key: cord-275786-etli5c3a
authors: MAGEE, Laura A.; KHALIL, Asma; KAMETAS, Nikos; VON DADELSZEN, Peter
title: TOWARDS PERSONALIZED MANAGEMENT OF CHRONIC HYPERTENSION IN PREGNANCY
date: 2020-07-18
journal: Am J Obstet Gynecol
DOI: 10.1016/j.ajog.2020.07.026
sha: 
doc_id: 275786
cord_uid: etli5c3a

ABSTRACT Objectives Chronic hypertension complicates 1-2% of pregnancies and it is increasingly common. Women with chronic hypertension are easily-recognized and in touch with a wide variety of healthcare providers before, during, and after pregnancy, mandating that chronic hypertension in pregnancy be within the scope of many practitioners. We reviewed recent data on management to inform current care and future research. Study design Narrative review of published literature. Results Compared with normotensive women, women with chronic hypertension are at increased risk of maternal and perinatal complications. Women wish to be involved in their care and are capable of measuring blood pressure (BP) at home. Accurate devices for home BP monitoring are now available. The diagnostic criteria for superimposed preeclampsia remain problematic, as most guidelines continue to include deteriorating BP control in the definition. It has not been established how angiogenic markers may aid in confirmation of the diagnosis of superimposed preeclampsia when suspected, over and above information provided by routinely-available clinical data and laboratory results. While chronic hypertension is a strong risk factor for preeclampsia and aspirin decreases preeclampsia risk, the effectiveness specifically among women with chronic hypertension has been questioned. It is unclear whether calcium has an independent effect in preeclampsia prevention in such women. Treating hypertension with antihypertensive therapy halves the risk of progression to severe hypertension, thrombocytopenia, and elevated liver enzymes, but a reduction in preeclampsia or serious maternal complications has not been demonstrated; however, the latter lack of evidence is possibly due to few events. Also, treating chronic hypertension neither reduces nor increases fetal/newborn death or morbidity, regardless of the gestational age at which the antihypertensive treatment is started. Antihypertensive agents are not teratogenic, but there may be an increase in malformations associated with chronic hypertension itself. At present, BP treatment targets used in clinic are the same as those used at home; although BP values tend to be inconsistently lower at home among hypertensive women. While starting all women on the same antihypertensive medication is usually effective in reducing BP, it remains unclear whether there is an optimal agent for such an approach, or how best to use combinations of antihypertensive medications. An alternative approach is to individualize care, using maternal characteristics and BP features beyond BP level (e.g., variability) that are of prognostic value. Outcomes may be improved by timed birth between 38+0-39+6 weeks based on observational literature; confirmatory trial evidence is pending. Postnatal care is facilitated by the acceptability of most antihypertensives (included angiotensin converting enzymes inhibitors) for use in breastfeeding. Conclusions The evidence base to guide the care of pregnant women with chronic hypertension is growing and aligning international guidance. Addressing outstanding research questions would inform personalized care of chronic hypertension in pregnancy.

Personal characteristics, symptoms, BP features beyond the BP level, and other physiological 26 characteristics are associated with adverse outcomes and offer opportunities to personalize care. 27 SHORTENED TITLE: Personalized care of chronic hypertension 28 29 has been questioned. It is unclear whether calcium has an independent effect in preeclampsia 48 prevention in such women. Treating hypertension with antihypertensive therapy halves the risk of 49 progression to severe hypertension, thrombocytopenia, and elevated liver enzymes, but a reduction 50 in preeclampsia or serious maternal complications has not been demonstrated; however, the latter 51 lack of evidence is possibly due to few events. Also, treating chronic hypertension neither reduces 52 nor increases fetal/newborn death or morbidity, regardless of the gestational age at which the 53 antihypertensive treatment is started. Antihypertensive agents are not teratogenic, but there may 54 be an increase in malformations associated with chronic hypertension itself. At present, BP 55 treatment targets used in clinic are the same as those used at home; although BP values tend to be 56 inconsistently lower at home among hypertensive women. While starting all women on the same 57 antihypertensive medication is usually effective in reducing BP, it remains unclear whether there is 58 an optimal agent for such an approach, or how best to use combinations of antihypertensive 59

medications. An alternative approach is to individualize care, using maternal characteristics and BP 60 features beyond BP level (e.g., variability) that are of prognostic value. Outcomes may be improved 61 by timed birth between 38 +0 -39 +6 Hypertension complicates up to 10% of pregnancies, and potentially twice that when considered per 79 woman (1). Chronic hypertension complicates 1-2% of pregnancies, and rates are rising (2). While 80 this has been attributed to secular trends in age and body mass index (1), a relationship with Black 81 race and rising maternal age, but not obesity or smoking, could be demonstrated in a population-82 based cross-sectional study of more than 150 million hospital deliveries in the United States (2). This 83 is a global phenomenon, with rates at least as high in resource-limited settings (3). 84

Definition 85

Clinical practice guidelines define chronic hypertension as a blood pressure (BP) ≥140/90mmHg 86 preconception or before 20 weeks' gestation (4). While this is consistent with how hypertension is 87 generally defined outside pregnancy, the American College of Cardiology/American Heart 88 Association (ACC/AHA) have lowered their threshold for diagnosis to 130/80mmHg, with 130-89 139/80-89mmHg designated as stage 1 hypertension and ≥140/90mmHg as stage 2 (5). If 130/80 90 mmHg were the threshold for diagnosing chronic hypertension in pregnancy, more women would be 91 identified who have a heightened risk of preeclampsia (with risk being intermediate between those 92 with BP <130/80 mmHg [defined as normal if <120/80 mmHg and 'elevated' if systolic is 120-129] 93 and stage 2 chronic hypertension), preterm birth, and gestational diabetes (6). Furthermore, women 94 with stage 1 hypertension would benefit from low-dose aspirin, based on a secondary analysis of a 95 larger trial (7). 96

Women with chronic hypertension experience increased maternal and perinatal complications. By 98 systematic review (55 studies, 795,221 pregnancies), women with chronic hypertension have high 99 rates of superimposed preeclampsia (26%), Cesarean delivery (41%), preterm delivery (28%), low 100 birthweight (17%), perinatal death (4%), and neonatal unit (NICU) admission (21%) (8). Stillbirths 101 occur earlier, at a median of 28 vs. 35 weeks, with an absolute risk at 36 weeks (1/1000 births) that 102 equates to that among low-risk nulliparae at 41 weeks (9, 10). Chronic hypertension is a singular 103 clinical risk factor for preeclampsia (11), that itself accentuates risk for adverse pregnancy outcomes 104 (12-15); however, development of preeclampsia, defined traditionally by new proteinuria, 105 inadequately accounts for the excess of complications. For example, preeclampsia accounts for 106 <50% of chronic hypertension-associated prematurity, small-for-gestational age (SGA) infants and 107 NICU care (16-20). 108

Early pregnancy evaluation 111

Over 90% of pregnant women with chronic hypertension have underlying primary (formerly called 112 'essential') hypertension, related to genetics or lifestyle factors (21), and most will have been 113 identified preconception. Extensive genetics studies have revealed two types of abnormalities: (i) 114 <20 rare mutations that are primarily genes regulating mineralocorticoid or renal pathways, 115 associated with substantial hypertension, and useful in a small number of families; and (ii) hundreds 116 of genetic variants associated with a very small increase in BP (i.e., ≈1 mmHg) that contribute to our 117 understanding of the pathogenesis of hypertension but not to the care of individuals (22). Excessive 118 intake of sodium (i.e., >3g/d of sodium chloride) or alcohol, or a sedentary lifestyle are all 119 modifiable, lifestyle risk factors for hypertension outside pregnancy; while little is known about 120 altering salt intake in women with chronic hypertension in pregnancy and pregnant women are 121 advised not to drink alcohol, encouraging physical activity is emerging as an important intervention 122 in pregnancy to prevent pre-eclampsia (23). While less likely to be an issue in pregnancy, it is 123 noteworthy that many medications can increase BP; oral contraceptives and non-steroid anti-124 inflammatory drugs [NSAIDs] will have been stopped in pregnancy, but women may take over-the-125 counter decongestants, prescription drugs for medical indications (such as immunosuppressants or 126 antidepressants), or consume illicit drugs like cocaine. 127 An underlying, 'secondary', cause of hypertension may be related to problems in renal (e.g., chronic 128 kidney disease or renal artery stenosis), vascular (e.g., coarctation of the aorta), endocrine causes 129 (e.g., primary aldosteronism, pheochromocytoma, Cushing syndrome, hypothyroidism or 130 thyrotoxicosis), or respiratory (e.g., obstructive sleep apnea) systems. While collectively, they are 131 thought to account for less than 10% of cases of hypertension, primary aldosteronism may be 132 underrecognized. With systematic screening, including aldosterone to renin ratios, 133 hyperaldosteronism is prevalent among individuals within stage 1 (16%) or stage 2 (22%) 134 hypertension, compared with normotensive individuals (11%) (24). 135

It is not cost-effective to perform a work-up for secondary causes of hypertension in all pregnant 136 women or all adults outside pregnancy. However, it is considered prudent to perform a basic work-137 up in early pregnancy if not performed before pregnancy. The objective is to rule-out obvious 138 secondary causes of hypertension and evaluate baseline cardiovascular risk, although most tests for 139 the latter are not recommended in pregnancy given differences in normal ranges and/or no 140 resultant change in management in pregnancy (Table 1) . Additional baseline tests may be useful for 141 later comparison when superimposed preeclampsia may be suspected (Table 1) . Of note, this 142 screening does not include hyperaldosteronism as associated hypertension usually improves in 143 pregnancy and the most commonly-used mineralocorticoid receptor antagonist (spironolactone) is 144 not recommended for use in pregnancy because of potential anti-androgen effects on male fetuses. 145

Hypertension secondary to renal, vascular, or endocrine causes are suggested by age of onset <30 146 years, uncontrolled blood pressure with three antihypertensives, or condition-specific symptoms; 147 however many symptoms are associated with normal pregnancy (e.g., dizziness 148 The baseline risk of fetal malformations should be clarified numerically, as many women may not 152 appreciate that 1-5% of all pregnancies are complicated by major birth defects. Additionally, 8 untreated chronic hypertension may further increase that risk, particularly for cardiovascular 154 defects, cleft lip or palate, and hypospadias (26-28). While the mechanism is not understood, 155 antihypertensive agents do not appear to be responsible (as discussed below), nor do they appear to 156 alter miscarriage risk (≈20%) (29, 30), although information is limited. 157

As approximately half of pregnancies are unplanned, women with chronic hypertension who are of 158 reproductive age would ideally be treated with antihypertensives that are safe in pregnancy. While 159 no antihypertensive medication is a proven human teratogen, initial associations between 160 angiotensin converting enzyme inhibitors (ACEIs) and birth defects may have suffered from residual 161 confounding from the underlying hypertension, as discussed above (31). Subsequent work has not 162 been consistently reassuring. In a prospective cohort (N=138 women), ACEIs and angiotensin 163 receptor blockers (ARBs) were associated with miscarriage (but not malformations), compared with 164 both hypertensive and normotensive controls; most women (79.8%) were exposed to ACEIs (32). 165

However, ACEIs, ARBs, and other antihypertensive agents have been associated with teratogenicity 166 in a meta-analysis of five controlled cohort studies (786 infants exposed to ACEIs or ARBs, 1723 to 167 other antihypertensives, and 1,091,472 unexposed) (33). The UK clinical practice guideline suggests 168 that thiazides are teratogenic (34), but this statement is not supported by animal or limited human 169 studies (35). Given the inconsistent literature, it is acceptable to continue antihypertensive agents, 170

including ACEIs and ARBs, until conception; this practice may be particularly important for women 171 taking ACEIs for renoprotection in chronic kidney disease (CKD). Conception may normally take up to 172 12 months, and women over 30 years of age suffer more subfertility, so replacing medication 173 prepregnancy can mean that such women's medication is suboptimal for 1-2 years. 174

The safety of antihypertensive agents beyond early pregnancy is further discussed below, under 175 'ANTIHYPERTENSIVE THERAPY'. 176

177 Home blood pressure monitoring (HBPM) 178 HBPM is recommended by most guidelines for care of hypertension outside pregnancy, based on 179 improved links between diagnoses and adverse outcomes, convenience, antihypertensive 180 compliance, and BP control (36). Therefore, women with chronic hypertension may have used HBPM 181 preconceptionally; the COVID-19 pandemic has broadened pregnancy HBPM implementation (37). 182

In pregnancy, women using HBPM report greater awareness of risks and empowerment (38, 39). Currently, similar BP targets should be used for HBPM and office BP to inform care pathways. While 205 systematic review (7 studies, up to 140 women in late pregnancy) found that home BP is widely 206 variable and probably lower than in clinic for hypertensive women (48). Importantly, subgroup 207 analyses before 20 weeks involved fewer than 100 women, and differences were seen primarily in 208 systolic BP (up to 16mmHg vs 7mmHg for diastolic BP [dBP]). Second, when multivariable screening identified women at high risk of preeclampsia, and they were 237 administered 150mg/evening of aspirin, the risk of preterm preeclampsia was substantially reduced 238 (76), but women with chronic hypertension were the only subgroup not to benefit (76). This 239 observation is consistent with subgroup analyses in the relevant individual participant data meta-240 analysis (77) and two randomised trials, although aspirin was used in low dose (78, 79) and/or often 241 started after 20 weeks (78); a trial is planned (NCT04356326). No practice guideline currently 242 recommends against administering aspirin to these women (4). These issues are discussed in detail 243 elsewhere(80). 244

Calcium 245

Increasing calcium intake to ≥1 g/day reduces the likelihood of preeclampsia in women with 246 low intake(81-83); most women in more-developed countries have adequate intake (84) 'Tight' BP control in CHIPS was achieved by a simple algorithm of antihypertensive up-or down-285 titration (Figure 1) , using single or multiple medications. Importantly, antihypertensive therapy was 286 decreased if dBP fell to 80mmHg or below, as frequently encountered in mid-pregnancy, and 287 therapy increased if systolic BP were ≥160mmHg, regardless of dBP, for safety. The mean BP 288 achieved in the 'tight' control group, 133/85mmHg (92), was in the lower half of the ACC/AHA 'stage 289 1 hypertension' range (5), and increasing antihypertensive medication when BP is 'high normal' 290 concurs with guidance from the Royal College of Obstetricians and Gynaecologists (99). Also of note 291 is that the BP achieved in 'less tight' control was not particularly high, at 139/90mmHg; the dBP goal 292 of 100mmHg was designed to minimize use of antihypertensives which were nevertheless required 293 by 73% of women post-randomization. While adherence to these algorithms was similar in 'less 294 tight' (74%) and 'tight' control (73%), adherence based on adjusting according to a range of ±5mmHg 295 around the target dBP was lower in 'less tight' (77%) than 'tight' control (82%, p=0.04), as clinicians 296 tended to leave current dosing of medication in 'tight' control when dBP was 86-89mmHg and 297 tended to increase medication in 'less tight' control when dBP was 96-99mmHg (92). It seems 298 unlikely that clinicians would be comfortable keeping BP below 130/80mmHg if ACC/AHA thresholds 299 were adopted. 300

Four national/international practice guidelines (Canada, UK, Poland, ISSHP) now endorse 'tight' BP 301 control for all forms of pregnancy hypertension, based on the results of the CHIPS trial (4). Other 302 14 (SMFM) considers as acceptable both 'tight' and 'less tight' control, by giving advice to maintain BP 304 at 120-159/80-104 mmHg in women with low-risk chronic hypertension. The American College of 305

Obstetricians and Gynaecologists recommends treating BP emergently when it reaches severe levels 306 (i.e., ≥160/110mmHg), but not at all before then unless there are comorbidities pending the results 307 of the CHAP trial (Control of Hypertension And Pregnancy, NCT02299414), as below (25). 308

There are two ongoing trials of an oral antihypertensive vs. another for non-severe pregnancy 309 hypertension. One is studying nifedipine vs. labetalol initiation to achieve 'tight' BP approach in each 310 group (Giant PANDA, NIHR128721), with randomization minimized by race. There is one ongoing 311 trial of antihypertensive therapy vs. 'treatment only when BP is severe' (CHAP) for women with 312 chronic hypertension randomized to treatment approaches similar to CHIPS, with a primary 313 composite maternal and perinatal outcome and a co-primary of birthweight <10 th centile (100). 314 SMFM is looking to CHAP to address two concerns. First, the average gestational age at recruitment 315 to CHIPS was >20 weeks (i.e., 24 weeks); while this was related in part to 25% of women recruited 316 having gestational hypertension, the adverse effects of 'less tight' control were seen in particular 317 before 24 weeks (101). Second, most women in 'less tight' control (77%) received an 318

antihypertensive before birth; this should be anticipated in CHAP as the interventions are similar. 319

Reporting in 2023, CHAP will be powered to address whether 'tight' control benefits the mother (i.e., 320 fewer serious maternal complications) and baby (i.e., fewer preterm births), or causes more 321 newborn side effects (i.e., more SGA infants). 322

Initial antihypertensive therapy should be monotherapy from accepted first-line drugs; ≥60% of 324 women take only one agent prenatally (92). The most commonly-used and recommended 325 antihypertensive medications come from different drug classes. All cross the placenta. 326

Labetalol is a combined alpha-and (nonselective) beta-blocker, used in oral and parenteral forms; 327 beta-blockade predominates, particularly when labetalol is administered parenterally. The overall 328 effect is vasodilatation without reflex tachycardia or a reduction in cardiac output. Labetalol should 329 be used with caution in women with mild-moderate asthma (or another contraindication to 330 nonselective beta-blockade) and not at all in women with severe or decompensated asthma. (including placebo/no therapy) (106), many agents decreased the incidence of severe hypertension 364 compared with placebo/no therapy: nifedipine, methyldopa, pindolol, and ketanserin; nifedipine 365 decreased severe hypertension compared with furosemide, as did pindolol compared with 366 furosemide or amlodipine. Both nifedipine and methyldopa decreased the incidence of placental 367 abruption compared with placebo/no therapy. Atenolol increased the incidence of SGA infants 368 compared with placebo/no therapy and other antihypertensives (labetalol, nifedipine, methyldopa, 369 and ketanserin). No differences were seen in preeclampsia, Cesarean, preterm birth, or perinatal 370 death. The 95% CIs around estimates of effect were often very wide, and one trial was counted twice 371 (107, 108). However, the results suggest that nifedipine and methyldopa are most beneficial. 372

Vitamin D may enhance the effectiveness of nifedipine (109). 373

These data concur with the broader systematic review of antihypertensive vs. placebo/no therapy in 374 pregnancy (31 trials, 3485 women) and head-to-head comparisons of different antihypertensives (29 375 trials, 2774 women); generally the type of hypertensive disorder was unspecified (90). Multiple 376 agents reduce the incidence of severe hypertension compared with no antihypertensive. However, 377 neither nifedipine nor methyldopa had previously been recognized to reduce abruption. While 378 comparison with methyldopa as the gold standard, has been reported to show that beta-blockers 379 (any, including labetalol) and calcium channel blockers taken together may reduce the risk of severe 380 hypertension, results were more different than could be expected by chance alone. Also, beta-381 blockers, but not calcium channel blockers, may decrease the risk of preeclampsia compared with 382 placebo/no therapy, but when beta-blockers and calcium channel blockers were compared directly, 383 beta-blockers did not decrease preeclampsia as anticipated. Of note, in the CHIPS Trial, women 384 treated with methyldopa (vs. labetalol) may have had better maternal and perinatal outcomes, 385 although there may have been residual confounding (110). 386

Other relevant short-and long-term outcomes have been understudied. An example is an 387 unsubstantiated belief that both oral labetalol and methyldopa may alter fetal heart rate ( although more efficiently with nifedipine than IV hydralazine (103). Using a minimally important 415 relative risk reduction of 10% between groups, an associated trial sequential analysis concluded that 416 there was no difference in effectiveness between IV labetalol and oral nifedipine or IV hydralazine, 417 but more data were needed to compare nifedipine and hydralazine. A second network meta-analysis 418 of first-line agents (17 trials, 1591 women) found that nifedipine more successfully treated severe 419 hypertension than IV hydralazine (116). 420

Oral labetalol and oral methyldopa compared favorably to oral nifedipine in a recent Indian trial for 421 severe pregnancy hypertension (115); an in-target BP (i.e., 120-150/70-100mmHg) was achieved 422 without fetal compromise at 6 hours in ≥75% of women in each group, similarly in the nifedipine 423 (84%) and labetalol (84%) groups, but slightly more often in the nifedipine vs. methyldopa 424 comparison (76%, absolute difference 7·1%, 95% CI 0·8, 13·5). However, more nifedipine group 425 babies received NICU care (for low birthweight) (18%) than labetalol (10%) or methyldopa (10%). 426 Table 3 presents a dose-escalation protocol consistent with recommendations by the Society of 427

Obstetricians and Gynaecologists of Canada and ACOG, and incorporating oral treatment (25, 115, 428 117). The protocol is more conservative in places with regards to dosing (at the lower limit of 429 published ranges) and/or time for repeat dosing (at or beyond the upper limit of recommendations) 430 to harmonize between medications for ease of implementation in urgent care and to minimize the 431 risk of maternal hypotension. Of note, a third dose of oral nifedipine capsules is given at 90min 432 because a dose of 20mg is not used, and when another agent is needed, one should choose from a 433 different drug class, and not hydralazine if nifedipine failed (or vice versa). Successful treatment is 434 resolution of severe hypertension. Consistent with ACOG guidance, routine antihypertensive therapy 435 should be instituted to avoid further episodes of severe hypertension(25). 436

No antihypertensive medication is a proven human teratogen. However, some agents may be best 438 avoided in pregnancy, given possible or proven concerns about fetotoxicity and the availability of 439 alternative agents. 440

Atenolol, a cardioselective beta-blocker, may reduce fetal growth velocity (56, 106, 118-121) . 441

Many practitioners are uncomfortable using thiazides and thiazide-like diuretics due to theoretical 442 concerns about reducing gestational plasma volume expansion (104); however, diuretics were not 443 associated with adverse outcomes when used throughout pregnancy for preeclampsia prevention. 444

Their use is probably best limited to specific circumstances (e.g., medullary sponge kidney). 445

ACEIs and ARBs should not be used in women once pregnant (Grades C and D, respectively) (94); 446 while they do not appear to be teratogenic (33, 122, 123) , there may be an excess of miscarriage, 447 FGR, and neonatal morbidity following use in early pregnancy, even when the medication is stopped 448 in early pregnancy (124). However, such associations have been based on low-quality data (e.g., case 449 reports and series), inconsistently observed, and may relate to underlying hypertension (27, 125, 450

Individualized antihypertensive therapy 452 Outside pregnancy, age and race reflect different hemodynamic profiles in hypertension and 453 response to antihypertensive therapy (127, 128); high renin hypertension is associated with young 454 age and higher HR, or volume expansion, and low renin hypertension is associated with Black race 455 (127). Antihypertensive therapy guided by these phenotypes halves poor BP control, by giving ACEIs 456 or ARBs to young and White patients, and calcium channel blockers to Black patients (129), and is 457 recommended outside pregnancy for adult hypertension (130). 458

In observational work, demographic and hemodynamic parameters identify individual pregnant 459 women less likely to achieve BP control with oral labetalol (131). These women were more often 460 Black, with lower HR and cardiac stroke volume (SV) ('vasoconstricted' or 'high resistance' 461 phenotype associated with more severe hypertension and FGR) and more likely to respond to a 462 vasodilator. In contrast, women with non-Black race and higher HR and SV ('hyperdynamic' 463 phenotype) were more successfully treated with oral labetalol. Importantly, maternal race alone was 464 a poor predictor of BP response to labetalol (area-under-the-receiver-operator curve only 0.65). In a 465 subsequent observational study of 84 hypertensive pregnancies, initiation and titration of 466 antihypertensive therapy (for BP ≥140/90mmHg) guided by this model resulted in a change in care 467 for 51% of women taking oral labetalol; 30% initially given labetalol required additional nifedipine, 468 and 20% initially given nifedipine required additional labetalol. Severe hypertension requiring 469 admission to a high dependency unit was reduced by 60%, without FGR (132). 470

Personalized hemodynamic assessment holds promise to deliver 'tight' BP control while optimizing 471 fetal growth and highlighting potential perinatal benefits. Neither of two ongoing trials of 472 were associated with a greater likelihood of preeclampsia (defined by new proteinuria), 500 preeclampsia that was more severe, early delivery, and adverse maternal and perinatal outcomes 501 (144-146); one study confirmed the observations in a cohort of 123 women with chronic 502 hypertension and CKD (145). As angiogenic imbalance is associated with risks for both placental FGR 503 and stillbirth, it is possible that defining preeclampsia broadly would improve the diagnostic test 504 performance of angiogenic markers (147-151) . 505

Detecting progression to preeclampsia when it occurs is why many professional organizations 507 emphasize evaluating maternal symptoms (113). In a systematic review of maternal risk stratification 508 in pregnancy hypertension (32 studies), miniPIERS (Preeclampsia Integrated Estimate of Risk Score) 509 was the only model for all pregnancy hypertension types, has been externally validated (152), and 510 quantifies the risk of adverse maternal outcome by BP, symptoms, urinalysis (if performed), 511 gestational age and parity (of particular importance for nulliparous women). 'High-risk' women have 512 a predicted risk ≥25%, as a 'rule-in' test for adverse maternal outcome within 48hr (likelihood ratio 513 of 5.1) and correct classification (86%). An online calculator is available (153). 514

If preeclampsia develops, the adverse maternal outcomes can be predicted by the fullPIERS model, 515

incorporating: gestational age, chest pain/dyspnea, pulse oximetry, platelet count, serum creatinine, 516 and AST/SGOT or ALT/SGPT) (154). Using ≥10% to define high risk, fullPIERS can be used as a 'rule-in' 517 test for adverse maternal outcome within 48hr, based on a good LR (9.2). An online calculator is 518 available (155). Determining the added value of angiogenic markers is warranted (156, 157). 519 520

Practise related to the timing of birth for women with chronic hypertension varies widely. In a 522 previously unpublished site survey of CHIPS Trial investigators, 70 respondents highlighted variable 523 practice, with delivery currently offered at 37 (16%), 38 (33%), 39 (20%), 40 (20%), and 41 (12%) 524 weeks gestation. Observational data suggest that delivery between 38 +0 -39 +6 weeks may optimize 525 perinatal outcomes, by balancing stillbirth and neonatal morbidity risks (9, 158). These observational 526 data are complemented by limited trial data related to 50 Egyptian women with chronic 527 hypertension (159), that suggest that earlier term delivery may benefit women without increasing 528 perinatal risks or Cesarean deliveries. However, there are insufficient data available to assess the 529 impact of planned delivery at term (i.e., between 37 +0 to 41 +6 weeks) on maternal morbidity or 530

Cesarean delivery (160). 531

The WILL trial (When to Induce Labour to Limit risk in pregnancy hypertension; ISRCTN 77258279) is 532 randomizing both chronically-and gestationally-hypertensive women to either a policy of delivery at 533 38 0-3 weeks or expectant care until ≥40 +0 weeks (or as clinical need dictates). The co-primary 534 outcomes are maternal death or serious morbidity (fullPIERS outcome(154); superiority) and NICU 535 admission for ≥ 4 hours (non-inferiority); Cesarean delivery rate is the core secondary outcome. 536

As most trials have evaluated antepartum, rather than postpartum, antihypertensive therapy, 539 evidence is insufficient to guide clinical practice; however, it is reasonable to continue 'tight' BP 540 control postpartum. BP is likely to rise after a woman leaves hospital (peaking on days three to six 541 postpartum), postnatal stroke is increasing in incidence, and most antihypertensives are acceptable 542 for use in breastfeeding (searchable information in LactMed (161) Women with chronic hypertension are at high-risk of pregnancy complications, but an easily-556 recognized group in touch with a wide variety of healthcare providers before, during, and after 557 pregnancy. We know that these women are at increased risk of maternal and perinatal 558 complications, that they are capable of measuring their BP values at home with accurate devices, 559 that treating their hypertension with antihypertensive therapy halves the risk of progression to 560 severe hypertension, and that they wish to be involved in their care. Priorities for future research 561 include whether or not: additional characteristics of BP and other physiological variables can be used 562 to predict preeclampsia; low-dose aspirin reduces their risk of preeclampsia specifically and/or 563 calcium has an independent preventative effect; use of angiogenic markers with clinical factors and 564 routine laboratory testing improves care; hemodynamically-guided care improves outcomes in 565 comparison with antihypertensive therapy titrated to BP level and, if the latter, with which 566 antihypertensive agent is best to initiate treatment from among labetalol, nifedipine, and 567 methyldopa; and optimal timing of birth. All of this will bring us closer to offering women more 568 personalized care of their chronic hypertension in pregnancy. 569 570 Medications or illicit substances that can increase BP (e.g., decongestants, NSAIDs, immunosuppressants, antidepressants, cocaine) * Not performed in pregnancy as the normal range is higher and management would not be changed. † Not routinely performed in pregnancy, but may be useful as part of haemodynamically-guided antihypertensive therapy. ‡ Even if done previously to rule out secondary causes of hypertension. 

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Methods and 719 considerations concerning cardiac output measurement in pregnant women: recommendations of 720 the International Working Group on Maternal Hemodynamics

Genetic and non-genetic risk factors for pre-723 eclampsia: umbrella review of systematic reviews and meta-analyses of observational studies

Prediction of pre-726 eclampsia: review of reviews

Multicenter 728 screening for pre-eclampsia by maternal factors and biomarkers at 11-13 weeks' gestation: 729 comparison with NICE guidelines and ACOG recommendations

Comparison of diagnostic 732 accuracy of early screening for pre-eclampsia by NICE guidelines and a method combining maternal 733 factors and biomarkers: results of SPREE

Can adverse maternal and 735 perinatal outcomes be predicted when blood pressure becomes elevated? Secondary analyses from 736 the CHIPS (Control of Hypertension In Pregnancy Study) randomized controlled trial

The performance of risk prediction 739 models for pre-eclampsia using routinely collected maternal characteristics and comparison with 740 models that include specialised tests and with clinical guideline decision rules: a systematic review

Prospective 743 evaluation of screening performance of first-trimester prediction models for preterm preeclampsia 744 in an Asian population

First-trimester 746 combined multimarker prospective study for the detection of pregnancies at a high risk of 747 developing preeclampsia using the Fetal Medicine Foundation-algorithm

First trimester combined 750 screening for preeclampsia and small for gestational age -a single centre experience and validation 751 of the FMF screening algorithm

Clinical evaluation of a first 753 trimester algorithm predicting the risk of hypertensive disease of pregnancy

Risk assessment for 756 preeclampsia in nulliparous women at 11-13 weeks gestational age: prospective evaluation of two 757 algorithms

First-trimester 759 screening for early and late preeclampsia using maternal characteristics, biomarkers, and estimated 760 placental volume

Risk assessment: risk for preeclampsia London: Fetal Medicine Foundation

Preeclampsia screening and prediction

ASPRE trial: incidence of 765 preterm pre-eclampsia in patients fulfilling ACOG and NICE criteria according to risk by FMF 766 algorithm

Cost-effectiveness of first-trimester 768 screening with early preventative use of aspirin in women at high risk of early

Preeclampsia 771 prevention using routine versus screening test-indicated aspirin in low-risk women

Strategies for Prescribing Aspirin to 774 Prevent Preeclampsia: A Cost-Effectiveness Analysis

Aspirin 776 versus placebo in pregnancies at high risk for preterm preeclampsia

Antiplatelet agents for 779 prevention of pre-eclampsia: a meta-analysis of individual patient data

Low-dose aspirin to 782 prevent preeclampsia in women at high risk

Development Network of Maternal-Fetal Medicine Units

Low dose aspirin in 785 hypertensive pregnant women: effect on pregnancy outcome and prostacyclin-thromboxane 786 balance in mother and newborn

Calcium supplementation during pregnancy 789 for preventing hypertensive disorders and related problems

Pre-eclampsia Study G. Low-dose calcium 792 supplementation for preventing pre-eclampsia: a systematic review and commentary

Prepregnancy and early pregnancy calcium supplementation among women at high risk of pre-796 eclampsia: a multicentre, double-blind, randomised, placebo-controlled trial

Calcium intake of the U.S. population What We Eat in America

New interventions for the prevention and treatment of preeclampsia

Prevention with heparin

Fall in mean arterial pressure and fetal growth restriction in 808 pregnancy hypertension: an updated metaregression analysis

Antihypertensive drug therapy for mild to moderate 814 hypertension during pregnancy

The CHIPS randomized 816 controlled trial (Control of Hypertension in Pregnancy Study): is severe hypertension just an elevated 817 blood pressure?

Less-tight versus 819 tight control of hypertension in pregnancy

Hypertensive 821 Disorders of Pregnancy: ISSHP Classification, Diagnosis, and Management Recommendations for 822 International Practice

Hypertension Canada's 824 2018 guidelines for the management of hypertension in pregnancy

Management of non-severe 827 pregnancy hypertension -A summary of the CHIPS Trial (Control of Hypertension in Pregnancy 828 Study) research publications

Gestational Age at Initiation of Antihypertensive Therapy: Secondary Analysis of CHIPS Trial Data 831 (Control of Hypertension in Pregnancy Study). Hypertension

Women's views and 833 postpartum follow-up in the CHIPS Trial (Control of Hypertension in Pregnancy Study)

The cost 836 implications of less tight versus tight control of hypertension in pregnancy

London: Royal College of Obstetricians and Gynaecologists; 2020. 840 100. Committee SP. SMFM Statement: benefit of antihypertensive therapy for mild-to-moderate 841 chronic hypertension during pregnancy remains uncertain

Blocker Exposure and Risks of Neonatal Hypoglycemia and Bradycardia

Drugs for treating severe hypertension in pregnancy: a network 848 meta-analysis and trial sequential analysis of randomized clinical trials

Diuretics for preventing pre-eclampsia

Impact of 853 antihypertensive treatment on maternal and perinatal outcomes in pregnancy complicated by 854 chronic hypertension: a systematic review and meta-analysis

Hypertension during pregnancy, with and 859 without specific hypotensive treatment. II. The growth and development of the infant in the first 860 year of life

Hypertension during pregnancy, with and 862 without specific hypotensive treatment. I. Perinatal factors and neonatal morbidity

Vitamin D enhances efficacy of oral nifedipine in 865 treating preeclampsia with severe features: a double blinded, placebo-controlled and randomized 866 clinical trial

Do labetalol and 868 methyldopa have different effects on pregnancy outcome? Analysis of data from the Control

Do commonly used oral 871 antihypertensives alter fetal or neonatal heart rate characteristics? A systematic review

In-utero exposure to 874 antihypertensive medication and neonatal and child health outcomes: a systematic review

Diagnosis and 877 management of hypertension in pregnancy: summary of updated NICE guidance

The hypertensive 880 disorders of pregnancy: the 2020 ISSHP classification, diagnosis & management recommendations 881 for international practice

Oral antihypertensive 883 regimens (nifedipine retard, labetalol, and methyldopa) for management of severe hypertension in 884 pregnancy: an open-label, randomised controlled trial

First-line 886 antihypertensive treatment for severe hypertension in pregnancy: A systematic review and network 887 meta-analysis

Canadian Hypertensive Disorders of 889 Pregnancy Working G. Diagnosis, evaluation, and management of the hypertensive disorders of 890 pregnancy

Fetal growth restriction

Treatment of hypertension in 893 pregnancy: effect of atenolol on maternal disease, preterm delivery, and fetal growth

Effect of atenolol on birth weight

Atenolol and fetal growth in pregnancies 898 complicated by hypertension

Maternal and perinatal 900 outcomes associated with the use of renin-angiotensin system (RAS) blockers for chronic 901 hypertension in early pregnancy

Angiotensin-903 converting enzyme inhibitors and the risk of congenital malformations

Pregnancy outcome following 906 exposure to angiotensin-converting enzyme inhibitors or angiotensin receptor antagonists: a 907 systematic review

Maternal 909 antihypertensive medication use and congenital heart defects: updated results From the National 910 Birth Defects Prevention Study

Maternal exposure to angiotensin converting 912 enzyme inhibitors in the first trimester and risk of malformations in offspring: a retrospective cohort 913 study

Ethnic 916 differences in blood pressure response to first and second-line antihypertensive therapies in patients 917 randomized in the ASCOT Trial

Consideration of Noninvasive Hemodynamic Monitoring to 919

Target Reduction of Blood Pressure Levels Study G. Value of noninvasive hemodynamics to achieve 920 blood pressure control in hypertensive subjects

London: National 922 Institute of Health and Care Excellence

A prediction model for the 924 response to oral labetalol for the treatment of antenatal hypertension

Longitudinal 927 hemodynamics in acute phase of treatment with labetalol in hypertensive pregnant women to 928 predict need for vasodilatory therapy

Patient 930 preferences and decisional needs when choosing a treatment approach for pregnancy hypertension: 931 a stated preference study

Pregnancy hypertension decision aid Vancouver: CHEOS/KCL/UBC; 2020

Endorsed resource -high blood pressure in pregnancy decision aid and 937 infographic London: National Institute of Health and Care Excellence

The 941 hypertensive disorders of pregnancy: ISSHP classification, diagnosis & management 942 recommendations for international practice

7th Brazilian 944 Guideline of Arterial Hypertension: Chapter 9 -Arterial Hypertension in pregnancy

Hypertension 947 and pregnancy. Expert consensus statement from the French Society of Hypertension

Short-term prediction of adverse 950 outcomes using the sFlt-1 (soluble fms-like tyrosine kinase 1)/PlGF (placental growth factor) ratio in 951 Asian women with suspected preeclampsia

Diagnostic accuracy 953 of placental growth factor in women with suspected preeclampsia: a prospective multicenter study. 954 Circulation

PlGF-based testing to help diagnose suspected pre-eclampsia (Triage PlGF test, Elecsys 956 immunoassay sFlt-1/PlGF ratio, DELFIA Xpress PlGF 1-2-3 test, and BRAHMS sFlt-1 Kryptor/BRAHMS 957 PlGF plus Kryptor PE ratio) [DG23]. London: National Institute of Health and Care Excellence

Predictive value of 959 the sFlt-1:PlGF ratio in women with suspected preeclampsia

Soluble fms-like 961 tyrosine kinase-1 to placental growth factor ratio: ruling out pre-eclampsia for up to 4 weeks and 962 value of retesting

Angiogenic factors 964 in superimposed preeclampsia: a longitudinal study of women with chronic hypertension during 965 pregnancy

Diagnostic and 967 predictive biomarkers for pre-eclampsia in patients with established hypertension and chronic 968 kidney disease

Angiogenic factor 970 abnormalities and risk of peripartum complications and prematurity among urban predominantly 971 obese parturients with chronic hypertension

Can placental growth factor in 973 maternal circulation identify fetuses with placental intrauterine growth restriction?

Placental 976 growth factor as a marker of fetal growth restriction caused by placental dysfunction

Diagnostic accuracy of 979 placental growth factor and ultrasound parameters to predict the small-for-gestational-age infant in 980 women presenting with reduced symphysis-fundus height

Diagnostic 983 performance of placental growth factor in women with suspected preeclampsia attending antenatal 984 facilities in Maputo

Early 986 diagnosis of preeclampsia using placental growth factor: An operational pilot study in Maputo

A risk prediction 989 model for the assessment and triage of women with hypertensive disorders of pregnancy in low-990 resourced settings: the miniPIERS (Pre-eclampsia Integrated Estimate of RiSk) multi-country 991 prospective cohort study

Partnerships and Treatment

Prediction 996 of adverse maternal outcomes in pre-eclampsia: development and validation of the fullPIERS model

Evidence: fullPIERS (fullPIERS calculator) Vancouver: PREgnancy Evidence

Partnerships and Treatment

Angiogenic factors in diagnosis, management, and 1002 research in preeclampsia

Angiogenic marker prognostic 1004 models in pregnant women with hypertension

Timing of Delivery 1006 in Women With Chronic Hypertension

Pregnancy 1008 outcomes of expectant management of stable mild to moderate chronic hypertension as compared 1009 with planned delivery

Planned early delivery versus expectant 1011 management for hypertensive disorders from 34 weeks gestation to term. Cochrane Database Syst 1012 Rev

Drugs and Lactation Database (LactMed) Bethesda: National Library of Medicine (US)

Furosemide in postpartum management of severe 1016 preeclampsia: A randomized controlled trial