By John C. Hobbins, MD
Professor, Department of Obstetrics and Gynecology, University of Colorado School of Medicine, Aurora
Dr. Hobbins reports no financial relationships relevant to this field of study.
Chronic hypertension complicates about 5% of pregnancies and has been associated with higher rates of intrauterine growth restriction (IUGR), stillbirth, and, most importantly, superimposed preeclampsia. Through the years, I have heard repeatedly that the person who solves preeclampsia will win the Nobel Prize. Although the condition is far from being solved, there have been some major inroads made into its understanding through contemporary investigation.
Until recently, tools used to characterize cardiovascular changes in normal and abnormal pregnancies had been limited. Standard brachial blood pressure assessment has been the only method to evaluate the dynamics of a very complex system. It simply depicts the pressures during systole and diastole against which the heart is pumping, measured less than a foot from the heart.
Resistance in the cardiovascular system is dependent on peripheral blood vessel size, large vessel compliance, and the overall size of the circulatory bed. In pregnancy, by adding a dynamic placental circulation, the cardiovascular system becomes even more complicated. Today, cardiac output can be assessed noninvasively through standard transthoracic echocardiograms or sonography of the common carotid. Peripheral resistance can be quantified by impedance cardiography monitored over the radial artery. These sonographic windows now enable a better understanding of the physiologic variations in the cardiovascular system in normal and hypertensive pregnancies.
Cardiovascular Findings in Normal and Hypertensive Pregnancy
In normal pregnancies, cardiac output increases in the first trimester by about 20%. It then increases by another 20% over the next eight to 16 weeks, after which it generally is sustained until term.1 Peripheral resistance trends downward in the middle trimester and then rises again toward term.2
In chronic hypertension, the cardiac output is higher than normal in the first trimester and consistently rises throughout pregnancy.3 Peripheral resistance remains unchanged throughout most of pregnancy but trends downward toward term.3
In preeclampsia, cardiac output is elevated (even above those patients with chronic hypertension) in the first trimester and rises even further until the diagnosis is clear. At that time, interestingly, a crossover occurs in which the cardiac output drops as the peripheral resistance increases.3
Standard Definitions
Chronic hypertension is defined as a brachial blood pressure of > 140/90 mmHg, found at two separate sittings, preferably four hours apart — usually before 20 weeks of gestation.
Preeclampsia is diagnosed when brachial blood pressures exceed 140/90 mmHg, with the addition of proteinuria, defined as a single urine sample having a protein/creatinine ratio of 0.3, or if total protein exceeds 300 mg in a 24-hour specimen, occurring after 20 weeks of gestation.
Complications Associated With Chronic Hypertension
The risk of superimposed preeclampsia is about 21% in patients with chronic hypertension vs. 2.1% of the overall population.4 Preeclampsia puts into play another mechanism, which involves a dysfunctional placental circulation and small vessel endothelial damage. The obvious threat of preeclampsia is eclampsia, and the best way to avoid this serious condition is to be prepared. Early predictive methods can cue preemptive action to prevent or treat severe hypertension, to initiate seizure prophylaxis, and to employ a plan of timely delivery.
Prediction of Preeclampsia
First-trimester algorithms and scoring systems use combinations of patient historical factors, uterine artery waveforms, and placental biomarkers, such as pregnancy-associated plasma protein-A, placental growth factor, and angiogenic soluble fins-like tyrosine kinase-1. One algorithm yielded detection rates of about 40% for late-onset preeclampsia and 70% for early-onset disease.5 In general, the more severe the preeclampsia, the better the predictive ability of all the methods. Also, many strategies have been designed for first trimester use, but the later in pregnancy they are applied, the better their predictive accuracy.
Baseline renal function tests will alert the clinician to the potential for preeclampsia. One recent study has shown that if patients with chronic hypertension had protein/creatinine ratios > 1.2 before 20 weeks, the odds ratio (OR) was 7.54 for severe preeclampsia prior to 34 weeks of gestation. If the ratio was below that cutoff, only 1.6% developed severe preeclampsia.6
The finding that 80% of chronic hypertension patients developing preeclampsia had an increase in cardiac output many weeks before the diagnosis was made could represent an additional early predictor for preeclampsia.3
Prevention of Preeclampsia
Low-dose aspirin. A large earlier study showed a weak effect (a 12% reduction) in preventing preeclampsia in general.7 The latest trial has shown a stronger effect in avoiding preeclampsia (OR, 0.38), especially when it is severe enough to result in delivery before 34 weeks.8 Evidence points to a greater benefit if it is initiated before 16 weeks.9 There is little doubt that patients with risk factors for preeclampsia would benefit from low-dose aspirin, but there has been confusion regarding which dosage to use (81 mg vs. 150 mg), since no comparison studies have been conducted.
Low-dose aspirin and low-molecular-weight heparin. A recent meta-analysis of three studies showed a 50% drop in preeclampsia when patients at high risk were given a combination of the two above medications, compared with low-dose aspirin alone.10 Pravastatin currently is being tested to prevent preeclampsia in high-risk patients and has passed a first step safety test in humans.11
Other attempted regimens. This includes calcium supplements and the antioxidants vitamin E and vitamin C, none of which has shown major benefit.
Avoidance of Fetal Complications in Chronic Hypertension
Stillbirth. Most studies have found a threefold incidence of stillbirth in patients with chronic hypertension vs. those without, and a recent study has shown that 68% occurred at less than 29 weeks of gestation and 93% were in IUGR fetuses.4 In patients without chronic hypertension, the average time of stillbirth was 34 weeks of gestation, and most fetuses were appropriate for gestational age. This suggests a primary placental cause of the stillbirth in chronic hypertension.
Early detection of IUGR through ultrasound enables timely surveillance methods (nonstress tests, Dopplers, and kick counts) to be employed, which can be life-saving for those of salvageable gestational age.
There is some evidence that uterine artery analysis will identify most fetuses of chronic hypertensives who would be destined for stillbirth. A decrease in fetal activity (by fetal kick counts), coupled with abnormal second-trimester uterine artery waveforms, carries a five times greater risk of stillbirth.12
Intrauterine growth restriction. Most of the perinatal morbidity associated with chronic hypertension is linked to IUGR, which is doubled in these pregnancies. Birth weights below the fifth percentile occur in 10% of patients with chronic hypertension and in 22% of those with superimposed preeclampsia.4 Since there is such a high predilection for IUGR, patients with chronic hypertension should have fetal growth assessments every four to six weeks through pregnancy.
Treatment of Chronic Hypertension
Patients with a previous history of chronic hypertension should be followed closely, even if their blood pressures are below 140/90 mmHg in the current pregnancy. Treatment should be instituted in patients with blood pressures between 140/90 mmHg and 160/110 mmHg (without proteinuria) with labetalol (200 to 400 mg every 12 hours up to 2,400 mg per day), methyldopa (250 mg every 8 to 12 hours, up to a total of 2 g per day), or nifedipine (10 mg every 8 hours or 30 to 60 mg extended release, not to exceed 1,200 mg per day).
Recent investigation has suggested that patients with chronic hypertension tend to be in a more hyper-dynamic state (increased heart rate and cardiac output) and, therefore, respond better to beta-blockers (labetalol), while those with preeclampsia, whose hypertension is linked more to increased peripheral resistance, appear to benefit more from a vasodilator, such as methyldopa or a calcium channel blocker (nifedipine).13 Although angiotensin-converting enzyme inhibitors have been shown to affect maternal aortic compliance beneficially, they are rated as category D drugs because of possible teratogenicity after first trimester exposure and adverse effects on the fetal kidney with second and third trimester exposures.
Patients with severe hypertension with blood pressures exceeding 160/110 mmHg should be treated aggressively. This would involve intravenous (IV) administration of hydralazine or labetalol. If IV access is not established, oral nifedipine can be used in the interim.
Magnesium sulfate is still the primary agent to prevent and/or treat seizures. This should be given in an IV bolus of 4 to 6 g per 100 mL of fluid infused over 20 minutes followed by 2 g per hour through 24 hours postpartum.
The National Partnership for Maternal Safety has drafted guidance bundles14 for treatment of hypertensive patients that now are being applied in many obstetrical care centers in the United States. A recent study of 23 hospitals involving 69,500 births in the United States showed an initial compliance rate with the guidelines of about 50%. However, by April 2016, 90% of these hospitals were complying and the incidence of eclampsia had decreased by 42% and severe maternal morbidity had dropped by 17%.15 The authors believed that continued monitoring of compliance was essential to the success of this initiative.
The message is clear. With chronic hypertension, heightened vigilance will bear rewards in perinatal outcome.
REFERENCES
- Mahendru AA, Everett TR, Wilkinson IB, et al. A longitudinal study of maternal cardiovascular function from preconception to the postpartum period. J Hypertens 2014;32:849-856.
- Fujime M, Tomimatsu T, Okane Y, et al. Central aortic blood pressure and augmentation index during normal pregnancy. Hypertens Res 2012;35:633-638.
- Bosio PM, McKenna PJ, Conroy R, O’Herlihy C. Maternal central hemodynamics in hypertensive disorders of pregnancy. Obstet Gynecol 1999;94:987-984.
- Panaitescu AM, Syngelaki A, Prodan N, et al. Chronic hypertension and adverse pregnancy outcome: A cohort study. Ultrasound Obstet Gynecol 2017;50:228-235.
- Scazzocchio E, Crovetto F, Triunfo S, et al. Validation of the first-trimester screening model for pre-eclampsia in an unselected population. Ultrasound Obstet Gynecol 2017;49:188-193.
- Kuper SG, Tita AT, Youngstrom ML, et al. Baseline renal function tests and adverse outcomes in pregnant patients with chronic hypertension. Obstet Gynecol 2016;128:93-103.
- Collaborative Low-dose Aspirin Study in Pregnancy Collaborative Group. CLASP: A randomized clinical trial of low-dose aspirin for the prevention and treatment of pre-eclampsia among 9364 pregnant women. Lancet 1994;343:619-629.
- Rolnik DL, Wright D, Poon LC, et al. Aspirin versus placebo in pregnancies at high risk for preterm preeclampsia. N Engl J Med 2017;377:613-622.
- Bujold E, Roberge S, Lacasse Y, et al. Prevention of preeclampsia and intrauterine growth restriction with aspirin started in early pregnancy: A meta-analysis. Obstet Gynecol 2010;116(2 Pt 1):402-414.
- Roberge S, Demers S, Nicolaides KH, et al. Prevention of pre-eclampsia by low-molecular-weight heparin in addition to aspirin: A meta-analysis. Ultrasound Obstet Gynecol 2016;47:548-553.
- Constantine MM, Cleary K, Hebert MF, et al. Safety and pharmacokinetics of pravastatin used for prevention of preeclampsia in high-risk pregnant women: A pilot randomized controlled trial. Am J Obstet Gynecol 2016;214:720.e.1-720.e1-17.
- Pagani G, D’Antonio F, Khalil A, et al. Association between reduced fetal movements at term and abnormal uterine artery indices. Ultrasound Obstet Gynecol 2014;43:548-552.
- Stott D, Bolten M, SalmanM, et al. A prediction model for the response of oral labetalol for the treatment of antenatal hypertension. J Hum Hypertens 2017;31:126-131.
- Bernstein PS, Martin JN Jr, Barton JR, et al. National partnership for maternal safety: Consensus bundle on severe hypertension during pregnancy and the postpartum period. Obstet Gynecol 2017;130:347-357.
- Shields LE, Wiesner S, Klein C, et al. Early standard treatment of critical blood pressure elevations is associated with a reduction in in eclampsia in severe maternal morbidity. Am J Obstet Gynecol 2017;216;415.e1-5
Chronic hypertension complicates about 5% of pregnancies and has been associated with higher rates of intrauterine growth restriction (IUGR), stillbirth, and, most importantly, superimposed preeclampsia. Although the condition is far from being solved, there have been some major inroads made into its understanding through contemporary investigation.
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