Disease Spectrum

Hypertension during pregnancy can occur in one of three forms: chronic hypertension, gestational hypertension (GH) and preeclampsia (PE). Chronic hypertension is defined as elevated blood pressure known before conception or diagnosed before 20 weeks of gestation. GH is hypertension that develops any time after 20 weeks of gestation without proteinuria. PE is defined as hypertension (blood pressure >140/90 mmHg) with organ damage that develops after 20 weeks of gestation and has the potential to result in serious adverse consequences for the mother and fetus. Target organ damage can be manifested by proteinuria, thrombocytopenia, elevated creatinine or liver transaminases, pulmonary edema or cerebral or visual symptoms. Severe hypertension is defined as systolic blood pressure above 170 mmHg or diastolic blood pressure above 110 mmHg.^1,2

Implications on Cardiovascular Outcomes

Chronic hypertension, GH and PE have been shown to have adverse effects on pregnancy and associations with a higher risk for cardiovascular disease (CVD) outcomes. Many studies have shown an association between PE and CV disease in later life.^3-5 A large meta-analysis from Wu et al. showed that women with a history of PE have a 71% increased risk of CV mortality, a 2.5-fold increase in risk of coronary artery disease (CAD), and a 4-fold increase in the development of heart failure when compared to normal cohorts.³ The Nurses' Health Study II reported that women with GH and PE had almost a 3-fold and 6-fold increased rate of chronic hypertension, respectively. It also showed that women who were hypertensive during their first pregnancy had a 70% increased risk of type 2 diabetes and 30% increased prevalence of hypercholesterolemia later in life.⁶ Recurrent PE is associated with a higher risk of future CVD events including hospitalization from heart failure or cardiac procedures compared with no PE, and significantly shorter time to a first cardiovascular event.⁷

Recent data has shown that PE is associated with complications such as preterm delivery (PTD) or small for gestational age (SGA) infant. A Norwegian study with a mean follow-up of 17.2 years found that women with PE alone had a 2-fold increased risk of a major CV event, whereas women with PE plus PTD or SGA were 4 times as likely to have a major cardiac event compared to women with uncomplicated pregnancies.⁸ A large meta-analysis demonstrated that women with chronic hypertension had a higher incidence of superimposed PE, caesarean section, preterm delivery before 37 weeks' gestation, birth weight less than 2500 grams, neonatal unit admission and perinatal death.⁹

In a recent prospective observational study, women with severe PE had higher right ventricular systolic pressure, decreased global right ventricular longitudinal systolic strain and lower mitral septal eʹ velocity when compared to the control cohort of normal pregnancies. Twelve percent of patients with PE also had grade II diastolic dysfunction and 9.5% had peripartum pulmonary edema.¹⁰ These data demonstrate that adverse outcomes of pregnancy are common and highlight the need for antenatal surveillance, risk stratification and close long term follow up of patients with these complications.

Guideline Directed Management

Hypertension is a key risk factor for CVD and its treatment reduces complications over time.¹² However, the benefits of tight blood pressure control during pregnancy are controversial. During pregnancy, the goal of pharmacologic management of hypertension is to prevent acute complications while minimizing risk to the fetus. There is no evidence that treatment of mild to moderate hypertension during pregnancy improves maternal or perinatal outcomes (including preeclampsia, preterm birth and small for gestational age or infant mortality).¹³ In fact, most women with mild hypertension can stop their antihypertensive medications during the first and second trimesters due to the physiological drop in blood pressure that occurs during this time. Those who require treatment can continue their medical regimen except for renin angiotensin aldosterone system inhibitors including angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers and direct renin inhibitors. This class of pharmacotherapy is contraindicated during pregnancy due to the increased risk of fetal renal malformations.14 Severe hypertension should be aggressively treated to reduce the risk of progression to preeclampsia and hemorrhagic stroke.

Data on treatment of chronic hypertension during pregnancy is limited and there is no consensus on the optimal agent. The non-selective beta blocker labetalol and the calcium channel blocker (CCB) nifedipine have similar efficacy in controlling hypertension during pregnancy and are commonly used due to their good safety profiles.¹⁵ Methyldopa has a long history of use in pregnancy and is still used, although it is not as effective and considered a second line therapy after CCBs and beta blockers.¹³ Diuretics can be used but are also second line agents due to the theoretical risk of intravascular volume depletion and fetal growth restriction. Given the lack of conclusive evidence regarding specific antihypertensive medications during pregnancy, side effects, contraindications and familiarity of the drug should guide the provider to choose an appropriate agent.¹⁶ The influence of ethnicity in the choice of antihypertensive therapy during pregnancy is unknown and has not been adequately studied.¹⁷ For severe hypertension, intravenous labetalol, oral nifedipine and intravenous hydralazine are equally effective.^18,19 In hypertensive emergencies, intravenous sodium nitroprusside or nitroglycerin can be used. Salt restriction and weight loss are not recommended during pregnancy due to the risk of volume contraction and neonatal growth restriction, respectively.^2,20,21

During the postpartum period, hypertension treatment is required and the treatment goals for hypertension are the same as those for the general non-pregnant population. Since breastfeeding is strongly encouraged by the American College of Obstetrics and Gynecologists (ACOG), medications that are not excreted into breast milk are preferred. Methyldopa, labetalol and propranolol are considered safe. Beta blockers such as metoprolol and atenolol can achieve high levels in breast milk and should be avoided for this reason. The angiotensin converting enzyme inhibitors captopril and enalapril are considered safe given their low concentrations in breast milk.² There are limited data for calcium channel blockers, but nifedipine is commonly used during breastfeeding. Diuretics are discouraged because of the risk of reducing breast milk production.^2,16 Nonsteroidal anti-inflammatories should also be avoided to prevent sodium retention and hypertension.

For primary prevention of PE, a recent meta-analysis showed a modest decrease in the risk of PE with the use of low dose aspirin in the late first trimester in high-risk populations. ACOG recommends the use of aspirin 60-80 mg daily in high risk women, defined as previous history of early onset PE and preterm delivery before 34 0/7 weeks of gestation or PE in more than one pregnancy.²

Future Directions

1. Pregnancy provides a unique opportunity for both patients and providers to engage in improving overall health. Many studies have shown that women are motivated to change their lifestyle habits during pregnancy and the postpartum period. Obstetricians and cardiologists can improve the cardiovascular health of women through enhanced collaboration. A recent joint presidential advisory from ACOG and the American Heart Association called for a multidisciplinary approach in management incorporating lifestyle and behavioral modifications including diet, exercise and smoking cessation as well as electronic medical record based standardized algorithms targeting cardiovascular risk factors. Shared information between the two disciplines can be used to assess risk, initiate interventions and facilitate significant and lasting lifestyle changes.²²
2. Cardiologists and primary care physicians should partner to develop a comprehensive pregnancy history tool for cardiovascular risk assessment. Roberts et al. proposed a simple and effective questionnaire (Table 1) that can be incorporated for risk assessment of women when seen by primary care providers and cardiologists. Understanding pregnancy related complications could help categorize women into higher risk groups for targeted therapies.²³ While a few of these questions are beyond the scope of this discussion, those that pertain to gestational history and hypertensive disorders during pregnancy may provide a window into non-traditional CV risk factors.
3. Evidence-based guidelines for screening and interventions remain an unmet need. More focused research on assessing biomarker profiles, vascular physiological and imaging parameters and successful lifestyle-directed interventions targeting this group must be pursued. A shared consensus statement written by key medical societies should be developed to guide management of this population.²⁴

Table 1

How many pregnancies have you had? How many miscarriages (fetal death prior to 20 weeks)? How many stillbirths (fetal death 20 weeks or later)? After how many pregnancies did you breast feed? How many months in each pregnancy? Were any of your babies born early (more than 3 weeks before your due date)? How many? Did this occur spontaneously or were you delivered early because you were ill? Did you have preeclampsia in any of your pregnancies? Which pregnancy? How many times? Were you delivered early because you had preeclampsia? How many weeks before your due date were you delivered? Did you have high blood pressure in any pregnancy? Did you have protein in your urine in that pregnancy? What was the weight of your babies and how many weeks before your due date were they delivered?

References

1. Whelton PK, Carey RM, Aronow WS, et al. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA guideline for the detection, evaluation, and management of high blood pressure in adults: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol 2018;71:e127-248.
2. American College of Obstetricians and Gynecologists, Task Force on Hypertension in Pregnancy. Hypertension in pregnancy. Report of the American College of Obstetricians and Gynecologists' Task Force on Hypertension in Pregnancy. Obstet Gynecol 2013;122:1122-31.
3. Wu P, Haththotuwa R, Kwok CS, et al. Preeclampsia and future cardiovascular health: a systematic review and meta-analysis. Circ Cardiovasc Qual Outcomes 2017;10.
4. McDonald SD, Malinowski A, Zhou Q, Yusuf S, Devereaux PJ. Cardiovascular sequelae of preeclampsia/eclampsia: a systematic review and meta-analyses. Am Heart J 2008;156:918-30.
5. Bellamy L, Casas JP, Hingorani AD, Williams DJ. Pre-eclampsia and risk of cardiovascular disease and cancer in later life: systematic review and meta-analysis. BMJ 2007;335:974.
6. Stuart JJ, Tanz LJ, Missmer SA, et al. Hypertensive disorders of pregnancy and maternal cardiovascular disease risk factor development: an observational cohort study. Ann Intern Med 2018;169:224-32.
7. Auger N, Fraser WD, Schnitzer M, Leduc L, Healy-Profitos J, Paradis G. Recurrent pre-eclampsia and subsequent cardiovascular risk. Heart 2017;103:235-43.
8. Riise HK, Sulo G, Tell GS, et al. Incident coronary heart disease after preeclampsia: role of reduced fetal growth, preterm delivery, and parity. J Am Heart Assoc 2017;6.
9. Bramham K, Parnell B, Nelson-Piercy C, Seed PT, Poston L, Cappell LC. Chronic hypertension and pregnancy outcomes: systematic review and meta-analysis. BMJ 2014;348:g2301.
10. Vaught AJ, Kovell LC, Szymanski LM, et al. Acute cardiac effects of severe pre-eclampsia. J Am Coll Cardiol 2018;72:1-11.
11. Rapsomaniki E, Timmis A, George J, et al. Blood pressure and incidence of twelve cardiovascular diseases: lifetime risks, healthy life-years lost, and age-specific associations in 1.25 million people. Lancet 2014;383:1899-911.
12. Abalos E, Duley L, Steyn DW. Antihypertensive drug therapy for mild to moderate hypertension during pregnancy. Cochrane Database Syst Rev 2014:CD002252.
13. Mancia G, Fagard R, Narkiewicz K, et al. 2013 ESH/ESC guidelines for the management of arterial hypertension: the task force for the management of arterial hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). Eur Heart J 2013;34:2159-219.
14. Pucci M, Sarween N, Knox E, Lipkin G, Martin U. Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers in women of childbearing age :risks versus benefits. Expert Rev Clin Pharmacol 2015;8:221-31.
15. Webster LM, Myers JE, Nelson-Piercy C, et al. Labetalol versus nifedipine as antihypertensive treatment for chronic hypertension in pregnancy: a randomized controlled trial. Hypertension 2017;70:915-22.
16. Duley L, Meher S, Jones L. Drugs for treatment of very high blood pressure during pregnancy. Cochrane Database Syst Rev 2013:CD001449.
17. 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;36:575-6.
18. Shekhar S, Sharma C, Thakur S, Verma S. Oral nifedipine or intravenous labetalol for hypertensive emergency in pregnancy: a randomized controlled trial. Obstet Gynecol 2013;122:1057-63.
19. Magee LA, Cham C, Waterman EJ, Ohlsson A, von Dadelszen P. Hydralazine for treatment of severe hypertension in pregnancy: meta-analysis. BMJ 2003;327:955-60.
20. Semlitsch T, Jeitler K, Berghold A, et al. Long-term effects of weight-reducing diets in people with hypertension. Cochrane Database Syst Rev 2016;3:CD008274.
21. Blumenthal JA, Babyak MA, Hinderliter A, et al. Effects of the DASH diet alone and in combination with exercise and weight loss on blood pressure and cardiovascular biomarkers in men and women with high blood pressure: the ENCORE study. Arch Intern Med 2010;170:126-35.
22. Brown HL, Warner JJ, Gianos E, et al. Promoting risk identification and reduction of cardiovascular disease in women through collaboration with obstetricians and gynecologists: a presidential advisory from the American Heart Association and the American College of Obstetricians and Gynecologists. Circulation 2018;137:2843-52.
23. Roberts JM, Hubel CA. Pregnancy: a screening test for later life cardiovascular disease. Womens Health Issues 2010;20:304-7.
24. Hauspurg A, Ying W, Hubel CA, Michos ED, Ouyang P. Adverse pregnancy outcomes and future maternal cardiovascular disease. Clin Cardiol 2018;41;239-46.

Clinical Topics: Diabetes and Cardiometabolic Disease, Prevention, Vascular Medicine, Hypertension

Keywords: Primary Prevention, Secondary Prevention, Hypertension, Hypertension, Pregnancy-Induced, Pregnancy

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