Caring for Women With Hypertension in Pregnancy

In pregnant women, chronic hypertension is defined as elevated blood pressure that is present and documented before pregnancy.¹ In women whose prepregnancy blood pressure is unknown, the diagnosis is based on the presence of sustained hypertension before 20 weeks of gestation. Chronic hypertension is a relatively common disorder occurring in approximately 1% to 5% of pregnant women.¹ Estimating a prevalence of chronic hypertension during pregnancy of 3%, there are at least 120 000 pregnant women with chronic hypertension (3% of 4 million pregnancies) per year in the United States, a rate expected to increase in the United States with the obesity epidemic and as age at childbearing increases.¹

The direct and indirect costs of managing hypertension in pregnancy are extremely high and include the expense of multiple health care visits to the physician's office and emergency department, multiple laboratory tests, antenatal fetal evaluation testing, frequent prenatal hospitalization, and prolonged hospitalization in complicated cases.² Additional costs are related to acute management and long-term care of women with maternal complications, which include high rates of cesarean delivery because of maternal-fetal indications and failed medical induction, superimposed preeclampsia, abruptio placentae, pulmonary edema, renal failure, and stroke.^{1 ,3 - 8} The direct and indirect costs also are extremely high for infants, including short- and long-term costs related to care of infants born with preterm growth restriction.^{1 - 4 ,9}

In the Clinical Crossroads article in this issue of JAMA, Powrie¹⁰ reviews important data pertaining to counseling and treatment of a 30-year-old woman with chronic hypertension who is trying to conceive. He describes the challenges facing the clinicians caring for Mrs F, the patient in question, regarding the paucity of existing information to guide them, including which antihypertensive medications to use, the threshold blood pressure levels at which to institute therapy, and the optimal blood pressure to achieve during therapy.¹¹ Reflecting the importance of the issue and the limited data to inform clinical decision making, there are numerous antihypertensive treatment guidelines that are based more on opinion than on scientific evidence.¹¹ However, the review does not address counseling for and management of complicated chronic hypertension, which is associated with high rates of maternal and perinatal complications.^{1 ,3 - 4 ,6 - 8} For management and counseling purposes, women with chronic hypertension should be categorized as having either low-risk or high-risk hypertension in pregnancy.¹ Women are considered at low risk when they have mild essential hypertension without any target organ involvement, and Mrs F presumably would fall into this category. All other women should be considered to have high-risk chronic hypertension and should receive care from physicians with training and expertise in managing these disorders.^{1 ,10}

Women with severe hypertension prior to pregnancy, hypertension in the first trimester despite use of antihypertensive medications, or both and those with adverse outcomes in a previous pregnancy are at very high risk of superimposed preeclampsia (50%-75%), fetal growth restriction (25%-40%), and abruptio placentae (10%-20%).^{1 ,3 - 4 ,10 ,12} As a result, these women should undergo thorough counseling about these risks before conception and should be advised about the importance of adequate blood pressure control before conception and early in pregnancy. The pharmacologic approach to blood pressure control should be individualized depending on the presence of other conditions, such as renal disease, diabetes, and left ventricular dysfunction. In general, if maternal blood pressure is adequately controlled with prescribed medications prior to conception, the patient can continue taking the same drug throughout gestation (except for angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, or atenolol) and after delivery.^{1 ,13}

Women with chronic hypertension should be monitored closely for early detection of superimposed preeclampsia, the most frequent complication associated with hypertension during pregnancy. Many clinical, biophysical, and biochemical markers have been proposed to either predict or detect the development of preeclampsia.^{14 - 18} These markers were generally chosen based on certain pathophysiologic abnormalities that have been described in preeclampsia. These have included impaired trophoblast differentiation and invasion, placental and endothelial dysfunction, coagulation and complement activation, immune maladaptation to paternal antigens, and exaggerated systemic inflammatory response. Recently, several reports have suggested an imbalance of circulating angiogenic factors prior to and after onset of early and severe preeclampsia and fetal growth restriction,^{14 ,16} finding that serum placental growth factor is reduced and serum soluble fms-like tyrosine kinase 1 and endoglin are elevated prior to and after onset of preeclampsia. An abnormal uterine artery Doppler velocimetry result (high resistance index or presence of diastolic notch) at 22 to 24 weeks of gestation has been proposed as a good predictor of subsequent preeclampsia,¹⁵ but when used alone, this test has low sensitivity with poor positive predictive value.¹⁵ The results of 2 recent systematic reviews revealed that none of these markers alone is specific or predictive enough for clinical use.^{15 - 16} However, using a combination of these tests improved their predictive values^{17 - 18} ; therefore, future research should focus on developing a model that incorporates maternal age, body mass index, preexisting medical conditions, and previous obstetric history plus multiple markers to be tested as a screening tool for early detection of preeclampsia, including confirming the diagnosis in suspected cases and identifying those at risk of adverse pregnancy outcomes.¹⁴

Adequate and proper prenatal care is the key to early detection of preeclampsia (ie, hypertension plus proteinuria). However, either hypertension or proteinuria may be absent in 10% to 15% of pregnant women who experience HELLP (hemolysis, elevated liver enzymes, and low platelet count) syndrome and in approximately 20% to 25% of women who develop eclampsia (both considered life-threatening complications).¹⁴ Therefore, physicians should be alert for cerebral (severe headaches, visual changes, altered mental status), gastrointestinal tract (nausea, vomiting, epigastric or right upper quadrant pain), and pulmonary (dyspnea, chest tightness) symptoms. In addition, abnormal blood test results, such as thrombocytopenia and elevated liver enzymes, are important clues. These tests should be obtained in women with aggravated hypertension and/or symptoms. These symptoms and blood tests are more important than the levels of hypertension and proteinuria in predicting adverse pregnancy outcomes.

Current management of preeclampsia includes rest at home or in the hospital, close monitoring of maternal and fetal conditions, antihypertensive drugs to control severe hypertension, and timely delivery (according to gestational age, disease severity, and results of maternal-fetal testing). Although this expectant management is recommended for a select group of patients in an attempt to improve perinatal outcome,¹⁹ it does not treat the underlying disease process because it does not affect the pathophysiologic changes of preeclampsia. As a result, expectant management is associated with significant maternal and perinatal complications. Consequently, there is a need to identify target molecules and diagnostic markers specific to the pathophysiologic abnormalities, which will ultimately aid in developing targeted interventions to arrest the disease process and improve pregnancy outcomes.²⁰ Some of the novel therapies under investigation include agents that decrease immune and complement complex production (eg, steroids, ritoximab),^{20 - 22} inhibit coagulation or inflammatory response syndrome (eg, antithrombin, human activated protein C),^{23 - 24} inhibit trophoblast apoptosis (eg, heparin plus aspirin),²⁵ and prevent or reverse the imbalance in angiogenic factors in favor of promoting angiogenesis (eg, soluble fms-like tyrosine kinase 1 receptor blockers, exogenous vascular endothelial growth factor, and drugs that stimulate vascular endothelial growth factor production).¹⁸

Despite the burden of illness and costs imposed by hypertension in pregnancy, evidence to date regarding benefits and risks of antihypertensive drugs and management plans to prolong gestation in preeclampsia remain scant and provide relatively little direction to clinicians. These problems have resulted, at least in part, from lack of support and, perhaps, reluctance by the government and pharmaceutical companies to conduct research in pregnant women because of regulatory and medicolegal concerns.² As a result, many important clinical issues faced by physicians who care for pregnant women with hypertension remain unresolved. Therefore, prospective studies are urgently needed to evaluate potential biomarkers to identify women at high risk of preeclampsia and to identify women with hypertensive disease who will develop adverse maternal and perinatal outcomes. Large multicenter trials are needed to test antihypertensive drugs and novel interventions that are designed to prolong pregnancy and reduce adverse maternal-perinatal outcomes in women with various hypertensive disorders. While such trials will be logistically challenging and will require careful oversight, they are an essential step for improving outcomes of both mother and child and reducing the burden of hypertensive disease in pregnancy.