Why is the treatment of hypertension in pregnancy still so difficult?

Keywords::

• clinical trials in hypertension
• drug treatment
• gestational hypertension
• nonpharmacological treatment
• preeclampsia
• pre-existing hypertension

Hypertensive disorders in pregnancy remain a major cause of maternal, fetal and neonatal morbidity and mortality, not only in developing, but also in developed countries. Pregnant women with hypertension are at higher risk for severe complications such as abruptio placentae, cerebrovascular accident, organ failure and disseminated intravascular coagulation. The fetus is at risk of intrauterine growth retardation, prematurity and intrauterine death.

Hypertension is the most common medical problem in pregnancy; it may complicate 10–15% of pregnancies and accounts for approximately a quarter of all antenatal admissions. As the age of pregnant women is getting higher, hypertension in pregnancy is becoming a major medical problem.

Sufficient data regarding treatment of hypertension in pregnancy are lacking as pharmaceutical companies have been reluctant to test drugs in this small market with a high potential of litigation. Child-bearing potential without reliable contraception is an exclusion criterion in basically all clinical trials testing antihypertensive drugs. Pharmaceutical companies are not willing to take any, even a small, risk and, therefore, no data are available for most of the antihypertensive drugs marketed over the last 20 years. As a consequence, the vast majority of newer antihypertensive drugs are strictly contraindicated in pregnancy.

The only trial of treatment for hypertension in pregnancy with adequate infant follow-up (7.5 years) was performed more than 30 years ago with α-methyldopa, now rarely used in nonpregnant women [1,2]. Past clinical trials have also not supported a beneficial effect on pregnancy outcome of treating mild hypertension. There has been no reduction in perinatal mortality, placental abruption or superimposed preeclampsia [3,4]. All these trials are subject to criticism including small patient numbers, starting the drug too late in pregnancy or flawed study design; however, no other data are currently available. These studies have led to recommendations to treat only on the basis of blood pressure (BP) sufficiently elevated to pose a potential acute risk to the mother [5]. Small and frequently poorly designed studies have recently suggested that therapy of mildly elevated BP may prevent progression to preeclampsia [6,7]. Even for women with BP elevation sufficient to justify therapy for their own benefit, it is not clear whether it is beneficial for, or detrimental to, the fetus. In several studies, treatment of hypertensive women resulted in an increased risk of growth restriction in their infants [8]. It is not known whether this is the inevitable consequence of lower BP during pregnancy or whether it is due to excessive BP decreases or to specific drugs.

The value of continued administration of antihypertensive drugs to pregnant women with chronic hypertension continues to be an area of debate. While there is a consensus that drug treatment of severe hypertension in pregnancy is required and beneficial [9], treatment of less severe hypertension is controversial. Although it might be beneficial for the mother with hypertension to reduce her BP, lower BP may impair uteroplacental perfusion and thereby jeopardize fetal development. Much uncertainty regarding the benefits of BP lowering in pregnant women with mild pre-existing hypertension stems from published trials too small to detect a modest reduction in obstetric complications.

All antihypertensive drugs have either been shown or are assumed to cross the placenta and reach the fetal circulation. While the goal of treating hypertension is to reduce maternal risk, the agents selected must be efficacious and safe for the fetus [10,11]. However, none of the antihypertensive agents in routine use have been documented to be teratogenic, although ACE inhibitors and angiotensin II antagonists are fetotoxic.

Treatment of severe hypertension

There is no absolute agreement in the definition of severe hypertension with values ranging between 160 and 180 mmHg/>110 mmHg. Systolic BP (SBP) ≥170 mmHg or diastolic BP (DBP) ≥110 mmHg in a pregnant woman should be considered an emergency, and hospitalization is absolutely essential. Pharmacological treatment with intravenous labetalol, or oral methyldopa or nifedipine is to be initiated. Intravenous hydralazine should no longer be thought of as the drug of choice as its use is associated with more perinatal adverse effects than other drugs. The drug of choice in hypertensive crises is sodium nitroprusside given as intravenous infusion. Prolonged treatment with sodium nitroprusside is associated with an increased risk of fetal cyanide poisoning as nitroprusside is metabolized into thiocyanate and excreted into urine [12]. The drug of choice in preeclampsia associated with pulmonary edema is nitroglycerine.

Treatment of mild-to-moderate hypertension

The majority of women with pre-existing hypertension in pregnancy have mild-to-moderate hypertension (140–179/90–109 mmHg), and are at low risk of cardiovascular complications within the short timeframe of pregnancy. Women with essential hypertension and normal renal function have good maternal and neonatal outcomes; they are candidates for nondrug therapy because there is no evidence that pharmacological treatment results in an improved neonatal outcome. Some women with treated pre-existing hypertension are able to stop their medication in the first half of pregnancy because of the physiological fall in BP during this period. However, close monitoring and, if necessary, resumption of treatment is essential.

The benefits of antihypertensive therapy for mildly to moderately elevated BP in pregnancy (<160/110 mmHg) have not been demonstrated in clinical trials. Recent reviews including a Cochrane analysis concluded there are insufficient data to determine the benefits and risks of antihypertensive therapy for mild-to-moderate hypertension (defined as 140–169 mmHg SBP and 90–109 mmHg DBP) [4,8,13–15]. Of note, with antihypertensive treatment, there seems to be less risk of developing severe hypertension (a risk ratio of 0.50 with a number-needed-to-treat of 10), but no difference in outcomes of preeclampsia, neonatal death, preterm birth and small-for-gestational-age babies with treatment [13].

International and national guidelines for the treatment of hypertension in pregnancy vary with respect to thresholds for initiating drug treatment and BP goals.

Current European Society of Hypertension (ESH)-European Society of Cardiology (ESC) guidelines for the management of hypertension [16] recommend thresholds for antihypertensive treatment at an SBP of 140 mmHg or a DBP of 90 mmHg in women with:

• • Gestational hypertension (with or without proteinuria);

• • Pre-existing hypertension with the superimposition of gestational hypertension;

• • Hypertension with subclinical organ damage or symptoms at any time during pregnancy.

In any other circumstances, the ESH-ESC thresholds are SBP of 150 mmHg and DBP of 95 mmHg. For nonsevere hypertension, methyldopa, labetalol and calcium antagonists are the drugs of choice. Methyldopa has the longest and safest record for use in pregnancy, and it is also the only substance with longitudinal follow-up of children [1,2]. However, its use outside of pregnancy is considered to be obsolete. In some countries, methyldopa has been withdrawn from the market. β-blockers appear to be less effective than calcium antagonists. Atenolol should be avoided in the early stages of pregnancy and given with caution in the later stages, as it is associated with fetal growth retardation related to duration of treatment [17]. Calcium-channel blockers are considered to be safe if not given concomitantly with magnesium sulfate (risk of hypotension due to potential synergism). ACE inhibitors, angiotensin II antagonists and direct renin inhibitors are strictly contraindicated in pregnancy. The plasma volume is reduced in preeclampsia; diuretic therapy is therefore inappropriate unless there is oliguria. Magnesium sulfate in vitro is recommended for the prevention of eclampsia and treatment of seizures [18].

Conclusion

There is a general consensus that severe hypertension in pregnancy (≥160/110 mmHg) should be treated with antihypertensive drugs. However, there is no evidence that drug treatment of mild-to-moderate hypertension in pregnancy is beneficial (no difference in outcome of preeclampsia, neonatal death, preterm birth and small-for-gestational-age babies). Most of the studies had limitations in the study design as they enrolled small numbers of participants and there is no longitudinal follow-up (except for one study with methyldopa). For nonsevere hypertension, old substances such as methyldopa and labetalol, together with calcium antagonists, are the drugs of choice recommended almost uniformly by all guidelines. No newer antihypertensive drugs have been tested in pregnancy. Therefore, further research in this area is desperately needed; however, it is not likely to be funded by a pharmaceutical company.

Financial & competing interests disclosure

The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.