Options — The following drugs are effective antihypertensive agents with an acceptable safety profile in pregnancy. The choice of drug depends on the acuity and severity of hypertension and whether or not parenteral or oral therapy is used; these factors are discussed below.
Methyldopa — Methyldopa has been widely used in pregnant women and its long-term safety for the fetus has been demonstrated, but it is only a mild antihypertensive agent and has a slow onset of action (three to six hours). Many women will not achieve blood pressure goals on this oral agent or are bothered by its sedative effect at high doses.
Although methyldopa is not widely used outside of pregnancy, it remains useful in this setting, particularly in women who develop adverse effects or are intolerant of other, more widely used medications. Methyldopa has been used for several decades, and its safety has been more extensively documented than other antihypertensive agents. Clinical trials (eg, CHIP) utilized this agent and demonstrated that women treated with methyldopa may have had better outcomes compared to those treated with labetalol, although these data may be biased by residual confounding
Beta-blockers — In a 2013 systematic review of 13 population-based case-control or cohort studies examining the risk of congenital malformations associated with first trimester oral beta-blocker exposure compared with no exposure, there was no overall increase in major congenital malformations (OR 0.90, 95% CI 0.91-1.10). Associations with some organ-specific malformations were observed: cardiovascular defects (OR 2.01; 95% CI 1.18-3.42; 4 studies), cleft lip/palate (OR 3.11; 95% CI 1.79-5.43; 2 studies), and neural tube defects (OR 3.56; 95% CI 1.19-10.67; 2 studies). A 2015 systematic review specifically examining the risk of congenital heart defects associated with treated and untreated hypertension reported an association regardless of treatment status, and an increased risk in women treated with beta-blockers compared with untreated hypertensive women (RR 2.1, 95% CI 1.6-2.7). Two subsequent studies have reported conflicting results. Although one found an association between beta-blocker use and congenital heart defects, the other did not after adjusting for maternal age, maternal body mass index, and maternal comorbidities. Further research is required given the limitations of these data, including inability to analyze data by type of beta-blocker, variability in timing of exposure within the first trimester, differences in indications for beta-blocker therapy, and recall, recording, publication, and survivor biases.
Labetalol has both alpha- and beta-adrenergic blocking activity, and may preserve uteroplacental blood flow to a greater extent than traditional beta-blockers. It has a more rapid onset of action than methyldopa(within two hours versus three to six hours). Randomized trials comparing labetalol to nicardipine or methyldopa have shown that labetalol is effective and generally safe in pregnancy, although data are limited. Labetalol has been associated with maternal hepatotoxicity, which although rare, is important to recognize as it may be confused with the elevated liver chemistries of the HELLP (Hemolysis, Elevated Liver chemistries, and Low Platelet count) syndrome. Most cases are reversible, but fatalities have been reported. A retrospective population-based cohort study observed slightly more adverse outcomes (respiratory distress syndrome, sepsis, seizure) among infants exposed in utero to labetalol than those exposed to methyldopa, but only when maternal treatment was for chronic hypertension rather than an acute pregnancy-related hypertensive disorder. These findings may be related to the duration of therapy in chronic hypertension and differences in baseline characteristics of the mothers in each treatment group (eg, severity of hypertension, control of hypertension), variables not accounted for in the analysis. Labetalol may be administered orally or parenterally. Although less well studied in pregnant women, pindolol and the long-acting form of metoprolol are acceptable alternative agents
The safety of beta-adrenergic blockers is controversial due to inconsistent reports of preterm birth, fetal growth restriction/small for gestational age infant, perinatal mortality, and neonatal apnea, bradycardia, and hypoglycemia as well as a possible increased risk of congenital malformations. Furthermore, myometrial relaxation of the gravid uterus is a beta2-receptor-mediated process, and nonselective beta-adrenergic blockers (such as propranolol) may counteract the effect of beta2 stimulation. Beta-adrenergic blockers that lack alpha-blocking properties (eg, atenolol) have been associated with slightly lower placental and fetal weight at delivery when used early in pregnancy, and are generally avoided if an effective drug with a better safety profile is available
Long-acting nifedipine (30 to 90 mg once daily as sustained release tablet, increase at 7- to 14-day intervals, maximum dose 120 mg/day) has been used without major problems . Although amlodipine is widely used in non-pregnant individuals with hypertension, there are sparse data of its use in pregnancy . Nondihydropyridine calcium antagonists such as verapamil and diltiazem have been used, as well, although most reports in the literature are of small numbers of women.
We caution against the use of immediate release oral nifedipine, although an American College of Obstetricians and Gynecologists committee opinion endorsed its use as an option for emergent treatment of acute, severe hypertension in pregnancy or postpartum (other options were sustained release nifedipine, labetalol, and hydralazine) . In most cases use of immediate release nifedipine will be safe and well tolerated; however, there is a small risk of an acute, precipitous fall in blood pressure, which may result in a reduction in uteroplacental perfusion and headache. In a 2014 meta-analysis of six trials of treatment of severe pregnancy-associated hypertension, less than 2 percent of women treated with nifedipine developed hypotension and short-acting nifedipine, parenteral hydralazine, and labetalol were associated with similar rates of adverse maternal and fetal outcomes.
Hydralazine — Intravenous hydralazine has been used extensively in the setting of preeclampsia for the acute treatment of severe hypertension. Although a meta-analysis demonstrated a slightly increased rate of adverse events with hydralazine compared to labetalol, the evidence was not sufficient to make a definitive recommendation for one drug over the other. Hydralazine has been widely used for many years in the setting of acute hypertension in pregnancy and is an acceptable antihypertensive drug in this setting. However, the hypotensive response to hydralazine is less predictable than that seen with other parenteral agents. Hydralazine can also be taken orally; however, it causes reflex tachycardia and fluid retention, which limit its usefulness in pregnancy.
Thiazide diuretics — The role of thiazide diuretics has been a source of controversy, although some guidelines suggest that these agents can be continued in women with chronic hypertension who were taking them prior to pregnancy. Significant volume depletion is not likely in this setting, since all of the fluid loss occurs within the first two weeks of use, assuming that drug dose and dietary sodium intake are relatively constant. Diuretics are not generally used in women with preeclampsia unless pulmonary edema has developed.
Clonidine — Clonidine has a similar mechanism of action as methyldopa and can be an effective drug for treatment of mild hypertension in pregnancy [31-33]. However, it has bothersome side effects and the possibility of rebound hypertension if it is stopped suddenly, so other agents are preferred. The author has prescribed it for rare patients in whom methyldopa, nifedipine, and labetalol could not be used. Because clonidine is available as a transdermal patch, it is particularly useful for patients who cannot take an oral antihypertensive drug.
Fonte uptodate – atualizado em outubro de 2017
Options for breastfeeding mothers
Breastfeeding does not increase blood pressure in nursing mothers. Beta-adrenergic blockers and calcium channel blockers enter breast milk; however, most appear to be safe during lactation and are considered “compatible” with breastfeeding by experts. It is prudent to consult with the infant’s pediatrician before initiating maternal antihypertensive drugs.
Within each class of antihypertensive agents, physicians should select the medication with the lowest transfer into human milk.
?Beta-blockers and alpha/beta-blockers – Propranolol, metoprolol, and labetalol have the lowest transfer into milk of this class of drug, with relative infant doses of less than 2 percent. None has been associated with adverse events in infants.
In contrast, atenolol and acebutolol are more extensively excreted into breast milk and beta-blockade in nursing infants has been reported; therefore, other agents are preferable for women who are nursing an infant less than 3 months of age or a preterm infant, or who are taking a high maternal dose.
?Angiotensin converting enzyme (ACE) inhibitors – These drugs are transferred into milk at very low levels. Captopril and enalapril may be used in lactating women. However, newborns may be more susceptible to the hemodynamic effects of these drugs, such as hypotension, and sequelae such as oliguria and seizures. Therefore, we suggest that the hemodynamic status of the infant be taken into account when deciding whether women taking these drugs should breastfeed.
There is no information on use of angiotensin II receptor blockers during breastfeeding.
?Diuretics – Theoretically, diuretics may reduce milk volume. Hydrochlorothiazide mg/day is considered safe during lactation. No information on furosemide is available, but the effect of intense diuresis is a concern.
Fonte uptodate – atualizado em outubro de 2017