Journal Pre-proof

Chronic Hypertension in Pregnancy

Ashley N. Battarbee, MD MSCR, Rachel G. Sinkey, MD, Lorie M. Harper, MD, MSCI,
Suzanne Oparil, MD, Alan T.N. Tita, MD, PhD

PII: S0002-9378(19)32613-4
DOI: https://doi.org/10.1016/j.ajog.2019.11.1243
Reference: YMOB 12957

To appear in: American Journal of Obstetrics and Gynecology

Received Date: 23 July 2019

Revised Date: 31 October 2019
Accepted Date: 2 November 2019

Please cite this article as: Battarbee AN, Sinkey RG, Harper LM, Oparil S, Tita ATN, Chronic
Hypertension in Pregnancy, American Journal of Obstetrics and Gynecology (2019), doi: https://
doi.org/10.1016/j.ajog.2019.11.1243.

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1 Chronic Hypertension in Pregnancy

3 Ashley N. BATTARBEE, MD MSCR1; Rachel G. SINKEY, MD1; Lorie M. HARPER, MD,

4 MSCI1; Suzanne OPARIL, MD2; Alan T.N. TITA, MD, PhD1

6 Affiliations:

7 1. Department of Obstetrics and Gynecology, Center for Women’s Reproductive

8 Health, University of Alabama at Birmingham, Birmingham, Alabama

9 2. Vascular Biology and Hypertension Program, Division of Cardiovascular Disease,

10 Department of Medicine, University of Alabama at Birmingham, Birmingham, AL

11

12 Disclosures: The authors have no conflicts of interest.

13

14 Funding: None

15

16 Corresponding author:

17 Ashley N. Battarbee

18 Department of Obstetrics and Gynecology, University of Alabama

19 1700 6th Ave South

20 Women & Infants Center Room 10270

21 Birmingham, AL 35233

22 Phone: 205-934-5612

23 E-mail: abattarb@uab.edu

1
24 Condensation: Chronic hypertension is associated with increased risk of maternal and

25 perinatal morbidity and mortality; however, the optimal blood pressure thresholds for

26 diagnosis and treatment remain uncertain.

27

28 Short title: Chronic hypertension in pregnancy

29

30

2
31 Abstract

32 Chronic hypertension and associated cardiovascular disease are among the leading

33 causes of maternal and perinatal morbidity and mortality in the United States. Chronic

34 hypertension in pregnancy is associated with a host of adverse outcomes, including

35 preeclampsia, cesarean delivery, cerebrovascular accidents, fetal growth restriction,

36 preterm birth, and maternal and perinatal mortality. There are several key issues related

37 to the diagnosis and management of chronic hypertension in pregnancy where data are

38 limited and further research is needed. These challenges and recent guidelines for the

39 management of chronic hypertension are reviewed. Well-timed pregnancies are of

40 utmost importance to reduce the risks of chronic hypertension and long-acting

41 reversible contraceptive options are preferred. Specifically, blood pressure thresholds

42 for diagnosis and treatment in order to optimize short- and long-term maternal and

43 perinatal outcomes should be prioritized along with interventions to reduce extant racial

44 and ethnic disparities.

45

46 Keywords: chronic hypertension, maternal morbidity, maternal mortality, preeclampsia

3
47 Introduction

48 In the last 3 years, the American College of Obstetricians and Gynecologists

49 (ACOG), the American College of Cardiology (ACC) and American Heart Association

50 (AHA) and the International Society for the Study of Hypertension in Pregnancy (ISSHP)

51 have published new guidelines for the management of chronic hypertension both during

52 and outside of pregnancy.1-3 Although some of these changes were driven by new

53 results from randomized controlled trials or meta-analyses, others are based on expert

54 opinion and low quality studies. The purpose of this document is to review the evidence

55 supporting the current recommendations for diagnosis and management of chronic

56 hypertension in pregnancy and highlight critical areas in need of further research.

57

58 Classification and prevalence of chronic hypertension

59 Chronic hypertension is one of the most common medical disorders encountered

60 in general practice, affecting 45.6%, or 103.3 million US adults4 and an estimated 10%

61 of reproductive-aged women.5 Chronic hypertension, defined as hypertension

62 diagnosed prior to pregnancy or before 20 weeks’ gestation (and persisting 12 weeks

63 after pregnancy), has doubled in prevalence over the last decade and now complicates

64 at least 100,000 pregnancies (2.36%) in the United States each year.6, 7 Historically,

65 the diagnostic criteria for hypertension in pregnancy were similar to those for non-

66 pregnant individuals and included a systolic blood pressure (SBP) of ≥ 140mm Hg or a

67 diastolic blood pressure (DBP) of ≥ 90mm Hg on at least 2 separate occasions more

68 than 4 hours apart for mild hypertension and a SBP ≥ 160 mm Hg or a DBP ≥ 110 mm

69 Hg for severe hypertension.1 In 2017, the ACC and the AHA changed the diagnostic

4
70 criteria for hypertension in non-pregnant adults based on evidence that cardiovascular

71 disease risk increases linearly with increasing BP even below a threshold of 140/90 mm

72 Hg.2 The ACC/AHA guideline recommended that hypertension be classified into four

73 categories (Table 1): (1) normal with SBP < 120 mm Hg and DBP < 80 mm Hg; (2)

74 elevated with SBP 120-129 mm Hg and DBP < 80 mm Hg; (3) stage 1 hypertension with

75 SBP 130-139 mm Hg or DBP 80-89 mm Hg; and (4) stage 2 hypertension with SBP >

76 140 mm Hg or DBP > 90 mm Hg. The 2017 ACC/AHA guideline specifically states that

77 a detailed discussion of the management of hypertension in pregnancy is beyond its

78 scope, and thus the pregnancy implications are not clear. Applying the new ACC/AHA

79 guideline to reproductive-aged women has been estimated to increase the number of

80 reproductive-aged women in the US diagnosed with chronic hypertension by an

81 additional 4.5 million.5, 8 At this time, ACOG and ISSHP continue to support a diagnosis

82 of chronic hypertension when the BP is confirmed to be ≥ 140/90 mm Hg. Although

83 there is evidence to support an association between stage 1 hypertension and

84 development of preeclampsia9, 10, there are no data to suggest that treatment of non-

85 severe hypertension at lower BP thresholds will improve maternal or perinatal

86 outcomes. Further research is needed to assess the risk and benefit of applying these

87 new diagnostic and therapeutic criteria for chronic hypertension to pregnant women.

88

89 Physiologic changes of pregnancy

90 In the absence of a clear diagnosis of hypertension preceding pregnancy,

91 establishing a diagnosis of chronic hypertension during pregnancy is complicated by

92 normal physiologic changes in the circulation. While maternal cardiac output gradually

5
 93 increases throughout pregnancy with a peak of approximately 1.5L/min above non-

94 pregnant values in the third trimester11, systemic vascular resistance does not follow a

95 simple linear trajectory. As early as 7 weeks of gestation, there is a 10% decrease in

96 systemic vascular resistance due in part to the effects of progesterone and the placental

97 circulation. Systemic vascular resistance decreases further as pregnancy progresses,

98 reaching a nadir of 30% decrease from baseline in the second trimester. Maternal blood

99 pressure appears to reach a nadir earlier among women with chronic hypertension who

100 develop preeclampsia, compared to those who do not develop preeclampsia (Figure

101 1).12,13,14 While systemic vascular resistance returns to pre-pregnancy levels by the third

102 trimester, the physiologic decrease in BP, especially DBP, can obscure the diagnosis of

103 chronic hypertension before 20 weeks’ gestation. When elevated BP information is

104 available only during pregnancy, particularly the second half of pregnancy, the

105 diagnosis of chronic hypertension versus gestational hypertension or preeclampsia

106 often can only be made retrospectively. Monitoring postpartum for resolution of

107 hypertension within 6-12 weeks is suggested to exclude the diagnosis of chronic

108 hypertension.1

109

110 Short-term maternal and perinatal complications of chronic hypertension

111 Chronic hypertension and associated cardiovascular disease are among the leading

112 causes of maternal and perinatal morbidity and mortality in the United States.15, 16

113 Women with chronic hypertension are at increased risk for preeclampsia and

114 gestational diabetes, likely due to shared risk factors such as obesity and shared

115 pathogenetic mechanisms such as increased insulin resistance, chronic inflammation

6
116 and endothelial dysfunction. It is important to note that obesity may be a residual

117 confounder.17-19 Women with chronic hypertension are also at increased risk for

118 cesarean delivery before the onset of labor and postpartum hemorrhage, compared to

119 women without chronic hypertension.20, 21 Furthermore, women with chronic

120 hypertension are at 5-fold or higher risk for maternal mortality, peripartum

121 cardiomyopathy, cerebrovascular accident, pulmonary edema or renal failure.22

122 Chronic hypertension is also associated with adverse perinatal outcomes. When

123 compared to normotensive controls, women with chronic hypertension are at increased

124 risk for low birthweight neonates (defined as birthweight < 2,500 grams) (risk ratio (RR)

125 2.7, 95% CI 1.9-3.8), preterm birth less than 37 weeks’ gestation (RR 2.7, 95% CI 1.9-

126 3.6), neonatal intensive care unit admission (RR 3.2, 95% CI 2.2-4.4) and perinatal

127 death (RR 4.2, 95% CI 2.7-6.5).23-25

128 Chronic hypertension in the mother has also been associated with increased risk

129 of congenital anomalies in the fetus. Cooper et al. reported that infants exposed to ACE

130 inhibitors in the first trimester have an increased risk of birth defects compared to infants

131 without exposure to antihypertensives.26 However, Bateman et al. evaluated a cohort of

132 over 1.3 million pregnancies with 4,107 exposed to ACE inhibitors (ACEI) in the first

133 trimester. When infants of mothers taking ACEI were compared with infants of mothers

134 who were not on an ACEI in the first trimester, there were no differences between

135 groups in malformations including those of the central nervous system (CNS) and

136 heart.27 New data including a systematic review raise the possibility that the in utero

137 environment of a patient with untreated chronic hypertension, aside from medication

138 exposure, may contribute to congenital malformations including esophageal atresia

7
139 (aOR 3.2, 95% CI 1.2-8.3)28 and congenital heart disease (RR 1.4; 95 % CI 1.2-1.7).29

140 Whether chronic hypertension itself or use of antihypertensives30 increases the risk of

141 congenital birth defects warrants further investigation.

142 The association between chronic hypertension and adverse perinatal outcomes

143 appears to be a continuum such that women with severe hypertension and

144 superimposed preeclampsia have progressively worse perinatal outcomes.31, 32 In

145 addition to the short-term maternal and neonatal risks discussed, chronic hypertension

146 is also associated with adverse long-term maternal and child outcomes.

147

148

149 Long-term maternal outcomes

150 Information on long-term outcomes of women with chronic hypertension is

151 limited, but we identified three retrospective cohort studies that assessed long-term

152 maternal outcomes (cardiovascular mortality and morbidity, end stage renal disease,

153 and diabetes) in women with chronic hypertension during pregnancy compared to those

154 without chronic hypertension.33-35 The studies lacked detailed patient-level information

155 regarding intended control of chronic hypertension and are complicated by varying

156 definitions of chronic hypertension such as: elevated SBP ≥ 140 mmHg or elevated

157 DBP ≥ 90 mm Hg; elevated SBP only; and physician-coded hypertension. Despite these

158 limitations, these studies showed that women with higher BP early in pregnancy are at a

159 greater risk than normotensive women for cardiovascular death (HR 1.18, 95% CI 1.05-

160 1.34).34 Those with pre-existing hypertension in pregnancy faced an even greater risk of

161 cardiovascular death with a hazard ratio of 3.5 (95% CI 2.35- 5.07).33 Future studies of

8
162 long-term outcomes of women with chronic hypertension should address two major

163 questions: 1) Does pregnancy adversely affect long-term cardiovascular morbidity and

164 mortality in chronic hypertension? 2) Does BP management during pregnancy affect

165 long-term cardiovascular morbidity and mortality?

166

167 Long-term child outcomes

168 Previous research has examined the long-term neurodevelopmental and

169 cardiometabolic outcomes in children born of pregnancies complicated by chronic

170 hypertension. Again, these studies are limited by the varying definitions of chronic

171 hypertension, insufficient information on the management of chronic hypertension

172 during pregnancy and small sample sizes. For example, the roles of preeclampsia and

173 gestational age at delivery are generally not well described in these studies. In studies

174 where chronic hypertension is well-defined, the focus appears to be whether exposure

175 to antihypertensive medication, not maternal hypertension alone, influences

176 cardiovascular and neurodevelopmental outcomes. However, analyses of the Helsinki

177 birth cohort with long-term follow up of male offspring suggest that chronic hypertension

178 during pregnancy is associated with more frequent subjective complaints of cognitive

179 failure, severe mental disorders (warranting hospital treatment or contributing to cause

180 of death), weak association with lower intellectual abilities at age 20, and greater

181 cognitive decline in old age.36-39 These studies use data from patients with chronic

182 hypertension, gestational hypertension, or preeclampsia, but the majority of

183 hypertensive patients were diagnosed with either chronic or gestational hypertension.

184 Furthermore, an Australian study suggested that motor development of offspring

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185 through the age of 14 is impacted by the presence of hypertension, and that this effect

186 is more prominent when preeclampsia is diagnosed.40

187

188 Pharmacologic treatment of chronic hypertension

189 The ACC/AHA guideline recommends that pharmacologic therapy be initiated for

190 adults with stage 1 hypertension who have or are at high risk of cardiovascular disease

191 based on an atherosclerotic cardiovascular disease (ASCVD) risk score (the estimated

192 10-year risk of myocardial infarction, cerebrovascular accident, or coronary heart

193 disease death) of 10% or higher. For those with elevated BP or stage 1 hypertension

194 whose 10-year cardiovascular risk disease risk is <10%, the new ACC/AHA guideline

195 recommends only non-pharmacologic interventions, i.e. lifestyle modifications, as the

196 first-line approach to treatment.2

197 While the new ACC/AHA guideline recommends initiation of pharmacologic

198 therapy for non-pregnant, high-risk adults with stage 1 hypertension,2 the optimal

199 treatment of mild chronic hypertension in pregnancy is uncertain. The standard

200 protocols for treatment of non-pregnant adults cannot be extrapolated to pregnant

201 women because of the potential effects on the fetus. Reduction in maternal BP has the

202 potential to reduce uteroplacental perfusion and adversely affect the developing fetus.41

203 We identified 3 randomized clinical trials and 2 systematic reviews that begin to

204 address the benefits and risks of treating mild chronic hypertension in pregnancy. In the

205 2 older and smaller randomized clinical trials, treatment of mild chronic hypertension

206 reduced the incidence of progression to severe hypertension, but did not improve

207 maternal or neonatal outcomes.42, 43 The more recent and larger Control of

10
208 Hypertension in Pregnancy Study (CHIPS) trial included women with chronic

209 hypertension (as well as gestational hypertension) and compared tight (goal DBP = 85

210 mmHg) vs. less tight (goal DBP = 100 mmHg) BP control.44 Of note, women known to

211 have severe hypertension were included if systolic blood pressure was below 160 mm

212 Hg with treatment. The incidence of adverse perinatal (primary) and maternal outcomes

213 did not differ by did not differ between groups. However, less tight BP control was

214 associated with a higher prevalence of severe hypertension as well as development of

215 thrombocytopenia and transaminitis. The risk of a small-for-gestational-age (SGA)

216 neonate < 10th percentile was not significantly lower with less tight BP control overall

217 (16.1% vs. 19.7%; aOR 0.78, 95% CI 0.56-1.08). However, it was lower in the sub-

218 group with chronic hypertension (aOR 0.66, 95% CI 0.44-1.00) mirroring concerns in

219 women with mild chronic hypertension who are treated. It is unclear how these findings

220 were influenced by whether women had mild vs. severe hypertension on entry.

221 Findings from the systematic reviews were consistent with those of the

222 randomized controlled trials. Among women with non-severe chronic or gestational

223 hypertension, antihypertensive treatment decreased the chances of progression to

224 severe hypertension. However, this was not accompanied by significant reductions in

225 key adverse pregnancy outcomes (Table 2).45, 46 In the subgroup of women with mild to

226 moderate chronic hypertension, treatment also reduced the risk of progression to

227 severe hypertension (aRR 0.57, 95% CI 0.34-0.98), without significant differences in

228 preterm birth, preeclampsia, or maternal or perinatal death. Furthermore, a reduction in

229 neonatal respiratory distress syndrome with treatment of women with chronic

230 hypertension (aRR 0.53; 95% CI 0.29- 0.99), was observed for the subgroup treated

11
231 with beta blockers, but not with other antihypertensive medications.45 The limitations of

232 these studies underscore the need for a well-designed and adequately powered

233 randomized clinical trial to delineate the benefits and risks of pharmacologic therapy

234 specifically for mild chronic hypertension during pregnancy as well as for gestational

235 hypertension in those without chronic hypertension.1, 8

236 Due to the lack of good evidence for benefit, ACOG does not recommend

237 pharmacologic treatment for pregnant women with mild chronic hypertension with BPs <

238 140/90 mm Hg. Although ACOG suggests it is reasonable for women with stage 1

239 hypertension by the ACC/AHA guideline to continue antihypertensives that were started

240 before pregnancy, initiation of antihypertensive medications is not recommended for

241 pregnant women with newly identified systolic blood pressures of 130-139 mm Hg or

242 diastolic blood pressures of 80-89 mm Hg.1 An observational study carried out in Egypt

243 reported that discontinuation of antihypertensive medications in women with mild to

244 moderate chronic hypertension was associated with an increase in maternal and

245 perinatal morbidity. However, significant differences in baseline maternal characteristics

246 such as baseline BP and gestational age at enrollment suggest bias as a potential

247 explanation for the findings, 47 Currently, ACOG recommends that antihypertensive

248 medication discontinuation should be considered in women with treated mild

249 hypertension who become pregnant, and lifestyle modifications such as healthy eating

250 and exercise should be recommended.1

251 Currently, pharmacologic treatment is recommended only for pregnant women

252 with severe hypertension ≥ 160/105-110 mm Hg, unless there is evidence of end-organ

253 damage such as left ventricular hypertrophy or renal insufficiency or severe

12
254 thrombocytopenia. In these select cases with end-organ damage, a lower BP threshold

255 of 150/100 mm Hg is recommended. It is important to note that these ACOG treatment

256 thresholds differ from the 2003 Seventh Report of the Joint National Committee on

257 Prevention, Detection, Evaluation and Treatment of High Blood Pressure (JNC7) and

258 2017 ACC/AHA recommendations for non-pregnant individuals. Most reproductive age

259 women will not meet criteria for initiation of therapy for ACC/AHA stage 1

260 hypertension.However, both JNC7 and ACC/AHA agree that BP treatment strategies

261 should be adapted specifically for pregnancy (Table 1). The ACOG guidelines also differ

262 from the recent recommendations from the National Institute for Health and Care

263 Excellence (NICE), which recommend offering treatment for systolic BP ≥140 mm Hg or

264 diastolic BP ≥90 mm Hg with target BP goals < 135/85 mm Hg48 and the International

265 Society for the Study of Hypertension in Pregnancy (ISSHP), which recommend

266 maintaining blood pressure in the range of 110-140/80-85 mm Hg.3 These guidelines

267 are based on the findings of the CHIPS trial. We believe there is insufficient evidence to

268 support routine antihypertensive therapy during pregnancy in women who have never

269 previously met criteria for severe chronic hypertension.

270 When treatment is indicated, several classes of medications, including beta-

271 blockers, vasodilators, calcium channel blockers, loop diuretics, and alpha-2 adrenergic

272 agonists can be safely used to control chronic hypertension in pregnancy (Table 3). It is

273 important to balance the efficacy of the medication against the potential risk for

274 congenital malformations and concern for growth restriction as well as side effects. As

275 summarized in Table 3, beta blockers such as labetalol and calcium channel blockers

276 such as nifedipine are considered the first line therapies in terms of safety and efficacy,

13
277 though data supporting efficacy are admittedly sparse. Additionally, the optimal dosing

278 and frequency of different antihypertensive medications in pregnant women are

279 unknown and require further study. The key principle of medical management of chronic

280 hypertension in pregnancy is to maintain ACOG BP goals on the fewest medications at

281 the lowest effective doses possible.

282

283 Racial and ethnic disparities in chronic hypertension

284 To optimize maternal and neonatal outcomes in pregnancies complicated by

285 chronic hypertension, we must appreciate the racial and ethnic disparities in the

286 prevalence and severity of chronic hypertension. It is well known that maternal race and

287 ethnicity are risk factors for chronic hypertension. The 2018 report of the CDC

288 Behavioral Risk Factor Surveillance System and the Pregnancy Risk Assessment

289 Monitoring System showed that chronic hypertension was present in 18.3% of non-

290 Hispanic black women, compared to only 9.5% of Hispanic women and 10.2% of non-

291 Hispanic white women in 2013-2015.49 Over the last decade, both the prevalence of

292 chronic hypertension and socioeconomic disparities have increased, with the burden

293 disproportionately falling on women in low-income communities and those on

294 Medicaid.7, 50, 51 Chronic hypertension also appears to modify the association between

295 maternal race and adverse pregnancy outcomes such as preterm birth and

296 preeclampsia.52 It remains unclear whether underlying genetic factors predispose

297 certain women to chronic hypertension and adverse outcomes, and if there are other

298 contributing psychosocial, demographic, or environmental factors.53 In one study, cell

299 phone text-based surveillance of home BP monitoring as compared with conventional

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300 in-person BP monitoring appeared to overcome the postpartum racial disparities in

301 hypertension, with improved compliance regardless of race.54 Additional studies should

302 evaluate interventions that overcome racial disparities in blood pressure prevalence and

303 outcomes.

304

305 Overview of management of pregnancies complicated by chronic hypertension

306 Preconception or first prenatal visit

307 In order to optimize both maternal and neonatal outcomes, all women with

308 chronic hypertension should receive preconception counseling. In addition to discussing

309 general recommendations for pregnancy, including folic acid supplementation, regular

310 exercise and nutritional intervention to achieve normal BMI and reduction in blood

311 pressure, and avoidance of alcohol and illicit drugs, women with chronic hypertension

312 also require problem-specific evaluation (Table 4). BP should be measured, and the

313 patient’s medication list should be reviewed. Women who are taking an ACEI or ARB

314 should be counseled about the potential risks, and those who wish to become pregnant

315 may consider switching to a preferred medication regimen either before or after

316 conception, depending on the indication for use of these medications (Table 3). ACOG

317 recommends avoiding use of atenolol because of a risk of SGA. However, the evidence

318 supporting this recommendation is limited. Atenolol has been associated with an

319 increased risk of SGA compared to untreated women (33.3% vs 20.9%), but not

320 compared to those treated with other antihypertensives.55,56 Thus, the question warrants

321 further study.

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322 Women who currently have elevated BP should have their medications adjusted

323 accordingly. A history and physical exam should be performed to assess for secondary

324 hypertension, target end-organ involvement, and other medical comorbidities such as

325 diabetes, obesity, and tobacco use. Laboratory tests such as serum aspartate

326 aminotransferase (AST), alanine aminotransferase (ALT), creatinine, blood urea

327 nitrogen, electrolytes, complete blood count, and urine protein/creatinine ratio may aid

328 in evaluation of secondary causes of chronic hypertension, provide baseline values for

329 future comparison, and can help assess the magnitude of pregnancy-associated risks. It

330 is unclear, however, whether it is beneficial or cost-effective to routinely obtain all of

331 these laboratory tests, especially ALT and/or AST for all women with chronic

332 hypertension. Among women at higher risk for cardiac disease (i.e. those with poorly

333 controlled hypertension for more than 4 years or suspected long-standing hypertension

334 based on maternal age > 30 years), an electrocardiogram should be considered. In an

335 unselected population of women with chronic hypertension, almost 10% of women had

336 signs of left ventricular hypertrophy on a screening electrocardiogram, associated with

337 an increased frequency of superimposed preeclampsia and lower median birthweight.57

338 Women who have an abnormal electrocardiogram or those with additional risk factors

339 should be further evaluated with echocardiography.1

340

341 Antepartum

342 After conception and confirmation of a viable pregnancy, women should establish

343 care with an obstetric provider that is comfortable managing chronic hypertension in

344 pregnancy. Women should be counseled about the benefits of low-dose aspirin to

16
345 reduce the risk of preeclampsia and fetal growth restriction.58-60 In a subgroup analysis

346 of women with chronic hypertension, there was suggestion that the beneficial effects of

347 aspirin only apply to term and not preterm pregnancy. However, power was limited to

348 detect a difference, with only 110 women having chronic hypertension.61 Although the

349 optimal gestational age to initiate aspirin is not clear,62, 63150 mg of aspirin (not readily

350 available in the United States) has been suggested to provide a greater reduction in

351 preeclampsia and fetal growth restriction, compared to lower doses (50-100 mg) of

352 aspirin.62 This requires further evaluation.

353 BPs should be monitored at least monthly and more often for women with

354 uncontrolled BP requiring medication adjustment. Some studies have suggested that

355 ambulatory and home BP monitoring may be a useful adjunct to in-person visits.64, 65

356 However, further studies are needed to specifically evaluate the effect of out of office

357 BP monitoring on maternal and neonatal outcomes in women with chronic hypertension.

358 Ultrasound should be utilized in the third trimester of pregnancy to assess fetal growth

359 given the increased risk among pregnancies complicated by chronic hypertension.

360 Additionally, antenatal fetal testing should be considered for women with chronic

361 hypertension that requires antihypertensive medications or is complicated by other

362 maternal or fetal conditions such as preeclampsia or fetal growth restriction. However,

363 data regarding the use of antenatal fetal testing in mild chronic hypertension are limited.

364 Delivery should be timed based on the severity of disease, taking into account

365 the degree of blood pressure control, need for medications, and other maternal and fetal

366 comorbidities. In the absence of any other maternal or fetal complications, ACOG

367 recommends avoiding delivery before 38 0/7 weeks’ gestation for women not on any

17
368 antihypertensive medications and avoiding delivery before 37 0/7 weeks’ gestation for

369 women well-controlled on antihypertensive medications.5 Expectant management up to

370 39 weeks’ gestation may also be considered with close maternal and fetal surveillance

371 as indicated. Earlier delivery should only be considered for women with severe disease

372 (i.e. those who have difficult to control BP) in order to reduce the risk of development of

373 superimposed preeclampsia with severe features and associated adverse maternal and

374 neonatal outcomes. The evidence base for these recommendations is limited primarily

375 to cohort studies with mixed results. This topic should be the focus of future research.64,
66-68
376

377

378 Postpartum

379 Following delivery, women with uncontrolled chronic hypertension remain at

380 increased risk for BP elevations and superimposed preeclampsia, which are among the

381 most common reasons for emergency room visits and hospital readmissions in the

382 postpartum period.69, 70 In order to mitigate the need for evaluation at a higher level of

383 care, ACOG recommends that these women should have routine BP evaluation in the

384 outpatient setting at 7-10 days postpartum, and antihypertensive medications should be

385 utilized to maintain SBP < 150 mmHg and DBP < 100 mmHg or to achieve BP

386 thresholds for the non-pregnant population.1, 2 More data are needed to support the

387 utility of this evaluation. Women should be encouraged to breastfeed as most

388 antihypertensive medications are detectable in breastmilk only at very low

389 concentrations and are not associated with neonatal effects. Labetalol and propranolol

390 are typically preferred over atenolol and metoprolol since the latter two are more

18
391 concentrated in breast milk. However, atenolol is not typically present in sufficient

392 concentrations to lower neonatal heart rate. 71

393 Appropriate timing of subsequent pregnancies and contraceptive options to

394 prevent unplanned pregnancies should be discussed. The Centers for Disease

395 Prevention and Control (CDC) Medical Eligibility Criteria (MEC) concluded that the risks

396 of estrogen-containing contraceptives in women with well controlled chronic

397 hypertension and chronic hypertension with BP ≥ 140/90 mm Hg usually outweigh the

398 advantages (Table 5).72 Among women with Stage 2 hypertension, the risks of

399 estrogen-containing contraceptives usually outweigh the advantages. Risks are

400 unacceptable in women with severe hypertension, established vascular disease or a

401 heavy burden of risk factors for cardiovascular disease. Progesterone implants,

402 intrauterine devices, and progestin-only pills should be considered as preferred options

403 and discussed with the patient in a shared-decision making model. Depot

404 medroxyprogesterone caproate can also be considered for women with well-controlled

405 mild chronic hypertension, but should be avoided in women with severe hypertension or

406 cardiac disease.72

407

408 Conclusions

409 Chronic hypertension is one of the most common major medical disorders

410 encountered during pregnancy with a broad range of associated adverse outcomes, and

411 yet the optimal management for both mother and baby and other questions remain

412 unanswered. Table 6 provides a listing of potential research priorities. Based on the

413 limitations of the published studies, the Society for Maternal-Fetal Medicine (SMFM)

19
414 issued a summary statement on the treatment of mild hypertension during pregnancy.8

415 At present, SMFM and ACOG recommend initiation of antihypertensive therapy for

416 women with known severe hypertension (BP ≥ 160/110 mm Hg) since the immediate

417 benefits and risks of pharmacologic treatment for these women and their fetuses are

418 well defined. The benefits and safety of treatment of women known to have mild chronic

419 hypertension remain uncertain, and thus, SMFM and ACOG suggest that these women

420 not be treated with antihypertensive medications. A multicenter National Institutes of

421 Health (National Heart, Lung, and Blood Institute)-funded randomized controlled trial

422 (clinicaltrials.gov NCT02299414; authors are part of this trial) will determine if

423 antihypertensive therapy for women with mild chronic hypertension to achieve BP

424 targets recommended for non-pregnant women (<140/90 mm Hg) is effective and safe,

425 compared to current recommendations for antihypertensive therapy in pregnancy only if

426 BP becomes severe.

20
427 References:

428 1. ACOG Practice Bulletin No. 203: Chronic Hypertension in Pregnancy. Obstetrics and gynecology
429 2019;133:e26-e50.
430 2. WHELTON PK, CAREY RM, ARONOW WS, et al. 2017
431 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA Guideline for the Prevention,
432 Detection, Evaluation, and Management of High Blood Pressure in Adults: Executive Summary: A
433 Report of the American College of Cardiology/American Heart Association Task Force on Clinical
434 Practice Guidelines. Hypertension (Dallas, Tex : 1979) 2018;71:1269-324.
435 3. BROWN MA, MAGEE LA, KENNY LC, et al. The hypertensive disorders of pregnancy: ISSHP
436 classification, diagnosis & management recommendations for international practice. Pregnancy
437 hypertension 2018;13:291-310.
438 4. MUNTNER P, CAREY RM, GIDDING S, et al. Potential US Population Impact of the 2017 ACC/AHA High
439 Blood Pressure Guideline. Circulation 2018;137:109-18.
440 5. TOPEL ML, DUNCAN EM, KRISHNA I, BADELL ML, VACCARINO V, QUYYUMI AA. Estimated Impact of the
441 2017 American College of Cardiology/American Heart Association Blood Pressure Guidelines on
442 Reproductive-Aged Women. Hypertension (Dallas, Tex : 1979) 2018;72:e39-e42.
443 6. BATEMAN BT, BANSIL P, HERNANDEZ-DIAZ S, MHYRE JM, CALLAGHAN WM, KUKLINA EV. Prevalence,
444 trends, and outcomes of chronic hypertension: a nationwide sample of delivery admissions.
445 American journal of obstetrics and gynecology 2012;206:134.e1-8.
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615 67. SPONG CY, MERCER BM, D'ALTON M, KILPATRICK S, BLACKWELL S, SAADE G. Timing of indicated late-
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628 2016. MMWR Recommendations and reports : Morbidity and mortality weekly report
629 Recommendations and reports 2016;65:1-103.
630

631

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632 TABLES

633 Table 1. Hypertension Nomenclature and Pharmacologic Treatment Guidelines

634 Stratified by 2019 ACOG, 2017 ACC/AHA and 2003 JNC7 Guidelines
<120/80 120-129/<80 130-139/80-89 ≥140/90 ≥160/110
ACOG <20 weeks GA <20 weeks GA
Normal
= mild CHTN = severe CHTN
JNC7 Normal Pre-HTN Pre-HTN* Stage 1 HTN Stage 2 HTN
ACC/AHA Normal Elevated BP Stage 1 HTN Stage 2 HTN
Adapted from Sinkey et al
Pharmacologic treatment recommended for the bolded and outlined categories above
*Pharmacologic treatment only recommended if comorbid diabetes or renal disease
Abbreviations: ACC / AHA = 2017 American College of Cardiology / American Heart Association
Hypertension Guideline; ACOG = 2019 American College of Obstetricians and Gynecologists Practice
Bulletin; BP = Blood Pressure; GA = Gestational Age; CHTN = Chronic Hypertension; GHTN =
Gestational Hypertension; HTN = Hypertension; JNC7 = 2003 Seventh Report of the Joint National
Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure; Pre-HTN =
Prehypertension
635

636

637

26
638 Table 2. 2018 Cochrane Review of any antihypertensive drug compared to no
639 antihypertensive drugs or placebo for mild to moderate hypertension during pregnancy
Outcomes Relative effect Number of GRADE of
(95% CI) participants (and evidence
studies)
Maternal
Severe hypertension RR 0.49 (0.40-0.60) 2558 (20 RCTs) Moderate
Proteinuria/preeclampsia RR 0.92 (0.75-1.14) 2851 (23 RCTs) Low
Fetal/neonatal/infant
Total reported fetal or RR 0.72 (0.50-1.04) 3365 (29 RCTs) Moderate
neonatal deaths (including
miscarriage)
Small-for-gestational-age RR 0.96 (0.78-1.18) 2686 (21 RCTs) Moderate
Preterm birth < 37 weeks RR 0.96 (0.83-1.12) 2141 (15 RCTs) Moderate
640 Adapted from 2018 Cochrane review

27
641 Table 3: Antihypertensive medications in pregnancy
Medication Dosing Comments
First-line
Labetalol 200-2400 mg/day by Avoid with moderate to severe
mouth in divided doses asthma, cardiomyopathy.
every 8-12 hours Rebound hypertension with
abrupt withdrawal.
Nifedipine extended- 30-120 mg/day by mouth May cause tachycardia
release
Second- or third-line
Methyldopa 250-3000 mg/day by May be less effective in
mouth in divided doses reducing blood pressure and
every 6-12 hours causes sedation
Hydrochlorothiazide 12.5-50 mg/day by mouth May cause dehydration
Not recommended
Angiotensin-converting -- Associated with congenital
enzyme inhibitors and malformations, impaired renal
angiotensin receptor function and oligohydramnios
blockers
Atenolol -- Increased risk of fetal growth
restriction
642 Recommendations based on ACOG guideline for chronic hypertension in pregnancy5
643

28
644 Table 4. Checklist for pregnancy management among women with chronic hypertension
Preconception or First Prenatal Visit
Baseline labs*: AST/ALT, BUN/Cr, Electrolytes, Complete blood count, UPC (+/-
24hr urine protein)
Baseline testing*: EKG (+/- Echocardiogram)
Review medication list and adjust as necessary to achieve target blood pressure
Optimize other medical comorbidities (i.e. diabetes, obesity, tobacco use)
Antepartum
Initiate low-dose aspirin 81mg daily after 12 weeks to reduce the risk of
preeclampsia
Monthly BP evaluation (or more if uncontrolled)
Third trimester ultrasound to assess fetal growth
Consider antenatal fetal testing for women with complicated chronic hypertension
(i.e. requiring medications or in the presence of other maternal or fetal
complications)
Deliver at:
38 0/7-39 6/7 weeks if BP well-controlled without medications
37 0/7-39 0/7 weeks if require medications or BP poorly controlled
Postpartum
BP evaluation 7-10 days postpartum if preeclampsia or uncontrolled
Encourage breastfeeding
Initiate contraception after discussion of risks and benefits in setting of chronic
hypertension
645 Abbreviations: AST, aspartate transferase; ALT, alanine transferase; BUN, blood urea
646 nitrogen; UPC, urine protein to creatinine ratio; EKG, electrocardiogram; BP, blood
647 pressure
648 *As appropriate based on past medical history and any other comorbid conditions
649

650

29
651 Table 5. Summary of U.S. Medical Eligibility Criteria for Contraceptive Use Among
652 Women with Chronic Hypertension
Condition CHC POP Injection Implant LNG-IUD Cu-IUD
Adequately controlled hypertension 3 1 2 1 1 1
Systolic BP 140-159 or diastolic BP 90-99 3 1 2 1 1 1
Systolic BP ≥ 160 or diastolic BP ≥ 100 4 2 3 2 2 1
Vascular disease 4 2 3 2 2 1
Multiple risk factors for arterial 3-4 2 3 2 2 1
cardiovascular disease (such as
hypertension, diabetes, older age, smoking)
653 Abbreviations: CHC=combined hormonal contraceptive (pill, patch, and ring); Cu-IUD=copper-containing
654 intrauterine device; LNG-IUD=levonorgestrel-releasing intrauterine device; POP=progestin-only pill
655 Legend: 1=No restriction; 2=Advantages generally outweigh theoretical or proven risks; 3=Theoretical or
656 proven risks usually outweigh the advantages; 4=Unacceptable health risk
657

30
658 Table 6. Areas of critically needed research on chronic hypertension in pregnancy
Impact of new ACC/AHA diagnosis of Elevated and Stage 1 HTN on pregnancy
pregnancy outcomes
Most effective dose of aspirin for preeclampsia prevention
Ambulatory and home blood pressure monitoring in pregnancy and pregnancy
outcomes
Adverse fetal effects of antihypertensive medications in pregnancy
Optimal dosing frequency of antihypertensive medications in pregnancy
Antihypertensive therapy and pregnancy outcomes of women with known mild chronic
hypertension
Ideal timing of delivery based on disease severity
Interventions to reduce disparities in diagnosis and outcomes of chronic hypertension
659
660

31
661 FIGURE LEGENDS
662

663 Figure 1. Blood pressure patterns in pregnancy.

664 Footnote: Figure adapted from Harper et al 201712. Error bars represent standarderror
665 around the predicted means.
666

32