The New England Journal of Medicine May 12, 2022

Treatment for Mild Chronic Hypertension during Pregnancy

Alan T. Tita, Jeff M. Szychowski, Kim Boggess, et al.

Bottom Line

The CHAP trial demonstrated that actively treating mild chronic hypertension in pregnant women to a target blood pressure of less than 140/90 mm Hg significantly reduces the risk of adverse pregnancy outcomes without impairing fetal growth.

Key Findings

1. The primary composite outcome (preeclampsia with severe features, medically indicated preterm birth at <35 weeks, placental abruption, or fetal/neonatal death) occurred in 30.2% of the active-treatment group compared to 37.0% of the control group (adjusted risk ratio [aRR], 0.82; 95% CI, 0.74 to 0.92; P<0.001).

2. The incidence of the primary safety outcome, small-for-gestational-age (SGA) birth weight below the 10th percentile, was not significantly different between the groups (11.2% in active treatment vs. 10.4% in control; aRR 1.04; 95% CI, 0.82 to 1.31; P=0.76).

3. Preeclampsia with severe features occurred less frequently in the active-treatment group (23.3%) compared to the control group (29.1%).

4. There was no significant difference in the incidence of serious maternal complications (2.1% active vs. 2.8% control) or severe neonatal complications (2.0% active vs. 2.6% control).

Study Design

Design

RCT

Open-Label

Sample

2,408

Patients

Duration

Until postpartum discharge

Median

Setting

Multicenter, US

Population Pregnant women with known or newly diagnosed mild chronic hypertension (blood pressure <160/110 mm Hg) carrying a singleton fetus at less than 23 weeks of gestation.

Intervention Active antihypertensive therapy (primarily utilizing labetalol or nifedipine) targeted to maintain maternal blood pressure below 140/90 mm Hg.

Comparator Usual care (control strategy), where antihypertensive therapy was withheld unless severe hypertension developed (systolic blood pressure ≥160 mm Hg or diastolic blood pressure ≥105 mm Hg).

Outcome A composite outcome of preeclampsia with severe features, medically indicated preterm birth at less than 35 weeks of gestation, placental abruption, or fetal or neonatal death.

Study Limitations

• The open-label design, while pragmatic for a blood pressure management trial, inherently introduces the risk of performance and detection biases, particularly regarding subjective clinical decisions like medically indicated preterm birth.

• The trial was not adequately powered to detect differences in rare but catastrophic outcomes, such as maternal mortality or severe maternal morbidity.

• Long-term maternal cardiovascular outcomes and neonatal neurodevelopmental outcomes were not evaluated in the initial primary publication.

• The composite primary endpoint was heavily driven by preeclampsia with severe features and medically indicated preterm birth rather than harder endpoints like fetal or neonatal death.

Clinical Significance

The CHAP trial represented a major paradigm shift in obstetrical practice. By definitively demonstrating that treating mild chronic hypertension improves maternal and perinatal outcomes without causing fetal growth restriction, the trial led to immediate clinical practice guideline updates. The American College of Obstetricians and Gynecologists (ACOG) and the Society for Maternal-Fetal Medicine (SMFM) promptly lowered the threshold for initiating or titrating antihypertensive therapy in pregnancy from 160/110 mm Hg to 140/90 mm Hg.

Historical Context

For decades, there was intense debate and a lack of consensus regarding the treatment of mild to moderate chronic hypertension in pregnancy. Clinicians were hesitant to lower maternal blood pressure, driven by theoretical concerns and older observational data suggesting that antihypertensive therapy might decrease uteroplacental perfusion, thereby precipitating fetal growth restriction (small-for-gestational-age infants). While the 2015 CHIPS trial suggested some benefits to 'tight' versus 'less tight' control, it included a mix of both gestational and chronic hypertension, leaving the specific question of treating mild chronic hypertension unresolved. The CHAP trial was explicitly designed to settle this long-standing clinical dilemma.

Guided Discussion

High-yield insights from every perspective

Med Student

Medical Student

What is the pathophysiological rationale behind the historical reluctance to treat mild chronic hypertension in pregnancy, and which antihypertensive medications are considered safe first-line options for this population?

Key Response

Historically, it was feared that lowering maternal blood pressure would decrease uteroplacental perfusion, leading to fetal growth restriction or small for gestational age (SGA) infants. Safe first-line agents include labetalol and nifedipine; ACE inhibitors and ARBs are strictly contraindicated due to fetal renal toxicity and teratogenicity.

Resident

Based on the CHAP trial results, how should you adjust your blood pressure targets for a pregnant patient presenting with a baseline BP of 145/95 mm Hg, and how does this impact your management plan?

Key Response

The CHAP trial supports initiating or continuing antihypertensive therapy for mild chronic HTN to a target of less than 140/90 mm Hg to reduce severe preeclampsia and preterm birth. Standard fetal growth monitoring can be confidently maintained because the trial proved this tighter control does not increase the risk of small for gestational age infants.

Fellow

The primary outcome of the CHAP trial was a composite that included medically indicated preterm birth at less than 35 weeks. How might the active treatment strategy have specifically influenced the iatrogenic component of this outcome compared to the spontaneous development of severe preeclampsia?

Key Response

By keeping blood pressures below 160/105 mm Hg, active treatment directly prevents the threshold criteria for severe hypertension that would mandate delivery, thereby decreasing iatrogenic preterm birth. The nuanced interpretation involves dissecting whether treatment arrests the underlying placental pathology of preeclampsia or merely prevents reaching the hypertensive diagnostic criteria, safely prolonging gestation either way.

Attending

Given the CHAP trial reassurance regarding fetal growth, how does this trial fundamentally shift our clinical teaching paradigm regarding uteroplacental autoregulation and shared decision-making for medication adherence?

Key Response

This study provides definitive evidence to counsel hesitant patients that treating mild HTN actively protects the pregnancy without causing fetal starvation. It shifts decades of dogma by proving that the maternal cardiovascular system can tolerate tighter blood pressure control without compromising the uteroplacental unit perfusion, changing how we teach obstetric pharmacology.

Scholarly Review

Critical appraisal through the lens of expert reviewers and guideline development

PhD

The CHAP trial utilized a composite primary outcome. From a methodological perspective, what are the potential statistical and interpretative vulnerabilities of using such a composite in this trial, particularly regarding the weighting of its individual components?

Key Response

Composite outcomes increase statistical power but can be driven heavily by their least severe, most frequent component, such as preterm birth versus neonatal death. Methodologists must evaluate if the treatment effect is consistent across all components or if the composite result primarily reflects a reduction in provider-driven interventions rather than a uniform reduction in actual physiological morbidity.

Journal Editor

As a peer reviewer evaluating the CHAP trial, how would you scrutinize the open-label nature of the trial design regarding the clinical decision-making for medically indicated preterm delivery, and could this introduce ascertainment bias?

Key Response

Because target BP strategies require active titration, obstetricians knew the assigned treatment groups. This open-label design introduces potential bias because the clinical threshold to diagnose superimposed preeclampsia or mandate medically indicated preterm birth might be subconsciously altered based on knowing the treatment arm, which could confound the composite primary outcome.

Guideline Committee

Prior to the CHAP trial, ACOG recommended treatment only for severe hypertension (greater than 160/110 mm Hg). How should current guidelines be updated to incorporate this new evidence, and what Level of Evidence should be assigned to the new treatment threshold?

Key Response

ACOG and SMFM guidelines must transition from the historical conservative approach to universally recommending treatment initiation for BP greater than 140/90 in pregnant women with chronic HTN. This merits a Level A recommendation based on a large, rigorously designed multicenter RCT, fundamentally rewriting international obstetric practice bulletins to prioritize stricter maternal cardiovascular control.

Clinical Landscape

Noteworthy Related Trials

2009

HYPITAT Trial

n = 756 · Lancet

Tested

Induction of labour

Population

Women with gestational hypertension or mild pre-eclampsia at term

Comparator

Expectant monitoring

Endpoint

Composite of poor maternal outcome including severe hypertension or HELLP syndrome

Key result: Induction of labour significantly reduced the risk of poor maternal outcomes without increasing the rate of caesarean section.

2015

CHIPS Trial

n = 987 · NEJM

Tested

Tight blood pressure control (target diastolic 85 mm Hg)

Population

Pregnant women with non-severe non-proteinuric maternal hypertension

Comparator

Less-tight control (target diastolic 100 mm Hg)

Endpoint

Composite of pregnancy loss or high-level neonatal care for >48 hours

Key result: There was no significant difference in the primary perinatal outcome, but severe maternal hypertension was significantly reduced in the tight-control group.

2017

ASPRE Trial

n = 1,776 · NEJM

Tested

Aspirin 150 mg per day

Population

Pregnant women at high risk for preterm preeclampsia

Comparator

Placebo

Endpoint

Delivery with preeclampsia before 37 weeks of gestation

Key result: Prophylactic use of low-dose aspirin from the first trimester significantly reduced the incidence of preterm preeclampsia.

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