JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY VOL. 77, NO.

10, 2021

ª 2021 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION

PUBLISHED BY ELSEVIER

Hypertensive Disorders of Pregnancy and

Subsequent Risk of Premature Mortality
Yi-Xin Wang, MD, PHD,a Mariel Arvizu, MD, SCD,a Janet W. Rich-Edwards, SCD,b,c Liang Wang, DRPH,a,d
Bernard Rosner, PHD,e,f Jennifer J. Stuart, SCD,b,c Kathryn M. Rexrode, MD,c Jorge E. Chavarro, MD, SCDa,b,f

ABSTRACT

BACKGROUND Hypertensive disorders of pregnancy (HDPs) are leading causes of maternal and perinatal morbidity
and mortality. However, it is uncertain whether HDPs are associated with long-term risk of premature mortality (before
age 70 years).

OBJECTIVES The objective of this study was to evaluate whether HDPs were associated with premature mortality.

METHODS Between 1989 and 2017, the authors followed 88,395 parous female nurses participating in the Nurses’
Health Study II. The study focused on gestational hypertension and pre-eclampsia within the term HDPs. Hazard ratios
(HRs) and 95% confidence intervals (CIs) for the associations between HDPs and premature mortality were estimated by
using Cox proportional hazards models, with adjustment for relevant confounders.

RESULTS The authors documented that 2,387 women died before age 70 years, including 1,141 cancer deaths and 212
CVD deaths. The occurrence of HDPs, either gestational hypertension or pre-eclampsia, was associated with an HR of 1.31
(95% CI: 1.18 to 1.46) for premature death during follow-up. When specific causes of death were examined, these
relations were strongest for CVD-related mortality (HR: 2.26; 95% CI: 1.67 to 3.07). The association between HDPs and
all-cause premature death persisted, regardless of the subsequent development of chronic hypertension (HR: 1.20
[95% CI: 1.02 to 1.40] for HDPs only and HR: 2.02 [95% CI: 1.75 to 2.33] for both HDPs and subsequent chronic
hypertension).

CONCLUSIONS An occurrence of HDPs, either gestational hypertension or pre-eclampsia, was associated with an
increased risk of premature mortality, particularly CVD mortality, even in the absence of chronic hypertension.
(J Am Coll Cardiol 2021;77:1302–12) © 2021 by the American College of Cardiology Foundation.

T he dramatic worldwide increase in the

standard of living, coupled with medical
and public health advances during the last
half of the 20th century, has resulted in a steady
reduction in age-specific mortality at a global scale
(1). However, premature mortality (death before age
70 years) from noncommunicable diseases (NCDs),
also known as chronic diseases, remains a major pub-
lic health challenge. According to the World Health
Organization, although the age-standardized rates of
NCD causes of death have decreased, the absolute
number of deaths due to NCDs in people ages 30 to
69 years increased from 12.5 million in 2000 to 15.2
million in 2016 (2,3).
Hypertensive disorders of pregnancy (HDPs),
which occur in approximately 10% of all pregnancies
worldwide, are the most common medical problem
encountered in pregnancy (4). There are 4 types of

Listen to this manuscript’s
audio summary by
Editor-in-Chief
Dr. Valentin Fuster on
JACC.org.
From the aDepartment of Nutrition, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA; bDepartment of
Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA; cDivision of Women’s Health, Department
of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA; dDepartment of Public Health,
Robbins College of Health and Human Sciences, Baylor University, Waco, Texas, USA; eDepartment of Biostatistics, Harvard T.H.
Chan School of Public Health, Boston, Massachusetts, USA; and the fChanning Division of Network Medicine, Department of
Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA.
The authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’
institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information,
visit the Author Center.

Manuscript received September 2, 2020; revised manuscript received December 21, 2020, accepted January 5, 2021.

ISSN 0735-1097/$36.00 https://doi.org/10.1016/j.jacc.2021.01.018

JACC VOL. 77, NO. 10, 2021
MARCH 16, 2021:1302–12
HDPs: chronic hypertension (i.e., hypertension pre-
dating pregnancy or diagnosed before 20 weeks of
pregnancy), gestational hypertension (GHTN), pre-
eclampsia, and chronic hypertension with super-
imposed pre-eclampsia (5). GHTN and pre-eclampsia,
which occur at or after 20 weeks’ gestation, are lead-
ing causes of maternal and perinatal morbidity and
mortality (6). Several retrospective cohorts and dis-
ease registry studies have documented an association
of GHTN and pre-eclampsia with the risk of all-cause
and cardiovascular disease (CVD) mortality (7–14).
Nevertheless, the relationship between HDPs with all-
cause and cause-specific mortality has not been
evaluated in a prospective cohort with careful control
for common confounding factors and updated life-
style characteristics. Moreover, although women with
a history of HDPs had 3 to 5 times higher risk of
developing chronic hypertension (15), it is unclear
whether the association between HDPs and prema-
ture mortality is fully explained by the subsequent
development of chronic hypertension and whether
this association exists among women who do not
develop chronic hypertension. Recurrent pre-
eclampsia and complicated pre-eclampsia (e.g., with
preterm birth and low birthweight) have been asso-
ciated with greater CVD risk (16); some studies also
suggest particularly increased CVD mortality among
women whose last pregnancy was complicated by
hypertension (7). However, it is unclear whether
these associations pertain to premature mortality. To
address these important questions, we focused on
GHTN and pre-eclampsia within the term HDPs and
examined the associations between HDPs and all-
cause and cause-specific premature mortality among
parous women participating in a large ongoing cohort
study, the NHS-II (Nurses’ Health Study II), which has
prospectively collected information on reproductive
characteristics and repeatedly ascertained numerous
lifestyle and health-related characteristics over 3
decades.
SEE PAGE 1313
METHODS
STUDY POPULATION. We included parous women
from the ongoing NHS-II cohort, which was estab-
lished in 1989 by recruiting 116,429 U.S. female
registered nurses ages 25 to 42 years. Biennial ques-
tionnaires are used to collect information on partici-
pants’ lifestyles and health. Participants were eligible
for inclusion in this analysis if they reported a preg-
nancy ($6 months) at or after age 18 years on the
baseline questionnaire or became pregnant for the
first time during follow-up through 2009, when most
Wang et al. 1303
Hypertensive Disorders of Pregnancy and Mortality
participants had completed their reproduc- ABBREVIATIONS
tive careers. We further excluded women AND ACRONYMS
who had missing data on date of birth (n ¼ 17)
AHEI = Alternative Healthy
and chronic hypertension diagnosis (n ¼ Eating Index
1,875); received a diagnosis of cancer, type 2
BMI = body mass index
diabetes, or CVD before baseline (1989) or
CVD = cardiovascular disease
before their first pregnancy (n ¼ 1,633); or
GHTN = gestational
never returned follow-up questionnaires hypertension
(n ¼ 1,324). After exclusions, 88,395 women
HDP = hypertensive disorders
were retained in our current analyses. of pregnancy
ICD = International
ETHICS. The study protocol was approved by
Classification of Diseases
the Institutional Review Boards of the Brig-
MI = myocardial infarction
ham and Women’s Hospital and Harvard T.H.
NCD = noncommunicable
Chan School of Public Health and those of
disease
participating registries as required (protocol
number: 2009-P-002375).
ASCERTAINMENT OF HDPs. Self-reports of physician
diagnosis of pre-eclampsia (“pregnancy-related high
blood pressure” [i.e., gestational hypertension] or
“pre-eclampsia/toxemia”) were ascertained on the
baseline questionnaire in 1989 and updated every 2
years through 2001. GHTN was ascertained on the
1993 questionnaire and then updated every 2 years
through 2001. Reports of GHTN and pre-eclampsia
from 2002 to 2009 were ascertained in the 2009
questionnaire, where participants retrospectively re-
ported information on all previous pregnancies,
including the sequence and year of birth, as well as
pregnancy complications such as HDPs, pre-term
birth, and low birthweight. Self-reports of pre-
eclampsia have been validated against medical re-
cords in a subgroup of 598 NHS-II participants who
received a diagnosis of pre-eclampsia or had evidence
of GHTN and proteinuria (protein excretion
of $300 min/24 h urine; protein-creatinine ratio
of $0.3, or dipstick reading of $1þ) (17). The positive
predictive value of self-reported pre-eclampsia was
89% when compared against medical records with
sufficient information to establish a diagnosis (18).
ASCERTAINMENT OF CHRONIC HYPERTENSION. The
1989 questionnaire retrospectively captured infor-
mation of any physician-diagnosed chronic hyperten-
sion (i.e., high blood pressure outside of pregnancy)
and the year of diagnosis, which was then updated
every 2 years. Women were not considered exposed to
GHTN or pre-eclampsia if chronic hypertension was
reported before pregnancy. Participants were consid-
ered exposed from the age reporting a diagnosis of
chronic hypertension. Self-reports of chronic hyper-
tension have been validated against medical records in
a subgroup of NHS-II participants, with a sensitivity
and specificity of 94% and 85%, respectively (19).
Antihypertensive medication use (e.g., thiazide
1304 Wang et al.
Hypertensive Disorders of Pregnancy and Mortality
diuretics, beta-blockers, and angiotensin-converting
enzyme inhibitors) was ascertained at baseline and
updated every 2 years.
OUTCOME ASCERTAINMENT. Deaths were identified
through the National Death Index, through state vital
statistics records, or by reports from the postal au-
thorities or close relatives. The validity of this
method was evaluated in a subgroup of participants
from the NHS (Nurses’ Health Study). Among 179
participants known to be dead and 1,997 known to be
alive, 98.0% and 100% of the true dead and living
participants were correctly identified, respectively
(20). The outcome of interest was premature mortal-
ity, defined as death before age 70 years (21). The
cause of death was ascertained by physician review of
medical records, autopsy reports, or death certifi-
cates. The International Classification of Diseases
(ICD)-Eighth Revision was applied to distinguish
deaths from CVD (ICD codes: 390 to 458), cancers (ICD
codes: 140 to 207), and any other reasons
(Supplemental Table 1).
ASSESSMENT OF COVARIATES. Participants re-
ported their race/ethnicity, height, current weight,
and weight at age 18 years in the 1989 questionnaire.
Body weight was self-reported every 2 years. We
calculated body mass index (BMI) at age 18 years and
during each follow-up cycle. Lifestyle characteristics
and health-related conditions such as smoking status;
medication use; menopausal status; and parental
histories of diabetes, myocardial infarction (MI), or
stroke were updated every 2 years. Physical activity
and alcohol consumption were ascertained at base-
line and updated every 4 to 6 years. Dietary intake
was assessed every 4 years by using a validated
semiquantitative food frequency questionnaire (22).
We calculated the Alternate Healthy Eating Index
(AHEI) 2010 to evaluate the overall dietary quality of
each participant (23).
DATA ANALYSIS. Participants’ follow-up time was
calculated from the return date of baseline or follow-
up questionnaires when the woman reported a preg-
nancy lasting at least 6 months until the date of death
or the end of follow-up (June 30, 2017), whichever
occurred first. Five women who died at or after age 70
years were treated as censored observations. Expo-
sure status (the occurrence of HDPs) was updated
every 2 years through 2009; participants were
considered exposed from the age at first report of a
pregnancy complicated by an HDP, regardless of
occurrence in subsequent pregnancies. Thus, a
woman with normotensive pregnancies who subse-
quently developed an HDP would contribute to both
unexposed (initially, following the unaffected
JACC VOL. 77, NO. 10, 2021
MARCH 16, 2021:1302–12
pregnancies) and exposed (after her first report of an
affected pregnancy) person-time over follow-up.
We fitted Cox proportional hazards models to es-
timate the hazard ratios (HRs) and 95% confidence
intervals (CIs) for the associations between the
occurrence of GHTN and/or pre-eclampsia with all-
cause and cause-specific premature mortality while
simultaneously adjusting for confounders and risk
factors (see the Supplemental Appendix). To control
as finely as possible for confounding by age, calendar
time, and any possible interactions between these 2
timescales, we stratified the analysis jointly by age in
months at the start of follow-up and calendar year for
the current questionnaire cycle. The timescale for the
analysis was months since the start of the current
questionnaire cycle, which is equivalent to age in
months. Multivariable models were adjusted for race/
ethnicity and pre-pregnancy BMI, as well as time-
varying menopausal status, current hormone ther-
apy use, daily aspirin use, and parental history of MI
or stroke. In the second set of multivariable models,
we further adjusted for time-varying breastfeeding
duration, parity, alcohol consumption, smoking sta-
tus, total physical activity, BMI, and AHEI-2010 diet
score. The Anderson-Gill data structure was used to
efficiently handle time-varying covariates (24): a new
data record is created for every questionnaire cycle at
which a participant is at risk, with covariates set to
the values at the time the questionnaire is returned.
For the covariates with missing values at a given time
point (<5% for any covariates), data from the prior
questionnaire was carried forward; otherwise,
missing indicator variables were used in the analysis.
We also assessed the risk of premature mortality by
jointly classifying GHTN and pre-eclampsia.
To explore whether the association between
HDPs and premature mortality was fully explained
by the subsequent development of chronic hyper-
tension and whether this association exists among
women who did not develop chronic hypertension,
we categorized exposure by taking into account the
subsequent development of chronic hypertension
and classified women as no HDPs or chronic hy-
pertension, HDPs only without subsequent chronic
hypertension, chronic hypertension only, or both
HDPs and subsequent chronic hypertension. We
updated the exposure status prospectively during
follow-up; participants without an occurrence of
either HDPs or chronic hypertension served as the
reference group. We also tested for effect modifi-
cation by performing analyses stratified by age at
first birth (#25 vs. >25 years), breastfeeding dura-
tion (#3 vs. >3 months), parity (1 vs. $2), parental
history of CVD (yes vs. no), pre-pregnancy BMI
JACC VOL. 77, NO. 10, 2021 Wang et al. 1305
MARCH 16, 2021:1302–12 Hypertensive Disorders of Pregnancy and Mortality

T A B L E 1 Age-Standardized Baseline (1989) Characteristics According to the Occurrence of HDPs Either at Baseline or During Follow-Up
Among 88,395 Parous Women (Nurses’ Health Study II, 1989–2017)*

With an Occurrence of HDPs

HDPs (Either GHTN or

No HDPs Pre-Eclampsia) GHTN Pre-Eclampsia
(n ¼ 75,990) (n ¼ 12,405)† (n ¼ 7,253) (n ¼ 10,742)

Age at first birth, yrs‡ 26.7  4.6 26.2  4.4 26.5  4.3 26.1  4.4
Parity (pregnancies $6 months) 1.8  1.1 1.9  1.0 1.9  1.0 1.9  1.0
Parous 87 92 93 92
History of gestational diabetes 3 7 8 7
Breastfeeding duration, months
<3.0 27 30 28 30
3.0–12.0 31 32 33 32
>12.0 42 38 39 38
Pre-pregnancy BMI, kg/m2 20.9  2.9 21.8  3.4 21.9  3.5 21.7  3.4
Baseline age, yrs‡ 34.9  4.7 34.6  4.6 34.4  4.5 34.6  4.6
Baseline BMI, kg/m2 23.7  4.4 26.0  5.6 26.4  5.8 26.0  5.6
White 92 92 93 92
Total physical activity, h/week 3.3  4.9 3.1  4.8 3.0  4.5 3.1  4.8
AHEI-2010 dietary score 47.4  10.6 47.0  10.5 46.9  10.5 47.0  10.4
Alcohol intake, g/day 2.9  5.6 2.5  5.4 2.5  5.4 2.5  5.4
Current regular aspirin use§ 10 12 11 12
Parental history of diabetes 16 20 20 20
Parental history of MI or stroke 14 18 18 18
Smoking status
Never 66 65 68 64
Past 21 22 21 22
Current 13 13 11 13

Values are mean  SD or %. *Mean  SD and percentage values were standardized to the age distribution of the study population in 1989. †Participants could experience both
GHTN and pre-eclampsia across their reproductive lifespan. ‡Value is not age adjusted. §Aspirin or aspirin-containing products used regularly at least once per week in the past
2 years.
AHEI ¼ Alternative Healthy Eating Index; BMI ¼ body mass index; GHTN ¼ gestational hypertension; HDP ¼ hypertensive disorder of pregnancy; MI ¼ myocardial infarction.

($25 vs. <25 kg/m 2), current BMI ($30, 25 to 29.9,
or <25 kg/m 2), subsequent development of type 2
diabetes (yes vs. no), antihypertensive medicine
use (yes vs. no), AHEI-2010 dietary score (in the
upper two-fifths vs. bottom three-fifths), smoking
status (never/past vs. current), and physical activity
at moderate to vigorous intensity
$150 min/week). Interaction on the multiplicative
scale was assessed by using likelihood ratio tests
comparing models with and without a multiplica-
tive interaction term between HDPs and the po-
tential effect modifier. Finally, we explored the
influence of changes in HDP status in the first and
subsequent pregnancies, the number of pregnancies
affected by HDPs, and coexposure to pre-term birth
and low birth weight. We restricted the analysis to
participants who responded to the 2009 question-
naire because that questionnaire captured total
reproductive history without risk
counting any pregnancies reported on biennial
questionnaires. Participants’ follow-up times were
calculated from the return date
questionnaire.
Three sensitivity analyses were conducted. First,
we reanalyzed the association between HDPs and
premature mortality by excluding deaths due to
complications of pregnancy, childbirth, and the pu-
erperium. Second, women were considered exposed
to HDPs even if previous chronic hypertension was
(<150 vs. reported. Third, we excluded multiple pregnancies
(e.g., twins, triplets) from the analysis. All data were
analyzed with SAS 9.3 for Unix (SAS Institute Inc.,
Cary, North Carolina).
RESULTS
PARTICIPANTS’ AGE-STANDARDIZED CHARACTERISTICS.
We followed 88,395 parous women during 28 years of
follow-up. They had a mean age at first birth of 26.7 
4.7 years and a mean pre-pregnancy BMI of 21.0 
3.0 kg/m 2. In total, 12,405 women (14.0%) experi-
of double- enced HDPs in at least 1 of their pregnancies. Partic-
ipants’ age-standardized characteristics at the
analytic baseline according to HDPs either reported at
of the 2009 baseline or during follow-up are shown in Table 1.
Compared with women without HDPs, women who
1306 Wang et al. JACC VOL. 77, NO. 10, 2021

Hypertensive Disorders of Pregnancy and Mortality MARCH 16, 2021:1302–12

C E NT R AL IL L U STR AT IO N Hazard Ratios for the Risk of All-Cause Premature Mortality According to the
Occurrence of Hypertensive Disorders of Pregnancy

The Occurrence Crude Incidence

Age-Adjusted Model Multivariable Model 1 Multivariable Model 2
of HDPs Deaths Per 1,000 PY

No HDPs 1,957 0.96 1.00 (ref) 1.00 (ref) 1.00 (ref)

Either GHTN or
430 1.34 1.42 (1.28-1.58) 1.32 (1.19-1.47) 1.31 (1.18-1.46)
pre-eclampsia
GHTN only 235 1.48 1.40 (1.22-1.60) 1.35 (1.18-1.55) 1.35 (1.17-1.55)
Pre-eclampsia
384 1.35 1.45 (1.30-1.62) 1.34 (1.20-1.49) 1.32 (1.18-1.48)
only

0.5 1.0 1.5 2.0 0.5 1.0 1.5 2.0 0.5 1.0 1.5 2.0
HR (95% CI) HR (95% CI) HR (95% CI)

Wang, Y.-X. et al. J Am Coll Cardiol. 2021;77(10):1302–12.

In the age-adjusted model, age in months at the start of follow-up and calendar year of the current questionnaire cycle were included as stratified variables.
Multivariable model 1 was further adjusted for White race/ethnicity; pre-pregnancy body mass index; and time-varying menopausal status, current hormone therapy
use, daily aspirin use, and parental history of myocardial infarction or stroke. Multivariable model 2 was further adjusted for time-varying breastfeeding duration, parity,
alcohol intake, smoking status, physical activity, Alternative Healthy Eating Index 2010 dietary score, and current body mass index. The associations of gestational
hypertension and pre-eclampsia with premature mortality were assessed separately and always against normotensive pregnancies. CI ¼ confidence interval; GHTN ¼
gestational hypertension; HDP ¼ hypertensive disorder of pregnancy; HR ¼ hazard ratio; PY ¼ person-years; ref ¼ reference.

experienced GHTN and/or pre-eclampsia had a
greater baseline BMI and higher baseline prevalence
of gestational diabetes and parental history of
diabetes and MI/stroke. Women who
GHTN and/or pre-eclampsia at baseline also had a
higher baseline prevalence of chronic hypertension
than women without HDPs (10%
(Supplemental Table 2).
HPDs AND MORTALITY. During 2,355,049 person-
years of follow-up, we documented 2,387 prema-
ture deaths during follow-up, including 1,141 cancer
deaths and 212 CVD deaths (Supplemental Table 1).
Age-adjusted Cox proportional models showed that
the occurrence of GHTN or pre-eclampsia was asso-
ciated with an HR of 1.42 (95% CI: 1.28 to 1.58) for
premature death during follow-up
Illustration). These associations were slightly atten-
uated but remained statistically significant after
additional adjustment for potential confounding
factors (HR: 1.32; 95% CI: 1.19 to 1.47), as well as
time-varying (post-pregnancy) dietary, lifestyle, and
reproductive characteristics (HR: 1.31; 95% CI: 1.18 to
1.46) (Central Illustration). There was no evidence of
effect modification by age at first birth, breastfeed-
ing duration, parity, parental history of CVD, anti-
hypertension treatment, subsequent development
of type 2 diabetes, pre-pregnancy/current BMI,
physical activity, diet quality, and smoking status
(Supplemental Table 3).
Analyses of cause-specific mortality showed that
the occurrence of HDPs was related to a higher risk of
premature CVD mortality (HR: 2.26; 95% CI: 1.67 to
reported 3.07) but was unrelated to premature cancer mortality
(HR: 0.97; 95% CI: 0.82 to 1.150) (Figure 1). In analyses
for less common causes of death (Supplemental
vs. 3%) Table 4), HDPs were associated with a greater risk of
deaths due to infectious diseases (HR: 2.77; 95% CI:
1.38 to 5.54); respiratory diseases (HR: 2.26; 95% CI:
1.29 to 3.98); nervous system diseases (HR: 2.51;
95% CI: 1.33 to 4.72); metabolic/immunity disorders
(HR: 4.85; 95% CI: 2.29 to 10.27); and symptoms,
signs, or ill-defined conditions (HR: 1.72; 95% CI: 1.13
to 2.60). The risk of all-cause and cause-specific
mortality was similar when GHTN and pre-eclampsia
were examined separately (Central Illustration,
(Central Figure 1). Moreover, when GHTN and pre-eclampsia
were jointly classified, a similar risk of all-cause
mortality was observed for GHTN only, pre-
eclampsia only, or both (Supplemental Table 5).
When we categorized exposure by taking into ac-
count the subsequent development of chronic hy-
pertension, in the fully adjusted models, we found an
elevated risk of all-cause premature mortality in
relation to the occurrence of HDPs only (HR: 1.20;
95% CI: 1.02 to 1.40), chronic hypertension only (HR:
1.67; 95% CI: 1.50 to 1.84), and both HDPs and sub-
sequent chronic hypertension (HR: 2.02; 95% CI: 1.75
to 2.33) (Table 2). A similar pattern of association was
observed for mortality due to CVD (Table 2).
JACC VOL. 77, NO. 10, 2021 Wang et al. 1307
MARCH 16, 2021:1302–12 Hypertensive Disorders of Pregnancy and Mortality

F I G U R E 1 Multivariable Adjusted HRs and 95% CIs for Cause-Specific Premature Mortality (Before Age 70 Years) According to the Occurrence of HDPs Among
88,395 Parous Women (Nurses’ Health Study II, 1989 to 2017)

Crude Incidence
Per 1,000
Type of Death Deaths Person-Years Age-Adjusted Model Multivariable Model 1 Multivariable Model 2

CVD Death

No hypertensive disorders
149 0.07 1.00 (ref) 1.00 (ref) 1.00 (ref)
of pregnancy

Either gestational
63 0.20 2.72 (2.03-3.66) 2.36 (1.75-3.18) 2.26 (1.67-3.07)
hypertension or pre-eclampsia

Gestational hypertension only 33 0.21 2.60 (1.78-3.80) 2.32 (1.58-3.42) 2.21 (1.49-3.28)

Pre-eclampsia only 60 0.21 2.96 (2.19-4.00) 2.54 (1.87-3.44) 2.40 (1.76-3.28)

Cancer Death

No hypertensive disorders
988 0.49 1.00 (ref) 1.00 (ref) 1.00 (ref)
of pregnancy

Either gestational
153 0.48 1.00 (0.84-1.18) 0.96 (0.80-1.13) 0.97 (0.82-1.15)
hypertension or pre-eclampsia

Gestational hypertension only 86 0.54 1.01 (0.81-1.26) 1.02 (0.82-1.27) 1.03 (0.83-1.29)

Pre-eclampsia only 133 0.47 0.99 (0.83-1.19) 0.94 (0.78-1.13) 0.95 (0.79-1.15)

Non-CVD/Cancer Death

No hypertensive disorders
551 0.27 1.00 (ref) 1.00 (ref) 1.00 (ref)
of pregnancy

Either gestational
159 0.50 1.88 (1.57-2.24) 1.70 (1.42-2.03) 1.68 (1.40-2.01)
hypertension or pre-eclampsia

Gestational hypertension only 87 0.55 1.85 (1.47-2.32) 1.73 (1.37-2.18) 1.74 (1.37-2.19)

Pre-eclampsia only 142 0.50 1.92 (1.59-2.31) 1.72 (1.43-2.07) 1.69 (1.39-2.04)

0 1.0 2.0 3.0 4.0 0 1.0 2.0 3.0 4.0 0 1.0 2.0 3.0 4.0
HR (95% CI) HR (95% CI) HR (95% CI)

In the age-adjusted model, age in months at the start of follow-up and calendar year of the current questionnaire cycle were included as stratified variables. Multi-
variable model 1 was further adjusted for White race/ethnicity; pre-pregnancy body mass index; and time-varying menopausal status, current hormone therapy use,
daily aspirin use, and parental history of myocardial infarction or stroke. Multivariable model 2 was further adjusted for time-varying breastfeeding duration, parity,
alcohol intake, smoking status, physical activity, AHEI-2010 dietary score, and current body mass index. The associations of GHTN and pre-eclampsia with premature
mortality were assessed separately and always against normotensive pregnancies. AHEI ¼ Alternative Healthy Eating Index; CI ¼ confidence interval;
CVD ¼ cardiovascular disease; HDP ¼ hypertensive disorder of pregnancy; HR ¼ hazard ratio; ref ¼ reference.

When the influence of the sequence in which
the affected pregnancies took place was tested
among participants who responded to the 2009
questionnaire (Table 3), women who experienced
HDPs after a normotensive pregnancy and those
reporting HDPs both in the first and subsequent
pregnancies were at the highest risk of dying
prematurely compared with women with normo-
tension in all pregnancies in the fully adjusted
model (HR: 1.82 [95% CI: 1.22 to 2.69] and HR: 1.23
[95% CI: 0.74 to 2.04], respectively). In addition,
the elevated risk of premature
appeared to be driven by the small number of
women who experienced HDPs in 2 or more preg-
nancies and those who simultaneously reported
HDPs and low birth weight (Table 3).
SENSITIVITY ANALYSES. The association of HDPs and
all-cause premature mortality was not substantially
changed when deaths due to complications of preg-
nancy, childbirth, and the puerperium were excluded
and when women were considered exposed to HDPs
even if previous chronic hypertension was reported
(Supplemental Table 6). The results were also robust
when we excluded multiple pregnancies (e.g., twins,
triplets) (Supplemental Table 6).
DISCUSSION
Results from this large prospective cohort show that
mortality also HDPs, either GHTN or pre-eclampsia, were associated
with an increased risk of premature mortality,
particularly mortality from CVD. These associations
persisted regardless of the subsequent development
of chronic hypertension. It is also noteworthy that the
elevated risk of premature mortality appeared to be
driven by the small number of women who
1308 Wang et al. JACC VOL. 77, NO. 10, 2021

Hypertensive Disorders of Pregnancy and Mortality MARCH 16, 2021:1302–12

T A B L E 2 Adjusted HRs and 95% CIs for the Risk of All-Cause and Cause-Specific Premature Mortality (Before Age 70 Years) According to
the Joint Categories of HDPs and Subsequent Chronic Hypertension Among 88,395 Parous Women (Nurses’ Health Study II, 2009–2017)

No HDPs and Chronic Both HDPs and

Cause of Death Chronic Hypertension HDPs Only Hypertension Only Chronic Hypertension

All-cause
Number of events 1,270 176 687 254
PY 1,686,019 204,717 348,316 115,997
Crude incidence, per 1,000 PY 0.75 0.86 1.97 2.19
HR (95% CI)
Age-adjusted model* 1.00 (ref) 1.27 (1.08–1.48) 1.63 (1.47–1.79) 2.05 (1.79–2.35)
Multivariable model 1† 1.00 (ref) 1.18 (1.01–1.38) 1.64 (1.48–1.80) 1.95 (1.70–2.24)
Multivariable model 2‡ 1.00 (ref) 1.20 (1.02–1.40) 1.67 (1.50–1.84) 2.02 (1.75–2.33)
CVD
Number of events 78 17 71 46
PY 1,687,129 204,858 348,873 116,178
Crude incidence, per 1,000 PY 0.05 0.08 0.20 0.40
HR (95% CI)
Age-adjusted model* 1.00 (ref) 1.92 (1.14–3.26) 3.36 (2.39–4.72) 6.96 (4.78–10.13)
Multivariable model 1† 1.00 (ref) 1.70 (1.00–2.88) 3.13 (2.21–4.42) 6.04 (4.11–8.87)
Multivariable model 2‡ 1.00 (ref) 1.71 (1.01–2.92) 3.23 (2.26–4.63) 6.35 (4.22–9.54)
Cancer
Number of events 722 75 266 78
PY 1,686,525 204,810 348,681 116,148
Crude incidence, per 1,000 PY 0.43 0.37 0.76 0.67
HR (95% CI)
Age-adjusted model* 1.00 (ref) 0.95 (0.75–1.20) 1.19 (1.02–1.37) 1.15 (0.91–1.46)
Multivariable model 1† 1.00 (ref) 0.90 (0.71–1.14) 1.22 (1.05–1.42) 1.14 (0.90–1.45)
Multivariable model 2‡ 1.00 (ref) 0.92 (0.73–1.17) 1.27 (1.09–1.48) 1.19 (0.93–1.52)
All other causes
Number of events 340 61 211 98
PY 1,686,866 204,816 348,743 116,134
Crude incidence, per 1,000 PY 0.20 0.30 0.61 0.84
HR (95% CI)
Age-adjusted model* 1.00 (ref) 1.60 (1.22–2.11) 2.13 (1.77–2.55) 3.28 (2.61–4.13)
Multivariable model 1† 1.00 (ref) 1.46 (1.11–1.92) 2.08 (1.73–2.51) 2.99 (2.37–3.78)
Multivariable model 2‡ 1.00 (ref) 1.49 (1.13–1.96) 2.08 (1.71–2.52) 3.09 (2.42–3.94)

*In the age-adjusted model, age in months at the start of follow-up and calendar year of the current questionnaire cycle were included as stratified variables. †Based on age-
adjusted models, multivariable model 1 was further adjusted for White race/ethnicity (yes, no); pre-pregnancy body mass index (<25, $25 kg/m2); and time-varying meno-
pausal status (pre-menopausal, post-menopausal, unsure/biologically uncertain), current hormone therapy use (never, past, current), daily aspirin use (yes, no), and parental
history of myocardial infarction or stroke (yes, no). ‡Multivariable model 2 was further adjusted for time-varying breastfeeding duration (#3.0, 3.1 to 12, >12 months), parity
(#1, 2, $3), alcohol intake (0, 1 to 14, $15 g/day), smoking status (never, former, current 1 to 34 cigarettes/day, current $35 cigarettes/day), physical activity (0, 0.1 to 1.0, 1.1
to 2.4, 2.5 to 5.9, or $6 h/week), AHEI-2010 dietary score (quintiles), and current body mass index (<18.5, 18.5 to 24.9, 25 to 29.9, $30 kg/m2).
CI ¼ confidence interval; HR ¼ hazard ratio; PY ¼ person-years; other abbreviations as in Table 1.

experienced HDPs in 2 or more pregnancies and those
who simultaneously reported HDPs and low birth
weight.
COMPARISON WITH OTHER STUDIES. Long-term
cohort studies have well documented that HDPs are
positively associated with CVD, chronic hyperten-
sion, and type 2 diabetes (25), which are increasingly
known to be related to a higher risk of mortality. To
date, however, few prospective cohort studies have
assessed the association between HDPs and mortality
(particularly premature mortality). In support of our
findings, Theilen et al. (10) reported a significantly
higher risk of mortality due to all causes, ischemic
heart disease, and stroke among women with a his-
tory of HDPs in a large retrospective study based on
the Utah Population Database. Similarly, several
retrospective studies and registry databases also
showed positive associations between pre-eclampsia
and risk of all-cause mortality (9,11) and CVD-related
mortality (7–9,12–14,26). In contrast, in a small retro-
spective cohort, Wilson et al. (27) reported that HDPs
were unrelated to all-cause mortality among 3,593
Aberdeen women. A lack of association between pre-
eclampsia and risk of all-cause mortality was also
reported in a large retrospective study based on
129,290 registered births (16).
JACC VOL. 77, NO. 10, 2021 Wang et al. 1309
MARCH 16, 2021:1302–12 Hypertensive Disorders of Pregnancy and Mortality

T A B L E 3 Adjusted HRs and 95% CIs for the Risk of All-Cause Premature Mortality (Before Age 70 Years) According to the Occurrence of HDP Status
Across Multiple Pregnancies Among 61,806 Parous Women (Nurses’ Health Study II, 2009–2017)

HR (95% CI)

Crude Incidence Age-Adjusted Multivariable Multivariable

HDP Status Deaths/PY per 1,000 PY Model* Model 1† Model 2‡

Change in HDP status

Normotension in first birth
Normotensive subsequent births or no additional births 530/415,338 1.28 1.00 (ref) 1.00 (ref) 1.00 (ref)
HDPs in subsequent births 27/11,767 2.29 1.86 (1.26–2.74) 1.78 (1.21–2.63) 1.82 (1.22–2.69)
HDP in the first birth
Normotensive subsequent births or no additional births 39/35,717 1.09 0.92 (0.66–1.27) 0.88 (0.63–1.22) 0.81 (0.58–1.13)
HDPs in subsequent births 16/10,272 1.56 1.33 (0.81–2.19) 1.27 (0.77–2.09) 1.23 (0.74–2.04)
Total number of pregnancies with HDPs
No HDPs 530/415,338 1.28 1.00 (ref) 1.00 (ref) 1.00 (ref)
1 61/46,371 1.32 1.09 (0.84–1.43) 1.05 (0.80–1.37) 0.99 (0.76–1.30)
$2 21/11,384 1.84 1.59 (1.02–2.46) 1.51 (0.97–2.35) 1.47 (0.94–2.30)
Co-exposure to HDPs and pre-term birth
No HDPs 530/415,338 1.28 1.00 (ref) 1.00 (ref) 1.00 (ref)
Only HDPs 66/45,493 1.45 1.19 (0.92–1.54) 1.14 (0.88–1.48) 1.10 (0.84–1.42)
HDPs and pre-term birth 16/12,262 1.30 1.18 (0.72–1.94) 1.13 (0.68–1.86) 1.03 (0.62–1.69)
Co-exposure to HDPs and low birth weight
No HDPs 530/415,338 1.28 1.00 (ref) 1.00 (ref) 1.00 (ref)
Only HDPs 67/48,197 1.39 1.16 (0.90–1.50) 1.11 (0.86–1.43) 1.06 (0.82–1.37)
HDPs and low birth weight 15/9,558 1.57 1.32 (0.79–2.21) 1.30 (0.78–2.18) 1.20 (0.72–2.02)

*In the age-adjusted model, age in months at the start of follow-up and calendar year of the current questionnaire cycle were included as stratified variables. †Based on age-adjusted models,
multivariable model 1 was further adjusted for White race/ethnicity (yes, no); pre-pregnancy body mass index (<25, $25 kg/m2); and time-varying menopausal status (pre-menopausal, post-
menopausal, unsure/biologically uncertain), current hormone therapy use (never, past, current), daily aspirin use (yes/no), and parental history of myocardial infarction or stroke (yes, no).
‡Multivariable model 2 was further adjusted for time-varying breastfeeding duration (#3.0, 3.1 to 12, >12 months), parity (#1, 2, $3), alcohol intake (0, 1 to 14, $15 g/day), smoking status
(never, former, current 1 to 34 cigarettes/day, current $35 cigarettes/day), physical activity (0, 0.1 to 1.0, 1.1 to 2.4, 2.5 to 5.9, or $6 h/week), AHEI-2010 dietary score (quintiles), and current
body mass index (<18.5, 18.5 to 24.9, 25 to 29.9, $30 kg/m2).
Abbreviations as in Tables 1 and 2.

Methodologic weaknesses of these retrospective hypertension to increased cardiovascular morbidity

studies and registry databases included retrospective
assessment of HDPs in the long-distant past and a
lack of detailed data on underlying risk factors of
premature mortality before (e.g., age at first birth,
parental history of chronic diseases, pre-pregnancy
BMI) and after pregnancy (e.g., parity), as well as
time-varying information on important covariates
such as chronic hypertension, BMI, dietary quality,
alcohol use, smoking status, and physical activity. In
the present study, although there was no effect
modification by reproductive characteristics, anti-
hypertension treatment, or dietary or lifestyle fac-
tors, we noted that the elevated risk of all-cause
premature mortality was strongest for the occurrence
of both HDPs and subsequent chronic hypertension.
This is not surprising given that HDPs are strong risk
factors for chronic hypertension (15), which, in turn,
is associated with premature mortality, particularly
CVD mortality (28). However, the association be-
tween HDPs and premature mortality also persisted,
even in the absence of chronic
Together, these findings suggest that although the
previously described progression of HDPs to chronic
and mortality is undoubtedly important (29), it may
not be the primary pathway through which HDPs
affect health and, ultimately, mortality. We found
that HDPs were associated with a greater risk of
deaths due to infectious diseases, respiratory dis-
eases, nervous system diseases, and metabolic/im-
munity disorders. In support of our findings, previous
studies showed that HDPs were associated with a
higher risk of respiratory, central nervous system,
and endocrine or metabolic morbidity (30,31). How-
ever, further studies are needed to verify these novel
findings.
To our knowledge, our study is the first to explore
the effect of change in HDP status throughout a
woman’s reproductive lifespan on mortality. We
found that the highest risk of premature mortality
was observed among women who experienced HDPs
after a normotensive pregnancy and those reporting
HDPs both in the first and subsequent pregnancies.
This finding is in contrast to the results by Skjaerven
hypertension. et al. (7), which suggested that pre-eclampsia is a
strong predictor of CVD mortality primarily among 1-
child mothers. However, that study followed women
1310 Wang et al.
Hypertensive Disorders of Pregnancy and Mortality
with a first singleton birth between 1967 and 2002
through linkage to the national Cause of Death Reg-
istry by 2009, which could result in exposure
misclassification because not all subsequent births
across the reproductive lifespan were included. In
addition, we found that the elevated risk of prema-
ture mortality appeared to be driven by the small
number of women who experienced HDPs in 2 or
more pregnancies and those who simultaneously re-
ported HDPs and low birth weight, which was in line
with growing evidence showing a particularly high
risk for cardiovascular morbidity and mortality
among women who had pre-eclampsia in 2 or more
pregnancies (14,29) and those who reported pre-
eclampsia complicated with low birth weight (16).
UNDERLYING MECHANISMS OF THE OBSERVED
RELATIONS. When specific causes of death were
examined, we did not find any evidence of an asso-
ciation between HDPs and cancer mortality, sup-
porting the existing evidence of no association
between HDPs and cancer risk (32,33). Instead, we
observed a strong association between HDPs and CVD
mortality before age 70 years. The relation of HDPs
and CVD mortality could be partly explained by some
shared risk factors of HDPs and CVD, such as insulin
resistance and systemic inflammation (34). In addi-
tion, the pathological processes implicated in HDPs,
including angiogenic imbalance, complement activa-
tion, inflammation, and hemodynamic changes, may
also contribute directly to cardiac stress that exceeds
normal pregnancy, leading to overt cardiac damage
(35,36). Finally, the association between HDPs and
CVD may also be mediated by epigenomic changes.
For instance, Julian et al. (37) identified 6 differen-
tially methylated regions predisposing the offspring
of women with HDPs to later-life vascular diseases.
There is also evidence showing that these mentioned
pathways are involved in the associations between
HDPs and other chronic diseases (38).
STUDY STRENGTHS AND LIMITATIONS. The
strengths of this study include the large study pop-
ulation, extensive prospective follow-up, and
rigorous ascertainment of key lifestyle and health
outcomes. Our analysis was carefully adjusted for
various confounding factors, including reproductive
characteristics and dietary and lifestyle factors that
were collected by using validated questionnaires. In
addition, information on all pregnancies from each
woman enabled us to estimate the effect of change
in HDP status during the reproductive lifespan on
mortality. However, our study also has some limi-
tations. First, the diagnosis of HDPs and chronic
JACC VOL. 77, NO. 10, 2021
MARCH 16, 2021:1302–12
hypertension was self-reported, which, despite vali-
dation against medical records in subgroup partici-
pants from this cohort, can result in misclassification
of disease status and biased risk estimates. Second,
although we have controlled for various confound-
ing factors and predictors of premature mortality,
residual confounding from unadjusted covariates
cannot be completely ruled out. However, strong
residual confounding is unlikely given that adjust-
ment for covariates did not change the estimates
substantially. Third, because our study population
mainly consisted of professional, non-Hispanic
White women, our findings may not be generaliz-
able to ethnic/racial minority groups. Fourth, the
cause of death was uncertain in 15% of women,
which may have resulted in imprecise estimates for
disease-specific mortality.
CONCLUSIONS
Our results suggest that HDPs, either GHTN or pre-
eclampsia, were associated with a greater risk of
premature mortality, especially CVD-related deaths,
even in the absence of chronic hypertension. Our re-
sults highlight the need for clinicians to screen for a
history of HDPs when evaluating CVD morbidity and
mortality risk of their patients.
ACKNOWLEDGMENTS The authors thank the partic-
ipants and staff of the Nurses’ Health Study II for
their invaluable contributions as well as staff from the
cancer registries in the following states for their help:
Alabama, Arizona, Arkansas, California, Colorado,
Connecticut, Delaware, Florida, Georgia, Idaho, Illi-
nois, Indiana, Iowa, Kentucky, Louisiana, Maine,
Maryland, Massachusetts, Michigan, Nebraska, New
Hampshire, New Jersey, New York, North Carolina,
North Dakota, Ohio, Oklahoma, Oregon, Pennsylva-
nia, Rhode Island, South Carolina, Tennessee, Texas,
Virginia, Washington, and Wyoming. The authors
assume full responsibility for analyses and the inter-
pretation of these data.
FUNDING SUPPORT AND AUTHOR DISCLOSURES
This study was supported by grants U01-HL145386, U01-CA176726,
R01-HL034594, and R01-HL088521 from the National Institutes of
Health. The authors have reported that they have no relationships
relevant to the contents of this paper to disclose.
ADDRESS FOR CORRESPONDENCE: Dr. Jorge E. Cha-
varro, Harvard T.H. Chan School of Public Health,
Building II 3rd Floor, Room #331, 655 Huntington
Avenue, Boston, Massachusetts 02115, USA. E-mail:
jchavarr@hsph.harvard.edu. Twitter: @jason19890203.
JACC VOL. 77, NO. 10, 2021
MARCH 16, 2021:1302–12
PERSPECTIVES
COMPETENCY IN MEDICAL KNOWLEDGE: Hyper-
tension during pregnancy, even in women without chronic
hypertension, is associated with accelerated long-term
mortality, particularly cardiovascular death.
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KEY WORDS cardiovascular diseases,
hypertensive disorders, mortality,
pregnancy, women
A PPE NDI X For supplemental tables and a
description of the Cox model, please see the
online version of this paper.