By Ahizechukwu C. Eke, MD, PhD, MPH
Associate Professor in Maternal Fetal Medicine, Division of Maternal Fetal Medicine, Department of Gynecology & Obstetrics, Johns Hopkins University School of Medicine, Baltimore
SYNOPSIS: Antihypertensive treatment of mild chronic hypertension in pregnant women was associated with reduced risk of preeclampsia with severe features, medically indicated preterm birth at < 35 weeks’ gestation, placental abruption, and fetal or neonatal demise compared to no treatment.
SOURCE: Tita AT, Szychowski JM, Boggess K, et al. Treatment of mild chronic hypertension during pregnancy. N Engl J Med 2022; Apr 2. doi: 10.1056/NEJMoa2201295. [Online ahead of print].
Chronic hypertension, defined as systolic blood pressure of ≥ 140 mmHg, a diastolic blood pressure of ≥ 90 mmHg, or both, on at least two occasions at least four hours apart before 20 weeks’ gestation, is a major cause of maternal and neonatal morbidity and mortality.1 Chronic hypertension complicates 2% to 5% of preg-nancies in the United States. It is the most common risk factor for cardiovascular and end-stage renal disease, preeclampsia, placental abruption, preterm birth, small-for-gestational-age infant, and intrauterine and neonatal demise.2-4
Chronic hypertension during pregnancy typically is classified either as mild (blood pressures between 140/90 mmHg to 159/109 mmHg) or severe (blood pressure ≥ 160/110 mmHg). Debate continues about the optimal threshold for initiating antihypertensive therapy for mild chronic hypertension during pregnancy, since prior studies suggest that antihypertensive therapy for mild chronic hypertension reduced the risk of severe and malignant hypertension, but did not improve neonatal outcomes.4-6 In addition, there is concern that treatment of mild chronic hypertension during pregnancy may reduce fetoplacental perfusion and increase the risk for intrauterine fetal growth restriction.7 As such, results from prior studies on whether to withhold antihypertensive therapy until the increase in blood pressure is severe or to continue antihypertensive therapies established previously were inconsistent. Therefore, Tita and colleagues designed this study, the Chronic Hypertension and Pregnancy (CHAP) trial, to determine if antihypertensives are beneficial in women with mild hypertension during pregnancy.8
CHAP was a pragmatic open-label, randomized clinical trial conducted at several centers in the United States.8 Inclusion criteria were pregnant women with chronic hypertension with a viable singleton gestation recruited at ≤ 23 weeks’ gestation. Systolic blood pressures of 140 mmHg to 159 mmHg or diastolic blood pressures of 90 mmHg to 104 mmHg (if not on antihypertensives) were required.8 Women were excluded if they had severe chronic hypertension, hypertension that required antihypertensive therapy with more than one medication, secondary hypertension, multiple gestation, high-risk comorbidities, morbidities that require antihypertensive therapy at a lower blood-pressure level (< 140 mmHg systolic and/or < 90 mmHg diastolic), obstetric conditions that increase fetal risk, and contraindications to first-line antihypertensive therapies recommended for use in pregnant women. Participants were randomized in a 1:1 ratio to receive antihypertensive therapy at a blood-pressure threshold of > 140/90 mmHg (active treatment group) vs. withholding antihypertensive therapy unless severe hypertension (systolic pressure ≥ 160 mmHg and/or diastolic pressure ≥ 105 mmHg) developed (control/standard therapy group).8
The primary outcome included a composite of preeclampsia with severe features occurring up to two weeks’ postpartum, medically indicated preterm birth < 35 weeks’ gestation, placental abruption, or fetal or neonatal death.8 The primary safety outcome was poor fetal growth, defined as a birth weight < 10th percentile for gestational age. Secondary outcomes included a composite of maternal death or serious complications (heart failure, stroke, or encephalopathy; myocardial infarction or angina; pulmonary edema; admission to an intensive care unit [ICU] or intubation; or renal failure), any preterm birth (< 37 weeks’ gestation), and a composite of serious neonatal complications (bronchopulmonary dysplasia, retinopathy of prematurity, necrotizing enterocolitis, or intraventricular hemorrhage of grade 3 or 4).8
Other maternal outcomes included preeclampsia and worsening chronic hypertension (severe hypertension without preeclampsia), mean clinic blood pressure levels, cesarean delivery, and blood transfusion. Additional newborn outcomes included neonatal ICU admission, length of hospital stay, birth weight of less than 2,500 g, hypoglycemia, bradycardia, hypotension, ponderal index, head circumference, and placental weight.8
A total sample size of at least 2,404 women with singleton gestations and chronic hypertension was sufficient to demonstrate a 33% reduction in the rate of the primary outcome (assuming a baseline incidence of 16% rate of the primary outcome in the control group), assuming 80% power and a type 1 error rate of 5%. The statistical analysis was performed using intention-to-treat analyses, and differences between groups were considered statistically significant if the P-value was < 0.05.
From September 2015 to March 2021, 2,408 pregnant women met inclusion criteria after investigators screened 29,772 women for eligibility. A total of 1,208 participants received the active treatment while 1,200 received standard therapy. The baseline characteristics were similar in both groups. The incidence of the primary outcome was lower in the active treatment group compared to the control group (30.2% vs. 37.0%), for an adjusted risk ratio (aRR) of 0.82 (95% confidence interval [CI], 0.74 to 0.92; P < 0.001), while the incidence of preeclampsia in the two groups was 24.4% and 31.1%, respectively (aRR, 0.79; 95% CI, 0.69 to 0.89). The number of patients who would need to be treated to prevent one primary outcome event (number needed to treat, NNT) was 14.7 (95% CI, 9.4 to 33.7).
The incidence of serious maternal complications was not statistically significantly different between the two groups (2.1% and 2.8%, respectively; aRR, 0.75; 95% CI, 0.45 to 1.26), and the percentage of small-for-gestational-age birth weights < 10th percentile was similar in both groups (11.2% in the active-treatment group vs. 10.4% in the control group; aRR, 1.04; 0.82 to 1.31; P = 0.76). The incidence of severe neonatal complications was 2.0% and 2.6% (aRR, 0.77; 95% CI, 0.45 to 1.30), while the incidence of preterm birth was 27.5% and 31.4% (aRR, 0.87; 95% CI, 0.77 to 0.99).
COMMENTARY
This study demonstrates that administration of antihypertensive therapy to pregnant women with systolic blood pressures of 140 mmHg to 159 mmHg and/or diastolic pressures of 90 mmHg to 104 mmHg improved outcomes compared to initiating antihypertensive therapy only when blood pressures exceeded the severe range (≥ 160 mmHg systolic and/or ≥ 105 mmHg diastolic). The NNT was 15, meaning that 15 pregnant women with mild-range blood pressures would have to be treated with antihypertensives to prevent one adverse primary outcome event, demonstrating the potential positive effect of antihypertensive therapy in pregnant women with mild-range blood pressures treated with antihypertensive therapy.
Guidelines for management of mild-range blood pressures vary substantially among major national obstetrics and gynecology societies. For example, the American College of Obstetricians and Gynecologists (ACOG), prior to publication of the findings of this study, recommended management of chronic hypertension with blood pressures < 160/105 mmHg expectantly, commencing antihypertensive therapy for a blood pressure threshold of ≥ 160/105 mmHg.9 The Society of Obstetric Medicine of Australia and New Zealand guidelines are very similar to those of ACOG.10 The Society for Obstetricians and Gynaecologists of Canada (SOGC) guidelines recommend anti-hypertensive therapy for mild chronic hypertension of 130/90 mmHg to 155/105 mmHg in the absence of comorbid conditions, while the National Institute for Clinical Excellence (NICE) guidelines of the United Kingdom recommend maintaining blood pressures at < 150 mmHg systolic and between 80 mmHg to 100 mmHg diastolic with antihypertensives for optimal pregnancy outcomes.11,12 Interestingly, the International Society for the Study of Hypertension in Pregnancy had endorsed commencement of antihypertensive therapy for persistent non-severe hypertension in the mild range (< 160/110 mmHg), but this recommendation has not been universally adopted by obstetric societies.13 Because of differences in how blood pressure is measured, and differences in outcome reporting data from several clinical trials, it has been difficult to interpret and compare treatment outcomes across studies.
Although the findings of this study are significant, it is important to note that the study did not determine the threshold blood pressure that increases the risk for intrauterine fetal growth restriction and did not determine a target blood pressure goal for women with mild hypertension on antihypertensive therapy. Also, since the antihypertensives studied in CHAP included labetalol, extended release nifedipine, amlodipine, and methyldopa, it is difficult to extrapolate if maternal and fetal outcomes would be similar with second-line antihypertensives used in pregnancy (e.g., hydralazine and hydrochlorothiazide). Recently, ACOG issued a practice advisory following the publication of the CHAP trial to recommend using a blood pressure value of 140/90 mmHg as the threshold for commencement or titration of medical therapy for chronic hypertension in pregnancy, rather than the threshold of 160/110 mmHg recommended previously.9,14
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- Ananth CV, Duzyj CM, Yadava S, et al. Changes in the prevalence of chronic hypertension in pregnancy, United States, 1970 to 2010. Hypertension 2019;74:1089-1095.
- Guedes-Martins L. Chronic hypertension and pregnancy. Adv Exp Med Biol 2017;956:395-407.
- Seely EW, Ecker J. Chronic hypertension in pregnancy. Circulation 2014;129:1254-1261.
- Abalos E, Duley L, Steyn DW, Gialdini C. Antihypertensive drug therapy for mild to moderate hypertension during pregnancy. Cochrane Database Syst Rev 2018;10:CD002252.
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- von Dadelszen P, Magee LA. Fall in mean arterial pressure and fetal growth restriction in pregnancy hypertension: An updated metaregression analysis. J Obstet Gynaecol Can 2002;24:941-945.
- Tita AT, Szychowski JM, Boggess K, et al. Treatment of mild chronic hypertension during pregnancy. N Engl J Med 2022; Apr 2. doi: 10.1056/NEJMoa2201295. [Online ahead of print].
- American College of Obstetricians and Gynecologists’ Committee on Practice Bulletins–Obstetrics. ACOG Practice Bulletin No. 203: Chronic hypertension in pregnancy. Obstet Gynecol 2019;133:e26-e50.
- Lowe SA, Brown MA, Dekker GA, et al. Guidelines for the management of hypertensive disorders of pregnancy 2008. Aust N Z J Obstet Gynaecol 2009;49:242-246.
- Magee LA, Pels A, Helewa M, et al. Diagnosis, evaluation, and
management of the hypertensive disorders of pregnancy: Executive summary. J Obstet Gynaecol Can 2014;36:575-576.
- National Collaborating Centre for Women’s and Children’s Health (UK). Hypertension in Pregnancy: The Management of Hypertensive Disorders During Pregnancy. RCOG Press; 2010.
- Brown MA, Magee LA, Kenny LC, et al. Hypertensive disorders of pregnancy: ISSHP classification, diagnosis, and management recommendations for international practice. Hypertension 2018;72:24-43.
- American College of Obstetricians and Gynecologists’ Committee on Clinical Practice Guidelines–Obstetrics; Kaimal AJ, Gandhi M, Pettker CM, Simhan H. Clinical guidance for the intergration of the findings of the Chronic Hypertension and Pregnancy (CHAP) study. American College of Obstetricians and Gynecologists. Published April 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
