What data support initiation of antihypertensive therapy for mild chronic hypertension in pregnancy?

Background
Hypertensive disorders of pregnancy are the leading cause of maternal mortality.^1,2 Chronic hypertension in pregnancy, meaning hypertension that existed prior to pregnancy, affected 2.3% of pregnant patients in the United States in 2019, and may cause rare but significant complications including stroke, heart failure, or death.^1-4 Additional potential maternal complications include myocardial infarction, superimposed preeclampsia, acute kidney failure, pulmonary edema, placental abruption, postpartum hemorrhage, gestational diabetes, hospitalization, Cesarean delivery, and long-term cardiovascular risk.^3,4 Fetal and neonatal risks include perinatal death, preterm birth, small-for-gestational age birth, and certain congenital malformations (eg, cardiac malformations, hypospadias, esophageal atresia). Risk factors for developing more severe disease (ie, superimposed preeclampsia) include obesity, Black race, smoking, longer hypertension duration, a baseline diastolic blood pressure > 100 mmHg, and preeclampsia history.⁴

Although the 2017 American Academy of Cardiology and American Heart Association guideline for hypertension defined stage 1 hypertension as systolic blood pressure of 130 to 139 mmHg and diastolic blood pressure of 80 to 89 mmHg, hypertension in pregnancy is defined differently.⁵ Chronic hypertension in pregnancy is classified as systolic blood pressure ≥ 140 mmHg and diastolic blood pressure ≥ 90 mmHg, and it is considered severe when the systolic blood pressure ≥ 160 mmHg and diastolic blood pressure ≥ 110 mmHg.⁴ Although antihypertensive treatment has been recommended for severe chronic hypertension, the benefits of treating women with systolic blood pressure of 140 to 159 mmHg and diastolic blood pressure of 90 to 109 mm Hg (ie, mild chronic hypertension) has been less clear, since the benefits of treatment must be considered with the potential fetal risk associated with antihypertensive exposure.^4,6,7 The purpose of this FAQ is to review recent evidence of earlier antihypertensive treatment of chronic hypertension in pregnancy.

Treatment of chronic hypertension in pregnancy
Guideline recommendations
In 2019, the American College of Obstetrics and Gynecology (ACOG) recommended treatment of chronic hypertension when blood pressure measured ≥ 160/110 mmHg, or potentially in patients with lower blood pressure and comorbidities or impaired renal function.⁴  However, ACOG updated its recommendation and reduced the treatment threshold for starting or titrating therapy to 140/90 mmHg based on the 2022 Chronic Hypertension and Pregnancy (CHAP) study which is discussed in detail below. The ACOG recommendation further stated that patients with chronic hypertension may be maintained on their medications when they become pregnant instead of discontinuing them until their blood pressure becomes severe. The Society for Maternal-Fetal Medicine echoed this recommendation.⁸

Preferred agents
Agents that are preferred for treatment of hypertension in pregnancy include labetalol and long-acting nifedipine, while methyldopa may be an alternative agent.^2,4,5,7  Other calcium channel blockers and beta-blockers (with the exception of atenolol which may be associated with fetal growth restriction) are also generally considered safe; clonidine is an option in the third trimester.^2,9 Angiotensin converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARB), and direct renal inhibitors are not recommended in pregnancy due to the potential for teratogenicity.

Evidence review
Although treatment of mild chronic hypertension in pregnancy had reduced the progression to severe disease, it had not been associated with other improved maternal, fetal, or neonatal outcomes.⁴ In addition, the major safety concern related to treatment was the reduction in uteroplacental blood flow which may result in growth restriction.^4,6

Evidence to support these statements in part included a 2015 Control of Hypertension in Pregnancy Study (CHIPS) and meta-analyses.^4,10-12  The CHIPS randomized controlled trial compared less tight control (target diastolic blood pressure < 100 mmHg) to tight control (target diastolic blood pressure < 85 mmHg) in 987 women with hypertension, including 74.6% with chronic hypertension.¹¹ The study found that tight control reduced the progression to severe disease but was not associated with other improved outcomes, including the primary outcome of pregnancy loss or need for neonatal care ≥ 48 hours in the first 28 days.  A limitation of this trial was the large number of patients enrolled later in gestation, which limited the number of patients with chronic hypertension.⁸

Meta-analyses also did not find improved outcomes other than a reduction in severe hypertension with use of antihypertensives for mild chronic hypertension in pregnancy. The 2018 Cochrane review of 63 trials found that treatment of mild-to-moderate chronic hypertension (systolic blood pressure 140 to 169 mmHg and/or diastolic blood pressure 90 to 109 mmHg) reduced the incidence of severe hypertension, but other outcomes including proteinuria/preeclampsia, total reported fetal or neonatal death, small-for-gestational age births, or preterm births were not improved with use of antihypertensives.¹⁰ A 2022 network meta-analysis included 61 studies found that antihypertensives decreased the risk of severe hypertension in patients; however, there was not a significant reduction in other maternal or perinatal outcomes, including small-for-gestation age births.¹²

CHAP study
Since the publication of these meta-analyses, the CHAP trial was published. The CHAP trial was an open-label, randomized trial of 2408 pregnant patients with mild chronic hypertension and singleton gestations < 23 weeks from 61 centers across the United States.¹³ Patients were randomized to either receive antihypertensive medications (active treatment) (n=1208) or no treatment (n=1200) until the patient had severe hypertension (systolic pressure ≥ 160 mmHg or diastolic pressure ≥ 105 mmHg). Patients assigned to the no treatment group on preexisting treatment had their antihypertensive treatment withheld or stopped at randomization. The goal was a blood pressure <140/90 mmHg. Exclusion criteria included secondary hypertension, multiple fetuses, and high-risk comorbid disease states. At baseline, patients were approximately 32 years old, most were non-Hispanic Black women (48%) and non-Hispanic white women (28%). Most patients had diagnosed chronic hypertension and were receiving medication (56%), 22% had chronic hypertension and were not receiving medication, and 22% had newly diagnosed chronic hypertension. There were about 45% of patients on aspirin at baseline, 16% with diabetes mellitus, and 6 to 7% were smokers. Most patients were on labetalol or extended-release nifedipine with 86% compliance.

The primary outcome (a composite of preeclampsia with severe features, medically indicated preterm birth at < 35 weeks’ gestation, placental abruption, or fetal or neonatal death) occurred in fewer patients assigned to the active treatment group (30.2%) compared to the control group (37%) (adjusted risk ratio, 0.82; 95% CI, 0.74 to 0.92; p<0.001).¹³ Although each component of the composite endpoint was numerically reduced with treatment, only preeclampsia with severe features and medically indicated preterm birth < 35 weeks’ gestation were statistically significant. Additional outcomes are listed in Table 1. The incidence of small-for-gestational age birth weight, serious maternal complications, and severe neonatal complications were not significantly different between groups. However, the incidence of any preeclampsia, preeclampsia with severe features, and preterm birth were lower with treatment.

Because of the CHAP trial, the ACOG guideline modified their recommendation for starting or increasing therapy to 140/90 mmHg instead of 160/110 mmHg for women with chronic hypertension in pregnancy.¹⁴ However, this trial has limitations as identified by ACOG and the Society for Maternal-Fetal Medicine. One was the exclusion of women with secondary hypertension and major comorbidities, including cardiac or renal diseases.^8,13 The effect of treatment of these populations is still not clear. In addition, the goal of treatment was blood pressure <140/90 mmHg, which is higher than the recommendation for non-pregnant adults (<130/80 mmHg).^8,14 The benefit of treatment to the lower target is unknown. The ACOG also stated that the study did not determine the blood pressure measurement at which growth restriction may become a risk.¹⁴ The ACOG guideline still recommended a third trimester ultrasound to determine that fetal growth, even though the CHAP study did not find an adverse effect on this measure. In addition, in this study, patients were evaluated for preeclampsia prior to the escalation of medication dose after 20 weeks’ gestation.

Conclusion

Overall, recommendations for the treatment of mild chronic hypertension in pregnancy have been significantly impacted by the CHAP study, which showed improvement in the composite endpoint of preeclampsia with severe features, medically indicated preterm birth at < 35 weeks’ gestation, placental abruption, or fetal or neonatal death without an increase in the risk of small-for-gestational age birth. The CHAP study results led to the updated ACOG recommendations to endorse treatment of chronic hypertension in women with blood pressure 140/90 mmHg. However, the study did not include women with major comorbidities, limiting the number of patients to whom these results may be applied. Further research to determine an optimal target blood pressure range is required.

References

1. Ford ND, Cox S, Ko JY, et al. Hypertensive disorders in pregnancy and mortality at delivery hospitalization – United States, 2017-2019. MMWR Morb Mortal Wkly Rep. 2022;71(17):585-591. doi:10.15585/mmwr.mm7117a1.
2. MacLaughlin EJ, Saseen JJ. Hypertension. In: DiPiro JT, Yee GC, Posey L, Haines ST, Nolin TD, Ellingrod V, eds. Pharmacotherapy: A Pathophysiologic Approach. 11th ed. McGraw Hill; 2020. Accessed September 24, 2022. https://accesspharmacy.mhmedical.com/content.aspx?bookid=2577&sectionid=220356112.
3. Jeyabalan A, Larkin JC. Chronic hypertension in pregnancy: prenatal and postpartum care. Simpson LL, ed. UpToDate. Wolters Kluwer; 2022. Accessed September 22, 2022. https://www.uptodate.com/contents/chronic-hypertension-in-pregnancy-prenatal-and-postpartum-care?search=chronic%20hypertension%20in%20pregnancy&source=search_result&selectedTitle=1~150&usage_type=default&display_rank=1
4. American College of Obstetricians and Gynecologists’ Committee on Practice Bulletins—Obstetrics. ACOG Practice Bulletin No. 203: Chronic hypertension in pregnancy. Obstet Gynecol. 2019;133(1):e26-e50. doi:10.1097/AOG.0000000000003020.
5. Whelton PK, Carey RM, Aronow WS, et al. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA guideline for the prevention, detection, evaluation, and management of high blood pressure in adults: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines [published correction appears in Hypertension. 2018 Jun;71(6):e136-e139] [published correction appears in Hypertension. 2018 Sep;72(3):e33]. Hypertension. 2018;71(6):1269-1324. doi:10.1161/HYP.0000000000000066.
6. Sharma G, Grobman WA, Khan SS. Blood pressure management in pregnancy: CHAP through the lens of SPRINT. JACC Adv. 2022;1(2):100037. doi:10.1016/j.jacadv.2022.100037.
7. Chandrasekaran S, Badell ML, Jamieson DJ. Management of chronic hypertension during pregnancy. JAMA. 2022;327(17):1700-1701. doi:10.1001/jama.2022.3919.
8. Society for Maternal-Fetal Medicine; Publications Committee. Society for Maternal-Fetal Medicine Statement: Antihypertensive therapy for mild chronic hypertension in pregnancy-The Chronic Hypertension and Pregnancy trial. Am J Obstet Gynecol. 2022;227(2):B24-B27. doi:10.1016/j.ajog.2022.04.011.
9. August P. Treatment of hypertension in pregnant and postpartum patients. Lockwood CJ, Bakris GL, eds. UpToDate. Wolters Kluwer; 2022. Accessed September 22, 2022. https://www.uptodate.com/contents/treatment-of-hypertension-in-pregnant-and-postpartum-patients?search=chronic%20hypertension%20in%20pregnancy&source=search_result&selectedTitle=2~150&usage_type=default&display_rank=2.
10. Abalos E, Duley L, Steyn DW, Gialdini C. Antihypertensive drug therapy for mild to moderate hypertension during pregnancy. Cochrane Database Syst Rev. 2018;10(10):CD002252. doi:10.1002/14651858.CD002252.pub4.
11. Magee LA, von Dadelszen P, Rey E, et al. Less-tight versus tight control of hypertension in pregnancy. N Engl J Med. 2015;372(5):407-417. doi:10.1056/NEJMoa1404595.
12. Bone JN, Sandhu A, Abalos ED, et al. Oral antihypertensives for nonsevere pregnancy hypertension: Systematic review, network meta- and trial sequential analyses. Hypertension. 2022;79(3):614-628. doi:10.1161/HYPERTENSIONAHA.121.18415.
13. Tita AT, Szychowski JM, Boggess K, et al. Treatment for mild chronic hypertension during pregnancy. N Engl J Med. 2022;386(19):1781-1792. doi:10.1056/NEJMoa2201295.
14. The American College of Obstetricians and Gynecologists (ACOG). Practice Advisory: Clinical guidance for the integration of the findings of the Chronic Hypertension and Pregnancy (CHAP) study. The ACOG website. April 2022. Accessed September 19, 2022. https://www.acog.org/clinical/clinical-guidance/practice-advisory/articles/2022/04/clinical-guidance-for-the-integration-of-the-findings-of-the-chronic-hypertension-and-pregnancy-chap-study

Prepared by:
Trisha Hartke, PharmD, BCPS
Clinical Assistant Professor, Drug Information Specialist
University of Illinois at Chicago College of Pharmacy

October 2022 

The information presented is current as of September 19, 2022.  This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.