be used in women with a history of asthma, glaucoma, or myocardial infarction. The major adverse effect is uterine hyperstimulation, which may be reversed more rapidly using the vaginal insert by removing it with the attached tape.
Misoprostol (cytotec), a synthetic derivative of PGE1, is FDA-approved for the prevention and treatment of acid peptic disease in patients who are receiving nonsteroidal anti-inflammatory agents (see Chapter 34). Its use in medical abortion is discussed earlier in "Pregnancy Termination." It also is used off label either orally or vaginally to induce cervical ripening; typical doses are 100 μg (orally) or 25 μg (vaginally); an advantage of misoprostol in this setting is its considerably lower cost. The vaginal dose typically is repeated every 4-6 hours depending on labor progression. Adverse effects include uterine hyperstimulation and, rarely, uterine rupture. Most experts therefore do not use misoprostol for cervical ripening in women who have had previous cesarean section or other uterine surgery. Misoprostol should be discontinued for at least 3 hours before initiating oxytocin therapy.
Oxytocin. The structure and physiology of oxytocin are discussed in Chapter 38. This section presents therapeutic uses of oxytocin in obstetrics, which include the induction of labor, the augmentation of labor that is not progressing, and the prophylaxis and/or treatment of postpartum hemorrhage. Although widely used, oxytocin recently was added to a list of drugs "bearing a heightened risk of harm" (Clark et al., 2009), and its role and specific application to most deliveries in the U.S. remain open to debate. Thus, careful review of the appropriate indications for oxytocin administration and attention to the dose and progress of labor during induction are essential.
Labor Induction. Oxytocin (pitocin, syntocinon) is the drug of choice for labor induction; for this purpose, it is administered by intravenous infusion of a diluted solution (typically 10 mIU/mL), preferably via an infusion pump. Current protocols start with an oxytocin dose of 6 mIU/minute, followed by advancement of dose as needed (in one protocol, increases of 6 mIU/minute can be made every 40 minutes if labor is not progressing in a satisfactory manner). Although there are little definitive data, 40 mIU/minute is a reasonable maximum dose, although doses of up to 72 mIU/minute have been used with apparent safety in some studies. Uterine hyperstimulation should be avoided; however, if it occurs, as evidenced by too-frequent contractions (more than five contractions in a 10-minute interval) or the development of uterine tetany, the oxytocin infusion should be discontinued immediately. Because the t1/2 of intravenous oxytocin is relatively short (12-15 minutes), the hyperstimulatory effects of oxytocin will dissipate fairly rapidly after the infusion is discontinued. Thereafter, the infusion can be reinitiated at a dose of half that at which hyperstimulation occurred and increased cautiously as tolerated.
Because of its structural similarity to vasopressin, oxytocin at higher doses activates the vasopressin V2 receptor and has antidiuretic effects. Particularly if hypotonic fluids (e.g., dextrose in water) are infused too liberally, water intoxication may result in convulsions, coma, and even death. Vasodilating actions of oxytocin also have been noted, particularly at high doses, which may provoke hypotension and reflex tachycardia. Deep anesthesia may exaggerate the hypotensive effect of oxytocin by preventing the reflex tachycardia.
Augmentation of Dysfunctional Labor. Oxytocin also is used when spontaneous labor is not progressing at an acceptable rate. To augment hypotonic contractions in dysfunctional labor, an infusion rate of 10 mIU/minute typically is sufficient; doses in excess of 40 mIU/minute rarely are effective when lower concentrations fail. As with labor induction, potential complications of uterine overstimulation include trauma of the mother or fetus due to forced passage through an incompletely dilated cervix, uterine rupture, and compromised fetal oxygenation due to decreased uterine perfusion. Oxytocin usually is effective when there is a prolonged latent phase of cervical dilation or when, in the absence of cephalo-pelvic disproportion, there is an arrest of dilation or descent.
Prevention/Treatment of Postpartum Hemorrhage
Postpartum hemorrhage is a significant problem in developed nations and is of even greater importance in developing countries. After delivery of the fetus or after therapeutic abortion, a firm, contracted uterus greatly reduces the incidence and extent of hemorrhage. Oxytocin (10 IU intramuscularly) often is given immediately after delivery to help maintain uterine contractions and tone. Alternatively, oxytocin (20 IU) is diluted in 1 L of intravenous solution and infused at a rate of 10 mL/minute until the uterus is contracted. The infusion rate then is reduced to 1-2 mL/minute until the mother is ready for transfer to the postpartum unit. Carbetocin, a longer-acting derivative of oxytocin, is under evaluation in clinical trials to prevent or treat postpartum hemorrhage; a dose of 100 μg is given intravenously (Leung et al., 2006).
Ergot alkaloids markedly increase the motor activity of the uterus. Although their capacity to induce sustained uterine tetany precludes their use in the induction or facilitation of labor, they are used to prevent or treat postpartum hemorrhage in normotensive women. In this setting, the preferred ergot alkaloids are ergonovine (ergotrate) or its methyl analog methylergonovine (methergine). They are administered intramuscularly or intravenously, exhibit rapid onsets of action (2-3 minutes intramuscularly, <1 minute intravenously), and their effects persist for 45 minutes to 3 hours depending on the route of administration. Adverse effects include nausea and vomiting, elevated blood pressure, and decreased pain threshold requiring analgesia.
Alternatively, the PGE1 analog misoprostol (600 μg administered orally or sublingually) may be used off label to stimulate uterine contractions and prevent or treat postpartum hemorrhage. Although meta-analyses suggest that it may be slightly less effective than oxytocin, the low cost and lack of need for refrigeration or sterile needles may make misoprostol the preferred agent for use in developing nations. Other approaches under investigation include recombinant factor VIIa and balloon tamponade.