| | |

Received: 5 February 2018    Revised: 17 May 2018    Accepted: 5 July 2018    First published online: 23 July 2018

DOI: 10.1002/ijgo.12592

CLINICAL ARTICLE
Obstetrics

Routine blood tests during pregnancy for predicting future

increases in risk of cardiovascular morbidity

Shira Yuval Bar-Asher1,‡ | Alexander Shefer2,‡ | Ilana Shoham-Vardi3 | 

Ruslan Sergienko3 | Arik Wolak1,4 | Eyal Sheiner5 | Talya Wolak1,6,*

1
Faculty of Health Sciences, Joyce & Irving
Goldman Medical School at Ben-Gurion Abstract
University of the Negev, Beer-Sheva, Israel Objective: To examine the association between routine blood tests during pregnancy
2
Internal Medicine Department H, Faculty of
and future risk of cardiovascular morbidity.
Health Sciences, Soroka University Medical
Center, Ben-Gurion University of the Negev, Methods: The present case–control study was conducted among women who deliv-
Beer-Sheva, Israel
ered at a teaching hospital in Israel between January 1, 2000, and December 31, 2012.
3
Department of Public Health, Faculty of
The cohort comprised women who were subsequently hospitalized owing to cardio-
Health Sciences, Ben-Gurion University of the
Negev, Beer-Sheva, Israel vascular morbidity (case group) and age-­matched non-­hospitalized women (control
4
Cardiology Department, Shaare Zedek group). Blood levels of creatinine, glucose, potassium, urea, and uric acid were meas-
Medical Center, Jerusalem, Israel
5
ured during pregnancy. Only women with at least one test result available for all five
Department of Obstetrics and
Gynecology, Faculty of Health measurements were included. The relationship between upper quartile blood test val-
Sciences, Soroka University Medical ues and cardiovascular hospitalization was assessed.
Center, Ben-Gurion University of the Negev,
Beer-Sheva, Israel Results: The study included 4115 women (212 in the case group and 3903 in the
6
Division of Internal Medicine, Shaare Zedek control group). Three measures were associated with a future risk of cardiovascular
Medical Center, Jerusalem, Israel
morbidity requiring hospitalization: creatinine (hazard ratio [HR] 1.86, 95% confi-
*Correspondence dence interval [CI] 1.37–2.53; P<0.001); potassium (HR 1.48, 95% CI 1.09–2.01;
Talya Wolak, Division of Internal
P=0.013), and urea (HR 1.60, 95% CI 1.17–2.19; P=0.003). The number of blood test
Medicine, Shaare Zedek Medical Center,
Jerusalem, Israel. results in the upper quartile also increased such risk. The HRs for two tests and at
Email: twolak@bgu.ac.il
least three tests were 1.65 (95% CI 1.06–2.56; P=0.026) and 3.32 (95% CI 2.19–5.04;
‡
These authors contributed equally. P<0.001), respectively.
Conclusions: Future cardiovascular morbidity was predicted by routine blood tests

The present study was presented at the
28th European Meeting on Hypertension and
Cardiovascular Protection; June 8–11, 2018; during pregnancy.
Barcelona, Spain.
KEYWORDS
Cardiovascular disease; Creatinine; Potassium; Pregnancy; Urea; Uric acid

1 | INTRODUCTION Overt adverse events of pregnancy (e.g. gestational diabetes mel-

Various physiologic changes occur in the cardiovascular system
1
during pregnancy, including increases in blood volume, cardiac
output, and glomerular filtration rate (GFR).2 Therefore, pregnancy
can be considered as a physiological stress test. Determining how
the body copes with such changes could aid prediction of future
maternal health.
litus and pre-­eclampsia) can develop in response to cardiovascular
and renal maladaptation.3 Women who experience such morbidities
during pregnancy are also at increased risk of future atherosclerotic-­
related morbidity.4,5 Further, subclinical conditions such as gestational
hypertension 6 and mild glucose intolerance 7 are indicators of future
cardiovascular morbidity. Acknowledging this relationship, the 2011
American Heart Association guidelines recommend that a detailed

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© 2018 International Federation of Int J Gynecol Obstet 2018; 143: 178–183
Gynecology and Obstetrics
Yuval Bar-­Asher ET AL.
pregnancy history should be obtained from all women as part of their
8
cardiovascular risk assessment.
The physiologic changes of pregnancy can be identified by alter-
ations in routine blood test results. For example, the rise in GFR leads to
decreased serum levels of creatinine, urea, and uric acid.2 Associations
9 10 10
between elevated blood levels of uric acid, urea, and creatinine
during uncomplicated pregnancy and future maternal atherosclerotic
morbidity have been demonstrated previously. Consequently, abnor-
mally high blood test results could provide an early marker for cardio-
vascular and renal maladaptation during pregnancy, thus identifying
maternal risk of future cardiovascular morbidity.
The aim of the present study was to determine whether five blood
tests that are routinely conducted during pregnancy could predict sub-
sequent cardiovascular morbidity requiring hospitalization.
2 |  MATERIALS AND METHODS
The present case–control study was conducted among women who
delivered at the Soroka University Medical Center (SUMC), Beer-­
Sheva, Israel, between January 1, 2000, and December 31, 2012.
The present study was approved by the ethics committee of SUMC
(0343-­15-­SOR). Informed consent was not required as the analysis
involved the retrospective review of electronic medical files (>100 000
deliveries). The identifying number of each patient was encrypted to
maintain anonymity.
The present study center is a 1000-­bed tertiary teaching hospital
serving a population larger than 800 000.
Inclusion criteria for the case group were delivery at SUMC and
subsequent hospitalization during the non-­pregnant period, with at
least one of the following diagnoses recorded in patient medical files:
cardiovascular disease; cerebrovascular disease; chronic renal failure;
and complicated diabetes mellitus and hypertension (including diabe-
tes mellitus and hypertension with target organ damage, and/or acute
adverse events such as diabetic ketoacidosis, hyperosmolar state,
and hypertensive crisis). Subtypes of cardiovascular morbidity were
derived using the relevant International Classification of Diseases, 9th
edition codes (Table S1).
Inclusion criteria for the control group were delivery at SUMC and
no atherosclerotic-­related hospitalizations during the non-­pregnant
period. Patients were identified for inclusion in the control group from
among women who were not hospitalized; those who had delivered on
the same dates as patients included in the case group and who were
the same age (year of birth) were included in the control group.
The exclusion criteria for both groups were multiple pregnancy
and known cardiovascular disease, renal failure, or cardiovascular risk
factors (diabetes mellitus, hypertension, and hyperlipidemia) before
the first pregnancy.
Blood levels of creatinine, glucose, potassium, urea, and uric acid were
measured during pregnancy. Only women with at least one test result
available for all five measurements were included in the present study. The
highest measurement recorded for each test during any one pregnancy
was identified for each woman. The upper quartile was then selected for
|
      179
each measure: creatinine (>0.06 mmol/L); glucose (>7.2 mmol/L); potas-
sium (>4.4 mmol/L); urea (>3.8 mmol/L); and uric acid (>0.285 mmol/L).
The existence of a comprehensive computerized database at
SUMC, coupled with the unique structure of the local health ser-
vice, allowed for full availability of follow-­up data. Follow-­up data for
patients in the case group was until hospitalization occurred, whereas
for the control group it was until the end of the present study period.
The minimum period of follow-­up for the case group between delivery
and hospitalization was at least 1 year after the last pregnancy.
The data were analyzed using SPSS version 24 (IBM, Armonk, NY,
USA). Qualitative variables were assessed using the χ2 test. Continuous
variables were assessed using one-­way analysis of variance. Logistic
regression analysis using Cox regression was performed to evaluate
the relationship between cardiovascular-­related hospitalization and
upper quartile blood test results during pregnancy. Known gestational
risk factors for cardiovascular morbidity (maternal age, parity, hyper-
tensive disorders of pregnancy, gestational diabetes mellitus, preterm
delivery, and small for gestational age [SGA]) were included in two
regression analyses to confirm that the blood tests results remained
linked to cardiovascular morbidity even after adjusting for these fac-
tors. P<0.05 was considered to be statistically significant.
3 | RESULTS
A total of 169 059 deliveries were recorded at SUMC during the pre-
sent study period (Fig. 1). In all, 4115 women met both the inclusion
and exclusion criteria, 212 in the case group (hospitalized) and 3903
in the control group (non-­hospitalized).
The characteristics of the present study population are shown in
Table 1. Statistically significant between-­group differences were found
for parity, hypertensive disorders of pregnancy, gestational diabetes
mellitus, and delivery before 37 weeks.
Table 2 outlines the results for the five blood tests conducted
during pregnancy. Statistically significant between-­group differences
were found for all of these tests, both in terms of the upper quartile
values and the mean concentrations.
The Cox regression analysis of the relationship between upper
quartile blood test values and cardiovascular-­related hospitalization
is shown in Table 3. Three of the five blood tests showed a relation-
ship with hospitalization: creatinine (hazard ratio [HR] 1.86, 95%
confidence interval [CI] 1.37–2.53; P<0.001); potassium (HR 1.48,
95% CI 1.09–2.01; P=0.013); and urea (HR 1.60, 95% CI 1.17–2.19;
P=0.003). Hypertensive disorders of pregnancy, preterm delivery,
and parity were also associated with increased risk of hospitalization.
Table 4 shows the Cox regression analysis of the relation-
ship between the number of upper quartile values recorded and
cardiovascular-­related hospitalization. Any two tests with values in
the upper quartile had an HR of 1.65 (95% CI 1.06–2.56; P=0.026).
Any three or more tests with values in the upper quartile had an HR
of 3.32 (95% CI 2.19–5.04; P<0.001). As before, hypertensive disor-
ders of pregnancy, preterm delivery, and parity were also associated
with increased risk of hospitalization.
180      | Yuval Bar-­Asher ET AL.

Women who
underwent
hospitalization plus
Total deliveries at Women who had at
non-hospitalized
SUMC between least one blood test
matched control
2000 and 2013 result for all test
individuals (n=26 960)
(n=169 059) types (n=4115)

Excluded:
No blood test during pregnancy; multiple
pregnancy; known cardiovascular disease;
renal failure; or cardiovascular risk factors
(diabetes mellitus, hypertension, or
hyperlipidemia) before the first pregnancy
(n=22 845)

F I G U R E   1   Flow chart of the present study cohort. Abbreviation: SUMC, Soroka University Medical Center.

T A B L E   1   Characteristics of the study population.a complicated and influenced by several factors.11 For example, an
increase in aldosterone levels causes potassium excretion, whereas
Case group Control group
b progesterone acts as mineralocorticoid-­receptor antagonist; conse-
Characteristic (n=212) (n=3903) P value
quently, the normal range for plasma levels of potassium remains to
Age at the end of the 34.9 ± 5.3 34.5 ± 6.0 0.395
be defined. High potassium levels during pregnancy are associated
last pregnancyc
with an increased risk of developing both gestational diabetes mel-
Parity 5.0 (1.0–14.0) 3.0 (1.0–18.0) <0.001
litus and severe pre-­eclampsia.12 Therefore, it seems reasonable to
Hypertensive disorders 87 (41.0) 865 (22.2) <0.001
conclude that the high levels of creatinine, glucose, potassium, urea,
of pregnancy
and uric acid found in the present study during pregnancy might
Gestational diabetes 72 (34.0) 837 (21.4) <0.001
mellitus indicate a subclinical anomaly that could lead to overt cardiovascu-

Small for gestational age 30 (14.2) 571 (14.6) 0.848
Preterm delivery 96 (45.3) 1209 (31.0) <0.001
(<37 wk)
a as potential risk factors for future cardiovascular disease.5,13 Indeed,
Values are given as mean ± SD, median (range), or number (percentage),
unless indicated otherwise.
b 2
χ test and one-­way ANOVA; P<0.05 was considered significant.
c
Data on age was missing for 41 women in the control group.
4 |  DISCUSSION
The present study demonstrated that women hospitalized with car-
diovascular morbidity after pregnancy had high upper quartile values
recorded in their medical files for each of five routine blood tests
(creatinine, glucose, potassium, urea, and uric acid) conducted during
pregnancy. The upper quartile values for creatinine, potassium, and
urea were found to be associated with cardiovascular morbidity, both
independently of each other and when controlled for known gesta-
tional complications (hypertensive disorders of pregnancy, gestational
diabetes mellitus, preterm delivery, and SGA). The risk of cardiovas-
cular morbidity increased as the number of test results in the upper
quartile increased.
The current findings should be considered in light of the phys-
iologic alterations known to occur during pregnancy. The rise in
GFR leads to decreased serum levels of creatinine, urea, and uric
acid.2 By contrast, metabolism of potassium during pregnancy is
lar morbidity later in life.
Adverse events of pregnancy such as pregnancy-­induced hyper-
tension and gestational diabetes mellitus have long been considered
pregnancy serves as a stress test that is characterized by cardiomet-
abolic and renal overload. Women who had experienced pregnancy-­
induced hypertension were found to exhibit an increased incidence
of obesity, metabolic syndrome, and hypertension; early onset of
hypertension; high estimated vascular age; and low estimated GFR,14
underlining the importance of pregnancy-­induced hypertension as
a marker of future atherosclerotic morbidity. In another study, Cain
et al.15 found that maternal placental syndromes (i.e. pre-­eclampsia,
placental infarction, and abruption) were associated with short-­term
cardiovascular disease. The results of the present study support this
concept. Renal adaptation anomalies during pregnancy manifested as
high levels of creatinine, potassium, and urea. The factors, together
with pregnancy-­induced hypertension, were independently associated
with an increased incidence of future hospitalization owing to cardio-
vascular morbidity.
Cardiovascular disease is the leading cause of death among
women; furthermore, although myocardial infarction it is less prev-
alent among women than men, women have a higher mortality
rate after myocardial infarction.16 This difference partly reflects the
increased age of women at presentation, as well as the high rate
of adverse events that occur after myocardial infarction such as
Yuval Bar-­Asher ET AL. |
      181

T A B L E   2   Comparison of blood test results.a

Measure Case group (n=212) Control group (n=3903) OR (95% CI)b P valuec

Potassium, mmol/L
>4.4d 85 (40.1) 933 (23.9) 2.13 (1.60–2.83) <0.001
Mean ± SD 4.4 ± 0.6 4.2 ± 0.4 <0.001
Uric acid, mmol/L
>0.285d 73 (34.4) 894 (22.9) 1.77 (1.32–2.37) <0.001
Mean ± SD 4.6 ± 1.6 4.1 ± 1.3 <0.001
Creatinine, mmol/L
>0.06d 93 (43.9) 901 (23.1) 2.60 (1.97–3.45) <0.001
Mean ± SD 0.7 ± 0.3 0.6 ± 0.2 <0.001
Urea, mmol/L
>3.8d 87 (41.0) 897 (23.0) 2.33 (1.76–3.10) <0.001
Mean ± SD 23.7 ± 10.4 19.6 ± 6.2 <0.001
Glucose, mmol/L
>7.2d 77 (36.3) 938 (24.0) 1.80 (1.35–2.41) <0.001
Mean ± SD 137.3 ± 41.9 113.1 ± 68.0 <0.001

Abbreviations: CI, confidence interval; OR, odds ratio.

a
Values given as number (percentage), unless indicated otherwise.
b
Mantel–Haenszel common odds ratio estimate.
c 2
χ test; P<0.05 was considered significant.
d
Stated values represent the upper quartile.

bleeding following intervention and heart failure.17 In addition, the T A B L E   3   Logistic regression analysis of the relationship between
diagnosis and treatment of ischemic heart disease among women is upper quartile blood test results and subsequent hospitalization.
often delayed.18 One of the reasons for such delay is the fact that
Adjusted
ischemic heart disease without coronary artery obstruction is more Variable HR (95% CI)a P valueb
prevalent among women than men.19 Diagnosis and treatment of
Potassium >4.4 mmol/L 1.48 (1.09–2.01) 0.013
non-­obstructive coronary artery disease can be challenging because
Uric acid >0.285 mmol/L 1.03 (0.74–1.43) 0.854
it is not apparent on angiography and so the benefits of revascular-
Creatinine >0.06 mmol/L 1.86 (1.37–2.53) <0.001
ization are reduced accordingly. Thus, although women with ischemic
Urea >3.8 mmol/L 1.60 (1.17–2.19) 0.003
heart disease have lower pretest clinical scores, lower rates of previ-
ous myocardial infarction, and less angiographic coronary obstruction Glucose >7.2 mmol/L 1.25 (0.90–1.73) 0.173

when compared with men, they are at increased risk of poor cardio- Hypertensive disorders of 1.83 (1.34–2.50) <0.001
20 pregnancy
vascular outcomes.
Gestational diabetes mellitus 1.25 (0.88–1.77) 0.212
For these reasons, it is essential to identify in advance the sub-
group of women that are at high risk of future cardiovascular disease. 13 Small for gestational age 0.73 (0.48–1.11) 0.136

However, the standard risk prediction methods currently in use such Preterm delivery (<37 wk) 1.46 (1.08–1.96) 0.013
21 Parity 1.07 (1.01–1.12) 0.012
as exercise tests are less effective for women than for men. Women
with cardiovascular risk factors are also less likely than men to be told Age at the end of the last 0.97 (0.95–1.00) 0.056
about their risk profile and potential risk-­modification strategies.22 As pregnancy

a result, women have low access to preventive cardiac care before
experiencing myocardial infarction.23 They also tend to have a longer
period of symptoms than men do before seeking medical help when
having a myocardial infarction.24 Consequently, it is essential that
specific tools are developed to identify women in the high cardiovas-
8
cular risk group. According to clinical guidelines, pregnancy adverse
event history is mandatory when evaluating cardiovascular risk among
women with suspected cardiovascular disease. Pregnancy provides
a window of opportunity to detect women who are at increased
risk of future atherosclerotic-­related morbidity. Pregnancy-­induced
Abbreviations: CI, confidence interval; HR, hazard ratio.
a
Logistic regression backward stepwise (conditional).
b
P<0.05 was considered significant.
hypertension and gestational diabetes mellitus probably reflect severe
vascular and metabolic anomaly that could become permanent.25
Therefore, identifying a laboratory marker of such subclinical injury
could aid detection of high-­risk women at a reversible stage.
The present study had some limitations, mostly owing to the ret-
rospective design. For example, the possibility existed that women
182       | Yuval Bar-­Asher ET AL.

T A B L E   4   Logistic regression analysis of the relationship investigator and contributed to the design of the study, data collec-
between the number of upper quartile blood test results and tion, and writing and revising the manuscript.
subsequent hospitalization.

Adjusted
CO NFL I C TS O F I NT ER ES T
Variable HR (95% CI)a P value b

No. of blood test results in the upper quartile The authors have no conflicts of interest.

0 1.00 NA
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S U P P O RT I NG I NFO R M AT I O N
Additional supporting information may be found online in the
Supporting Information section at the end of the article.
Table S1. Cardiovascular morbidity stratified into three groups on the
basis of the International Classification of Diseases, 9th edition codes.