Hypertension in Pregnancy: Diagnosis, Blood Pressure Goals, and Pharmacotherapy: A Scientific Statement From the American Heart Association

HomeHypertensionVol. 79, No. 2Hypertension in Pregnancy: Diagnosis, Blood Pressure Goals, and Pharmacotherapy: A Scientific Statement From the American Heart Association Free AccessReview ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyRedditDiggEmail Jump toSupplementary MaterialsFree AccessReview ArticlePDF/EPUBHypertension in Pregnancy: Diagnosis, Blood Pressure Goals, and Pharmacotherapy: A Scientific Statement From the American Heart Association Vesna D. Garovic, MD, PhD, FAHA, Chair, Ralf Dechend, MD, Thomas Easterling, MD, S. Ananth Karumanchi, MD, Suzanne McMurtry Baird, DNP, RN, Laura A. Magee, MD, FRCPC, Sarosh Rana, MD, MPH, Jane V. Vermunt, MBChB, MSc, Phyllis August, MD, MPH, FAHA, Vice Chair and on behalf of the American Heart Association Council on Hypertension; Council on the Kidney in Cardiovascular Disease, Kidney in Heart Disease Science Committee; Council on Arteriosclerosis, Thrombosis and Vascular Biology; Council on Lifestyle and Cardiometabolic Health; Council on Peripheral Vascular Disease; and Stroke Council Vesna D. GarovicVesna D. Garovic Search for more papers by this author , Ralf DechendRalf Dechend Search for more papers by this author , Thomas EasterlingThomas Easterling Search for more papers by this author , S. Ananth KarumanchiS. Ananth Karumanchi Search for more papers by this author , Suzanne McMurtry BairdSuzanne McMurtry Baird Search for more papers by this author , Laura A. MageeLaura A. Magee Search for more papers by this author , Sarosh RanaSarosh Rana Search for more papers by this author , Jane V. VermuntJane V. Vermunt Search for more papers by this author , Phyllis AugustPhyllis August Search for more papers by this author and on behalf of the American Heart Association Council on Hypertension; Council on the Kidney in Cardiovascular Disease, Kidney in Heart Disease Science Committee; Council on Arteriosclerosis, Thrombosis and Vascular Biology; Council on Lifestyle and Cardiometabolic Health; Council on Peripheral Vascular Disease; and Stroke Council Search for more papers by this author Originally published15 Dec 2021https://doi.org/10.1161/HYP.0000000000000208Hypertension. 2022;79:e21–e41Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: December 15, 2021: Ahead of Print AbstractHypertensive disorders of pregnancy (HDP) remain one of the major causes of pregnancy-related maternal and fetal morbidity and mortality worldwide. Affected women are also at increased risk for cardiovascular disease later in life, independently of traditional cardiovascular disease risks. Despite the immediate and long-term cardiovascular disease risks, recommendations for diagnosis and treatment of HDP in the United States have changed little, if at all, over past decades, unlike hypertension guidelines for the general population. The reasons for this approach include the question of benefit from normalization of blood pressure treatment for pregnant women, coupled with theoretical concerns for fetal well-being from a reduction in utero-placental perfusion and in utero exposure to antihypertensive medication. This report is based on a review of current literature and includes normal physiological changes in pregnancy that may affect clinical presentation of HDP; HDP epidemiology and the immediate and long-term sequelae of HDP; the pathophysiology of preeclampsia, an HDP commonly associated with proteinuria and increasingly recognized as a heterogeneous disease with different clinical phenotypes and likely distinct pathological mechanisms; a critical overview of current national and international HDP guidelines; emerging evidence that reducing blood pressure treatment goals in pregnancy may reduce maternal severe hypertension without increasing the risk of pregnancy loss, high-level neonatal care, or overall maternal complications; and the increasingly recognized morbidity associated with postpartum hypertension/preeclampsia. Finally, we discuss the future of research in the field and the pressing need to study socioeconomic and biological factors that may contribute to racial and ethnic maternal health care disparities.Hypertensive disorders of pregnancy (HDP) encompass chronic hypertension, gestational hypertension, preeclampsia/eclampsia, and preeclampsia superimposed on chronic hypertension.1 The diagnostic criteria for HDP in the United States have evolved over the past 5 decades1; the most current definition of hypertension in pregnancy from the American College of Obstetricians and Gynecologists (ACOG) was published in 2013,1 with updates and recommendations made in 2019 and 2020 (Table S1 and Table S2 in the Supplemental Material).2,3 Most guidelines around the world are aligned in defining hypertension in pregnancy as blood pressure (BP) ≥140/90 mm Hg (see the Treatment of Hypertension in Pregnancy section). There is variability in the threshold for initiating antihypertensive treatment attributable to uncertainty about the maternal benefits of lowering BP and the potential fetal risks from medication-induced reductions in utero-placental circulation and in utero exposure to antihypertensive medications.2 In contrast, diagnostic and treatment thresholds for the general population have evolved over the years4,5; in the 2017 American College of Cardiology/American Heart Association (AHA) Hypertension Clinical Practice Guidelines, the threshold for the diagnosis of stage 1 hypertension was further lowered to 130/80 from 140/90 mm Hg6 on the basis of observational studies and clinical trials demonstrating reduced cardiovascular disease (CVD) events with treatment to lower levels.7,8This scientific statement presents a synthesis of the scientific evidence (from literature published until August 31, 2020) that is relevant to the current controversies concerning HDP diagnostic and treatment strategies. It is a timely statement given that current trends indicate that the incidence of HDP continues to increase9,10 as a result of advanced age at first pregnancy and increased prevalence of obesity and other cardiometabolic risk factors. CVD, including cerebrovascular accidents and cardiomyopathy, now accounts for up to half of all maternal deaths.11 Pregnancy-related stroke hospitalizations increased >60% from 1994 to 2011, and HDP-associated stroke rates increased 2-fold compared with non–HDP-related stroke.10 Thus, in the discussion that follows, we emphasize the need for future research aimed at recognizing and appropriately treating HDP.EpidemiologyHDP are the second leading cause of global maternal mortality behind maternal hemorrhage12 and are a significant cause of short- and long-term maternal and fetal/offspring morbidity (Tables 1 and 2). Elevated systolic BPs throughout pregnancy, even below the diagnostic threshold for hypertension, also are associated with increased risk of preterm delivery and infants who are small for gestational age and have low birth weight.42,43Table 1. Immediate Maternal and Fetal Complications of HDPEffect estimate (95% CI)Maternal outcomes Mortality Chronic hypertensionaOR, 1.7 (1.2–2.4)13 PreeclampsiaOR, 2.7 (1.0–7.1)14*aOR, 2.6 (2.1–3.4)13 Preeclampsia superimposed on chronic hypertensionaOR, 2.3 (1.5–3.6)13 Myocardial infarction Chronic hypertensionaOR, 3.4 (2.2–5.1)13 Gestational hypertensionaOR, 1.0 (0.5–2.2)13 PreeclampsiaaOR, 3.0 (2.0–4.6)13 Preeclampsia superimposed on chronic hypertensionaOR, 5.2 (3.1–8.7)13 Stroke Chronic hypertensionaOR, 3.4 (2.8–4.1)13 Gestational hypertensionaOR, 1.4 (1.1–1.8)13aOR, 1.6 (1.1–2.3)15 PreeclampsiaaOR, 5.7 (5.0–6.5)13aOR, 7.1 (5.3–9.6)15 Preeclampsia superimposed on chronic hypertensionaOR, 7.8 (6.3–9.8)13 EclampsiaaOR, 65.9 (43.6–99.6)15 Peripartum cardiomyopathy HDPaOR, 3.2 (2.1–4.9), White women16aOR, 4.0 (2.3–7.1), Black women16aOR, 3.0 (1.3–7.0), Hispanic women16 Chronic hypertensionaOR, 3.8 (3.3–4.3)13 Gestational hypertensionaOR, 1.7 (1.5–2.1)13 PreeclampsiaaOR, 3.3 (2.9–3.7)13 Preeclampsia superimposed on chronic hypertensionaOR, 4.4 (3.6–5.3)13 SCAD7.6% higher prevalence of preeclampsia in women with SCAD vs US women of childbearing age17Fetal/neonatal outcomes SGA (birth weight <10th centile) HDPRR, 1.6 (1.5–1.6)18 Severe hypertensionOR, 1.8 (1.2–2.6)19 PreeclampsiaOR, 1.5 (1.0–2.2)19 Stillbirth HDPRR, 1.4 (1.1–1.8)18 Chronic hypertensionaOR, 1.7 (1.6–1.8)13 PreeclampsiaaOR, 1.3 (1.2–1.3)13 Preeclampsia superimposed on chronic hypertensionaOR, 1.8 (1.7–1.9)13 Preterm delivery (<37 wk) Chronic hypertensionaOR, 1.3 (1.2–1.3)13 Severe hypertensionOR, 2.6 (1.8–3.7)19 PreeclampsiaOR, 3.5 (2.5–4.9)19aOR, 3.1 (3.0–3.1)13 Preeclampsia superimposed on chronic hypertensionaOR, 4.7 (4.5–4.8)13 Preterm delivery (<34 wk) Severe hypertensionOR, 3.1 (2.0–4.8)19 PreeclampsiaOR, 2.6 (1.6–4.2)19 Placental abruption Chronic hypertensionaOR, 1.4 (1.4–1.5)13 Gestational hypertensionaOR, 1.1 (1.1–1.2)13 PreeclampsiaaOR, 2.3 (2.2–2.3)13 Preeclampsia superimposed on chronic hypertensionaOR, 2.2 (2.1–2.4)13 Postpartum hemorrhage Chronic hypertensionaOR, 1.3 (1.2–1.3)13 Gestational hypertensionaOR, 1.5 (1.4–1.5)13 PreeclampsiaaOR, 2.3 (2.2–2.4)13 Preeclampsia superimposed on chronic hypertensionaOR, 1.7 (1.6–1.7)13Effect estimates are unadjusted unless specified as ARR/aOR. Different studies have adjusted for different variables; for specifics, please refer to the original references. Comparison groups are women who had normotensive pregnancies.aOR indicates adjusted odds ratio; ARR, absolute risk reduction; HDP, hypertensive disorders of pregnancy; OR, odds ratio; RR, risk ratio; SCAD, spontaneous coronary artery dissection; and SGA, small for gestational age.* The study end point was a composite of mortality and other serious complications.Table 2. Long-Term Maternal and Offspring Complications of HDPEffect estimate (95% CI)Maternal outcome Hypertension (≥140/90 mm Hg) HDPHR, 2.3 (1.9–2.8)20OR, 11.6 (10.6–12.7)21 PreeclampsiaaHR, 4.5 (4.3–4.6)22aHR, 2.2 (2.1–2.3)22RR, 3.1 (2.5–3.9)23RR, 3.7 (2.7–5.1)24OR, 3.4 (3.1-5.0)25 Type 2 diabetes HDPHR, 1.8 (1.5–2.1)20OR, 2.0 (1.7–2.4)21HR, 1.4 (1.3–1.7)26 PreeclampsiaaHR, 1.8 (1.6–1.9)22OR, 2.14 (1.5-3.0)25 Hyperlipidemia HDPHR, 1.3 (1.4–1.5)20OR, 1.5 (1.3–1.7)21 PreeclampsiaaHR, 1.3 (1.3 to 1.4)22 Subclinical markers of vascular damage Augmentation indexWeighted mean difference, 5.5% (1.6%–9.4%)27 Carotid intima-media testWeighted mean difference, 0.02 mm (0.00–0.04)27>0.77 mm; aOR, 3.2 (1.1–9.1)28 Carotid–femoral pulse wave velocityWeighted mean difference, 0.6 m/s (0.2–1.1)27 Arterial stiffness indexUnadjusted difference, 0.32 m/s (0.13–0.51)21 CVD* Gestational hypertensionaHR, 1.4 (1.1–1.9)29†OR, 1.7 (1.3–2.2)30 PreeclampsiaaHR, 1.7 (1.3–2.1)29HR, 1.7 (1.6–1.8)31OR, 1.7 (2.5–3.0)30 Preeclampsia with severe featuresOR, 2.7 (2.5–3.0)30 Early-onset preeclampsia (<34 wk of gestation)aHR, 4.9 (3.0–7.8)32OR, 5.6 (1.5-21.4)25 Coronary heart disease HDPaHR, 1.9 (1.4–2.5)29HR, 1.7 (1.3–2.3)20HR, 1.8 (1.3–2.6)21 PreeclampsiaaHR, 2.1 (1.5–3.0)29HR, 1.7 (1.5–1.8)31RR, 2.5 (1.4–4.4)33 Heart failure HDPaHR, 1.5 (1.3–1.9)31HR, 2.7 (1.6–4.6)20HR, 1.7 (1.0–2.6)21 PreeclampsiaaHR, 2.1 (1.6–2.8)31aHR, 2.0 (1.1–3.7)28RR, 4.2 (2.1–8.4)33 Atrial fibrillation HDPHR, 1.4 (1.1–1.6)20 PreeclampsiaaHR, 1.7 (1.4–2.2)31 All stroke HDPaHR, 1.8 (1.6–2.1)31HR, 1.9 (1.3–2.6)20 PreeclampsiaaHR, 1.9 (1.5–2.4)31aHR, 1.5 (1.1–2.1)29RR, 1.8 (1.3–2.6)33 Ischemic hemorrhageaHR, 1.7 (1.4–2.1)31 Intracerebral hemorrhageaHR, 1.7 (1.2–2.4)31 Subarachnoid hemorrhageaHR, 2.0 (1.6–2.5)31 Vascular dementia Gestational hypertensionaHR, 3.0 (2.1–4.3)34 PreeclampsiaaHR, 2.4 (1.8–3.2)34HR, 3.5 (2.0–6.1)35 Chronic kidney disease Gestational hypertensionRR, 1.5 (1.1–2.0)36 PreeclampsiaRR, 2.3 (1.5–3.5)36 End-stage kidney disease Gestational hypertensionRR, 3.6 (2.3–5.7)36 PreeclampsiaRR, 6.6 (2.7–14.8)36 Venous thromboembolism HDPOR, 1.5 (1.2–1.9)21 Gestational hypertensionaHR, 1.4 (1.3–1.5)37 PreeclampsiaaHR, 1.6 (1.4–2.0)37Offspring outcome CVD‡ Severe preeclampsia, term deliveryaHR, 2.3 (1.1–4.7)38 Stroke Gestational hypertensionHR, 1.4 (1.0–1.8)39 PreeclampsiaHR, 1.9 (1.2–3.0)39 BMI PreeclampsiaMean difference, 0.36 kg/m2 (0.04–0.68)40 Hypertension (≥140/90 mm Hg) Gestational hypertensionSBP, 2.0 mm Hg (1.4–2.7)41DBP, 1.1 mm Hg (0.6–1.5)41 PreeclampsiaSBP, 5.2 mm Hg (1.6–8.7)40DBP, 4.1 mm Hg (0.7–7.4)40All effect estimates are unadjusted unless specified as aHR. Different studies have adjusted for different variables; for specifics, please refer to the original references. Comparison groups are women who had normotensive pregnancies.aHR indicates adjusted hazard ratio; aOR, adjusted odds ratio; BMI, body mass index; CVD, cardiovascular disease; DBP, diastolic blood pressure; HDP, hypertensive disorders of pregnancy; HR, hazard ratio; OR, odds ratio; RR, risk ratio; and SBP, systolic blood pressure.* CVD included ischemic/hypertensive heart disease or stroke.† Chronic hypertension was included as a CVD end point in this study.‡ CVD included cardiomyopathy, hypertension, pulmonary heart disease, arrhythmia, or heart failure.Traditionally, the incidence of HDP was reported on a per-pregnancy basis to assist prediction of pregnancy-related complications (both maternal and fetal) in an obstetric clinical setting (Table 1). However, the HDP population-based incidence expressed per pregnancy (7.5%) underestimates the number of women affected by this condition during their reproductive years (15.3%).20 Per-woman rather than per-pregnancy incidence provides better assessment of the number of women at risk for future CVD on the basis of their reproductive histories,30 including development of diabetes and hypertension20,21 (Table 2).It is well accepted that hypertension develops significantly more frequently after HDP, but studies indicate that hypertension also develops faster in women with HDP and is diagnosed up to 10 years earlier compared with women with normotensive pregnancies,20,26,44–46 although the precise timing requires further examination. Earlier onset of cardiometabolic risk factors and CVD events,22,31,44 as well as higher rates of accumulated chronic conditions and multimorbidity,20 supports the thesis of accelerated aging among women who have a history of HDP.20,21,47Pathophysiology of HDPHemodynamic Changes in Normal Pregnancy and PreeclampsiaSystemic vascular resistance decreases while plasma volume and cardiac output increase during pregnancy. There is a physiological drop in BP, often detectable before the end of the first trimester,48,49 attributable to vasodilation.50 Meta-analyses and high-quality longitudinal studies found that compared with BP at 10 or 12 weeks, the BP drop during the second trimester was on average 1 to 2 mm Hg.51–53 There is wide interindividual variability, and BP trajectories likely relate to preexisting maternal health factors53 such as chronic hypertension and require further clarification. Renal blood flow and glomerular filtration rate increase by 50% in normal pregnancy but are ≈30% lower in women with preeclampsia as a result of both decreases in renal blood flow and the ultrafiltration coefficient, attributable to endotheliosis in the glomerular capillary bed.54 Plasma volume increases in normal pregnancy, and earlier studies have suggested that it may be decreased in women with preeclampsia.55 However, multiple longitudinal and cross-sectional studies in preeclamptic women have demonstrated that suppressed plasma renin activity, high BP, decreased glomerular filtration rate, and frequent development of edema are more consistent with an overfilled, vasoconstricted circulation rather than true hypovolemia and underfilling.56 Cardiometabolic changes in normal pregnancy are more pronounced in women who develop preeclampsia and include increased insulin resistance, total cholesterol, triglycerides, high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol.57 Hypercoagulability, a feature of normal pregnancy, may be exaggerated in preeclampsia and is caused by increased thrombin generation, fibrinogen, and activated protein C resistance and reduced protein S and fibrinolysis.58Abnormal Placentation and the Pathogenesis of the Maternal Preeclampsia SyndromeThe diameter of the uterine spiral arteries increases greatly during normal pregnancy as a result of remodeling of the endothelium and vascular smooth muscle, stimulated by release of proteases from endovascular trophoblast and uterine natural killer cells.59 Failure of spiral artery remodeling (ie, retention of smooth muscle) is a feature of preeclampsia60,61 and leads to decreased utero-placental perfusion, demonstrated by noninvasive blood flow and perfusion studies using Doppler ultrasound or magnetic resonance imaging (Figure).61Download figureDownload PowerPointFigure. Pathogenesis of HDP. Preexisting maternal comorbidities, nonmodifiable patient characteristics, reproductive history, and genetic and immune factors increase the risk of developing a hypertensive disorder of pregnancy (HDP). The molecular and pathophysiological mechanisms of preeclampsia are largely unknown, but the cause is likely a combination of, and interaction between, factors from both maternal and placental pathways.61 Variable contributions of the underlying maternal and placental pathophysiological pathways result in the heterogeneous phenotypes of HDP. The associated widespread endovascular damage and dysfunction may be long-lasting with a possible intergenerational effect. In podocyturia, the urinary loss of podocytes (glomerular epithelial cells) in preeclamptic women contributes to the development of proteinuria and has been documented both before and at the time of preeclampsia diagnosis.62 Senescence is an irreversible cell-cycle arrest mechanism that leads to systematic metabolic and functional decline and may play a role in impaired angiogenesis in preeclampsia.63 ACE indicates angiotensin-converting enzyme; AKI, acute kidney injury; Ang, angiotensin; AT1-AA, angiotensin II receptor 1 autoantibodies; ATR1, angiotensin II type 1 receptor; CAD, coronary artery disease; CKD, chronic kidney disease; CO, cardiac output; DIC, disseminated intravascular coagulation; ESKD, end-stage kidney disease; ET-1, endothelin-1; FGR, fetal growth restriction; GFR, glomerular filtration rate; HF, heart failure; IL, interleukin; MI, myocardial infarction; PCM, peripartum cardiomyopathy; PlGF, placental growth factor; PRES, posterior reversible encephalopathy syndrome; RAS, renin angiotensin system; ROS, reactive oxygen species; SASP, senescence-associated secretory phenotype; SCAD, spontaneous coronary artery dissection; sENG, soluble endoglin; sFlt1, soluble fms-like tyrosine kinase 1; SGA, small for gestational age; Th-1, type 1 T helper cell; TNF-α, tumor necrosis factor-α; TPR, total peripheral resistance; uNK, uterine natural killer cell; VEGF, vascular endothelial growth factor; and VTE, venous thromboembolism.Placental pathology attributable to rheological consequences includes villous architectural changes caused by turbulent jets entering the intervillous space at rates of 1 to 2 m/s (10–20 times normal), causing the rupture of anchoring villi and the formation of echogenic cystic lesions that are visible by ultrasound.64 In addition, retention of vascular smooth muscle preserves the ability of spontaneous vasoconstriction and ischemia-reperfusion injury, which may result in oxidative stress.Alterations in angiogenic factors are recognized as a likely consequence of abnormal placentation occurring in early pregnancy. Increased circulating soluble fms-like tyrosine kinase 1, an antiangiogenic factor of placental origin, leads to neutralization and decrease of proangiogenic factors such as placental growth factor and vascular endothelial growth factor, which then contribute to the hypertension and glomerulopathy characteristic of the maternal syndrome.61 Measurements of angiogenic biomarkers have been incorporated into risk stratification in several innovative therapeutic trials for preeclampsia prevention65,66 but are not routinely used to guide clinical care in most countries, including the United States. An increased soluble fms-like tyrosine kinase 1/placental growth factor ratio may be particularly pronounced in women with early (<34 gestational weeks), severe preeclampsia, which has been designated by some as placental preeclampsia67 because of the association between placental ischemia and adverse fetal outcomes (fetal growth restriction in particular). Preeclampsia occurring later in pregnancy, labeled maternal preeclampsia by some, has been associated with more pronounced maternal vascular dysfunction before pregnancy (secondary to hypertension, diabetes, or obesity), less pronounced placental pathology, and fewer fetal complications. In maternal preeclampsia, pregnancy acts as a physiological stress test that exacerbates preexisting endothelial dysfunction. This underscores the heterogeneity of HDP, whereby the extremes of clinical subtypes (early versus late, mild versus severe, and presence or absence of fetal growth restriction) may reflect distinct underlying mechanisms.67 Sharp discrimination between maternal and placental preeclampsia is overly simplistic and artificial because both processes likely play a role but with varying contributions. Regardless of the clinical subtype, diagnosis and treatment of hypertension remain a mainstay of the prevention of immediate maternal complications and permanent cardiovascular injury, together with seizure prevention with magnesium sulfate.Prevention of Preeclampsia and Adverse Maternal and Fetal OutcomesPreconception health and its impact on both pregnancy outcomes and future health have gained attention.68 Lifestyle changes before and during pregnancy may ameliorate both maternal and fetal risks. A meta-analysis of 44 randomized controlled trials reported that dietary interventions reduce maternal gestational weight gain and improve pregnancy outcomes.69 Exercise may reduce gestational hypertension and preeclampsia risk by ≈30 and 40%, respectively.70,71 The first Canadian guideline for physical activity throughout pregnancy published in 2019 recommends that all women without contraindication should be physically active during pregnancy.72 Low-dose aspirin, starting between 12 and 16 weeks of gestation, reduces the risk of preeclampsia and related adverse outcomes by 10% to 20% in women at increased risk (Table 3).97,99–101 The ACOG recommends daily low-dose aspirin for women with a history of early-onset preeclampsia and preterm delivery or for women with >1 pregnancy complicated by preeclampsia.97Table 3. Risk Factors for PreeclampsiaRisk factorsEffect estimate (95% CI)High* Prior preeclampsiaRR, 8.4 (7.1–9.9)73 Chronic stage 2 hypertension† (≥140/90 mm Hg)RR, 5.1 (4.0–6.5)73 Pregestational diabetesRR, 3.7 (3.1–4.3)73 Multifetal pregnancyRR, 2.9 (2.6–3.1)73 Antiphospholipid syndromeRR, 2.8 (1.8–4.3)73 Systemic lupus erythematosusRR, 2.5 (1.0–6.3)73 Chronic kidney diseaseOR, 10.4 (6.3–17.1)74Moderate* Maternal age >35 yRR, 1.2 (1.1–1.3)73 Prepregnancy BMI >30 kg/m2aOR, 3.7 (3.5–3.9)75RR, 2.8 (2.6–3.1)73 Family history (first-degree relative)RR, 2.9 (1.7–4.9)76 Race (Black)aHR, 1.6 (1.5–1.6)77HR, 2.2 (1.9–2.6), early onset78HR, 1.3 (1.2–1.4), late onset78 Low socioeconomic statusaOR, 4.91 (1.9–12.5)79 NulliparityRR, 2.1 (1.9–2.4)73 History of adverse pregnancy outcome: StillbirthRR, 2.4 (1.7–3.4)73 Placental abruptionRR, 2.0 (1.4–2.7)73Other Chronic hypertension (130–134/80–84 mm Hg)aOR, 2.2 (1.9–2.5), mild80aOR, 2.7 (2.0–3.5), severe80 Chronic hypertension (135–139/85–90 mm Hg)aOR, 2.7 (2.3–3.2), mild80aOR, 3.8 (2.8–5.1), severe80 Severe hypertensionOR, 6.1 (4.4–8.5)19 White coat hypertensionRR, 2.4 (1.2–4.8)81 Prepregnancy BMI >25 kg/m2RR, 2.1 (2.0–2.2)73 Insulin resistance >75th centileaOR, 1.9 (1.1–3.2)82 Gestational diabetesaOR, 1.6 (1.4–1.9)83 Recovered acute kidney injuryaOR, 2.9 (1.9–4.4)84 HyperthyroidismaOR, 1.8 (1.1–2.9)85 Hydatidiform moleOR, 10.1 (3.4–30.0)86 Fetus with trisomy 13Incidence with 24%–44% vs without 2%–8%87Genetic susceptibility88,89 Assisted reproductive technologyRR, 1.8 (1.6–2.1)73 Oocyte donationOR, 4.3 (3.1–6.1)90 New paternityOR, 2.3 (1.2–4.4)91 Pregnancy interval >4 yOR, 1.1 (1.0–1.2), recurrent preeclampsia92OR, 2.1 (1.3–3.3)91 MigraineOR, 2.1 (1.5–2.9)93ACOG indicates American College of Obstetricians and Gynecologists; aHR, adjusted hazard ratio; aOR, adjusted odds ratio; BMI, body mass index; HR, hazard ratio; OR, odds ratio; and RR, relative risk.Other risk factors are based on an emerging number of factors that may increase risk of preeclampsia. Cohabitation of >12 months94 and smoking95,96 have an inverse association with preeclampsia risk. All estimates are unadjusted unless specified as aHR/aOR. Different studies have adjusted for different variables; for specifics, please refer to the original references. Comparison groups are women without the risk factor of interest.* Classification of risk factors as high or moderate is based on the ACOG recommendations for aspirin therapy to prevent preeclampsia. Therapy is indicated when ≥1 high or ≥2 moderate risk factors are present.97,98† Based on the 2017 Hypertension Clinical Practice Guidelines.6The optimal dose of aspirin has not been formally tested, with most trials using 81 to 150 mg daily.100 Promising results from experimental studies and a pilot trial of pravastatin102,103 need to be critically viewed because of concerns related to fetal safety. Experimental evidence suggests that metformin may prevent preeclampsia by reducing soluble fms-like tyrosine kinase 1 and soluble endoglin secretion from primary endothelial tissue and through senomorphic mechanisms.63,104,105 Clinical studies have indicated that metformin may reduce the odds of gestational hypertension in women with gestational diabetes and that it may prevent preeclampsia.106BP Measurement in PregnancyAccurate BP measurement is crucial for classifying hypertension and initiating treatment, regardless of pregnancy status. Because mercury sphygmomanometers are less available, aneroid devices are commonly used, although they require calibration and are less accurate. Several oscillometric automated devices have been validated in pregnant women, including those with gestational hypertension and preeclampsia.107Although most current guidelines recommend hypertension management based on office BP in pregnancy, for the general population, out-of-office BP measurements are widely endorsed as more accurate and better predictors of cardiovascular morbidity and mortality.6,108 Although several studies report BP levels during pregnancy using self-measured BP or ambulatory BP monitoring, current data describing appropriate out-of-office cutoffs for HDP diagnosis are limited.109 The ACOG and the International Society for the Study of Hypertension in Pregnancy recommend the use of self-measured BP in women with chronic or gestational hypertension, particularly when uncontrolled.1,110 Available information does not demonstrate a systematic difference between self-measurements and office BP measurements in pregnancy, which suggests that appropriate treatment and diagnostic thresholds for self-monitoring during pregnancy may be equivalent to standard clinic thresholds; however, additional information on appropriate methodology and validation of devices is needed.Nonsustained HypertensionWhite coat hypertension is reported in 25% of the nonpregnant adult population. Its prevalence in pregnancy is less certain, ranging from 4% to 30%.2 According to 24-hour BP measurements, 32% of women with hypertension had white coat hypertension, but just 8% were diagnosed as such.111 A meta-analysis of studies addressing white coat hypertension reported increased risks of preeclampsia and adverse fetal outcomes compared with women with normotension. Risks were lower compared with women with sustained chronic or gestational hypertension.81 The frequency and clinical significance of masked hypertension in pregnancy have not been extensively studied. Any category of nonsustained BP elevation in pregnancy can progress to sustained hypertension and requires follow-up. Self-measured BP is important for diagnosing nonsustained BP elevations, including masked hypertension and white coat hypertension, that occur before 20 weeks of gestation. For clinical purposes, the definition of hypertension in pregnancy requires 2 elevated BP measurements 4 hours apart (Table S1).BP VariationIn the nonpregnant population, the association between BP variation, independent of baseline BP, and CVD risk is mixed, although greater variability is more convincingly associated with increased stroke risk.112–118 Limited small studies of gestational short-term and visit-to-visit BP variation suggest that greater variation is associated with adverse maternal and perinatal outcomes,119,120 but evidence is currently inconclusive, and there is need for consensus on the methodology for the measurement of BP variability in pregnancy.Standard gestational age–specific BPs and centiles can assist in clinical interpretation of BP changes from expected levels.53,120 Nationally representative, population-specific gestational BP references have been reported from China and the United Kingdom.49,51 Studies addressing the association of BP changes in relation to healthy BP standards with maternal and perinatal outcomes are needed.Secondary HypertensionMost (≈90%) women with chronic hypertension have primary hypertension. Secondary hypertension may occur in a small proportion of women and is associated with