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Original Article

Comparing the severity of second preeclampsia with

first preeclampsia: a multicenter retrospective
longitudinal cohort study
Lizi Zhang a,
, Shilei Bi a,
, Jingjin Gong c, Xinghe Wang d, Jingying Liang a, Shifeng Gu a,
Minglian Su a, Weiwei Wang a, Manna Sun d, Jingsi Chen a, Weitan Zheng c, Junwei Wu c,
Zhijian Wang e, Jianmeng Liu b, Hong-tian Li b, Dunjin Chen a, and Lili Du a

Objective: Compare the clinical severity of second Abbreviations: ALT, alanine transaminase; AST, aspartate
preeclampsia with the first preeclampsia. transaminase; CDs, caesarean deliveries; IQR, interquartile
Methods: This retrospective longitudinal cohort study was range; IVF, in-vitro fertilization; NICU, neonatal ICU; SCr,
conducted in three teaching hospitals in Guangzhou, serum creatinine; TT, thrombin time; USPSTF, US
where there were a total of 296 405 deliveries between Preventive Services Task Force; WBC, white blood cells
2010 and 2021. Two consecutive singleton deliveries
complicated with preeclampsia were included. Clinical
features, laboratory results within 1 week before delivery, INTRODUCTION
and maternal and neonatal outcomes of both deliveries

P
reeclampsia is a significant obstetric complication,
were collected. Univariate analyses were made using affecting approximately 2–8% of pregnancies. It is
paired Wilcoxon tests and McNemar tests. Multivariable among the leading causes of maternal mortality,
logistic regression and generalized linear models were responsible for about 10% of all pregnancy-related maternal
performed to assess the association of adverse maternal deaths in developed countries [1]. Preeclampsia not only
and neonatal outcomes with second preeclampsia. poses immediate risks to the health of both mother and
Results: A total of 151 women were included in the fetus but also increases the likelihood of developing recur-
study. The mean maternal age was 28 and 33 years for the rent preeclampsia in subsequent pregnancies [2]. Further-
first and second deliveries, respectively. The proportion of more, women who experience preeclampsia are at an
preventive acetylsalicylic acid use was 4.6% for the first increased risk of chronic hypertension later in life [3].
delivery and 15.2% for the second delivery. No significant The recurrence rate of preeclampsia has been reported
differences were observed in terms of blood pressure on to be as high as 65%, which is three to eight times higher
admission, gestational weeks of admission and delivery, than the rate observed in nulliparous women [4,5]. Despite
application of perinatal antihypertensive agents, rates of efforts to implement preventive measures and reduce the
preterm delivery, and severe features between the two risk of second preeclampsia and its associated maternal
occurrences. However, the rates of heart disease, edema, complications, the recurrence rates of preeclampsia have
and admission to the ICU were lower, and hospital stays remained unchanged over the past two decades [6].
were shorter in the second preeclampsia compared with
the first preeclampsia. Sensitivity analysis conducted
among women who did not use preventive acetylsalicylic Journal of Hypertension 2024, 42:000–000
a
acid yielded similar results. After adjusting for potential Department of Obstetrics and Gynecology, Guangdong Provincial Key Laboratory of
confounding variables, the occurrence of second Major Obstetric Diseases; Guangdong Provincial Clinical Research Center for Obstet-
rics and Gynecology; Guangdong-Hong Kong-Macao Greater Bay Area Higher
preeclampsia was associated with significantly decreased Education Joint Laboratory of Maternal-Fetal Medicine; The Third Affiliated Hospital
risks of heart disease, edema, complications, and of Guangzhou Medical University, Guangzhou, bInstitute of Reproductive and Child
Health, National Health Commission Key Laboratory of Reproductive Health, Peking
admission to the NICU, with odds ratios ranging between University Health Science Center, Beijing, cGuangzhou Panyu District Maternal and
0.157 and 0.336. Child Health Hospital, dDongguan Maternal and Children Health Hospital and
e
Department of Obstetrics and Gynecology, Nanfang Hospital, Southern Medical
Conclusion: Contrary to expectations, the second University, Guangzhou, China
preeclampsia did not exhibit worse manifestations or Correspondence to Lili Du, 63 Duobao Road, Guangzhou, 510150 Guangdong,
outcomes to the first occurrence. In fact, some clinical China. E-mail: [email protected]


features and outcomes appeared to be better in the These authors have contributed equally to this work and share first authorship.
second preeclampsia. Received 6 September 2023 Revised 16 November 2023 Accepted 27 November
2023
Keywords: maternal outcome, neonatal outcome,
J Hypertens 42:000–000 Copyright © 2024 Wolters Kluwer Health, Inc. All rights
preeclampsia, severity reserved.
DOI:10.1097/HJH.0000000000003642

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Zhang et al.

Given the adverse consequences and high recurrence from 2015, the prophylactic use of 75–100 mg of acetylsa-
risk associated with preeclampsia, understanding the rela- licylic acid at 11–14 weeks of pregnancy has been recom-
tive severity of second preeclampsia compared with the first mended. This recommendation has been updated to 100–
occurrence is crucial for both patients and physicians. 150 mg of acetylsalicylic acid starting from 2020.
However, previous studies have yielded inconsistent results
on this matter. For instance, Hnat et al. [7] reported signifi- Statistical analyses
cantly higher rates of severe preeclampsia, preterm, pla- The normality of continuous variables was assessed using
centa abruption, and fetal death in women with second the Kolmogorov–Smirnov test. As the continuous variables
preeclampsia compared with nulliparous women with pre- did not follow a normal distribution, they were reported as
eclampsia. Similarly, two other studies found that women median (interquartile range, IQR), and the paired Wilcoxon
with second preeclampsia experienced more early-onset test was used to compare the between-group differences.
preeclampsia, C-section deliveries, very low birthweight Categorical variables were reported as frequency (percent-
(<1500 g) [8], and fetal loss [9] compared with multiparous age), and the McNemar test or Fisher exact test in cases of
women with preeclampsia. In contrast, Chen et al. [10] small numbers was employed for comparisons. Multivari-
discovered that women with second preeclampsia appeared able logistic regression analysis and generalized linear mod-
to have less severe symptoms, including lower blood pres- els were performed to adjust for confounding factors such as
sure and dipstick proteinuria, as well as higher birthweights age, gravidity, in-vitro fertilization (IVF), number of caesar-
compared with their first preeclampsia occurrence. Howev- ean deliveries (CDs), diabetes mellitus, and delivery weeks
er, these prior studies were either based on cross-sectional when assessing the association of adverse maternal and
comparisons of different populations or relied on longitu- neonatal outcomes with second preeclampsia. All statistical
dinal comparisons of small patient cohorts. Thus, further analyses were conducted using SAS 9.4 software. The null
investigation is needed to clarify the differences between hypothesis was rejected for values of P less than 0.05.
second preeclampsia and first preeclampsia, which could
enhance clinical consultation and counseling. Therefore, RESULTS
our primary objective was to compare the clinical features,
laboratory results, and maternal and perinatal outcomes The median interval between deliveries with the second
between women experiencing second preeclampsia and preeclampsia and the first preeclampsia was 46 months as
their first preeclampsia occurrence. shown in Table 1. Among the 151 women included in the
study, 23 (15.2%) took acetylsalicylic acid to prevent the
MATERIALS AND METHODS recurrence of preeclampsia, and 7 (4.6%) took acetylsali-
cylic acid to prevent preeclampsia in their first deliveries.
This multicenter retrospective cohort study was conducted We found that 14.57% (22 out of 151) of women experi-
by the Third Affiliated Hospital of Guangzhou Medical enced chronic hypertension with superimposed pre-
University in collaboration with Guangzhou Panyu District eclampsia. Among these women, 31.82% (7 out of 22)
Maternal and Child Health Hospital and Dongguan Mater- had chronic hypertension before their second pregnancies,
nal and Children Health Hospital. This study was approved whereas 68.18% (15 out of 22) developed chronic hyper-
by the Research Ethics Board of the Third Affiliated Hospital tension before reaching 20 weeks gestation during their
of Guangzhou Medical University and all participants pro- second pregnancies. The characteristics of deliveries
vided informed consent. The study period spanned from from three hospitals were presented in Table S1, http://
2010 to 2021, during which a total of 296 405 deliveries took links.lww.com/HJH/C363. When comparing the second
place in the three hospitals. The study cohort consisted of preeclampsia with the first preeclampsia, there were no
women who had two consecutive singleton deliveries at the significant differences in the application of perinatal anti-
same hospital, with the first delivery complicated by pre- hypertensive agents, blood pressure on admission, gesta-
eclampsia. To ensure the homogeneity of the study cohort, tional weeks of admission and delivery, severe features,
we included women who experienced de novo preeclamp- mode of delivery, and rates of preterm delivery (Table 2).
sia in their first deliveries, and experienced de novo pre- However, the second preeclampsia exhibited lower rates of
eclampsia and chronic hypertension with superimposed heart disease and edema, lower SBP at the first postpartum
preeclampsia in their second deliveries. Women with con- day, lower admission to the ICU, shorter hospital stays, and
current medical conditions, such as chronic hypertension higher 1-min Apgar scores compared with the first pre-
before their first deliveries (n ¼ 43), heart diseases (n ¼ 5), eclampsia group, with a P value less than 0.05. Additionally,
renal diseases, or autoimmune disorders (n ¼ 3) in either of the second preeclampsia group had lower levels of white
the two deliveries, were excluded from the analysis. After blood cells (WBC), alanine transaminase (ALT), aspartate
applying these exclusion criteria, a final sample of 694 transaminase (AST), serum creatinine (SCr), thrombin time,
women met the inclusion criteria. Among them, 151 women and urine protein, as shown in Table 3. The detailed
experienced preeclampsia (n ¼ 128) or chronic hyperten- composition of heart disease, edema, severe features,
sion with superimposed preeclampsia (n ¼ 22) in the sec- and complications between the two groups can be found
ond delivery (Fig. 1). in Table S2, http://links.lww.com/HJH/C363. Overall, these
Information regarding the clinical characteristics, labo- findings suggest that the second occurrence of preeclamp-
ratory tests conducted within 1 week before delivery, and sia is not worse than the first occurrence.
maternal and neonatal outcomes of both deliveries were Among the 151 women included in the study, 78 were
extracted from the medical records. Additionally, starting from the Third Affiliated Hospital of Guangzhou Medical

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Second preeclampsia vs. first preeclampsia

82840 94352 119213

Deliveries in the Third Affiliated Hospital Deliveries in He Xian Memorial Affiliated Deliveries in Dong Guan Maternal and
of Guangzhou Medical University Hospital of Southern Medical University Child Health Care Hospital

745
Two consecutive deliveries at the same hospital,
the first delivery with PE

51
43 Prior hypertensive disorders of pregnancy
3 Complicated with renal disease
5 Complicated with heart disease

694
The first delivery with PE

151
The second delivery with PE

23 128
Take aspirin Without aspirin

FIGURE 1 The flow chart of the study.

University, 59 were from Guangzhou Panyu District Mater- of the study remained consistent across all three hospitals,
nal and Child Health Hospital, and 18 were from Dongguan indicating a trend towards the second occurrences of pre-
Maternal and Children Health Hospital. It was observed that eclampsia not being worse in terms of severity compared
women from the Third Affiliated Hospital of Guangzhou with the first occurrences. Additional details can be found in
Medical University had more severe conditions compared Tables S3, http://links.lww.com/HJH/C363 and S4, http://
with the other two hospitals. This was reflected in earlier links.lww.com/HJH/C363.
delivery weeks, a higher proportion of perinatal antihyper- To account for any potential confounding effects result-
tensive agent usage, and a higher occurrence of complica- ing from the preventive use of acetylsalicylic acid, we
tions. However, it is important to note that the main findings conducted additional analyses on a subset of 128 women

TABLE 1. The general characteristics of the first preeclampsia and the second preeclampsia
Variables First PE (N ¼ 151) Second PE (N ¼ 151) P
Age, median (IQR) (year) 28 (5) 33 (5) <0.001
Interval months, median (IQR) (month) – 46 (30)
Acetylsalicylic acid [No. (%)] 7 (4.64) 23 (15.2) 0.001
Parity [No. (%)] <0.001
0 139 (92.1) 9 (6)
1 12 (8.6) 142 (94)
Gravity [No. (%)] <0.001
1 89 (58.9) 0
2 34 (22.5) 73 (48.3)
3 28 (18.5) 78 (51.7)
Number of CD [No. (%)] <0.001
0 146 (96.7) 46 (30.5)
1 5 (3.3) 105 (69.5)
IVF [No. (%)] 8 (5.3) 3 (2) 0.063
DM [No. (%)] 35 (23.18) 37 (24.5) 0.868

CD, caesarean delivery; DG, Dongguan Maternal and Children Health Hospital; DM, diabetes mellitus; GYSY, The Third Affiliated Hospital of Guangzhou Medical University; IVF, in-vitro
fertilization; PY, Guangzhou Panyu District Maternal and Child Health Hospital; DM includes GDM (gestational diabetes mellitus) and PGDM (pregestational diabetes mellitus).

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Zhang et al.

TABLE 2. The severity of the first preeclampsia and the second preeclampsia
Variables First PE (N ¼ 151) Second PE (N ¼ 151) P
Admission characteristics
Heart diseasea [No. (%)] 21 (13.91) 6 (3.97) <0.001
Edemab [No. (%)] 90 (59.6) 48 (31.79) <0.001
Admission week, median (IQR) (week) 37 (6) 37 (5) 0.882
Delivery week, median (IQR) (week) 38 (6) 38 (5) 0.999
Antihypertensive agents during pregnancy [No. (%)] 92 (60.9) 82 (54.3) 0.218
Admission SBP, median (IQR) (mmHg) 147 (15) 148 (20) 0.675
Admission DBP, median (IQR) [mmHg] 95 (12) 97 (12) 0.283
Complicationsc [No. (%)] 32 (21.19) 23 (15.23) 0.124
Severe featuresd [No. (%)] 54 (35.8) 47 (31.1) 0.345
Postpartum characteristics
CD [No. (%)] 110 (72.8) 115 (76.2) 0.404
Preterm [No. (%)] 57 (37.7) 53 (35.1) 0.584
ICU [No. (%)] 15 (9.9) 5 (3.3) 0.024
SBP at the first postpartum day, median (IQR) (mmHg) 139 (15) 137 (13) 0.034
DBP at the first postpartum day, median (IQR) (mmHg) 87 (14) 87 (12) 0.944
Antihypertensive agents after delivery [No. (%)] 103 (68.2) 97 (64.2) 0.376
Days in hospital, median (IQR) (day) 7 (5) 6 (4) 0.007
Neonatal outcomes
Newborn weight, median (IQR) (g) 2640 (1515) 2800 (1260) 0.091
1 min Apgar score [median (IQR)] 10 (1) 10 (0) 0.037
5 min Apgar score [median (IQR)] 10 (0) 10 (0) 0.052
NICU [No. (%)] 48 (34.3) 37 (24.5) 0.058

CD, caesarean delivery; NICU, neonatal ICU.

a
Heart disease refers to pericardial effusion or heart failure.
b
Edema refers to pleural effusion, ascites, or lower extremity edema, and so forth.
c
Complications refer to any of FGR, abruption, HELLP, and eclampsia.
d
Severe features refer to SBP at least 160 mmHg or DBP at least 110 mmHg or thrombocytopenia or impaired liver function or severe persistent right upper quadrant or epigastric pain
unresponsive to medication or renal insufficiency or pulmonary edema or new-onset headache or visual disturbances [14].

who did not use acetylsalicylic acid for prevention in either first preeclampsia, while 83 did not. Interestingly, we
their first or second deliveries. Encouragingly, these anal- found that 55.56% (25/45) of women who had severe
yses yielded similar results, as demonstrated in Table S5– features in their first preeclampsia did not experience
S8, http://links.lww.com/HJH/C363. Furthermore, we in- the same severity in their second preeclampsia. On the
vestigated whether the clinical outcomes of the second other hand, 24.1% (20/83) of women who did not have
preeclampsia differed based on the presence or absence of severe features in their first preeclampsia developed se-
severe features in the first occurrence. Among the 128 vere features in their second preeclampsia. Detailed infor-
women who did not use acetylsalicylic acid for prevention mation can be found in Table 4 and Table S9, http://links.
in either delivery, 45 women had severe features in their lww.com/HJH/C363.

TABLE 3. The lab test before delivery of the first preeclampsia and the second preeclampsia
Variables First PE (N ¼ 151) Second PE (N ¼ 151) P
12
RBC, median (IQR) (
10 /l) 4.02 (0.57) 4.12 (0.72) 0.223
WBC, median (IQR) (
109/l) 10.3 (3.09) 9.57 (2.98) <0.001
Neutrophils, median (IQR) (%) 73.9 (6.9) 73.7 (7.7) 0.332
Hb, median (IQR) (g/l) 116 (21) 117 (20) 0.797
Hct, median (IQR) (%) 34.9 (4.29) 35.24 (4.26) 0.45
Plt, median (IQR) (
109/l) 210 (77) 223 (85) 0.023
ALT, median (IQR) (U/l) 12.8 (7.5) 10 (7.5) <0.001
AST, median (IQR) (U/l) 17.9 (7) 15.1 (8.2) <0.001
SCr, median (IQR) (mmol/l) 57.1 (23) 53 (22) 0.017
TT, median (IQR) (s) 16.8 (3.6) 15.2 (3.3) <0.001
APTT, median (IQR) (s) 26.7 (4.1) 26.9 (3.5) 0.698
PT, median (IQR) (s) 10.5 (1.4) 10.3 (0.9) 0.913
Fbg, median (IQR) (g/l) 3.83 (0.79) 4.16 (0.82) <0.001
INR, median (IQR) 0.89 (0.09) 0.91 (0.07) <0.001
Urine gravity, median (IQR), 1.02 (0.01) 1.02 (0.01) 0.006
Urine protein [No. (%)] <0.001
þ 45 (29.8) 69 (47.3)
þþ 19 (12.6) 27 (18.5)
þþþ 87 (57.6) 50 (34.2)

ALT, alanine transaminase; APTT, activated partial thromboplastin time; AST, aspartate transaminase; Fbg, fibrinogen; Hb, hemoglobin; Hct, hematocrit; INR, international normalized
ratio; Plt, platelet; PT, prothrombin time; RBC, red blood cell; SCr, serum creatinine; TT, thrombin time; WBC, white blood cell.

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Second preeclampsia vs. first preeclampsia

TABLE 4. The severity of the second preeclampsia and the first preeclampsia with or without severe features
First PE without severe features First PE with severe features
First PE Second PE First PE Second PE
Variables (N ¼ 83) (N ¼ 83) P (N ¼ 45) (N ¼ 45) P
a
Heart disease [No. (%)] 6 (7.23) 2 (2.41) 0.125 11 (24.44) 3 (6.67) 0.022
Edemab [No. (%)] 38 (45.78) 15 (18.07) <0.001 38 (84.44) 25 (55.56) 0.004
Headache [No. (%)] 1 (1.2) 1 (1.2) 1 6 (13.33) 6 (13.33) 1
Admission week, median (IQR) [week] 38 (3) 38 (3) 0.141 34 (8) 35 (5) 0.143
Delivery week, median (IQR) [week] 38 (3) 38 (2) 0.103 35 (7) 35 (5) 0.147
Admission SBP, median (IQR) (mmHg) 142 (12) 147 (17) <0.001 160 (21) 153 (12) 0.082
Admission DBP, median (IQR) (mmHg) 93 (11) 97 (9) <0.001 101 (17) 99 (19) 0.294
SBP at the first postpartum day, median (IQR) (mmHg) 139 (13) 135 (11) 0.334 142 (15) 139 (12) 0.021
DBP at the first postpartum day, median (IQR) (mmHg) 86 (11) 87 (10) 0.579 91 (13) 91 (10) 0.403
Antihypertensive agents during pregnancy, No. (%) 43 (51.81) 31 (37.35) 0.074 35 (77.78) 32 (71.11) 0.607
Antihypertensive agents after delivery [No. (%)] 47 (56.63) 42 (50.6) 0.441 37 (82.22) 36 (80) 1
Complicationsc [No. (%)] 9 (10.84) 5 (6.02) 0.344 17 (37.78) 13 (28.89) 0.344
Preterm [No. (%)] 17 (20.48) 18 (21.69) 1 27 (60) 25 (55.56) 0.727
CD [No. (%)] 53 (63.86) 55 (66.27) 0.754 39 (86.67) 41 (91.11) 0.688
ICU [No. (%)] 3 (3.61) 4 (4.82) 1 8 (17.78) 0 (0) –
Days in hospital 6 (3) 5 (4) 0.033 8 (3) 6 (3) 0.008
Severe featuresd [No. (%)] 0 (0) 20 (24.1) – 45 (100) 20 (44.44) –
Newborn weight, median (IQR) (g) 2920 (800) 3040 (780) 0.129 2205 (1730) 2410 (1460) 0.429
1 min Apgar score [median (IQR)] 10 (0) 10 (0) 0.492 10 (3) 10 (1) 0.101
5 min Apgar score [median (IQR)] 10 (0) 10 (0) 0.484 10 (1) 10 (0) 0.277
NICU [No. (%)] 19 (23.75) 11 (13.25) 0.17 23 (52.27) 18 (40) 0.33

CD, caesarean delivery; NICU, neonatal ICU.

a
Heart disease refers to pericardial effusion or heart failure.
b
Edema refers to pleural effusion, ascites, or lower extremity edema.
c
Complications refer to any kind of complication such as FGR, abruption, HELLP, and eclampsia.
d
Severe features refer to SBP at least 160 mmHg or DBP at least 110 mmHg or thrombocytopenia or impaired liver function or severe persistent right upper quadrant or epigastric pain
unresponsive to medication or renal insufficiency or pulmonary edema or new-onset headache or visual disturbances [14].

Among the subset of 128 women who did not use the study, as demonstrated in Table S10, http://links.lww.
acetylsalicylic acid for prevention in either their first or com/HJH/C363.
second preeclampsia, the second preeclampsia was signifi-
cantly associated with decreased risks of heart disease, DISCUSSION
edema, complications, and admission to the NICU. After
adjusting for potential confounding variables, the odds Principal findings
ratios for these outcomes ranged between 0.157 and Our study revealed that the rates of heart disease, edema,
0.336, indicating a lower risk in the second occurrence and admission to the NICU were lower in the second
compared with the first preeclampsia. Importantly, the preeclampsia compared with the first preeclampsia. Addi-
second preeclampsia did not increase the risk of the severe tionally, hospital stays were shorter for women experienc-
features, admission to the ICU, longer hospital stays, or ing the second preeclampsia. These findings were
lower newborn weight, as shown in Table 5. These findings consistent even after conducting a sensitivity analysis that
were consistent when analyzing all 151 women included in focused on women who did not use acetylsalicylic acid for

TABLE 5. The association of adverse maternal and neonatal outcomes with second preeclampsia
Variables OR/b 95% CI P aOR/b 95% CI P
a
Heart disease 0.265 0.095–0.743 0.012 0.157 0.03–0.819 0.028
Edemab 0.311 0.186–0.52 <0.001 0.297 0.124–0.714 0.007
Complications 0.642 0.332–1.24 0.187 0.251 0.071–0.889 0.032
Severe featuresd 0.838 0.498–1.411 0.507 0.694 0.282–1.704 0.425
ICU 0.343 0.106–1.108 0.074 1.515 0.313–7.332 0.606
NICU 0.572 0.328–0.998 0.049 0.336 0.123–0.916 0.033
Days in hospital 1.199 2.19 to 0.207 0.018 1.323 2.696 to 0.05 0.059
Newborn weight 0.108 0.125 to 0.342 0.361 0.106 0.994 to 0.311 0.311

Confounding factors included age, gravity, IVF, diabetes mellitus, number of CDs, and the delivery weeks. CI, confidence interval; NICU, neonatal ICU; OR, odds ratio.
a
Heart disease refers to pericardial effusion or heart failure.
b
Edema refers to pleural effusion, ascites, or lower extremity edema.
c
Complications refer to any kind of complication such as FGR, abruption, HELLP, and eclampsia.
d
Severe features refer to SBP at least 160 mmHg or DBP at least 110 mmHg or thrombocytopenia or impaired liver function or severe persistent right upper quadrant or epigastric pain
unresponsive to medication or renal insufficiency or pulmonary edema or new-onset headache or visual disturbances [14].

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Zhang et al.

prevention. The results from the multivariable logistic re- with the first preeclampsia. In terms of other preventive
gression analysis further confirmed that the second pre- measures, such as calcium supplementation, there are no
eclampsia did not increase the risk of severe features. specific recommendations in relevant guidelines, and their
clinical application is also limited. The use of prophylactic
Results anticoagulation, even in women with hereditary thrombo-
Previous studies have reported conflicting findings regard- philia, remains a topic of controversy [6].
ing the severity and outcomes of second preeclampsia
compared with the first preeclampsia. Some studies have Research implications
suggested that second preeclampsia is associated with more Preeclampsia is a multisystem pregnancy disorder [15]. It
severe manifestations and higher maternal and perinatal not only has immediate effects on pregnancy outcomes but
morbidities than the first preeclampsia [7–9]. However, also has long-term implications for women’s health. How-
these studies often compared different populations of ever, the specific cellular and molecular mechanisms un-
women with second preeclampsia and first preeclampsia, derlying how a previous pregnancy influences the
which may introduce selection and confounding biases. In outcomes of future pregnancies are still not well defined.
line with our findings, Chen et al. [10] observed that women In general, the risk of most complications is consistently
with recurrent preeclampsia tended to have less severe higher when similar complications occurred in a previous
symptoms and better perinatal outcomes compared with pregnancy [16]. Nevertheless, a previous study has sug-
their previous preeclampsia. On the other hand, Zhang gested that proper maternal cardiovascular adaptation dur-
et al. [11] reported that women with recurrent preeclampsia ing pregnancy plays a crucial role in preventing gestational
experienced more serious clinical outcomes and compli- hypertensive complications, including preeclampsia [17]. It
cations compared with their previous preeclampsia. It is is possible that women with a history of preeclampsia may
worth noting that Zhang’s study included cases of chronic exhibit better adaptation in subsequent pregnancies, lead-
hypertension with superimposed preeclampsia, and the ing to reduced symptoms and improved maternal and
incidence of recurrent preeclampsia was higher than pre- neonatal outcomes compared with their first preeclampsia.
viously reported [5]. Neither Chen’s nor Zhang’s studies Opportunities for future research in this area include inves-
explored the impact of preventive acetylsalicylic acid use or tigating genetic factors and immunologic predispositions
the characteristics associated with severe features in the that may contribute to the development of preeclampsia
previous preeclampsia. [17]. Additionally, further studies on the pathogenesis of the
In our study, we observed that 14.57% (22 out of 151) of disease, a deeper understanding of its outcomes, and close
women experienced chronic hypertension with superim- monitoring are essential for reducing maternal and fetal
posed preeclampsia in the second pregnancies. It is well morbidity and mortality associated with preeclampsia.
documented that chronic hypertension increases the risk of
heart disease. However, surprisingly, we found that the Strengths and limitations
incidence rate of heart disease was lower in the second In terms of strengths of our study, it was a multicenter
preeclampsia compared with the first preeclampsia. This retrospective study that allowed us to compare the char-
unexpected finding could be attributed to the fact that the acteristics of first and second preeclampsia within the same
majority of blood pressure elevations occurred before the cohort. This design helped to reduce potential selection and
20 weeks gestation during pregnancy. Additionally, it is confounding biases that could arise from comparing differ-
important to note that the impact of chronic hypertension ent cohorts or populations. Additionally, the inclusion of
on the heart is a long-term process. multiple centers with varying degrees of disease severity
that yielded consistent results increased confidence and
Clinical implications generalizability of our findings. Furthermore, we collected
During the study period, the US Preventive Services Task detailed clinical features, laboratory results obtained within
Force (USPSTF) recommended the use of low-dose acetyl- 1 week before delivery, and maternal and neonatal out-
salicylic acid as preventive medication for women with a comes for both the first and second preeclampsia. This
history of preeclampsia in 2014 [12]. However, a recent comprehensive data collection enabled us to make a robust
multicenter randomized controlled trial conducted in China comparison of the severity between the two occurrences.
found that low-dose acetylsalicylic acid did not reduce the Additionally, during our analysis, we took into consider-
incidence of preeclampsia [13]. As a result, the use of ation the use of acetylsalicylic acid prophylaxis and the
acetylsalicylic acid for prevention is not widely adopted severity of the first preeclampsia, further enhancing the
in China because of concerns about its efficacy and safety reliability and accuracy of our results.
[13,14]. In our study, only a small percentage of women Our study does have certain limitations that should be
with a history preeclampsia (8.1%, 56 out of 694) used acknowledged. Firstly, it is important to note that the
acetylsalicylic acid, and the initiation of acetylsalicylic acid diagnostic criteria for preeclampsia have undergone slight
before 20 weeks of gestation was even rarer (5.3%, 37 out of changes during the study period. Initially, preeclampsia
694). To ensure that our results were not influenced by the was primarily defined as gestational hypertension accom-
use of acetylsalicylic acid, we compared the severity of the panied by proteinuria [18]. However, in 2019, the definition
first preeclampsia and the second preeclampsia without was expanded to include women with gestational hyper-
acetylsalicylic acid use. Further investigation is needed to tension and other signs or symptoms of preeclampsia, even
determine whether acetylsalicylic acid has any impact on in the absence of proteinuria [19]. In our study, all pregnant
reducing the severity of the second preeclampsia compared patients diagnosed with preeclampsia in 2019 or later did

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JH-D-23-00675

Second preeclampsia vs. first preeclampsia

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ACKNOWLEDGEMENTS 10. Chen Y-Y, Wu M-L, Kao M-H, Su T-H. Chie-Pein Chen perinatal
outcome of recurrent preeclampsia versus preeclampsia in nulliparas.
Funding: this work was supported by National Key R&D J Obstet Gynaecol Res 2009; 35:1042–1046.
Program of China No. 2022YFC2704501 and No. 11. Zhang JZ, He J. Risk factors of recurrent preeclampsia and its relation to
2022YFC2704503, the National Natural Science Foundation maternal and offspring outcome. Zhejiang Da Xue Xue Bao Yi Xue Ban
2015; 44:258–263.
No. 82171666, 81830045, 82071652, and 82201861, General 12. LeFevre ML, U.S. Preventive Services Task Force. Low-dose aspirin use
program of Guangdong province Natural Science Founda- for the prevention of morbidity and mortality from preeclampsia: U.S.
tion No. 2021A1515011039 and 2022A1515012405, Science Preventive Services Task Force recommendation statement. Ann In-
and Technology Projects in Guangzhou No. 202102010005 tern Med 2014; 161:819–826.
and SL2022A03J00891, and China Postdoctoral Science 13. Lin L, Huai J, Li B, Zhu Y, Juan J, Zhang M, et al. A randomized
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Foundation No. 2021M700945. This funding source had in women at high risk in China. Am J Obstet Gynecol 2022; 226:251.e1–
no influence on the content of this study. 251.e12.
Contribution to authors: Z.L.Z. and B.S.L.: investigation, 14. Hastie R, Tong S, Wikstrom AK, Sandstrom A, Hesselman S, Bergman L.
data analysis, software, and writing; G.J.J., W.X.H., L.J.Y., G. Aspirin use during pregnancy and the risk of bleeding complications: a
Swedish population-based cohort study. Am J Obstet Gynecol 2021;
S.F., S.M.L, W.W.W., S.M.N., C.J.S., Z.W.T., W.J.W., W.Z.J., 224:95.e1–95.e12.
and L.J.M.: data collection and investigation, L.H.T.: meth- 15. Chappell LC, Cluver CA, Kingdom J, Tong S. Preeclampsia. Lancet
odology, software, review, and editing; C.D.J. and D.L.L.: 2021; 398:341–354.
project administration, supervision, and conceptualization. 16. Deshmukh H, Way SS. Immunological basis for recurrent fetal loss and
pregnancy complications. Annu Rev Pathol 2019; 14:185–210.
17. Valensise H, Lo Presti D, Gagliardi G, Tiralongo GM, Pisani I, Novelli
Conflicts of interest GP, et al. Persistent maternal cardiac dysfunction after preeclampsia
There are no conflicts of interest. identifies patients at risk for recurrent preeclampsia. Hypertension
2016; 67:748–753.
18. Sibai BM. Diagnosis and management of gestational hypertension and
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