Preeclampsia: Review

Long-Term Cognitive Impairment

After Preeclampsia
A Systematic Review and Meta-analysis
Malik Elharram, MD, Natalie Dayan, MD, MSc, Amanpreet Kaur, MSc, Tara Landry, MLIS,
and Louise Pilote, MD, PhD

OBJECTIVE: To systematically review and summarize number of self-reported deficits in perception, memory,
studies investigating an association between a history and motor functioning on the Cognitive Failure Ques-
Downloaded from http://journals.lww.com/greenjournal by BhDMf5ePHKbH4TTImqenVHPymkXZPg+VTfW8rkq9VxTJNOUKDxfs9z90l2Sh0FjG on 08/12/2018

of preeclampsia and cognitive function later in life.
DATA SOURCES: Studies published before August 2017
were identified without any language restriction or study
design limits through electronic searches of 10 main
databases including MEDLINE and ClinicalTrials.gov.
METHODS OF STUDY SELECTION: We considered all
observational studies that included preeclampsia as a clearly
defined prespecified risk factor and that examined a cogni-
tion-related outcome measure including validated cognitive
tests, magnetic resonance brain imaging, or a clinical
diagnosis of dementia. Study quality was assessed using
the New-Castle Ottawa scale. All review stages were
conducted independently by two reviewers, and disagree-
ment was resolved by a third reviewer. Where possible,
data were pooled using a random-effects model.
TABULATION, INTEGRATION, AND RESULTS: Of 3,126
potentially relevant studies, 13 were included in our
review (1,314 women with prior preeclampsia and
289,080 women with prior normotensive pregnancy);
median time since pregnancy was 6 years. A higher
tionnaire was reported in women with vs without prior
preeclamptic pregnancies (Cognitive Failure Question-
naire mean total score 41.5 vs 36.8 out of 100, weighted
mean difference of 25.1 points [29.4 to 20.8]). Our
meta-analysis did not reveal significant differences in
studies assessing attention (Digit Symbol Substitution
or Coding); however, women with preeclampsia per-
formed worse on one of two meta-analyzed tests assess-
ing memory (Letter Number Sequencing mean total
score: 10.6 vs 10.1 out of 21, weighted mean difference
of 0.63 points 0.06–1.2). Pooling of cognitive outcome
measures for studies assessing brain imaging or a clinical
diagnosis of dementia were limited by differences in re-
porting and marked heterogeneity between studies.
CONCLUSION: Although preeclampsia is associated with
subjective cognitive symptoms, our systematic review did
not demonstrate clear evidence of impairment on standard
neurocognitive tests. There is a paucity of high-quality
studies assessing cognitive outcomes after preeclampsia.
(Obstet Gynecol 2018;132:355–64)
DOI: 10.1097/AOG.0000000000002686

From the Department of Experimental Medicine and the Division of General

Internal Medicine, McGill University, the Research Institute, McGill University
Health Centre, and the Library of the Montreal General Hospital, Montreal,
Quebec, Canada.
Supported by the Canadian Vascular Network.
Each author has indicated that he or she has met the journal’s requirements for
authorship.
Received January 10, 2018. Received in revised form March 15, 2018. Accepted
March 29, 2018.
Corresponding author: Louise Pilote, MD, MPH, PhD, Center for Outcomes
Research and Evaluation, 5252 boulevard de Maisonneuve West, Montreal, QC,
H3A 1A1, Canada; email: louise.pilote@mcgill.ca.
Financial Disclosure
The authors did not report any potential conflicts of interest.
© 2018 by the American College of Obstetricians and Gynecologists. Published
by Wolters Kluwer Health, Inc. All rights reserved.
ISSN: 0029-7844/18
P reeclampsia is a leading cause of maternal and fetal
morbidity and mortality, complicating 3–5% of
pregnancies worldwide.1 It is characterized by an
abnormal vascular response to placentation, resulting
in widespread endothelial dysfunction in multiple
organ systems including the brain.2 Delivery of the
placenta remains the standard of care for patients with
preeclampsia; however, years after pregnancy, long-
term effects of endothelial dysfunction may persist,3,4
Formerly preeclamptic women have been shown to
be at an increased risk of hypertension, ischemic heart
disease, stroke, and premature cardiovascular mortal-
ity compared with women without a history of pre-
eclampsia, years after pregnancy.5 Although these risk
factors are common to neurovascular conditions such

VOL. 132, NO. 2, AUGUST 2018 OBSTETRICS & GYNECOLOGY 355

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as cognitive impairment, the long-term consequences
of preeclampsia on cognitive function have been rel-
atively understudied.
The hypothesized mechanism of preeclampsia
relates to widespread endothelial dysfunction charac-
terized by an imbalance in proangiogenic and anti-
angiogenic proteins.6,7 Furthermore, former
preeclamptic women (elapsed time 0.25–6 years) have
been shown to have dampened responses to visually
evoked cerebral blood flow responses on transcranial
Doppler ultrasonography.8 We hypothesized that
these changes may affect cerebral hemodynamic func-
tion, manifested clinically through cognitive
impairment.
Formerly preeclamptic women report cognitive
slowing months to years after pregnancy.9,10 How-
ever, objective evidence of cognitive impairment from
validated neurocognitive tests has shown conflicting
results, with some studies showing worsening of cog-
nitive performance,4,11 whereas others have shown no
difference in cognitive performance when compared
with women with prior normotensive pregnancies.12
Furthermore, studies evaluating neuroimaging results
after preeclampsia have also reported conflicting re-
sults with select studies reporting an increased fre-
quency and severity of white matter lesions in
formerly preeclamptic women compared with pa-
tients with prior normotensive pregnancy13,14 and
other studies reporting no such difference.15 Studies
in elderly patients have shown white matter lesions to
be associated with a higher risk for ischemic strokes,
cognitive decline, and dementia,16 yet the clinical im-
plications of these white matter lesions in young pre-
eclamptic women remain largely unknown.
Because there is uncertainty about the long-term
association between preeclampsia and cognitive
impairment, we carried out a systematic review of
studies that compared objective and validated cogni-
tive measures in women with and without prior
preeclampsia. If a clear signal of impaired cognitive
performance is found in formerly preeclamptic
women, our study may indicate a potential role for
serial screening of cognitive function in addition to
routine cardiovascular surveillance after delivery.
SOURCES
The review was conducted using a predefined pro-
tocol in accordance with Preferred Reporting Items
for Systematic Reviews and Meta-analysis guide-
lines.17 Studies published before August 2017 were
identified without any language restriction or study
design limits through electronic searches of MED-
LINE via Ovid (including Epub ahead of print), reg-
356 Elharram et al Cognitive Impairment After Preeclampsia
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Unauthorized reproduction of this article is prohibited.
istered trials on Clinicaltrials.gov, PubMed, EMBASE
via Ovid, Biosis via Ovid, Global health via Ovid,
Popline, the Cochrane Central Register of Controlled
Trials, the Cochrane Database of Systematic Reviews,
and Web of Science. The MEDLINE search strategy
was developed by a librarian experienced in system-
atic review searching (T.L.) and peer-reviewed by
another librarian using the peer review of electronic
search strategy standard. The Full MEDLINE strategy
(Appendix 1, available online at http://links.lww.
com/AOG/B105) was applied to all databases with
modifications to search terms as necessary. Further
studies (n51) were identified in Web of Science and
SCOPUS by carrying out citation searches for studies
that cited our included studies as well as by examining
their reference lists.
STUDY SELECTION
We considered all observational studies that reported
preeclampsia as a clearly defined prespecified risk
factor and that examined any of the following neuro-
cognitive outcomes: brain imaging using magnetic
resonance, clinical diagnosis of dementia, or a battery
of validated neurocognitive tests, or all of these
(Appendix 2, available online at http://links.lww.
com/AOG/B105). Women of any parity, age, or
severity of preeclampsia were included. We excluded
case reports, case series, and studies that examined
eclampsia alone or where cognitive outcome data on
patients with preeclampsia could not be separated
from patients with eclampsia. The reason we excluded
patients with eclampsia is because of the well-known
findings of cerebral edema on magnetic resonance
imaging (MRI) of patients with eclampsia and the
association of eclampsia with long-term subjective
cognitive impairment as reported in several stud-
ies.9,18 We also excluded studies that did not report
a comparison group of women without prior
preeclampsia.
Two independent reviewers (M.E., A.K.) per-
formed the study selection using specific inclusion
criteria to ensure accuracy and reproducibility. The
first screening was based on titles and abstracts of
identified publications. All potentially relevant studies
were retrieved for full-text evaluation. Both reviewers
independently evaluated full-text articles and reasons
for exclusion were recorded. Disagreement was
resolved by a third reviewer (L.P.). If duplicate studies
were found within the same data source, either the
most recent or most complete publication was
selected. The study selection process is displayed in
Appendix 3, available online at http://links.lww.com/
AOG/B105.
OBSTETRICS & GYNECOLOGY
 Within the included studies, women underwent
a variety of standardized neurocognitive tests, which
are each described in detail in Appendix 2 (http://
links.lww.com/AOG/B105). Briefly, the tests
included were designed to assess subjective cognitive
symptoms (Cognitive Failure Questionnaire)19,20;
attention, processing speed, and visuospatial skills
(Digit Symbol Substitution or Coding test,21 memory
[Letter Number Sequencing22], and Rey Auditory
Verbal Learning Test).23
Using standardized data extraction sheets, two
investigators (M.E. and A.K.) independently extracted
data on several study characteristics for all studies that
met inclusion criteria including study design, location,
sampling strategy, population, exposure and outcome
measurements, participant characteristics, duration of
follow-up, any adjustment in the analysis, and type of
effect measure. For studies examining cognitive func-
tion using neurocognitive tests, the mean or median
score of the respective cognitive tests was recorded.
Authors reporting insufficient study details or results
were contacted and allotted 3 weeks of time for
a response.
The Newcastle-Ottawa Scale was used to assess
the quality of observational studies. This scale uses
a “star” system to assess the quality of a study in three
domains: selection of participants, comparability of
study groups, and ascertainment of outcomes of inter-
est. Case–control and cohort studies were evaluated
out of a total score of 9, and cross-sectional studies
were evaluated out of a total score of 10 using a mod-
ified Newcastle-Ottawa Scale designed for cross-
sectional studies.24 A study with a high risk of bias
was defined as a score of 0–4, medium risk of bias was
defined as a score of 4–6, and a low risk of bias was
defined as a score from 7-9 out of 10. No study
was excluded based on quality alone.
The mean scores and standard deviation (SD) of
the neurocognitive test measures, relative risk for
developing white matter lesions on MRI, and the
relative risk of developing dementia for normotensive
and preeclamptic patients was pooled using a random-
effects model if there were at least three studies using
the same outcome measure. Results for neurocogni-
tive tests were pooled only if they used the same
neurocognitive test in women with the same exposure
(ie, preeclampsia). A mean score and a SD for
neurocognitive tests were estimated for studies report-
ing a median, range, and sample size using the
method by Hozo et al.25 Results of the meta-analysis
were presented as a weighted mean difference
between former preeclamptic and normotensive preg-
nant patients with the corresponding 95% CI. We
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used the I2 statistic to quantify the degree of hetero-
geneity among trials in each meta-analysis. The choice
between fixed- and random-effects meta-analysis has
been performed on the basis of the I2 index, where I2
greater than 25% led us to conduct random-effects
meta-analyses based on linear (mixed-effects) models
with inverse-variance weights.26 Studies were pooled
only if the I2 was below 75%. A funnel plot for pub-
lication bias was planned for summaries of cognitive
measures with at least 10 pooled studies. Analysis was
conducted using SAS version 9.4.
RESULTS
In the initial literature search, 3,126 studies were
identified, of which 32 were selected for full-text
review (Appendix 3, http://links.lww.com/AOG/
B105). Fifteen studies were included for the final
review, after which one study was excluded during
data entry because it was not possible to separate pa-
tients with preeclampsia from those with eclampsia27
(author contacted), and another study was excluded
because it used the same cohort of patients analyzed
in a previously included study28 (author contacted).
The characteristics of the 13 remaining studies, com-
prising a total of 1,314 (range 4-419) women with
prior preeclampsia and 289,080 (range 4–283,902)
women with prior normotensive pregnancy, are
represented in Appendix 4, available online at
http://links.lww.com/AOG/B105. Seven of the
included studies examined cognitive function using
neurocognitive tests,4,9,12,15,18 four studies examined
MRI,13–15,29and three studies examined a clinical
diagnosis of dementia.30–32 The most commonly used
cognitive tests were the Letter Number Sequencing,
Digit Symbol Substitution or Coding, Rey Auditory
Verbal Learning Test, and Cognitive Failure
Questionnaire.
Across seven studies, there were 26 neurocogni-
tive tests that were evaluated in 527 (range 10–208),
formerly preeclamptic and 1,430 (range 10–959) for-
merly normotensive pregnancies. The median time
between the index preeclamptic pregnancy and the
measure of cognitive function was 5 years (range 3
months to 35 years). Eight main cognitive domains
were studied. Because several neurocognitive tests
examined multiple cognitive domains, the tests were
divided based on the principal domain as determined
by the authors, indicated in Appendix 2 (http://links.
lww.com/AOG/B105). Of the seven studies reporting
data on neurocognitive tests, only four studies used
the same cognitive tests, which allowed for collective
pooling of the results.
Cognitive Impairment After Preeclampsia 357
 The Rey Auditory Verbal Learning Test (total
score out of 75),9,11,12 and the Letter Number
Sequencing (score out of 21) (three studies)9,11,12
were used to assess memory across 398 patients
(202 women with preeclampsia and 196 women
with normotensive pregnancy. Women with a prior
normotensive pregnancy had better memory func-
tion as assessed by the Rey Auditory Verbal Learn-
ing Test and Letter Number Sequencing compared
with those with a history of preeclampsia; however,
significant heterogeneity precluded any pooled
estimate of the results (mean Rey Auditory Verbal
Learning Test score: 53.8 vs 47.6 correct responses
out of 75, I 2 592%; Letter Number Sequencing
mean total score: 10.6 vs 10.1 out of 21, weighted
mean difference of 0.63 points [0.063–1.2], I2 50%)
(Figs. 1 and 2).
Other tests used to examine memory, including
the Corsi block-tapping test,9 incidental learning
task,15 California Verbal Learning Test,4 logical mem-
ory I and II,12 visual reproduction I and II,12 and the
Location Learning Test,9 did not reveal any signifi-
cant differences between patients with and without
a history of preeclampsia.
The Digit Symbol Substitution or Coding Test (total
score achieved in 90 seconds)4,9,12 was used as a measure
of attention across 225 patients (118 women with pre-
eclampsia and 107 with normotensive pregnancy).
Within this group, pooled results did not demonstrate
any significant difference between patients with and with-
out prior preeclampsia (mean Digit Symbol Substitution
or Coding Test score 63.0 vs 67.3 correct responses in 90
seconds, weighted mean difference of 2.27 correct re-
sponses [20.91 to 5.47], I2552.1%) (Fig. 3).
The Stroop I and II test,9,11 digit span task,9,11,12
and the Trail Making Test parts 1–39 used to assess
attention demonstrated a trend toward worse perfor-
mance in women with preeclampsia; however, the
results were limited by a small patient population.
Results of neurocognitive tests used to examine
visual spatial ability including the block design,11,12
clock design,11 picture completion,12 and incomplete
figures test9 were not significantly different between
patients with and without a history of preeclampsia.

Fig. 1. Weighted mean difference in Rey Auditory Verbal Learning Test score between former preeclamptic (PE) and nor-
motensive (NTP) pregnancies (score out of 75).
Elharram. Cognitive Impairment After Preeclampsia. Obstet Gynecol 2018.

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Fig. 2. Weighted mean difference in score on the Letter Number Sequencing task between former preeclamptic (PE) and
normotensive (NTP) pregnancies (score out of 21).
Elharram. Cognitive Impairment After Preeclampsia. Obstet Gynecol 2018.

Similarly, the semantic fluency,9,11,12,15 phono-
logic fluency,9,12,15 similarities (Wechsler Adult Intel-
ligence Scale IV),11 and the Boston Naming Test,11
used to examine language, were not significantly dif-
ferent between patients with and without a history of
preeclampsia.
Results of neurocognitive tests used to examine
motor speed including the Grooved Pegboard Test,4,9
Trail Making Test part 5,9 and Reaction Time Test4
were not significantly different between patients with
and without a history of preeclampsia.
Information processing as measured using
Paced Auditory Serial Addition Test revealed a sig-
nificantly lower number of correct answers in
patients with compared with those without a history
of preeclampsia in one study (mean total correct
answers: 37.6 [9.1] vs 44.0 [7.0], in 160 patients).4
The digit symbol search was not significantly differ-
ent between patients with and without a history of
preeclampsia.9
The score on the Stroop part III,9,11 Trail Making
Test part B,9,11,12 figure fluency test,9 and the tower
test9 did not reveal any significant difference between
patients with and without a history of preeclampsia.
The Mini Mental State Examination15 and the
national Dutch reading test9,11 used to examine global
cognitive performance were not significantly different
between women with and without a history of
preeclampsia.
Subjective cognitive impairment was assessed
using the Cognitive Failure Questionnaire (score
out of 100) across 330 patients (148 women in the
case group and 182 in the control group in three
studies).4,9,18 Pooled results demonstrated overall
higher subjective deficit in memory, perception,
and motor functioning in women with prior pre-
eclamptic pregnancies compared with normoten-
sive pregnancies (Cognitive Failure Questionnaire
mean total score 41.5 vs 36.8 out of 100, weighted
mean difference of 25.12 points [29.4 to 20.87],
I2557.5%) (Fig. 4).
In a separate study, women with recent pre-
eclampsia admitted to a greater number of “mental pro-
blems” (67% vs 29%) and loss of concentration (67% vs

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Fig. 3. Weighted mean difference in Digit Symbol Substitution or coding score between former preeclamptic (PE) and
normotensive (NTP) pregnancies (number of correct responses in 90 seconds).
Elharram. Cognitive Impairment After Preeclampsia. Obstet Gynecol 2018.

45%) compared with women without recent preeclamp-
sia 6–18 months earlier.10
We were unable to assess for publication bias in
studies on neurocognitive performance because there
were fewer than 10 pooled studies for each neuro-
cognitive test.
Four studies with 1,352 patients (357 women with
a history of a hypertensive disorder of pregnancy and
995 with a history of a normotensive pregnancy)
examined radiologic changes on MRI with a prespecified
technique to characterize white matter lesions (median
time between pregnancy and MRI scan 5.3 years, range
5–9 years).13–15,29 Magnetic resonance imaging was per-
formed in all patients with a history of a hypertensive
disorder of pregnancy or a normotensive pregnancy.
The characteristics of the studies examining radiologic
changes are listed in Appendix 5, available online at
http://links.lww.com/AOG/B105. The studies used dif-
fering techniques to characterize white matter lesions
with one study comparing the number of lesions,13
two studies examining for the presence of white matter
lesions,14,22 and three studies comparing the volume of
white matter lesions.13,15,29 Of the studies reporting on
the location of white matter lesions, the frontal lobe was
predominately affected (two studies).13,14 Prior pre-
eclampsia was also associated with either a greater vol-
ume of white matter lesions (two of three studies)13,29 or
presence of white matter lesions (two of two studies).11,29
As a result of the limited number of studies and signif-
icant heterogeneity in the assessment and measurement
of white matter lesions, pooling of results was not
performed.
Three studies examined a clinical diagnosis of
dementia as a measure of cognitive function
in 287,671 patients (1,119 cases of dementia [range
4–696] and 286,552 control participants [range
4–283,902]).30–32 The mean age of patients with and
without preeclampsia at the time of diagnosis of
dementia was 73 and 74 years of age, respectively.
One study examined Alzheimer dementia,31 one
study examined vascular dementia along with demen-
tia (unspecified),30 and one study included all patients
with dementia (unspecified).32 Across all three studies,
there was no reported increased risk of dementia after
a history of preeclampsia; however, a pooling of the
risk was not possible as a result of heterogeneity

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Fig. 4. Weighted mean difference in Cognitive Failure Questionnaire between former preeclamptic (PE) and normotensive
(NTP) pregnancies (score out of 100). *Study used preterm preeclampsia and preterm pregnancy in their analysis. †Study
used preeclampsia at term and normotensive pregnancy at term in their analysis.
Elharram. Cognitive Impairment After Preeclampsia. Obstet Gynecol 2018.

between the studies (Appendix 6, available online at
http://links.lww.com/AOG/B105).
Quality assessment is presented in Appendix 4
(http://links.lww.com/AOG/B105). Six studies had
a medium risk of bias (4–6 stars), and seven studies
had a low risk of bias (7–9 stars). None of the studies
included were at high risk of bias. Within our review,
5 of 13 studies did not adjust for any confounders in
their analysis. Of the four pooled studies examining
neurocognitive tests, two studies had a low risk of bias
and two had a medium risk of bias.
DISCUSSION
In this systematic review, we summarized available
evidence on the association between preeclampsia
and long-term cognitive function as measured through
neurocognitive tests, MRI, and a clinical diagnosis of
dementia. Our hypothesis was that long-term vascular
changes after preeclampsia,3 which contribute to the
development of hypertension, ischemic heart disease,
and stroke,5 might also manifest with subtle but clin-
ically perceptible cognitive deficits. Among the 13
studies included, there was significant between-study
heterogeneity in participant age, sample size, clinical
definition of preeclampsia, length of time between
pregnancy and cognitive outcome measurement, and
cognitive tests used, which precluded summary assess-
ments in all cognitive domains. Thus, although our
meta-analysis demonstrates a small but significant
association between preeclampsia and self-reported
cognitive impairment, there are insufficient data to
conclude about the presence or absence of subtle
objective cognitive changes in memory, attention, or
executive function. Preeclampsia did appear to be cor-
related with the presence and severity of white matter
lesions, particularly in the frontal lobe. There was no
clear association between preeclampsia and a clinical
diagnosis of dementia in the three studies that assessed
this outcome.
Women with a history of preeclampsia reported
subjective losses in perception, memory, and motor
function more often than women with normotensive
pregnancy. This significant finding was mainly driven
by the study by Postma et al,9 which had the highest
sample size of women (51 with prior preeclampsia,
n548 control participants). The authors of this study
also adjusted for age in their analysis and used a strict
definition of preeclampsia. A similar trend was found

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in the other three studies. Although women per-
formed slightly worse on the Letter Number Sequenc-
ing test assessing memory, this finding did not persist
in other neurocognitive tests assessing memory (Rey
Auditory Verbal Learning Test).
There are a number of explanations for the lack
of a clear association in objective cognitive outcomes
in our systematic review despite finding consistently
lower subjective cognitive scores. First, the studies
within our review had a relatively short follow-up
between preeclampsia and the measure of cognitive
function using neurocognitive tests (median 5 years)
with the majority of studies reporting a follow-up less
than 10 years. Consequently, women in our review
were relatively young at the time of assessment. It is
possible that more clinically apparent cognitive issues
might become apparent only with time as the neuro-
vascular changes and white matter disease progress.
Furthermore, individual studies may have been
underpowered to detect subtle but significant differ-
ences in neurocognitive tests. Indeed, statistical trends
observed in small studies12,33 may well translate to
significant effects if repeated with larger sample sizes.
Alternatively, our findings of self-reported cognitive
decline in formerly preeclamptic women could be
limited by the confounding effects of psychologic
stressors4 and recall bias.
An interesting finding in our review is the
consistent reporting of abnormal presence or number
of white matter lesions on brain MRI after pre-
eclampsia, predominantly in the frontal lobe. It is less
clear whether these white matter lesions are more
severe, with one large study showing no difference15
but smaller studies suggesting a difference between
women with prior preeclampsia compared with those
without prior preeclampsia.13,29 We were not able to
pool the severity of white matter lesions on MRI
together in our meta-analysis as a result of differences
in reporting of white matter lesions. The clinical rele-
vance of white matter lesions in young asymptomatic
individuals is unknown. Studies in elderly patients
have shown white matter lesions to be associated with
a higher risk for ischemic strokes, cognitive decline,
and dementia.16 In contrast, however, white matter
lesions have previously been reported in relatively
young and healthy cohorts34 and is known to develop
in patients with a history of hypertensive disease.34
Within our review, patients with preeclampsia under-
went MRI soon after preeclampsia and on average
were relatively young. These white matter lesions
could be a manifestation of hypertensive disease often
coexistent in patients with preeclampsia or could rep-
resent an irreversible pathologic insult during pre-
362 Elharram et al Cognitive Impairment After Preeclampsia
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eclampsia. We suspect, however, that given the
compensatory capacity of the brain at a young
age,33 the clinical manifestation of white matter le-
sions in patients with preeclampsia might not be
apparent until much later in life, which necessitates
the need to follow these women for a longer period
and evaluate cognitive function objectively at later
time points.
Given the evidence supporting the increased
presence and severity of white matter lesions in
former preeclamptic patients and the elevated risk
for ischemic stroke,5 we hypothesized that preeclamp-
sia could be linked with an early onset of dementia.
Within our review, however, there did not appear to
be any association between preeclampsia and a clinical
diagnosis of dementia. These studies, however, often
evaluated dementia collectively without separating
neurodegenerative causes from dementia secondary
to a vascular insult. Two of the three studies evaluat-
ing the association between preeclampsia and demen-
tia included dementia that was unspecified,30,32 and
one study examined preeclampsia with Alzheimer
dementia.31 In one of the three studies, vascular
dementia was analyzed in a subanalysis of patients
with hypertension and proteinuria in pregnancy and
an elevated risk for vascular dementia was found (haz-
ard ratio 6.27, CI 1.64–27.44)30; however, this was
analyzed in only two patients with vascular dementia.
Further studies, however, are needed to support this
finding, and future research should focus on examin-
ing the association between preeclampsia and vascular
dementia.
Our review has several strengths. Although much
is known about the association between preeclampsia
and cardiovascular disease, considerably less is known
about the spectrum of cerebrovascular conditions that
might ensue after this pregnancy complication. We
used a rigorous approach following Preferred Report-
ing Items for Systematic Reviews and Meta-analysis
guidelines17 and did not limit our search based on
time or language. We pooled results only among stud-
ies with moderate or low heterogeneity and reported
results separately for subjective and objective cogni-
tive measures. Despite these strengths, our review has
several limitations that should be considered. Substan-
tial heterogeneity in the outcome measurements of
our studies assessing neurocognitive tests or radio-
logic imaging made it challenging to pool existing
results together in a meta-analysis. Thus, although
we provide a summary of existing data, we are unable
to comprehensively estimate an overall effect of pre-
eclampsia on cognition. A second limitation inherent
to systematic reviews of observational studies is the
OBSTETRICS & GYNECOLOGY
potential for both known and unknown confounders
in individual studies that may explain any observed
estimates of effect. Within our review, 5 of 13 studies
did not adjust for any additional factors in their assess-
ment of cognitive function in patients with preeclamp-
sia. Furthermore, despite a comprehensive search of
the literature, we were limited by a small number of
studies and sample size of patients in our meta-
analysis with a relatively short follow-up for cognitive
outcomes.
The results of our systematic review and meta-
analysis shed light on the gaps and limitations in
existing studies examining the association between
preeclampsia and cognitive outcomes. Future studies
are needed that follow large cohorts of women with
and without preeclampsia over a long period of time,
use well-validated and uniform neurocognitive tests
assessing each cognitive domain, and attempt to
control for confounders and mediators including
hypertension, education, and psychologic variables.
The concomitant use of MRI with neurocognitive
test will provide a more comprehensive picture of
the presence of absence of clinically significant
cerebrovascular pathology. The use of sensitive tests
to detect subtle cognitive alterations in young
individuals should be prioritized. If cognitive
impairment does indeed persist after preeclampsia,
such tests should be added to the recommended
cardiovascular screening in these women after
pregnancy.
Abundant data now exist that preeclampsia and
other pregnancy complications increase a woman’s risk
for hypertension and premature cardiovascular dis-
eases.5 International consensus is needed to establish
a core outcome set and standardized reporting recom-
mendations after preeclampsia. Cognitive testing, MRI,
and functional brain imaging may be additional meas-
ures to be included in this core outcome set to gain
a comprehensive picture of the extent of both clinical
and subclinical vascular injury in these women.
Preeclampsia is associated with subjective cogni-
tive impairment after pregnancy without clear evi-
dence of deficits in attention or memory on
neurocognitive tests. Future research efforts should
focus on designing studies with long-term follow-up,
using well-validated and uniform neurocognitive tests,
and controlling for confounders.
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