Almost half of all women report using four or more medications (other than prenatal vitamins) during their pregnancy.1 In one study of eight US health maintenance organizations, 64% of the 152,531 pregnancies analyzed showed documentation of at least one prescription medication during pregnancy, with an average of two prescriptions.2 Once women are hospitalized for delivery, medications including analgesics/anesthetics, oxytocics, antibiotics, and antihypertensives form the basis of many of our interventions. Most of the time, these medications are used off-label, without supporting studies in pregnancy. Because of ethical, medicolegal, and fetal safety concerns regarding pregnant women, few pharmacokinetic, pharmacodynamic or clinical trials were conducted during pregnancy until the past decade. Toxicologists focused on fetal exposure, but, in the absence of evidence, few pharmacologists or obstetricians recognized that pregnancy itself was a “special population.” Pregnant women have a unique drug response to the classical formulation of ADME (which stands for “absorption, distribution, metabolism and excretion”), which differs significantly from the average adult male or nonpregnant female.
Extrapolation of pharmacokinetic data from drug studies largely conducted in nonpregnant subjects to pregnant women fails to account for the impact of physiologic and metabolic changes that occur during pregnancy. To optimally use medications in pregnancy, we need the information that comes from studying drugs in pregnant women.
Concerns about the lack of studies in pregnant women were addressed by both the US Food and Drug Administration (FDA) and the National Institutes of Health (NIH) in a series of conferences in the 1990s and early 2000s that led to a number of significant changes. A guidance for industry on the design and conduct of pharmacokinetic studies in pregnant women was published by the FDA in November 2004.3 In 2002, the FDA started requiring the pharmaceutical industry to establish postmarketing registries for drugs that can provide data to be used in the new labeling. After many years of review, the FDA introduced new pregnancy labeling in June 2015, which eliminates the old A, B, C, D, and X pregnancy categories.4 Instead, the new labeling provides descriptive summaries from animal and human data and a large section on clinical considerations to help guide the prescribing provider. In 2004, the NIH began funding an obstetrical pharmacology research network that has produced multiple pharmacokinetic studies with drugs we frequently use.
The 21st Century Cures Act, passed by Congress in December 2016, included a Task Force on Research Specific to Pregnant and Lactating Women to advise the Secretary of Health and Human Services regarding gaps in knowledge and research on safe and effective therapies for pregnant women and lactating women. A report will be submitted to the secretary in September 2018.
In this chapter, guidelines for commonly used medications in our hospitalist practice will be presented based on recommendations from the American College of Obstetricians and Gynecologists (ACOG), other societies, and the research literature. When pharmacokinetic background supporting these recommendations is known, that information also will be included.
CASE 26-1
38yo G1P0 at 37 2/7 weeks of gestation, with an unremarkable medical history and antepartum course, is sent to Ob Triage for the evaluation of preeclampsia. Her blood pressure at her routine prenatal visit was 155/95. The patient reported a mild headache for the past two days but is otherwise asymptomatic. Her initial blood pressure in Ob Triage is 165/98, and the repeat pressure 15 minutes later is 172/102. She has a Category 1 FHR tracing. How should her blood pressure be managed?
CASE 26-2
41yo G3P1102 at 31 0/7 weeks of gestation, with chronic hypertension previously with stable pressures on labetalol 300 mg bid (8 a.m. and 8 p.m.), calls the office with the following blood pressure report: 8 a.m. 165/98, 11 a.m. 125/82, 4 p.m. 134/88, 7 p.m. 164/102. After documenting that the patient’s preeclampsia blood and urine tests are negative, her physician increases her labetalol to 400 mg twice daily. Two days later, she calls the office, reporting that she was feeling mildly orthostatic several hours after her morning dose. Why is this happening, and what can we do to better manage her blood pressure?
In 2013, the ACOG convened a task force to review and redefine our society’s guidance for the diagnosis and management of hypertension in pregnancy. This culminated in the publication of their summary report, Hypertension in Pregnancy.5 Two years later, ACOG revised its Committee Opinion on the management of acute-onset severe hypertension, ACOG Committee Opinion No. 623: Emergent Therapy for Acute-Onset, Severe Hypertension During Pregnancy and the Postpartum Period.6 These two position papers resulted in new recommendations for pharmacologic management of hypertension in pregnancy. The choice of antihypertensive medications depends upon whether the goal is acute lowering of severe-range blood pressure or chronic treatment of maternal hypertension. Of note, some of the medications we use are not considered first-line antihypertensive medications outside of pregnancy (e.g. methyldopa and hydralazine), but they are prescribed by providers because we are familiar with them, and they have a long record of safety in pregnancy.
ACOG Committee Opinion No. 623: Emergent Therapy for Acute-Onset, Severe Hypertension During Pregnancy and the Postpartum Period proposed standardized, evidence-based guidelines for the management of severe-range blood pressure in women with preeclampsia/eclampsia or chronic or gestational hypertension, with the stated goal of reducing both maternal and fetal adverse outcomes associated with elevated maternal pressure.6 This opinion defined severe-range blood pressure as either systolic pressure ≥160 mmHg, diastolic pressure ≥110 mmHg, or both. The diagnosis of severe-range blood pressure requires the persistence of these pressures in two consecutive readings over an interval of 15 minutes. Once this diagnosis is made, the situation is considered a medical emergency and administration of rapid-acting antihypertensive medication should be initiated immediately. The goal of therapy is not to normalize pressure readings completely, but to bring them into the range of 140–150/90–100, where the risk of cerebral complications is reduced. Because of the concomitant potential to reduce placental perfusion, care should be taken not to overcorrect the blood pressure. Stabilization of maternal blood pressure is recommended prior to delivery (Table 26-1).
| Medication | Recommended Dosing6 |
| Labetalol injection | 10–20 mg IV, followed by an escalating dose of 20–80 mg IV every 10 min as needed, to a maximum dose of 300 mg |
| Hydralazine injection | 5 mg IV, followed by 5–10 mg IV every 20 min as needed, to a maximum dose of 20 mg |
| Nifedipine IR | 10 mg PO, followed by 20 mg PO every 20 min × 2 as needed |
The primary change between the 2015 Committee Opinion on the management of hypertensive emergencies and the previously published opinion is the addition of oral immediate-release (IR) nifedipine to the standard therapies of intravenous (IV) labetalol and hydralazine.6 None of these medications has been shown to be superior to the others in either efficacy or safety.7 Choice among them depends on the clinician’s familiarity and experience as well as the patient’s clinical presentation and possible contraindications.
Because of its beta-antagonist effects, labetalol should not be administered to women with asthma, heart disease, congestive heart failure, or maternal bradycardia. Maternal coronary artery disease is an absolute contraindication for the use of hydralazine. Adverse events associated with these medications include hydralazine and nifedipine—maternal tachycardia and maternal hypotension; and labetalol—fetal bradycardia and maternal bradycardia. Although the risk is hypothetical, because both nifedipine and magnesium sulfate are calcium channel blockers, there is the potential for synergistic neuromuscular blockade and hypotension when these medications are used together.5
It is not uncommon for women to require a combination of medications to lower blood pressure. The sequence is determined by an inadequate response to one of the medications, the development of an associated adverse event, or both, such as a decrease in maternal heart rate with labetalol or maternal tachycardia with hydralazine or nifedipine.
Oral IR nifedipine provides an effective option for women in whom IV access is not readily available. Despite its oral formulation, IR nifedipine has been shown to have comparable onset of action and efficacy in pregnant women as the IV alternatives. Shekhar et al (2013) reported that the median time to achieve the target blood pressure of 150/100 in women treated with oral nifedipine IR was 40 minutes (interquartile range, 20–60 minutes) compared with 60 minutes (interquartile range 40–85 minutes) for women treated with IV labetalol (P = .008).8
However, the use of oral IR nifedipine for the treatment of maternal hypertension may require a special review by your hospital’s pharmacy and therapeutics committee. In 1995, the FDA mandated that the hypertension indication be removed from the IR nifedipine labeling because of the number of reported adverse events, primarily due to the unpredictable rate and degree of blood pressure reduction and the associated profound hypotension, myocardial infarction, and death when nifedipine was used to lower blood pressure acutely.
After initiation of therapy, the recommended frequency of blood pressure assessments until pressure stabilization is medication specific.6 After IV labetalol, the blood pressure assessment interval changes to every 10 minutes, while after oral nifedipine or IV hydralazine, blood pressure should be measured every 20 minutes.
CASE 26-1 FOLLOW-UP
Because the patient had two consecutive blood pressures within the severe range, IV access was quickly initiated, and she was dosed with labetalol 20 mg intravenously. Her laboratory evaluation supported a diagnosis of preeclampsia with severe features, and labor was induced. Over her intrapartum course, she required additional antihypertensive medications with a combination of both IV labetalol and hydralazine.
Although the Task Force on Hypertension in Pregnancy5 did not find supportive evidence to identify a precise blood pressure at which antihypertensive therapy is indicated in pregnant women with chronic or gestational hypertension, they strongly recommended that women with persistently elevated systolic pressure ≥160 and/or diastolic pressure ≥105 be treated with antihypertensive medications (Table 26-2). Once medication is started, the task force recommended that blood pressure be maintained between 120 and 160 mmHg systolic and 80 and 105 mmHg diastolic. They made one exception to this recommendation: women with chronic hypertension and end-organ damage (renal, cardiac, or ophthalmic) should be treated to keep their pressure below 140 systolic and 90 diastolic to avoid disease progression. The task force also concluded that evidence to support initiating treatment for women with pressures in the mild to moderately elevated ranges (systolic pressure ≥140 but <160 and diastolic pressure ≥90 but <105) was less strong. Use of antihypertensives in these women slowed the progression to severe-range pressure but did not change perinatal outcomes.9 However, they also concluded that the use of antihypertensive medications during the second or third trimester is associated with an increased risk of small-for-gestational-age infants.10–12
| Medication | Recommended Dosing5 |
| Labetalol (oral tablets) | 200–2400 mg/day orally in two to three divided doses |
| Nifedipine XL | 30–120 mg orally, once daily |
| Methyldopa | 500–3000 mg/day orally in two to three divided doses |
Because of the physiologic changes that occur in pregnancy, blood pressures naturally become lower during the end of the first trimester. The Task Force on Hypertension in Pregnancy supports the option of discontinuing or decreasing antihypertensive drugs early in pregnancy, and then restarting medication if pressure increases throughout pregnancy. Of note, stopping or reducing medication in the first trimester was not associated with an increased risk of developing preeclampsia or eclampsia.5
Women with chronic hypertension usually require continuation of their medications postpartum. In addition, older women, women with comorbidities (obesity, renal, cardiovascular, diabetes), and women who develop severe preeclampsia earlier in pregnancy are more likely to require antihypertensive medications postpartum. The task force recommends that blood pressure during the postpartum period be maintained below 160 mmHg systolic and 100 mmHg diastolic.5
Of the recommended medications, α-methyldopa, a centrally acting α-2 adrenergic agonist, is one of the longest-used antihypertensive medications in pregnancy. Its onset of action is gradual and slow, taking at least 6 to 8 hours to reach maximum effect.5 No fetal adverse effects have been observed with the use of α-methyldopa,13 and infant development at 1 year was normal compared to no therapy.14 Although α-methyldopa may be equally effective as other antihypertensives in controlling mild to moderate hypertension, it is less effective than labetalol or nifedipine in preventing the development of severe hypertension.9 Adverse effects associated with methyldopa include hepatic dysfunction and necrosis and hemolytic anemia.
Labetalol is a nonselective β-antagonist with vascular α-blocking activity. It is one of the most commonly used oral antihypertensives in pregnancy. The oral formulation has similar contraindications as its IV preparation. Labetalol should not be administered to women with asthma, heart disease, or congestive heart failure. Commonly reported side effects with labetalol are lethargy, fatigue, sleep disturbances, and bronchoconstriction.9 Chronic treatment with labetalol has been associated with an increased risk of small-for-gestational-age infants (relative risk [RR], 1.23; 95% confidence interval [CI], 1.01–1.79) compared to no treatment.15
A third class of drugs used to treat chronic and gestational hypertension is calcium channel blockers, of which the extended-release formulation of nifedipine is most often prescribed. Blocking the transmembrane flow of calcium ions into smooth muscle cells causes smooth muscle relaxation of both arteries and the myometrium. Calcium channel blockers also reduce systemic vascular resistance and increase renal blood flow, which subsequently improves urinary output. No adverse fetal effects have been associated with nifedipine exposure,16 and it does not appear to have the same adverse effect on uteroplacental blood flow as labetalol.17 Nifedipine is available in two primary formulations. The IR, short-acting capsule whose levels are first detectable in plasma at 10 minutes and peak at 30 minutes18 is used in pregnancy for control of acute-onset, severe hypertension. The slow, extended release formulation reaches peak levels at 6 hours and continues to deliver nifedipine over 24 hours.19 The once-daily, extended-release formulation (Procardia XL) is the drug used for the outpatient treatment of chronic and gestational hypertension.
Diuretics are considered a second-line therapy for hypertension in pregnancy and are uncommonly prescribed.5 The principal concern voiced against their use is the potential to decrease intravascular volume and placental blood flow. However, studies in pregnancy using diuretics have not shown an adverse effect on fetal growth.20 Their primary benefit may be for use in women with salt-sensitive chronic hypertension with renal impairment.5
Angiotensin-converting enzyme (ACE) inhibitors and the related angiotensin receptor blockers are contraindicated in pregnancy because of the associated complications of renal failure, oligohydramnios, pulmonary hypoplasia, skull abnormalities, and fetal growth restrictions with second and third trimester exposure.21 The task force recommended that ACE inhibitors be stopped immediately if pregnancy is discovered. Because unintended pregnancy is so common, ACE inhibitors are probably not the drug of choice for women of reproductive age who require antihypertensive therapy.5
Clearance of labetalol is significantly increased in pregnancy due to increases in both glucuronidation and renal clearance. Because the reported elimination half-life of labetalol in the third trimester of pregnancy is one-quarter that in nonpregnant women (mean, 1.7 ± 0.27 hours compared to mean, 6–8 hours),22 blood pressure should be monitored at the end of the dosing period when drug concentrations are lowest. If needed, the dosing interval may be shortened to every 8 hours to provide appropriate control.
Labetalol is rapidly absorbed after oral administration.23 Peak serum concentrations in pregnancy have been recorded to occur within 20 minutes after oral ingestion.22 Food can delay the time to peak serum concentration to 60 minutes.22 Labetalol is initially cleared by glucuronidation, a Phase II metabolic pathway. The primary hepatic enzymes involved in glucuronidation (uridine 5′-diphosphate glucuronosyltransferase, UGT) of labetalol are UGT1A1 and UGT2B7.24 Known inducers of the UGT1A family are pregnane X receptor (PXR) activators, which include many of the steroid hormones that are dramatically increased in pregnancy: progesterone, pregnenolone, estrogen, and dehydroepiandrosterone.25 In a study that specifically examined the glucuronidation of labetalol in cultured human hepatocytes, progesterone, but not estrogen, was shown to increase PXR-mediated induction of UGT1A1 activity.24 After glucuronidation, 60% of labetalol and its glucuronide conjugates are renally cleared, and 40% is excreted in the feces via biliary elimination.26
Clearance of nifedipine is increased and nifedipine concentrations are lower in pregnant women compared to their nonpregnant counterparts because of the increase in hepatic metabolism from the induction of cytochrome P450 (CYP) 3A4. A total of 75% of African Americans carry a CYP3A5 variant, which further increases the metabolism of nifedipine and may adversely affect their response to the standard dosing regimen of nifedipine.
Even before nifedipine can reach the liver, a portion of the drug is metabolized by intestine mucosal CYP3A4 and further metabolism occurs by the same CYP3A4 enzyme within the liver. In nonpregnant adults, the elimination half-life of nifedipine is approximately 2 hours.18,19 Activity of CYP3A4 is known to increase in pregnancy by 30% to 70% based on prior studies with medications that are known CYP3A4 substrates.27,28 Several studies have examined nifedipine pharmacokinetics in pregnancy and have shown that both plasma concentrations are lower and clearance is increased. Plasma concentrations of nifedipine were reported to be decreased in 15 women with pregnancy-induced hypertension who were studied during the third trimester of pregnancy compared to historic controls.29 The same study reported that the mean elimination half-life (1.3 +/‒ 0.5 hours) was shorter and the apparent oral elimination clearance of 2.0 +/‒ 0.8 L/hr/kg was more rapid than that in healthy volunteers (mean 0.49 +/‒ 0.09 L/hr/kg).
Pharmacogenetics may also play a role in nifedipine plasma concentrations and efficacy. CYP3A5 is a drug-metabolizing enzyme that is closely related to CYP3A4 and often works in conjunction with CYP3A4 to metabolize the same drugs. The active version of the enzyme is the allele, CYP3A5*1, and people with two CYP3A5*1 alleles have significantly increased clearance of CYP3A4 substrates because both CYP3A4 and CYP3A5 enzymes are contributing to metabolism. In contrast, the CYP3A5*3 allele is an inactive version of the enzyme, and people with two CYP3A5*3 alleles have decreased metabolism because only CYP3A4 is actively working.30 The distribution of the CYP3A5 alleles has important ethnic differences with 75% of African Americans, but only 10% to 20% of people of European descent carrying the active allele.31 Nifedipine efficacy may be affected similarly by the pharmacogenetics of CYP3A5. In a pharmacokinetic study of 14 women undergoing nifedipine tocolysis, the four women with the CYP3A5*1 active allele had significantly lower nifedipine plasma concentrations and increased nifedipine clearance compared to the women with inactive CYP3A5.32 With 75% of African-American women possessing this active variant, some of the failed tocolysis that we see in this at-risk population may occur because the nifedipine dose they are receiving is inadequate to achieve the necessary tocolysis.
Hydralazine is a vasodilator that has been in use since 1952. It is primarily metabolized by the enzyme N-acetyltransferase (NAT), which deactivates the drug by attaching an acetyl group.33 Although NAT has not been well studied in pregnancy, one small study with caffeine suggested that its activity did not significantly change,34 and another study reported that its activity decreased in pregnancy.35 There may be important ethnic differences in a person’s ability to metabolize hydralazine. Over 50% of Caucasians are slow acetylators, which can lead to increased plasma hydralazine concentrations compared to their fast acetylator counterparts.
CASE 26-2 FOLLOW-UP
The blood pressures recorded in this patient demonstrate the effects of pregnancy-induced increase in labetalol clearance: adequate control initially, with loss of effect as labetalol concentrations fall. When the dose was increased to 400 mg bid, she became orthostatic because the higher peak labetalol concentrations overcorrected her blood pressure. Changing her regimen to 300 mg q 8 hours produced a more even control of her blood pressure.
TAKE-HOME POINTS
Antihypertensive Medications
The persistence of two consecutive severe-range blood pressures (either ≥160 mmHg systolic or ≥110 mmHg diastolic, or both) is considered a medical emergency and rapid-acting antihypertensive medication should be administered immediately, with the goal of achieving a blood pressure range of 140–150/90–100 mmHg.
Medications used to acutely lower blood pressure include IV labetalol, IV hydralazine, and oral IR nifedipine.
In women with chronic or gestational hypertension, antihypertensive medications should be started when blood pressure ≥160/90 mmHg.
The increase in labetalol clearance that occurs in pregnancy may require shortening the dosing interval to every 8 hours to achieve sustained blood pressure control.
See Chapter 31 for more information about hypertension in pregnancy.
IV magnesium sulfate is the drug of choice for both eclampsia treatment and prevention. ACOG recommends that magnesium sulfate be administered to all women with preeclampsia with severe features. However, they support selective administration to asymptomatic women whose systolic blood pressure is <160 and diastolic blood pressure is <110 mmHg.5 Magnesium is contraindicated in women with myasthenia gravis because it can precipitate a severe myasthenic crisis.
Dosing regimens vary at different institutions, but a fairly common regimen includes a loading dose of 4 to 6 g intravenously over 20 to 30 minutes, followed by a constant infusion of 1 to 2 g/hour, depending on renal function. Although routine monitoring of magnesium levels is not required in uncomplicated patients, the usual therapeutic range is 4.8 to 8.4 mg/dL (2.0–3.5 mmol/L). Urinary function should be closely monitored because magnesium is renally cleared. The decrease in urinary function that is frequently encountered in the preeclamptic patient can significantly affect magnesium clearance, placing the woman at risk for magnesium toxicity. Patellar reflexes and urinary output should be routinely checked every 2 hours and, in appropriate women, magnesium levels every 6 hours. The antidote, calcium gluconate (10–30 mL of a 10% solution pushed intravenously over 2–5 minutes), should be readily available. Magnesium therapy is usually continued for 12 to 24 hours after delivery, depending on the woman’s clinical picture. (See the section “Magnesium Sulfate for Tocolysis,” later in this chapter, for a further discussion of the pharmacology of magnesium.)
TAKE-HOME POINTS
Magnesium Sulfate for Eclampsia Prophylaxis
Magnesium sulfate should be administered for eclampsia prevention to all women with preeclampsia with severe features.
Because magnesium is renally cleared, women with preeclampsia-associated renal insufficiency can quickly develop magnesium toxicity.
CASE 26-3
When M.B., a 27yo G1P0 patient, was 26 0/7weeks of gestation, she was diagnosed with preterm labor and administered a course of betamethasone and nifedipine for tocolysis. She now returns at 31 3/7 weeks gestation, with preterm premature rupture of membranes. Should she receive a second course of betamethasone? What if, instead, she ruptures her membranes at 35 4/7 weeks—is a second course of steroids still recommended?
Administration of antenatal corticosteroids to pregnant women at imminent risk of a preterm delivery has profoundly improved neonatal outcomes. Numerous studies have shown that preterm infants exposed to antenatal corticosteroids have significantly lower severity and/or frequency of respiratory distress syndrome, intracranial hemorrhage, necrotizing enterocolitis, and death than do neonates whose mothers did not receive steroids.36
In October 2016, ACOG published a revised Committee Opinion on Antenatal Corticosteroids for Fetal Maturation,37 which included new data on the benefits of steroid administration in the late preterm pregnancy.38 The following recommendations reflect the positions outlined in this ACOG document:
A single course of antenatal corticosteroids is recommended for pregnant women between 24 0/7 and 33 6/7 weeks of gestation at imminent risk of preterm delivery, including women with ruptured membranes and multiple gestations. If obstetrically indicated, tocolysis may be used to prolong pregnancy for 48 hours to obtain the maximal steroid effect.
Antenatal steroids may also be considered for a pregnancy starting at 23 0/7 weeks where the woman is at risk of delivery within 7 days, including a woman with ruptured membranes or multiple gestations, after consultation with the family.
Pregnant women between 34 0/7 and 36 6/7 weeks of gestation at imminent risk of late preterm delivery, who have not previously received antenatal steroids, should be treated with a single course of antenatal corticosteroids. Tocolysis is not recommended to prolong pregnancy, nor should delivery be delayed if medically or obstetrically indicated. Corticosteroids should not be administered to late preterm pregnancies where chorioamnionitis is suspected.
A rescue course of corticosteroids should be administered to women who are <34 0/7 weeks of gestation who have an imminent risk of preterm delivery within the next 7 days and whose prior course of antenatal corticosteroids was administered more than 14 days earlier.39
Repeat courses of corticosteroids greater than a single rescue course are not recommended because of the associated risks of fetal growth restriction.
Two corticosteroids, betamethasone and dexamethasone, have been the most extensively studied and are equivalently recommended by ACOG. Although multiple studies have suggested the superiority in either the safety or efficacy of one of these steroids or the other, in 2000, the Eunice Kennedy Shriver National Institute of Child and Human Development Consensus Panel did not find significant evidence to support one medication over the other and a Cochrane review in 2013 came to the same conclusion.40
Dosing Regimens:
Betamethasone suspension 12 mg intramuscularly for two doses, 24 hours apart
or
Dexamethasone suspension 6 mg intramuscularly for four doses, 12 hours apart
Because treatment for <24 hours has still been associated with improved neonatal outcomes, steroids should still be initiated even if delivery is anticipated prior to the administration of the second dose. However, ACOG strongly advises against shortening the dosing interval to administer the second dose, even when an imminent delivery seems inevitable. Because the greatest neonatal benefit of steroid administration occurs between 2 and 7 days after administration, ACOG advises against steroid administration unless there is concern about an imminent delivery.37 Although initial reviews failed to demonstrate a consistent benefit to antenatal steroid administration in pregnancies with multiple gestations,36 a subsequent study in 2016 clearly demonstrated a comparable benefit for steroid-exposed preterm twins as for their singleton counterparts.41 Following antepartum glucocorticoid administration, diabetics may transiently require adjustment of their medication to accommodate the loss of glycemic control, and women are at an increased risk of having an abnormal hyperglycemic response when tested.42
Betamethasone injection for fetal maturation is a mixture of two pro-drugs: betamethasone sodium phosphate ester and betamethasone sodium acetate ester.43 Both pro-drugs require hydrolysis to the active betamethasone for them to take effect. The fast-releasing phosphate ester is highly ionized and water soluble and is rapidly absorbed after intramuscular injection. In contrast, the acetate ester is hydrophobic. Because of its low aqueous solubility, the acetate ester must dissolve into the fluids of the intercellular space within the muscle before it can diffuse into the vascular space for distribution to the fetus. As a result, the phosphate ester is responsible for the rapid, initial betamethasone concentration peak, and the acetate ester provides a slowly releasing depot effect. This is the formulation studied by Liggins and Howie in their seminal 1972 publication.44
Betamethasone and dexamethasone are stereoisomers of each other, differing only in the direction relative to the plane of the molecule of the methyl group at carbon 16. However, unlike the betamethasone injection, which contains two different esters, one short- and the other long-acting, only the short-acting phosphate ester is used with dexamethasone.45 As a result, dexamethasone requires four doses administered every 12 hours for a full steroid course. Historically, the choice of one steroid over the other has been based on familiarity (dexamethasone has been more commonly used in Great Britain), medication availability, and ease or frequency of administration.
Both betamethasone and dexamethasone cross the placenta in sufficient concentrations to take fetal effect. In contrast, other corticosteroids (e.g. prednisone or prednisolone) are extensively metabolized by the placental enzyme, 11β-hydroxysteroid dehydrogenase type 2, so fetal concentrations are only about 10% of maternal plasma concentrations.46,47 Of the glucocorticoids, betamethasone and dexamethasone have the longest elimination half-lives (in nonpregnant adults about 6 hours), and the longest biological effect (35–54 hours). In contrast, the elimination half-life of prednisone is about 1 hour, and its biological effect only 18 to 36 hours. In addition, other glucocorticoids have been studied in pregnancy and were not effective at reducing respiratory distress syndrome.48,49
Most of the metabolism of betamethasone occurs in the liver, via CYP 3A4/5, followed by glucuronidation or sulfation and subsequent renal excretion. In an early pharmacokinetic study in pregnant women using 12 mg of the intramuscular combined betamethasone phosphate and acetate mixture,50 maximal maternal concentrations of betamethasone were recorded 1 hour after administration (~100 mg/mL) and 1 to 2 hours after treatment in the fetus (~20 mg/mL in cord blood). The elimination half-life was about 6 hours in the mother and about 12 hours in the fetus with a mean umbilical cord to maternal plasma ratio of about 0.37. No betamethasone was detected in umbilical cord blood in infants delivered >40 hours after the last steroid injection.
CASE 26-3 FOLLOW-UP
Because M.B. received her initial course of antepartum steroids more than 2 weeks prior to her current admission for premature rupture of membranes at 31 3/7 weeks, and because delivery is anticipated in the near future, a rescue course of steroids is indicated. However, if her membranes ruptured at 35 4/7 weeks, a second course of steroids is not indicated. Late preterm steroids (between 34 0/7 and 36 6/7 weeks) are indicated only for women who have not previously received antepartum steroid therapy.
TAKE-HOME POINTS
Corticosteroids for Fetal Lung Maturity
A single course of antenatal corticosteroids is recommended for pregnant women between 24 0/7 and 33 6/7 weeks of gestation at imminent risk of preterm delivery.
Pregnant women between 34 0/7 and 36 6/7 weeks of gestation at imminent risk of late preterm delivery, who have not previously received antenatal steroids, should be treated with a single course of antenatal corticosteroids.
A rescue course of corticosteroids should be administered to women who are <34 0/7 weeks of gestation who have an imminent risk of preterm delivery, and whose prior course of antenatal corticosteroids was administered more than 14 days earlier.
CASE 26-4
34 yo G1P0 at 33 0/7 weeks of gestation is admitted to OB Triage with painful contractions every 3 minutes. Cervical exam at presentation is 1 cm dilated, 2.5 cm long, with the fetal vertex at -3 station. IV hydration with lactated Ringer’s solution is begun. Two hours later, her cervical exam is 2 cm dilated, 0.5 cm long, with the presenting part well applied to the lower uterine segment at -1 station. In addition to starting antepartum steroids, what else should be done? If her pregnancy were 34 5/7 weeks of gestation, what would be your management?
Medications that relax uterine smooth muscle, or tocolytics, can be used on the obstetrics floor for short-term uterine relaxation (e.g. in the setting of a fetal version procedure, uterine tachysystole with fetal hyperstimulation, or during the replacement of an inverted uterus). However, more often, tocolytic medications are used for women in preterm labor. In this setting, the goal is to prolong pregnancy for 48 hours to obtain the neonatal benefits of antepartum steroid exposure.
ACOG recommends the use of short-term tocolytics (during the 48 hours after initiation of corticosteroids) in acute preterm labor for gestations between 24 0/7 and 33 6/7 weeks.51 Tocolytics are not recommended after 33 6/7 weeks of gestation, even when antenatal steroids are administered. The lower limit of tocolytic use is more controversial and somewhat dependent on the definition of fetal viability. ACOG does not recommend the use of tocolytics prior to viability because there is minimal data regarding the efficacy of corticosteroids in previable pregnancies.51 However, in their Practice Bulletin,51 ACOG suggests that tocolytics can be used in the week before viability (after 23 0/7 weeks) after careful consultation with the patient. Other authors suggest the use of tocolytics as early as 20 weeks, if the pregnant woman has a self-limited condition that could cause an isolated episode of preterm labor, such as abdominal surgery or infection.52,53
Tocolytics are contraindicated when the maternal or fetal risks of prolonging the pregnancy are greater than the risks associated with preterm birth;51 intrauterine fetal demise, lethal fetal anomaly, nonreassuring fetal status, severe preeclampsia or eclampsia, maternal bleeding with hemodynamic instability, chorioamnionitis (intrauterine infection or inflammation), and maternal allergy to or contraindication to a particular tocolytic medication.
In the absence of intrauterine infection, tocolytics can be used with preterm premature rupture of membranes to prolong pregnancy for steroid administration or to facilitate maternal transport.51 There is no evidence to support the use of tocolytics for women with contractions without cervical change, especially if the cervical dilation is <2 cm.51 Maintenance therapy with tocolytics beyond the initial 48 hours is not recommended because studies with extended use of tocolytics have not been shown to prolong pregnancy, prevent preterm birth, or improve neonatal outcomes.51,54 There is also no evidence to support the repetitive use of tocolytics for recurrences of preterm labor, other than to accompany one course of appropriately timed rescue steroids.51
Multiple different classes of drugs have been used for their tocolytic effects; they include nonsteroidal anti-inflammatory drugs (NSAIDs), calcium channel blockers, magnesium sulfate, beta-adrenergic receptor agonists (betamimetics), and oxytocin antagonists (the latter are not licensed in the United States, though). The choice of one tocolytic vs. another is a reflection of a physician’s or hospital’s preferences as well as the patient’s clinical presentation. Although beta-mimetics and magnesium sulfate previously were popular, they have fallen out of favor because of the maternal adverse events associated with them. Currently in the United States, indomethacin and nifedipine have become the most commonly used tocolytics.
A 2009 meta-analysis55 reviewed 58 randomized, controlled trials of tocolysis and compared maternal and neonatal outcomes. All tocolytic medications were superior to placebo in their ability to delay delivery for both 48 hours (75%–93% for tocolytics, compared to 53% for placebo) and 7 days (61%–78% for tocolytics, 39% for placebo), but not for delivery after 37 weeks of gestation. The same primary author and team repeated their meta-analysis in 2012,56 this time reviewing 95 tocolytic trials. Compared to placebo, the probability of delaying delivery by 48 hours was highest with prostaglandin inhibitors (odds ratio 5.39, 95% credible interval 2.14–12.34), followed by magnesium sulfate (2.76, 1.58–4.94), calcium channel blockers (2.71, 1.17–5.91), betamimetics (2.41, 1.27–4.55), and the oxytocin receptor blocker atosiban (2.02, 1.10–3.80).
However, the side effects profiles vary widely among the different classes of medications. Compared to placebo, side effects requiring a change of medication were significantly higher for betamimetics (22.68, 7.51–73.67), magnesium sulfate (8.15, 2.47–27.70), and calcium channel blockers (3.80, 1.02–16.92). They concluded that prostaglandin inhibitors and calcium channel blockers had the highest probability of delaying delivery and improving neonatal and maternal outcomes. In addition, multiple Cochrane reviews have been performed, analyzing the tocolytic efficacy and safety profiles of these medications and reaching similar conclusions.54,57–62
Dosing Regimen:
50 to 100 mg orally; followed by 25 to 50 mg orally every 4 to 6 hours for 48 hours61
It is well established that prostaglandins, predominantly prostaglandin E2 (PGE2), increase in amniotic membranes immediately prior to the onset of labor and that administration of prostaglandins stimulate uterine contractions.63 One of the first steps in prostaglandin production involves the enzyme cyclo-oxygenase (COX), which converts arachidonic acid to PGH2.64 PGH2 then serves as the substrate for the production of several prostaglandins, including PGE2. There are two COX isoenzymes, each encoded by a different gene, COX-1 and COX-2. COX-1 is constitutively expressed in many tissues, particularly the gastrointestinal tract, kidney, and platelets. In contrast, COX-2 is expressed in most cell types at low levels, and its expression dramatically increases when induced by cytokines, growth factors, and mitogens. In the pregnant human uterus, both COX-1 and COX-2 are expressed within fetal membranes, decidua and myometrium, but only amniotic COX-2 significantly increases in term and preterm labor.65 Selective inhibition of COX-266,67 or nonspecific inhibition of both COX-1 and COX-268 can block uterine prostaglandin production and stop uterine contractions. Indomethacin, a nonspecific inhibitor of both COX-1 and COX-2, is the most widely used tocolytic of this class.
Indomethacin is uniquely valuable for the treatment of preterm labor associated with uterine myoma degeneration. The potent anti-inflammatory effects of indomethacin both reduce the pain and stop the associated increased uterine tone. However, it is important to note that the use of indomethacin for this indication should not exceed 48 hours. The dosage used is similar to the standard tocolytic regimen.
Adverse effects in both mother and fetus are primarily related to indomethacin’s COX-1 inhibition: gastrointestinal ulcerative disease, hepatic dysfunction, platelet dysfunction or bleeding, decreased urinary output, asthma in women with aspirin sensitivity, oligohydramnios, and in utero closure of the ductus arteriosus. Because the risk of ductal stricture increases with advancing fetal age, use of indomethacin after 32 0/7 weeks is contraindicated.69 However, transient increases in ductal blood flow, indicative of ductal narrowing during indomethacin exposure, can be seen at all gestational ages.67 Reduction in amniotic fluid volume from indomethacin’s effect on fetal renal blood flow can occur by 24 hours of therapy.67 Amniotic fluid gradually normalizes after cessation of therapy.
In 2014, a steady-state pharmacokinetics study70 in 25 women treated with indomethacin (50 mg loading dose, followed by 25 mg every 6 hours) demonstrated that the mean clearance of indomethacin was approximately double that seen in nonpregnant subjects (14.5 ± 5.5 L/h vs. 6.5–9.8 L/h, respectively), and the average plasma concentration in pregnant women following 50 mg every 6 hours was either the same or lower than in studies of nonpregnant subjects who received only 50 mg three times daily. Indomethacin is primarily cleared through a combination of Phase I hepatic metabolism by CYP2C9 and Phase II glucuronidation (predominantly UGT1A9 and UBT2B7).71 Activity of CYP2C9 has been shown to increase twofold during pregnancy.72 The mean umbilical cord/maternal ratio was 4.0 ± 1.1, which is consistent with our understanding that the fetus has a decreased ability to clear indomethacin: the elimination half-life of indomethacin in premature neonates has been reported to be seven times longer than that in adults. In addition, clearance may be impaired by the effect of indomethacin on fetal renal blood flow.
The most commonly used calcium channel blocker for uterine tocolysis is IR nifedipine, although some studies have been published on the use of nicardipine.59 The optimal dosing regimen has not been established. The following describes a composite regimen and includes the range of published regimens.59
Dosing Regimens:
20 to 30 mg orally, followed by 10 to 20 mg orally every 3 to 8 hours for 48 hours, with a maximum daily dose of 180 mg
or
20 mg orally with one repeat dose 30 minutes later if contractions persist, followed by 20 mg orally every 6 hours for 48 hours of therapy
Calcium channel blockers impede the influx of calcium ions through specific calcium pores within the cell membrane and increase the efflux transport of calcium from inside the cell. These medications also inhibit the release of calcium from the sarcoplasmic reticulum into the cytoplasm. The net effect is to reduce the concentration of free calcium ions within the cytoplasm relative to the extracellular environment. This calcium deficit inhibits the calcium-dependent myosin light-chain kinase phosphorylation process and results in myometrial smooth muscle relaxation.
The arterial smooth muscle relaxation seen with nifedipine can precipitate the adverse effects commonly seen with the drug: decreased total vascular resistance, maternal hypotension, and a compensatory increase in maternal heart rate. Other related side effects include nausea, flushing, headache, dizziness, and cardiac palpitations. Nifedipine is contraindicated in women with cardiac disease, especially preload dependent cardiac lesions, congestive heart failure, or maternal hypotension or tachycardia at onset of tocolysis.51 Because both calcium-channel blockers and magnesium sulfate affect intracellular calcium concentrations, concomitant use of these two medications theoretically could act synergistically, resulting in respiratory depression.73
Similar to nifedipine, various terbutaline dosing regimens have been employed, with no particular regimen shown to be superior to the others. The following regimens provide an intermittent, subcutaneous version and a continuous infusion option.
Dosing Regimens:
Terbutaline injection 0.25 mg subcutaneously, repeated up to four times, every 20 to 30 minutes or until tocolysis is achieved. Once labor is inhibited, continue 0.25 mg subcutaneously every 3 to 4 hours until the uterus is quiescent for 24 to 48 hours.
Continuous infusion, starting at 2.5 to 5 mcg/min and increasing by 2.5 to 5 mcg/min every 20 to 30 minutes to a maximum of 25 mcg/min, or until contractions have spaced out. Then, decrease the infusion rate by decrements of 2.5 to 5 mcg/min to the lowest dose that maintains uterine quiescence, and continue for 24 to 48 hours.
Ritodrine, the first betamimetic used for tocolysis and the only drug approved by the FDA for the treatment of preterm labor, is no longer available in the United States. Although there have been studies utilizing other betamimetics, most studies have used either ritodrine or, currently, terbutaline.
The use of betamimetic medications for tocolysis is associated with numerous maternal side effects, some of them intolerable: increased maternal heart rate and stroke volume, peripheral vasodilation, diastolic hypotension, bronchial relaxation, and palpitations. These side effects are common and debilitating. In a 1999 review of tocolytic studies,74 women treated with betamimetics complained of tremor (39% vs. 4% for placebo), palpitations (18% vs. 4%), shortness of breath (15% vs. 1%), and chest discomfort (10% vs. 1%). In addition, metabolic complications are frequently seen, including hypokalemia (39% betamimetic vs. 6% placebo) and hyperglycemia (30% vs. 10%).74
The 2004 Cochrane review57 of betamimetic tocolytics reported, “Betamimetics were significantly associated with the following: withdrawal from treatment due to adverse effects; chest pain; dyspnea; tachycardia; palpitation; tremor; headaches; hypokalemia; hyperglycemia; nausea/vomiting; and nasal stuffiness; and fetal tachycardia.” Betamimetic tocolytics are contraindicated in women with tachycardia-sensitive cardiac disease and in women with poorly controlled diabetes or hyperthyroidism.51 Even in women without cardiac disease, withholding medication is recommended if the maternal heart rate exceeds 120 beats/min. Maternal glucose and potassium should be monitored every 4 to 6 hours in women receiving IV terbutaline infusion.
In addition to ACOG’s strong recommendation against prolonged or maintenance use of tocolysis for both safety and lack of efficacy reasons, the FDA included a black box warning on the terbutaline label in 2011:75 “The U.S. Food and Drug Administration (FDA) is warning the public that injectable terbutaline should not be used in pregnant women for prevention or prolonged treatment (beyond 48–72 hours) of preterm labor in either the hospital or outpatient setting because of the potential for serious maternal heart problems and death. The agency is requiring the addition of a Boxed Warning and Contraindication to the terbutaline injection label to warn against this use. In addition, oral terbutaline should not be used for prevention or any treatment of preterm labor because it has not been shown to be effective and has similar safety concerns.”
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