Blood pressure control in hypertensive disorders of pregnancy

Helsi Rismiati; Hae-Young Lee

doi:10.36011/cpp.2022.4.e16

Articles

Page Path: HOME > Cardiovasc Prev Pharmacother > Volume 4(3); 2022 > Article

Review Article Blood pressure control in hypertensive disorders of pregnancy: Helsi Rismiati, Hae-Young Lee; Cardiovascular Prevention and Pharmacotherapy 2022;4(3):99-105.
DOI: https://doi.org/10.36011/cpp.2022.4.e16
Published online: July 29, 2022

Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea

Correspondence to Hae-Young Lee, MD Department of Internal Medicine, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul 03080, Korea. E-mail: hylee612@snu.ac.kr

• Received: July 1, 2022 • Accepted: July 17, 2022

This is an open-access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

3,381 Views
145 Download
1 Crossref

Full Article

Download PDF

ABSTRACT
INTRODUCTION
EPIDEMIOLOGICAL CHARACTERISTICS OF HYPERTENSION IN PREGNANCY
DEFINITION AND SUBTYPES OF HYPERTENSION IN PREGNANCY
MANAGEMENT OF HYPERTENSION IN PREGNANCY
CONCLUSIONS
ARTICLE INFORMATION
REFERENCES

ABSTRACT

Hypertension is a major cause of maternal morbidity and occurs as a complication in up to one in ten pregnancies. Hypertensive disorders of pregnancy encompass gestational hypertension, preeclampsia, chronic hypertension, and chronic hypertension with superimposed preeclampsia. However, the management of hypertensive disorders of pregnancy remains a matter of debate, particularly the blood pressure thresholds and targets for managing hypertension in pregnancy. Previously, there was no clear evidence of the effectiveness of aggressive blood pressure control in pregnancy due to the risk of fetal growth restriction. Recent clinical trials have shown that aggressive control of blood pressure in pregnant women is safe for both the mother and fetus. The purpose of this paper is to present a clinically oriented guide to the drugs of choice in patients with hypertension during pregnancy, present contrasts among different guidelines and recent clinical trials, and discuss the blood pressure thresholds and targets for hypertension during pregnancy based on recent studies.
Keywords: Pregnancy; Hypertension; Blood pressure

INTRODUCTION

Hypertension is the most common medical disorder and occurs as a complication in up to one in ten pregnancies [1,2]. The prevalence of hypertension in pregnancy is predicted to double in the future to reach one in five gestations [3]. High blood pressure during gestation increases the risk for cardiovascular disease later in life, independently of conventional cardiovascular disease risks [4,5]. However, the optimal threshold to start therapy and blood pressure targets remain a matter of debate. This review presents contrasts between different guidelines and outlines the blood pressure thresholds and targets for hypertension during pregnancy. Our purpose is to offer a clinically oriented guide to the drugs of choice in patients with hypertensive disorders during pregnancy, present contrasts among different guidelines and recent clinical trials, and outline the blood pressure thresholds and targets for hypertension during gestation.

EPIDEMIOLOGICAL CHARACTERISTICS OF HYPERTENSION IN PREGNANCY

Hypertensive disorders are among the main contributors to pregnancy-related maternal and perinatal morbidity and mortality, implicated in 10% to 13% of United States maternal deaths [6]. According to the Korea National Health and Nutrition Examination Survey (KNHANES), hypertensive disorders during pregnancy have become more common over the past 10 years. In the KNHANES VIII, one-tenth of women had hypertension during gestation out of approximately 299,000 childbirths [7]. The prevalence of hypertensive disorders as a complication of pregnancy is 1.8% for preeclampsia or eclampsia, 3.1% for pregnancy-induced hypertension, and 5.4% for chronic hypertension [6,7].

Hypertensive disorders of pregnancy (HDPs) also cause maternal morbidity. A secondary analysis of the Eunice Kennedy Shriver National Institute of Child Health and Human Development Maternal-Fetal Medicine Network Units Network cohort of women and neonates in 25 United States hospitals between 2008 and 2011, concluded that hypertensive complications (20.5%) were the second highest cause of severe maternal morbidity after postpartum hemorrhage (47.6%) [8]. Severe morbidity occurred in 2.9 per 1,000 women who gave birth. The composite of postpartum hemorrhage and HDPs accounted for more than two-thirds of the primary underlying causes of severe morbidity [8]. According to data from the National Center for Health Statistics, HDPs contribute to eight maternal deaths per one million live births in the United States [9]. Two recently published observational studies by Wu et al. [10] and Liu et al. [11] showed higher risks for incident stroke, myocardial infarction, peripartum cardiomyopathy, arrhythmia, and maternal death in mothers with chronic hypertension, preeclampsia, and preeclampsia superimposed on chronic hypertension, as presented in Fig. 1.

DEFINITION AND SUBTYPES OF HYPERTENSION IN PREGNANCY

The terminology for hypertensive disorders in pregnant women has evolved through the years [12]; the most recent definition of hypertension in pregnancy is from the American College of Obstetricians and Gynecologists [12]. There are four categories of HDPs: gestational hypertension, preeclampsia, chronic hypertension, and chronic hypertension with superimposed preeclampsia [12]. In terms of the onset of hypertension, HDPs are classified as gestational or chronic hypertension. In terms of the presence of proteinuria and abnormal systemic findings, HDPs are classified as preeclampsia and chronic hypertension with superimposed preeclampsia. The classification of HDPs is presented in more detail below.

Gestational hypertension is defined as systolic blood pressure ≥140 mmHg or diastolic blood pressure ≥90 mmHg that develops in pregnancy after 20 weeks of gestation and resolves before 12 weeks postpartum in the absence of proteinuria or systemic findings [12]. Chronic hypertension is systolic blood pressure ≥140 mmHg or diastolic blood pressure ≥90 mmHg diagnosed before pregnancy or 20 weeks of gestation. Hypertension first diagnosed after 20 weeks of gestation that persists for greater than 12 weeks postpartum is also considered chronic hypertension [12]. Preeclampsia is hypertension after 20 weeks of gestation in a previously normotensive patient with the finding of proteinuria. In the absence of proteinuria, preeclampsia is diagnosed as hypertension in association with thrombocytopenia (platelet count less than 100,000/μL), impaired liver function (elevated blood levels of liver transaminases to twice the normal threshold concentration), the new development of renal insufficiency (elevated serum creatinine greater than 1.1 mg/dL or a doubling of serum creatinine in the absence of other renal diseases), pulmonary edema, or new-onset cerebral or visual disturbances [12]. Severe preeclampsia involves a systolic blood pressure of at least 160 mmHg or diastolic blood pressure of at least 110 mmHg on two occasions at least 4 hours apart with systemic findings [12]. Chronic hypertension with superimposed preeclampsia is chronic hypertension in the setting of new-onset worsening blood pressures, proteinuria (≥0.3 g of protein in 24 hours), thrombocytopenia, or any other systemic features of the preeclampsia syndrome [12].

According to blood pressure values, there are three levels of hypertension in gestation: mild, moderate, and severe. The definition of mild hypertension is diastolic blood pressure 90 to 99 mmHg or systolic blood pressure of 140 to 149 mmHg. Moderate hypertension is defined as a diastolic blood pressure of 100 to 109 mmHg or systolic blood pressure of 150 to 159 mmHg. Severe hypertension occurs when the diastolic blood pressure is 110 mmHg or higher or the systolic blood pressure is 160 mmHg or higher [13].

MANAGEMENT OF HYPERTENSION IN PREGNANCY

The management of hypertension aims to reduce maternal risk and ensure safety for the fetus. The guidelines from the European Society of Cardiology and the European Society of Hypertension and the International Society for the Study of Hypertension in Pregnancy recommend the initiation of antihypertensive medication for all subtypes of hypertension in pregnancy when the blood pressure exceeds 140/90 mmHg [14,15], which is in line with the recommendations of the National Institute for Health and Care Excellence guidelines [3]. Jung et al. [16] recently reported that maternal and fetal morbidity was more likely in women with stage I hypertension than in the normotensive group (systolic blood pressure: odds ratio [OR] 1.68, 95% confidence interval [CI] 1.59–1.78; diastolic blood pressure: OR 1.56, 95% CI 1.42–1.72). A linear association was found between prepregnancy blood pressure and the primary outcome. Even worse, women with HDP in their first pregnancy had a 63% higher likelihood of cardiovascular disease (95% CI, 1.37–1.94) than women with normotensive pregnancies [5]. Established cardiovascular disease risk factors arising after pregnancy explained most of the increased risk of cardiovascular disease. Therefore, most hypertension guidelines recommend vigorous blood pressure control even in pregnancy.

According to the American College of Obstetricians and Gynecologists and the Korean Society of Hypertension, the threshold for initiating pharmacological treatment is when the blood pressure exceeds 160/90 mmHg [12,17]. While there is little dissent about the need for pharmacological treatment in patients with a blood pressure of 160/110 mmHg or higher, there is no clear evidence for the effectiveness of aggressive blood pressure treatment. The Korean guideline recommends controlling the blood pressure to less than 150/100 mmHg and avoiding a reduction of the diastolic blood pressure to less than 80 mmHg [17]. Patients with severe hypertension should receive treatment to avoid maternal morbidity (eclampsia or stroke) [10–12,15,17]. The European guidelines recommend a blood pressure target of <140/90 mmHg, which is also suggested for pregnant women receiving antihypertensive therapy [14]. The blood pressure thresholds and targets from several guidelines are depicted in Fig. 2 [3,7,12,14,15,17].

The Control of Hypertension in Pregnancy Study (CHIPS) compared a tight diastolic blood pressure target of less than 85 mmHg as opposed to a less tight target of less than 100 mmHg in pregnant women with nonsevere, nonproteinuric preexisting or gestational high blood pressure, with regard to maternal and perinatal events. The primary outcome was composite pregnancy loss or neonatal intensive care unit admission for longer than 48 hours. The secondary outcomes were serious maternal complications until hospital discharge or puerperium mortality. The study reported a significantly higher incidence of severe hypertension in the less tight control group (40.6% vs. 27.5%, P<0.001), and the primary outcome of pregnancy loss or high-level neonatal care rates was similar between the two groups (OR, 1.02; 95% CI, 0.77–1.35). The CHIPS study concluded that although tighter versus much less tight control showed comparable results in the risk of adverse events and composite severe maternal complications, stricter blood pressure control may diminish the risk of developing more severe hypertension and preeclampsia [18].

A recent randomized, open-label, and multicenter clinical trial in the United States—namely, the Chronic Hypertension and Pregnancy trial—compared the outcomes of two interventions at different blood pressure target thresholds: either receiving antihypertensive medications recommended for use in pregnancy (active-treatment group) or receiving no such treatment unless severe hypertension (systolic pressure ≥160 mmHg or diastolic pressure ≥105 mm Hg) developed (control group) [19]. This trial included 2,408 pregnant women with mild hypertension. This study’s primary endpoint was a composite of severe preeclampsia, placental abruption, preterm birth <35 weeks of gestation due to a medical indication, or perinatal death [19]. The active-treatment group had a lower incidence of the primary endpoint than the control group (30.2% vs. 37.0%; adjusted risk ratio, 0.82; 95% CI, 0.74–0.92; P<0.001) [19]. In terms of infant safety, babies whose sizes fell below the 10th percentile or below the 5th percentile for gestational age did not differ significantly between the groups [19]. Further assurance of the safety of active treatment was provided by virtually identical placental weights in the two treatment groups [19]. The results of the Chronic Hypertension and Pregnancy trial were supported by the findings of the CHIPS trial that there was no evidence of decreased fetal growth in patients with maternal hypertension who received more aggressive treatments [18,19].

The preference for antihypertensive therapy in most guidelines is methyldopa, labetalol, or long-acting nifedipine. In Korea, methyldopa is not readily available, long-acting nifedipine is easily available in clinics, and labetalol is available through the Korea Orphan and Essential Drug Center. Therefore, pregnancy-associated hypertension is usually controlled by long-acting nifedipine and labetalol. The benefits of drug treatment for the mother and fetus in pregnancies complicated by hypertension have not been extensively studied; the best data were obtained from a single trial using methyldopa, performed 40 years ago. Pharmacological treatment includes oral methyldopa, labetalol, and nifedipine, and alternative agents include hydralazine and prazosin [14,15]. Intravenous hydralazine is not the drug of choice, as it is associated with more significant perinatal adverse effects than other antihypertensive drugs. Nonetheless, hydralazine is still used when other treatment regimens fail to achieve adequate blood pressure control [14,20]. The use of renin-angiotensin system inhibitors may cause congenital malformations in pregnancy, so these medications should be substituted before pregnancy or during pregnancy planning [14,15,21]. Diuretics should be prescribed cautiously because they may aggravate electrolyte abnormalities and volume depletion [20]. The pharmacological treatment options based on the latest guidelines and evidence are listed in Table 1 [12,14,20–22].

There is no agreed-upon definition of severe hypertension, with values ranging between 160 and 180 mmHg for systolic blood pressure and >110 mmHg for diastolic blood pressure. The 2018 European Society of Cardiology Task Force on cardiovascular disease during pregnancy considers a systolic blood pressure ≥170 mmHg or diastolic blood pressure ≥110 mmHg an emergency in a pregnant woman, who should be immediately admitted to the hospital for treatment [14]. The administration of intravenous labetalol has been recommended for emergency situations, although nitroglycerin or nitroprusside might be used as alternative medications [17].

CONCLUSIONS

The management of HDPs is important to minimize maternal mortality and morbidity. Antihypertensive drugs safe for pregnant women are methyldopa, labetalol, and nifedipine. Although the blood pressure reduction targets vary among guidelines, setting more aggressive blood pressure reduction targets (below 140/90 mmHg, with diastolic blood pressure not below 80 mmHg) may be useful for reducing maternal complications. The preferred medications for antihypertensive therapy are labetalol, long-acting nifedipine, and methyldopa (not readily available in Korea). Research on the active management of maternal hypertension is needed that involves various races so that it can be generalized to a wide range of populations.

ARTICLE INFORMATION

Ethical statements

Not applicable.

Conflicts of interest

The authors have no conflicts of interest to declare.

Funding

None.

Author contributions

Conceptualization: all authors; Data curation: all authors; Investigation: HR; Methodology: HYL; Validation: HYL; Writing–original draft: all authors; Writing–review & editing: all authors.

All authors read and approved the final manuscript.

Fig. 1.

Odds ratios for maternal complications according to the subtype of hypertension in pregnancy.

Fig. 2.

Hypertensive disorders of pregnancy: blood pressure thresholds and targets. NICE, National Institute for Health and Care Excellence; ESC/ESH, European Society of Cardiology/European Society of Hypertension; ISSHP, International Society for the Study of Hypertension in Pregnancy; ACOG, American College of Obstetricians and Gynecologists; KSH, Korean Society of Hypertension; DBP, diastolic blood pressure.

Table 1.

Common pharmacological therapies for hypertensive disorders of pregnancy

Drug class	Drug (daily dose)	Safety and efficacy	Side effect	Study
First-line drugs of choice
Central alpha-2 adrenergic agonists	Methyldopa (0.5–3 g/day in 2 divided doses)	Fetal and neonatal safety with FDA class B, class I level B	Particular concern for hemolytic anemia and hepatic disturbance	ACOG report [12]
		Drug choice for severe hypertension	May aggravate depressive disorder	Williams et al. [14]
				Brown et al. [20]
				Easterling et al. [22]
Beta-blockers	Labetalol (200–1,200 mg/day PO in 2–3 divided doses)	Safe and FDA class C, class I level	May be associated with fetal growth restriction	ACOG report [12]
		Drug choice for severe hypertension	Neonatal hypoglycemia with larger doses	Williams et al. [14]
				Easterling et al. [22]
Second-line drugs of choice
Calcium channel blockers	Nifedipine (slow-release tablet, 10–30 mg PO)	Safe and FDA class C, class I level C, avoid sublingual capsule use (risk of fetal distress)	Tocolytic effect may inhibit birth delivery	Williams et al. [14]
		Drug of choice for severe hypertension	Concern that using a short-acting agent in combination with magnesium may induce profound hypotension	Brown et al. [20]
				Easterling et al. [22]
Central alpha-2 adrenergic agonists	Clonidine (0.1–0.6 mg/day in 2 divided doses)	Limited data in pregnancy, FDA class C	Similar to methyldopa	Brown et al. [20]
Alternative option
Diuretics	Hydrochlorothiazide (12.5–25 mg/day)	FDA class B, and few studies in patients with hypertension	Should not be used for preeclampsia prevention because it may aggravate volume depletion and electrolyte abnormalities	Brown et al. [20]
Direct vasodilators	Hydralazine (50–300 mg/day in 2–4 divided doses)	FDA class D	Drug-induced symptoms: nausea, headache, light-headedness, flushing, and palpitation	Brown et al. [20]
Direct vasodilators	Hydralazine (50–300 mg/day in 2–4 divided doses)	May be orally used as a third choice or used intravenously for hypertensive crisis	Drug-induced lupus, neonatal lupus, maternal polyneuropathy, tachyphylaxis, and thrombocytopenia	Brown et al. [20]
Alpha-1 adrenergic-blockers	Prazosin (0.5–5 mg three times a day)	No fetal adverse effects reported	Associated with palpitations and postural hypotension	Brown et al. [20]
Alpha-1 adrenergic-blockers	Prazosin (0.5–5 mg three times a day)	Considered a second-line agent	Associated with palpitations and postural hypotension	Brown et al. [20]
Proscribed or not recommended
Renin-angiotensin system inhibitors	Angiotensin 2 converting enzyme inhibitors	FDA class C in first trimester	Associated with adverse fetal effects	Williams et al. [14]
		FDA class D second and third semester		Brown et al. [20]
		Teratogenic effect on fetus, class III level C
	Angiotensin 2 receptor antagonists	Teratogenic effect on fetus, class III level C		Williams et al. [14]
	Angiotensin 2 receptor antagonists	Teratogenic effect on fetus, class III level C		Bortolotto et al. [21]
Aldosterone receptor antagonists	Spironolactone	Not recommended in pregnancy due to antiandrogenic effects	Feminization of male infants	Brown et al. [20]
Aldosterone receptor antagonists	Spironolactone	Not recommended in pregnancy due to antiandrogenic effects	Feminization of male infants	Bortolotto et al. [21]

FDA, Food and Drug Administration; ACOG, American College of Obstetricians and Gynecologists; PO, per oral.

REFERENCES

1. Zulfeen M, Tatapudi R, Sowjanya R. IV labetalol and oral nifedipine in acute control of severe hypertension in pregnancy-a randomized controlled trial. Eur J Obstet Gynecol Reprod Biol 2019;236:46–52.Article PubMed
2. Lo JO, Mission JF, Caughey AB. Hypertensive disease of pregnancy and maternal mortality. Curr Opin Obstet Gynecol 2013;25:124–32.Article PubMed
3. National Institute for Health and Care Excellence (NICE). Hypertension in pregnancy: diagnosis and management [Internet] London: NICE; 2019 [cited 2022 Jan 22]. Available from: https://www.ncbi.nlm.nih.gov/pubmed/31498578
4. Garovic VD, Dechend R, Easterling T, Karumanchi SA, McMurtry Baird S, Magee LA, et al. Hypertension in pregnancy: diagnosis, blood pressure goals, and pharmacotherapy: a scientific statement from the American Heart Association. Hypertension 2022;79:e21–41.Article PubMed
5. Stuart JJ, Tanz LJ, Rimm EB, Spiegelman D, Missmer SA, Mukamal KJ, et al. Cardiovascular risk factors mediate the long-term maternal risk associated with hypertensive disorders of pregnancy. J Am Coll Cardiol 2022;79:1901–13.Article PubMed PMC
6. Berg CJ, Callaghan WM, Syverson C, Henderson Z. Pregnancy-related mortality in the United States, 1998 to 2005. Obstet Gynecol 2010;116:1302–9.Article PubMed
7. Kim HC, Lee H, Lee HH, Seo E, Kim E, Han J, et al. Korea hypertension fact sheet 2021: analysis of nationwide population-based data with special focus on hypertension in women. Clin Hypertens 2022;28:1. Article PubMed PMC PDF
8. Grobman WA, Bailit JL, Rice MM, Wapner RJ, Reddy UM, Varner MW, et al. Frequency of and factors associated with severe maternal morbidity. Obstet Gynecol 2014;123:804–10.Article PubMed PMC
9. Joseph KS, Boutin A, Lisonkova S, Muraca GM, Razaz N, John S, et al. Maternal mortality in the United States: recent trends, current status, and future considerations. Obstet Gynecol 2021;137:763–71.Article PubMed PMC
10. Wu P, Chew-Graham CA, Maas AH, Chappell LC, Potts JE, Gulati M, et al. Temporal changes in hypertensive disorders of pregnancy and impact on cardiovascular and obstetric outcomes. Am J Cardiol 2020;125:1508–16.Article PubMed
11. Liu S, Chan WS, Ray JG, Kramer MS, Joseph KS. Stroke and cerebrovascular disease in pregnancy: incidence, temporal trends, and risk factors. Stroke 2019;50:13–20.Article
12. Hypertension in pregnancy: report of the American College of Obstetricians and Gynecologists’ task force on hypertension in pregnancy. Obstet Gynecol 2013;122:1122–31.Article PubMed
13. Visintin C, Mugglestone MA, Almerie MQ, Nherera LM, James D, Walkinshaw S, et al. Management of hypertensive disorders during pregnancy: summary of NICE guidance. BMJ 2010;341:c2207. Article PubMed
14. Williams B, Mancia G, Spiering W, Agabiti Rosei E, Azizi M, Burnier M, et al. 2018 ESC/ESH guidelines for the management of arterial hypertension. Eur Heart J 2018;39:3021–104.Article PubMed
15. Brown MA, Magee LA, Kenny LC, Karumanchi SA, McCarthy FP, Saito S, et al. Hypertensive disorders of pregnancy: ISSHP classification, diagnosis, and management recommendations for international practice. Hypertension 2018;72:24–43.Article PubMed
16. Jung YM, Oh GC, Noh E, Lee HY, Oh MJ, Park JS, et al. Pre-pregnancy blood pressure and pregnancy outcomes: a nationwide population-based study. BMC Pregnancy Childbirth 2022;22:226. Article PubMed PMC PDF
17. Kim KI, Ihm SH, Kim GH, Kim HC, Kim JH, Lee HY, et al. 2018 Korean Society of Hypertension guidelines for the management of hypertension: part III-hypertension in special situations. Clin Hypertens 2019;25:19. Article PubMed PMC PDF
18. Magee LA, von Dadelszen P, Rey E, Ross S, Asztalos E, Murphy KE, et al. Less-tight versus tight control of hypertension in pregnancy. N Engl J Med 2015;372:407–17.Article PubMed
19. Tita AT, Szychowski JM, Boggess K, Dugoff L, Sibai B, Lawrence K, et al. Treatment for mild chronic hypertension during pregnancy. N Engl J Med 2022;386:1781–92.Article PubMed PMC
20. Brown CM, Garovic VD. Drug treatment of hypertension in pregnancy. Drugs 2014;74:283–96.Article PubMed PMC PDF
21. Bortolotto MR, Francisco RP, Zugaib M. Resistant hypertension in pregnancy: how to manage? Curr Hypertens Rep 2018;20:63. Article PubMed PDF
22. Easterling T, Mundle S, Bracken H, Parvekar S, Mool S, Magee LA, et al. Oral antihypertensive regimens (nifedipine retard, labetalol, and methyldopa) for management of severe hypertension in pregnancy: an open-label, randomised controlled trial. Lancet 2019;394:1011–21.Article PubMed PMC

Figure & Data

References

Citations

Citations to this article as recorded by

Combined Effects of Methyldopa and Baicalein or Scutellaria baicalensis Roots Extract on Blood Pressure, Heart Rate, and Expression of Inflammatory and Vascular Disease-Related Factors in Spontaneously Hypertensive Pregnant Rats
Michał Szulc, Radosław Kujawski, Przemysław Ł. Mikołajczak, Anna Bogacz, Marlena Wolek, Aleksandra Górska, Kamila Czora-Poczwardowska, Marcin Ożarowski, Agnieszka Gryszczyńska, Justyna Baraniak, Małgorzata Kania-Dobrowolska, Artur Adamczak, Ewa Iwańczyk-S
Pharmaceuticals.2022; 15(11): 1342. CrossRef