Chronic hypertension in pregnancy

Chronic hypertension (CHTN) is a condition in which elevated blood pressure (BP) predates pregnancy or is first diagnosed in pregnancy before 20 weeks’ gestation.^1,2 It affects approximately 2% or more of pregnant patients, depending on diagnostic criteria,^3,4 and is associated with increased short- and longterm adverse maternal and neonatal outcomes.^1,2,5-9 The American College of Obstetricians and Gynecologists (ACOG) defines CHTN during pregnancy as elevated BPs greater than 140/90 mm Hg on at least 2 occasions, 4 hours apart, and occurring before 20 weeks’ gestation.² However, in the nonpregnant patient, the diagnosis of CHTN is now ≥130/80 mm Hg on at least 2 occasions at least 4 hours apart, following recent changes to diagnosis guidelines in 2017 by the American College of Cardiology(ACC) and the American Heart Association (AHA).^10,11 These changes in diagnostic criteria were a result of the increased long-term cardiovascular morbidity in individuals with BPs in the range of 130- to 139/80- to 89 mm Hg. Therefore, nonpregnant patients will be diagnosed with CHTN using lower BP thresholds than those used in pregnancy and will in turn increase the prevalence of pregnant patients with CHTN.²

Diagnosis and classification

The AHA/ACC guidelines classify CHTN into normal, elevated, stage 1 hypertension, stage 2 hypertension, or hypertensive crisis categories based on BP levels (Table 1).¹¹ Hypertension in pregnancy is classified as severe (BP ≥ 160/110 mm Hg) or mild (BP, 140-159/90-109 mm Hg) by ACOG. Classification of hypertension correlates with the degree of maternal and fetal risks and identifies patients who need acute therapy to lower BPs during pregnancy.¹² Accurate measurement of BP is crucial to correctly identify patients with CHTN during pregnancy (Box).^13,14

Risk factors and adverse outcomes

Nonmodifiable risk factors for CHTN include increasing age, Black race, and family history of CHTN. Modifiable risk factors include obesity (approximately 40% of reproductive-aged individuals in the United States),¹⁵ excess alcohol and tobacco consumption, physical inactivity, diabetes mellitus, chronic kidney disease, and diet that is high in sodium and cholesterol. CHTN is associated with short- and long-term risks. In nonpregnant adults with CHTN, compared with individuals with normal BPs, the risks of myocardial infarction, heart failure, chronic kidney disease, stroke, vision loss, and sexual dysfunction are increased.^16-20 Similarly, during pregnancy, patients with CHTN have a 2-fold higher risk of maternal mortality, a 3-fold higher risk of cerebrovascular accidents and pulmonary edema, and up to a 16-fold higher risk of renal failure.^13,21

Preeclampsia, a leading indication for indicated preterm delivery that occurs in 25% to 50% of patients with CHTN, is a leading mediator of adverse outcomes. Additionally, gestational diabetes and cesarean deliveries are also more frequent in patients with CHTN.² The fetal risks of CHTN includes a 2- to 3-fold higher risk of low birth weight, preterm delivery, placental abruption, and stillbirth (Table 2).^2,13,22,23 There are also increased risks of additional cardiovascular disease in later life in both individuals with CHTN and their off-spring (including hypertension, stroke, obesity, and cardiovascular disease) conceived in pregnancies complicated by CHTN or preeclampsia.^13,24,25

Prevention

CHTN Lifestyle modification of risk factors remains the initial approach to CHTN prevention (Table 3). Gradual weight loss for overweight or obese patients²⁶; cessation of tobacco use; regular moderate exercise; reduction in consumption of high-calorie, nutrient poor foods; and limitation of alcohol consumption^27,28 are frequently cited effective strategies in nonpregnant patients. Alcohol consumption, even in small to moderate quantities, is not recommended in pregnancy or in the preconception period.

Treatment

Prior to pregnancy, the lifestyle modification measures outlined above have been shown to reduce systolic BPs in patients with CHTN, with greater reductions when multiple measures are combined. Lifestyle measures also augment medication effectiveness in lowering BP, particularly in patients with drug-resistant hypertension. Bariatric surgery is recommended for patients with class 3 obesity (body mass index [BMI] ≥ 40 kg/m2 ) or who have a BMI greater than or equal to 35 kg/m2 and an obesity-related comorbidity.²⁹ Pharmacologic BP reduction is associated with improved cardiovascular outcomes.^30,31 The decision to initiate pharmacologic treatment in nonpregnant adults aged at least 40 years depends on the stage of CHTN and estimated atherosclerotic cardiovascular disease (ASCVD) risk, taking into consideration personal and family history. Pharmacologic treatment is generally recommended for ACC/AHA stage 2 CHTN, and for patients with ACC/AHA stage 1 hypertension with an ASCVD risk greater than 10% (Figure 1). In most patients, treatment goals are a systolic and diastolic BP of less than 130/80 mm Hg outside of pregnancy. However, in pregnancy, current evidence supports treatment to less than 140/90 mm Hg, although secondary analyses have reported improved outcomes with BPs at less than 130/80 mm Hg compared with less than 140/90 mm Hg.^32,33 This remains an active area of investigation. However, another important note is that intensive treatment to lower BP goals in nonpregnant patients reduced adverse cardiovascular events in a clinical trial and was associated with significant adverse effects in a small subset of patients.^35,36

Angiotensin receptor blockers (ARBs), angiotensin-converting enzyme inhibitors (ACEIs), calcium channel blockers, or thiazide diuretics are the recommended first-line medications for treatment of CHTN in nonpregnant patients.³⁶

Preconception and during pregnancy The ACC/AHA 2017 guidelines addressed first-line medications in pregnancy and medications to avoid but not treatment thresholds and goals. In the preconception period, antihypertensive agents including ARBs and ACEIs are associated with fetal harm (eg, oligohydramnios, renal failure, growth restriction, and bone abnormalities), especially with second- and third-trimester exposure, and should be discontinued. Patients should then be transitioned to labetalol or nifedipine.³⁷ Although data are limited, patients who become pregnant while using alternate calcium channel blockers (such as amlodipine) with well-controlled BPs, or their physicians managing them, may choose to continue rather than switch to nifedipine during pregnancy.

Guidance regarding treatment thresholds and goals in pregnancy are provided by ACOG.^2,32 Treatment was previously recommended only for severe hypertension (systolic blood pressure [SBP] ≥160 or diastolic blood pressure [DBP] ≥110 mm Hg) but not mild CHTN due to limited data regarding benefits and concerns that lowering BP beyond a certain threshold will lower placental perfusion, which in turn may lead to fetal growth restriction, as well as older studies reporting such associations.^38-40 More recently, the Control of Hypertension in Pregnancy Study (CHIPS) study (NCT01192412), a multicountry trial of 987 women (75% with CHTN) found that tight control (target DBP of 85 mm Hg) compared with less tight (target DBP of 100 mm Hg) was not associated with an increased risk of pregnancy loss or high-level neonatal care more than 48 hours in the first 28 days of life (adjusted odds ratio [aOR], 1.02; 95% CI, 0.77-1.35) or maternal complications. However, severe hypertension was more prevalent in the less-tight group.⁴⁰

Subsequently, the CHAP trial (NCT02299414) was published, which was a US-based, multicenter, pragmatic, open-label, randomized, controlled trial that focused on pregnant patients with mild CHTN (n = 2408). Patients were assigned to active treatment with a goal to reach BP of less than 140/90 mm Hg or standard care (no treatment unless BP ≥ 160/110 mm Hg). The rate of a composite primary outcome (1 or more of severe preeclampsia, medically indicated births prior to 35 weeks’ gestation, abruption, and fetal or neonatal death) was 18% lower in patients randomly assigned to active treatment to BP of less than 140/90 mm Hg (Figure 2).³³ This was achieved without any significant difference in the risk of small for gestational age infants. In addition, other outcomes, including any preeclampsia, preterm birth, and low birth weight, were less frequent in the active group. Following publication, professional societies in the United States, including ACOG and the Society for Maternal-Fetal Medicine, have issued statements recommending patients with mild CHTN during pregnancy be treated to BP goals of less than 140/90 mm Hg.^33,39

For patients with ACC/AHA stage 1 hypertension during pregnancy, the data are extremely limited on whether antihypertensive treatment or even prophylaxis with aspirin reduces the risks of adverse pregnancy outcomes.^41,42 Thus, no firm recommendations can be made for this growing subset of pregnant patients other than lifestyle measures in pregnancy. Also, whether to treat CHTN to a goal of BP less than 130/80 mm Hg to align with recommendations outside of pregnancy vs BP of 140/90 mmHg after CHAP remains uncertain. These are areas for future investigation, given that stage 1 hypertension is associated with worse adverse outcomes

Nifedipine and labetalol are 2 recommended oral first-line agents with established safety profiles for the treatment of CHTN in pregnancy, but the preferred medication is not known.² In a Cochrane review of randomized trials of treatment for mild to moderate CHTN in pregnancy, although β-blockers and calcium channel blockers reduced the risk of severe hypertension (risk ratio [RR], 0.70; 95% CI 0.56-0.88), there was no difference when methyldopa and calcium channel blockers were compared with β-blockers (RR, 1.18; 95% CI, 0.95- 1.48).⁴³ Similarly, there were no differences in the risks of preeclampsia, fetal or neonatal death, small for gestational age, or preterm delivery of less than 37 weeks’ gestation when other antihypertensives were compared with calcium channel blockers or with β-blockers.⁴⁵ Thus, the superiority of nifedipine compared with labetalol or vice versa is not established.

ACOG recommends low-dose aspirin for prophylaxis of preeclampsia in patients with CHTN during pregnancy. However, more recent studies have failed to find that aspirin prophylaxis in women with CHTN is beneficial in reducing the risk of preeclampsia.⁴⁴ Although this recommendation is yet to change, clinical care providers should recognize the limitations of the efficacy of aspirin in patients with CHTN who already may have cardiovascular remodeling of their blood vessels and therefore may not benefit from aspirin prophylaxis.

There are active areas requiring investigation for patients with CHTN in pregnancy. The diagnosis of CHTN during pregnancy, superimposed preeclampsia, new-onset preeclampsia, and gestational hypertension continue to rest on the thresholds of 140/90 mm Hg during pregnancy despite multiple large observational studies showing increased risks of preeclampsia, small for gestational age, low birth weight, and preterm delivery in patients with persistent BPs of 130-139/80-89 mm Hg.^5-8,45-48 Logistic concerns about increased health care utilization for up to 1 in 4 pregnant patients if the ACC/AHA criteria were applied to pregnancy—even though no effective proven prophylaxis or treatment exists—likely contributes to the hesitancy to adopt the ACC/AHA guidelines in pregnancy. Ongoing research to identify effective interventions may tip this balance.

Conclusion

The incidence of CHTN in pregnancy is rising and is associated with maternal and neonatal adverse outcomes. Pregnant patients should be treated with antihypertensive medications to less than 140/90 mm Hg. Optimal treatment BP goals, diagnostic BP threshold in pregnancy, and long-term cardiovascular outcomes following treatment started in pregnancy are active areas of research.

References

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