Abstract

We present Hypertension Canada’s inaugural evidence-based Canadian recommendations for the management of hypertension in pregnancy. Hypertension in pregnancy is common, affecting approximately 7% of pregnancies in Canada, and requires effective management to reduce maternal, fetal, and newborn complications. Because of this importance, these guidelines were developed in partnership with the Society of Obstetricians and Gynaecologists of Canada with the main common objective of improving the management of women with hypertension in pregnancy. Guidelines for the diagnosis, assessment, prevention, and treatment of hypertension in adults and children are published separately. In this first Hypertension Canada guidelines for hypertension in pregnancy, 7 recommendations for the management of nonsevere and severe hypertension in pregnancy are presented. For nonsevere hypertension in pregnancy (systolic blood pressure 140-159 mm Hg and/or diastolic blood pressure 80-109 mm Hg), we provide guidance for the threshold for initiation of antihypertensive therapy, blood pressure targets, as well as first- and second-line antihypertensive medications. Severe hypertension (systolic blood pressure ≥ 160 mm Hg and/or diastolic blood pressure ≥ 110 mm Hg) requires urgent antihypertensive therapy to reduce maternal, fetal, and newborn adverse outcomes. The specific evidence and rationale underlying each of these guidelines are discussed.

Hypertensive disorders of pregnancy (HDP) occur in approximately 7% of all pregnancies in Canada.1 HDP represent a broad range of conditions including: chronic hypertension (ie, preexisting hypertension), gestational hypertension (ie, hypertension that develops after 20 weeks’ gestation), and/or preeclampsia/eclampsia (gestational hypertension with proteinuria and/or other target organ involvement).23 HDP have a major effect on maternal, fetal, and newborn outcomes including: fetal growth restriction, preterm delivery, and fetal and neonatal morbidity and mortality.2 After pregnancy, emerging evidence shows that women with HDP represent a high-risk population for the development of cardiovascular risk factors (hypertension, type 2 diabetes, and obesity), chronic kidney disease, premature cardiovascular disease (cardiac, cerebrovascular, and peripheral arterial), and cardiovascular mortality.3456 Notably, HDP are an independent risk factor for cardiovascular disease associated with gradually elevated risk of cardiovascular disease with increasing severity of HDP from 1.7 (adjusted hazard ratio; 95% confidence interval [CI], 1.3-2.2) in women with gestational hypertension to 4.4 (adjusted hazard ratio; 95% CI, 2.4-7.9) in women with severe preeclampsia with fetal death.34Because HDP are prevalent and have important short- and long-term health effects, Hypertension Canada’s target audience expressed a need for guidance on the management of hypertension in pregnancy. In response, a Pregnancy Subgroup was formed in 2014 to develop evidence-based blood pressure (BP) management guidelines for pregnancy. A formal partnership was then established between Hypertension Canada and the Society of Obstetricians and Gynaecologists of Canada (SOGC) to ensure harmonization of guidelines through shared guideline development as well as for broader reach of the guidelines through knowledge translation and dissemination strategies.These inaugural Hypertension Canada guidelines for hypertension in pregnancy are intended to provide a framework for evidence-based care of hypertension in pregnancy but should not replace clinical judgement. Practitioners are advised to consider patient preferences, values, and clinical circumstances when determining how to best apply these guidelines to individual patients.

Methods

The Hypertension Canada guidelines are developed annually through a highly structured and systematic process designed to minimize bias. Hypertension Canada’s guideline process has been externally reviewed and is in concordance with the Appraisal of Guidelines for Research and Evaluation II (AGREE II) instrument for guideline development (guidelines.hypertension.ca/about/overview-process).7 The Hypertension Canada Guidelines Committee (HCGC) is comprised of a multidisciplinary panel of content as well as methodological experts divided into 16 subgroups in distinct areas of hypertension (see Supplemental Appendix S1 and S2 for list of members and conflicts of interest, respectively). The Pregnancy Subgroup consisted of 8 members with a broad range of expertise, including internal medicine subspecialties as well as obstetrics (2 members from the SOGC Maternal Fetal Medicine subcommittee).The comprehensive literature search was performed by a highly trained medical librarian on the basis of key words and terms provided by the subgroup. The initial literature search was performed in June 2015 and updated in June 2016 (details of search strategies and retrieved articles are available upon request). The literature was reviewed and graded using the standardized method developed by Hypertension Canada (Supplemental Table S1) and according to the Hypertension Canada guidelines established process.8The proposed pregnancy guidelines were then reviewed and modified by the Central Review Committee, unbiased experts in clinical epidemiology, to ensure that the guidelines reflected the evidence and to verify proposed grading. The draft guidelines and supporting evidence were presented to the HCGC in Toronto, on October 12, 2017. After the discussions, the guidelines were further revised and finalized for an electronic vote by all 81 members of the HCGC, with > 70% support required for approval of each new/revised guideline.

Challenges in Pregnancy Research

There are several methodologic challenges in the obstetrical research related to BP that were taken into consideration during the hypertension in pregnancy guidelines development process (Table 1). First, the definition of hypertension in pregnancy has changed over time.9 Older studies included pregnant women with a diastolic BP (DBP) ≥ 90 mm Hg, whereas more recent studies have included women with a systolic BP (SBP) ≥ 140 mm Hg or a DBP ≥ 90 mm Hg. Similarly, the definition of severe hypertension in pregnancy was reduced from ≥ 170/110 mm Hg to ≥ 160/110 mm Hg after the association of stroke in pregnancy with a lower BP level.9 Second, as outlined previously, the HDP represent a broad range of conditions with differing underlying pathophysiologies. Thus, the clinical outcomes (eg, the neonate’s birth weight) might be a result of the underlying process (ie, maternal endothelial dysfunction) and not solely the maternal BP values. Further, there is a lack of consensus on the definition of preeclampsia ranging from a restrictive definition (gestational hypertension plus proteinuria) to a broader definition (gestational hypertension plus either proteinuria or ≥ 1 relevant target organ complication).10 This heterogeneity might influence clinical outcomes and as such it was taken into consideration when examining the findings of the studies. Third, the duration of antihypertensive treatment in pregnancy is relatively short (often a few weeks to months) compared with studies of hypertension in nonpregnant populations. Fourth, the clinical outcomes in studies of hypertension in pregnancy are generally not hard cardiovascular outcomes (ie, cardiovascular events or cardiovascular mortality), which are associated with higher grades in the Hypertension Canada grading system (Supplemental Table S1).8 Studies of hypertension in pregnancy use other clinical outcomes (eg, severe hypertension ≥ 160/110 mm Hg, preterm birth, etc). Whereas severe hypertension is considered a validated surrogate outcome because of its relationship with adverse maternal, fetal, and newborn outcomes, it is associated with a lower grade of evidence.11 Finally, the sample size of studies of hypertension in pregnancy are generally small and, therefore, this limits accurate assessment of rates of adverse events associated with individual antihypertensive medications.

Table 1Hypertension in pregnancy research: methodologic challenges

1.Definitions of HDP:a.Change in definition of hypertension in pregnancy over timeb.Variable definition of preeclampsia between studies:Restrictive (GHTN ≥ 140/90 mm Hg plus ≥ 300 mg proteinuria in 24 hours)Broad (GHTN ≥ 140/90 mm Hg plus either ≥ 300 mg proteinuria in 24 hours or other end-organ involvement)2.Heterogeneity in types of HDP included might differentially affect clinical outcomes:a.Variable severity of disease (ranging from GHTN to severe preeclampsia)b.Represent different underlying pathophysiology3.Clinical outcomes not cardiovascular events or mortalitya.Use of surrogate outcomes4.Small sample sizes5.Short duration of follow-up (hours to months)

GHTN, gestational hypertension; HDP, hypertensive disorders of pregnancy.

Hypertension Canada’s 2018 Guidelines: Management of Hypertension in Pregnancy

 Measurement and diagnosis

Accurate BP measurement is essential to appropriately recognize and treat HDP. Detailed information on BP measurement as well as the classification and definitions of the HDP, are presented in SOGC’s 2014 guideline, “Diagnosis, Evaluation and Management of the Hypertensive Disorders of Pregnancy.”2 In brief, women should have their BP measured using a standardized protocol after a period of rest in a quiet environment, be in sitting position with their arm at the level of the heart using an appropriately sized cuff (ie, length 1.5 times the circumference of the arm).2 The arm with higher BP values should be used for hypertension diagnosis and BP monitoring.2 Nonsevere elevated BP should be remeasured at the same visit, with at least a gap of 15 minutes from the first measurement. More than 50% of women with a first BP reading of ≥ 140/90 mm Hg have white coat effect.121314 Hypertension in pregnancy is defined as an SBP ≥ 140 mm Hg and/or a DBP ≥ 90 mm Hg (average of at least 2 measurements taken at least 15 minutes apart). Severity of hypertension in pregnancy is considered on the basis of the presence of target organ involvement (ie, maternal or the fetus itself) as well as the actual BP level. BP levels between 140/90 mm Hg and < 160/110 mm Hg are considered nonsevere hypertension in pregnancy. A BP level of ≥ 160/110 mm Hg is associated with increased risk of maternal stroke in pregnancy and is therefore considered the diagnostic threshold of severe hypertension in pregnancy.210 Classification of HDP are summarized in Figure 1.

Hypertension Canada’s 2018 Guidelines: Management of Hypertension in Pregnancy

 Measurement and diagnosis

Accurate BP measurement is essential to appropriately recognize and treat HDP. Detailed information on BP measurement as well as the classification and definitions of the HDP, are presented in SOGC’s 2014 guideline, “Diagnosis, Evaluation and Management of the Hypertensive Disorders of Pregnancy.”2 In brief, women should have their BP measured using a standardized protocol after a period of rest in a quiet environment, be in sitting position with their arm at the level of the heart using an appropriately sized cuff (ie, length 1.5 times the circumference of the arm).2 The arm with higher BP values should be used for hypertension diagnosis and BP monitoring.2 Nonsevere elevated BP should be remeasured at the same visit, with at least a gap of 15 minutes from the first measurement. More than 50% of women with a first BP reading of ≥ 140/90 mm Hg have white coat effect.121314 Hypertension in pregnancy is defined as an SBP ≥ 140 mm Hg and/or a DBP ≥ 90 mm Hg (average of at least 2 measurements taken at least 15 minutes apart). Severity of hypertension in pregnancy is considered on the basis of the presence of target organ involvement (ie, maternal or the fetus itself) as well as the actual BP level. BP levels between 140/90 mm Hg and < 160/110 mm Hg are considered nonsevere hypertension in pregnancy. A BP level of ≥ 160/110 mm Hg is associated with increased risk of maternal stroke in pregnancy and is therefore considered the diagnostic threshold of severe hypertension in pregnancy.210 Classification of HDP are summarized in Figure 1.

Hypertension Canada’s 2018 Guidelines: Management of Hypertension in Pregnancy

 Measurement and diagnosis

Accurate BP measurement is essential to appropriately recognize and treat HDP. Detailed information on BP measurement as well as the classification and definitions of the HDP, are presented in SOGC’s 2014 guideline, “Diagnosis, Evaluation and Management of the Hypertensive Disorders of Pregnancy.”2 In brief, women should have their BP measured using a standardized protocol after a period of rest in a quiet environment, be in sitting position with their arm at the level of the heart using an appropriately sized cuff (ie, length 1.5 times the circumference of the arm).2 The arm with higher BP values should be used for hypertension diagnosis and BP monitoring.2 Nonsevere elevated BP should be remeasured at the same visit, with at least a gap of 15 minutes from the first measurement. More than 50% of women with a first BP reading of ≥ 140/90 mm Hg have white coat effect.121314 Hypertension in pregnancy is defined as an SBP ≥ 140 mm Hg and/or a DBP ≥ 90 mm Hg (average of at least 2 measurements taken at least 15 minutes apart). Severity of hypertension in pregnancy is considered on the basis of the presence of target organ involvement (ie, maternal or the fetus itself) as well as the actual BP level. BP levels between 140/90 mm Hg and < 160/110 mm Hg are considered nonsevere hypertension in pregnancy. A BP level of ≥ 160/110 mm Hg is associated with increased risk of maternal stroke in pregnancy and is therefore considered the diagnostic threshold of severe hypertension in pregnancy.210 Classification of HDP are summarized in Figure 1.

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I. Management of nonsevere hypertension (BP 140-159/90-109 mm Hg) in pregnancy

Background. HDP treatment of nonsevere hypertension in pregnancy is important to reduce maternal, fetal, and newborn complications including: pregnancy loss, need for high-level neonatal care, preterm birth, and low birth weight.1115 In a 2014 Cochrane Collaboration systematic review, antihypertensive medication use for nonsevere hypertension in pregnancy (49 randomized trials; n = 4723)16 was associated with a halving in the risk of progression to severe hypertension (relative risk, 0.49; 95% CI, 0.40-0.60). The number needed to treat was 10 (95% CI, 8-13). This finding was consistent across all HDP ranges of conditions.16 There was no consistent statistically significant reduction in other clinically important maternal, fetal, or newborn outcomes.16 Although this Cochrane systematic review was methodologically strong, the primary studies were relatively old (only 4 after 2001), had small sample sizes, and were of low methodologic quality.

The international multicentre randomized controlled trial, Control of Hypertension in Pregnancy Study (CHIPS), examined the effects of maternal BP targets on perinatal and maternal outcomes.15 Pregnant women with nonsevere gestational hypertension or chronic hypertension were randomized to either less tight BP control (target DBP of 100 mm Hg) or tight BP control (target DBP of 85 mm Hg).15 The CHIPS trial reported an increase in the incidence of severe hypertension (defined as ≥ 160/110 mm Hg) in the less-tight group (relative risk, 1.8; 95% CI, 1.34-2.28).15 In post hoc analyses of the CHIPS trial, the occurrence of severe hypertension was associated with an increased risk of pregnancy loss, the need for high-level neonatal care > 48 hours, low birth weight, and preterm delivery

In considering specific antihypertensive agents for the management of nonsevere hypertension in pregnancy, the previously mentioned Cochrane systematic review showed a similar benefit in reduction of severe hypertension among the following oral agents: labetalol, methyldopa, long-acting nifedipine, or other β-blockers (Table 2).16 Additionally, a secondary analysis of the CHIPS trial showed no statistically significant difference in clinical outcomes between different antihypertensive medications used (ie, labetalol, methyldopa, or others).17 Other oral antihypertensive medications such as clonidine, hydralazine, and thiazide diuretics can be considered as second-line drugs because they have not been associated with congenital malformations or other evidence to suggest harms. Angiotensin-converting enzyme (ACE) inhibitors have not been consistently associated with congenital malformations but are associated with fetotoxic adverse effects to the developing fetal renal system (ie, acute kidney injury and oligohydramnios) and, as such, should be avoided in pregnancy.18 Similarly, angiotensin receptor blockers have limited published safety data in pregnancy and should be avoided in pregnancy because of similar fetotoxic mechanisms associated with ACE inhibitors

Table 2 Antihypertensive medications commonly used in pregnancy

First-line oral drugs (Grade C)Second-line oral drugs (Grade D)Medications to avoid
LabetalolClonidineACEi (Grade C)
MethyldopaHydralazineARBs (Grade D)
Long-acting oral nifedipineThiazide diuretics
Other β-blockers (acebutolol, metoprolol, pindolol, and propranolol)

ACEi, angiotensin-converting enzyme inhibitors; ARBs, angiotensin receptor blockers. ∗ Fetotoxicity of renal system.

Overall, decisions regarding a specific antihypertensive drug must consider the context of the patient and fetus, medication side effect profile (including maternal hypotension), availability of medications, clinician experience, and a woman’s preference. Other components of the management of women with nonsevere hypertension in pregnancy are beyond the scope of this guideline. The involvement of an interdisciplinary team of care providers (ie, obstetrics, maternal fetal medicine, and medical specialists as appropriate) is prudent to ensure the ongoing well-being of the mother and fetus through frequent assessments, monitoring, and delivery planning, as indicated (Figure 2).

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 Guidelines

  • 1.Antihypertensive therapy is recommended for average SBP measurements of ≥ 140 mm Hg or DBP measurements of ≥ 90 mm Hg in pregnant women with chronic hypertension, gestational hypertension, or preeclampsia (Grade C).
  • 2.A. Initial antihypertensive therapy should be monotherapy from the following first-line drugs: oral labetalol, oral methyldopa, long-acting oral nifedipine, or other oral β-blockers (acebutolol, metoprolol, pindolol, and propranolol) (Grade C).
    • B.Other antihypertensive drugs can be considered as second-line drugs including: clonidine, hydralazine, and thiazide diuretics (Grade D).
    • C.ACE inhibitors (Grade C) and angiotensin receptor blockers (Grade D) should not be used in pregnant women.
  • 3.A. A DBP of 85 mm Hg should be targeted for pregnant women receiving antihypertensive therapy with chronic hypertension or gestational hypertension (Grade B). A similar target could be considered for pregnant women with preeclampsia (Grade D).
    • B.Additional antihypertensive drugs should be used if target BP levels are not achieved with standard-dose monotherapy (Grade C). Add-on drugs should be from a different drug class chosen from first-line or second-line options (Grade D).

II. Management of severe hypertension (BP ≥ 160/110 mm Hg) in pregnancy

Background. In a secondary analysis of the CHIPS trial, BP ≥ 160/110 mg Hg was associated with significantly worse maternal and perinatal outcomes, independent of the development of preeclampsia. These included: increased maternal hospital length of stay > 10 days, pregnancy loss or need for high-level neonatal care > 48 hours, increased risk of preterm birth at < 34 and < 37 weeks’ gestation, low birth weight (ie, weight less than the 10th percentile), maternal platelets < 100 × 109/L, and elevated maternal liver enzymes.11 The CHIPS trial did not find a significant difference in the rate of stroke between study arms because of a low event rate (n = 1; 0.2% in the tight arm vs n = 0 in the less tight arm), because stroke in pregnancy and the immediate postpartum period is a relatively uncommon adverse outcome (30 per 100,000 pregnancies).1519 Importantly, BP ≥ 160/110 mm Hg and the presence of HDP are both considered risk factors for ischemic and hemorrhage stroke in pregnancy.101920 Specifically, a large US population-based study reported that women with HDP were 5.2 times more likely to be hospitalized for stroke compared with pregnant women with normal BP.20 In a case series of 28 women with HDP with stroke in pregnancy or early postpartum, immediately before the stroke, SBP was recorded as ≥ 160 mm Hg in 95.8% (23 of 24) and DBP ≥ 110 mm Hg in 12.5% of women (3 of 24).10 Although no trials included in a Cochrane systematic review of the management of severe hypertension in pregnancy directly examined the effect of immediate BP lowering on stroke, BP reduction below this threshold of ≥ 160/110 mm Hg is considered to play an important role in the prevention of stroke in pregnancy and is recommended.1921 Accordingly, severe hypertension is considered an obstetrical emergency from maternal and fetal perspectives, which requires immediate in-hospital care and urgent antihypertensive therapy (Figure 2).

The specific antihypertensive management of severe hypertension is beyond the scope of this guideline and requires the involvement of an interdisciplinary team of care providers (ie, obstetrics, maternal fetal medicine, and medical specialists as appropriate) in a hospital setting to ensure the ongoing well-being of the mother and fetus through frequent assessments, monitoring, and delivery planning, as indicated.

 Guidelines

  • 1.Women with severe hypertension with SBP ≥ 160 or DBP ≥ 110 mm Hg in pregnancy require urgent antihypertensive therapy because it is considered an obstetrical emergency (Grade D).