PREECLAMPSIA AND COGNITIVE IMPAIRMENT LATER IN LIFE

Abstract

BACKGROUND

Hypertension is a risk factor for cerebrovascular disease and cognitive impairment. Women who suffer hypertensive episodes during pregnancy report variable neurocognitive changes within the first decade following the affected pregnancy. However, long-term follow-up of these women into their post-menopausal years has not been conducted.

OBJECTIVE

The aim of this study was to examine whether women with a history of preeclampsia were at increased risk of cognitive decline 35–40 years after the affected pregnancy.

STUDY DESIGN

Women were identified and recruited through the medical linkage, population-based Rochester Epidemiologic Project. Forty women with a history of preeclampsia were age- and parity-matched to 40 women with a history of normotensive pregnancy. All women underwent comprehensive neuropsychological assessment and completed self-report inventories measuring mood, i.e., depression, anxiety, and other symptoms related to emotional state. Scores were compared between groups. In addition, individual cognitive scores were examined by neuropsychologists and a neurologist blinded to pregnancy status, and a clinical consensus diagnosis of normal, mild cognitive impairment, or dementia for each participant was conferred.

RESULTS

Age at time of consent did not differ between preeclampsia (59.2 years, range 50.9–71.5) and normotensive (59.6 years, range 52.1–72.2) groups, nor did time from index pregnancy (34.9 years, range 32.0–47.2 vs 34.5 years, range 32.0–46.4, respectively).There were no statistically significant differences in raw scores on tests of cognition and mood between women with histories of preeclampsia compared to women with histories of normotensive pregnancy. However, a consensus diagnosis of mild cognitive impairment or dementia trended towards greater frequency in women with histories of preeclampsia compared to those with normotensive pregnancies (20% versus 8%, p = 0.10) and affected more domains among the preeclampsia group (p = 0.03), most strongly related to executive dysfunction (d = 1.96) and verbal list learning impairment (d = 1.93).

CONCLUSIONS

These findings suggest a trend for women with a history of preeclampsia to exhibit more cognitive impairment later in life than those with a history of normotensive pregnancy. Furthermore, the pattern of cognitive changes is consistent with that observed with vascular disease/white matter pathology.

Introduction

Hypertensive disorders of pregnancy, including preeclampsia, confer increased risk of cardiovascular disease (CVD) morbidity and mortality.¹ Preeclampsia occurs in about 3% of pregnancies,² and is associated with an approximate two-fold increased risk of CVD and cerebrovascular disease.³ Some risk factors associated with preeclampsia are shared with those for CVD and cognitive decline, including hypertension, metabolic syndrome, and insulin resistance.^4–7

Women with a history of hypertensive pregnancy more frequently report subjective cognitive complaints and endorse more physical and psychological symptoms that negatively impact physical, social, and emotional well-being and quality of life than women with a history of normotensive pregnancy.^8–10 In addition, reported changes in cognition associate with the severity of preeclampsia¹¹ or post-traumatic stress symptoms of preeclampsia.¹² However, studies examining the impact of hypertensive pregnancy on cognitive performance report mixed results. For example, no differences in sustained attention or executive functioning were reported in women in their late 30s to early 40s, up to a decade following an index pregnancy of preeclampsia or eclampsia, compared to age-matched women with normotensive pregnancies.¹³ In contrast, others have found slower motor speed,⁸ poorer attention,¹² or poorer learning and memory¹¹ in women with a history of hypertensive pregnancy. Long-term follow-up of these women into their post-menopausal years has not been conducted. Therefore, in the present study, cognition and mood were evaluated in women approximately 35 years after preeclamptic or normotensive pregnancy. We hypothesized that women with a history of preeclampsia (hPE) would be more likely than women with a history of normotensive pregnancy (hNTP) to have cognitive impairment and that the pattern would resemble changes characteristic of vascular/white matter disease.

Materials and Methods

Participants

Recruitment details have been previously reported.¹⁴ In brief, HICDA (Hospital Adaptation of the International Classification of Diseases Adapted) codes and the population-based Rochester Epidemiology Project medical records-linkage system¹⁵ were used to identify 40 women with hPE and 40 women with hNTP. Sample size was based on power calculation to detect differences in cardiovascular parameters. To be eligible for the study, a woman had to be a resident of Olmsted County, MN when delivering a baby from a pregnancy lasting >20 weeks (live birth or stillbirth) between January 1, 1976 and December 31, 1982, had to have had a documented clinical visit within the last 2 years to confirm that women did not have a cardiovascular or other neurological event that could potentially confound results, and had to live within 120 miles of Olmsted County in order to be available for in-person visits.

The medical records of all women were fully abstracted for demographic and clinical information. A potential exposure was confirmed as preeclampsia if a woman had at least one preeclamptic pregnancy between 1976–1982 that met the standard definition: 1) two or more blood pressure readings of a systolic blood pressure (SBP) > 140 mm Hg or a diastolic blood pressure (DBP) >90 mm Hg at least 4 hours apart after 20 weeks gestation and 2) new onset proteinuria, as defined by a urine dipstick 1+, or proteinuria ≥0.300 g /24 hours, or a protein/creatinine ratio equivalent to ≥ 0.300 g per 24 hours. Emergency room visits were not included. Women were sequentially contacted and recruited. Each of the 40 women with hPE was age and parity- matched to a woman with hNTP. All women were postmenopausal and index pregnancies were first pregnancies. Eligible women were sent a letter describing the study, given contact information, and if no response within two weeks, contacted by phone. Of the 77 women with confirmed hPE, 25 (32%) refused and 7 (9%) did not respond. Five (6%) were found to be ineligible after further screening. For women with hNTP, 104 women were contacted, 18 (17%) refused, 41 (39%) did not respond, and 5 (5%) wanted to participate but another matched control had already agreed.

As the primary focus of this study was to understand the potential mechanisms that place women with hPE at risk for subclinical CVD and cognitive decline, women were excluded with a medical-record confirmed clinical diagnosis of myocardial infarction, congestive heart failure, stroke, dementia, cancer (excluding non-melanoma skin cancer), autoimmune disease (e.g., multiple sclerosis, lupus), and neurological conditions (e.g., epilepsy). All protocols were approved by Mayo Clinic and Olmsted Medical Center Institutional Review Boards (PR10-005198-05) and all participants gave written informed consent.

Clinical Assessment of Cardiovascular Risk

Demographic and clinical data obtained from medical records and patient interviews at the time of the in-clinic assessment included age, body mass index (BMI), SBP, DBP, anti-hypertensive and-lipid lowering medications, and chart-abstracted and physician-confirmed diagnoses of hypertension, hyperlipidemia and diabetes mellitus. The diagnosis of hypertension was confirmed if a prior diagnosis and/or use of prescription anti-hypertensive medication were confirmed upon medical record review, or if a SBP≥ 140 mm Hg or DBP≥ 90 mm Hg was documented in the medical records on two separate occasions. The diagnosis of dyslipidemia was confirmed if one or more of the following criteria were met: use of lipid-lowering drugs or laboratory measurements revealing a total cholesterol ≥ 200 mg/dL, triglycerides ≥ 150 mg/dL, or HDL ≤ 50 mg/dL. Diabetes mellitus was diagnosed by either a HgA1c≥ 6.5% or a fasting glucose > 126 mg/dL, or a physician diagnosis in the past, with or without current glucose-lowering agents. Coronary artery calcification (CAC) is a measurement of the amount of calcium in the walls of the arteries that supply the heart muscle and is recorded in Agatston Units (AU). The higher the number, the greater the amount of plaque. CAC was evaluated by computed tomography and has been previously reported.¹⁴

Cognitive Assessment

Women underwent comprehensive cognitive testing administered by an experienced psychometrist under the supervision of a neuropsychologist. The 2.5-hour battery included standardized and validated tests of attention, working memory, psychomotor processing speed, executive functioning, language, perceptual processing, learning and memory administered in a fixed order. Women also completed self-report mood questionnaires one week prior to or at the same time as cognitive testing. (See Table 1 for complete description of cognitive and mood measures.)

Table 1.

Measures of cognition and mood

Attention	Wechsler Adult Intelligence Scale-III Digit Span measures auditory attention and working memory capacity. This test involves repetition of oral sequences of numbers of increasing length exactly as they are presented in the Forward condition and then in reverse in the Backward condition. Digit Span Forward measures simple auditory attention capacity and Digit Span Backward measures working memory capacity. Score is total number of forward and backward sequences repeated correctly.
	Trail Making Test-Part A measures visual attention and processing speed. It is a paper-and-pencil test requiring rapid connection of consecutively numbered circles. Score is time (in seconds) to complete the trial, with a higher score reflecting poorer performance.
Working Memory	Wechsler Adult Intelligence Scale-III Letter-Number Sequencing measures auditory working memory. Letters and numbers of increasing length are orally presented in random order. Mental manipulation is required to rearrange the numbers and letters and then repeat in ascending order. Score is total number of correct sequences
Psychomotor Processing	Wechsler Adult Intelligence Scale-III Digit Symbol Coding measures visual scanning, motor persistence, sustained attention, response speed, and visuomotor coordination. It involves quickly transcribing symbols into blank spaces below numbers that correspond to symbol-number pairs presented in a key above. Score is the total number of symbols correctly transcribed within a specified amount of time.
Executive Functioning	Trail Making Test-Part B measures visuomotor speed, divided attention, and cognitive flexibility. It increases demands of Trail Making Test-Part A by requiring rapid connection of not only consecutively numbered circles but also lettered circles and alternating between them. Score is time (in seconds) to complete the trial, with a higher score reflecting poorer performance.
Language	Phonemic (C, F, L) and Semantic (animals, fruits, vegetables) Verbal Fluency measure the ability to produce fluent speech. It has also been used to assess the ability to think flexibly and to gauge how efficiently one uses search and retrieval strategies to organize thoughts. The objective is to rapidly generate as many words as possible within a certain amount of time that begin with specified letters and belong to specified categories. Scores are total number of words generated for the three letters and the three categories.
	Boston Naming Test measures the ease and accuracy of word retrieval and how intact semantic networks are. It also gives some indication of vocabulary level. This test requires providing the name for common objects presented in black and white drawings. Score is total number of objects correctly named.
Visuospatial Processing	Wechsler Adult Intelligence Scale-III Picture Completion measures the ability to measure attention to visual detail. Pictures of common objects and scenes with a detail missing from them are presented, and the examinee is asked to identify what is missing. Score is total number of correct responses.
	Wechsler Adult Intelligence Scale-III Block Design measures visual problem-solving and understanding of part-to-whole relationships. It involves manual manipulation of 3-dimensional blocks to match 2-dimensional line drawings. Score is total number of correct designs.
Learning and Memory	Auditory Verbal Learning Test measures learning efficiency, immediate memory span, sensitivity to interference with learning and recall, and rates of forgetting and retention. A list of unrelated words is serially presented. The object is to learn as many words as possible over repeated trials, recall them after being presented a distractor list, and recall them again after a 30-minute delay. Several scores are derived: The Learning score is the sum of the number of words recalled immediately on each trial, the Delay score is the number of words recalled after a long delay, and the % Retention score is the number of words on the delayed recall trial divided by the number of words recalled on the last learning trial.
	Wechsler Memory Scale-Revised Logical Memory I & II measure learning, recall, and retention of logically organized verbal information. Paragraph-length prose passages are read out loud to the examinee, who is to recall as much information from the stories as possible immediately following presentation and again after a 25- to 35-minute delay. Logical Memory I score is the total number of story details recalled immediately following presentation, Logical Memory II is the total number of story details recalled after a longer delay, and % Retention is the number of story details on delayed recall divided by immediate recall.
	Wechsler Memory Scale-Revised Visual Reproduction I & II measure visual learning, memory, and retention of geometric designs. Cards with line drawings are presented for a brief amount of time, taken away, and then the examinee is asked to reproduce the designs as accurately as possible. After a 25- to 35-minute delay, the examinee is asked to again reproduce as many of the designs as possible, but this time without being shown the cards. Visual Reproduction I score is the total number of design details recalled immediately following presentation, Visual Reproduction II is the total number of design details recalled after a longer delay, and % Retention is the number of design details on delayed recall divided by immediate recall.
Mood State	Beck Depression Inventory-II is a 21-item self-report scale measuring a range of affective, cognitive, and physiologic symptoms of depression (e.g., sense of failure, loss of interest, indecisiveness, appetite, libido). Each item contains four statements of graded severity expressing how a person might feel or think about the aspect of depression under consideration, with scores ranging from 0 for absence of problems in that area to 3 for the most severe level of that problem. The score is the sum of all of all statements endorsed, with a higher score representing greater severity.
	Beck Anxiety Inventory is a 21-item self-report scale measuring a range of subjective, physiologic, autonomic, and panic-related symptoms of anxiety (e.g., unable to relax, hands trembling, heart pounding or racing, fear of the worst happening). Each item contains four statements of graded severity expressing how a person might feel or think about the aspect of depression under consideration, with scores ranging from 0 for absence of problems in that area to 3 for the most severe level of that problem. The score is the sum of all of all statements endorsed, with a higher score representing greater severity.
	Profile of Mood States is a 65-item self-report measure of six mood states: Tension-Anxiety, Depression-Dejection, Anger-Hostility, Vigor-Activity, Fatigue-Inertia, and Confusion-Bewilderment. It contains adjectives that describe how a person may be feeling (e.g., unhappy, relaxed, exhausted, rebellious, efficient), and individuals are asked to rate how much during the past week they have had that feeling. Scores range from 0 to 4, with 0 being not at all and 4 being extremely. A sub-scale score is derived for each of the six mood states, with a higher score representing greater difficulty in all but the Vigor-Activity state, where a higher score is better.

Clinical Assessment of Cognitive Impairment

Three experienced neuropsychologists and a behavioral neurologist blinded to pregnancy status independently examined age-corrected scaled scores for each of the 80 women and assigned ratings of normal, single-domain mild cognitive impairment (MCI), multiple-domain MCI, or dementia. A consensus diagnosis was determined based on agreement of at least three raters.

Most diagnostic criteria require objective evidence of mild impairment (typically 1 to 1.5 standard deviations below the normative mean and a decline from baseline functioning) in one or more cognitive domains. For this study, incorporating published guidelines and criteria,^16–18 MCI was defined as mild impairment on two or more measures within a single domain, or mild impairment on one or more measures within at least two domains. A diagnosis of dementia was considered if there were cognitive deficits ≥ 2 SD below the mean in two or more domains. Education was used to estimate baseline functioning.

Statistical Analyses

Demographic, clinical, and cognitive test data were summarized with descriptive statistics, including percentages for discrete variables and quartiles (median, 25^th and 75^th percentiles) for continuous variables. Bivariate comparisons between groups with hPE or hNTP were performed using the Chi-square test or Wilcoxon rank sum test, or with a Cochran-Armitage trend test for ordinal measures of cognitive impairment. To correct for multiple comparisons among all cognitive tests that were included, P-values were adjusted according to the method described by Benjamini and Hochberg.¹⁹ The magnitude of effect on measures of cognitive functioning was estimated with Cohen’s d standardized effect size.²⁰ Convention suggests .2 is a small effect size, .5 moderate, and .8 large. All data were recorded and managed in a secure database (Medidata Rave, Medidata Solutions Inc.), and were analyzed using SAS statistical software (version 9.4, SAS Institute Inc., Cary, NC).

Results

Demographics and current clinical characteristics by pregnancy status are presented in Table 2. Compared to women with hNTP, women with hPE had higher BMI (29.8 kg/m² [IQR 25.9–33.7] vs 25.3 kg/m² [IQR 23.1–32.0], p = 0.004), more CAC (0.0 AU [IQR 0.0–28.0] vs 0.0 AU [IQR 0.0–0.3], p = 0.007), and were also more frequently diagnosed with hypertension (60% vs 20%, p < 0.001). More women with hPE than with hNTP were taking medications that could potentially affect cognition (73% vs 40%, p = 0.003). In the hNTP group, none of the women with MCI were taking them. In the hPE group, three of the women with MCI were taking them but not the one with dementia.

Table 2.

Demographics and clinical characteristics by hypertensive pregnancy status

Variable	Normotensive (n=40)	Preeclampsia (n=40)	P-value
Age at study consent	59.6 (56.2, 62.5)	59.2 (56.3, 62.5)	0.814
Age at 1st live birth	24.0 (22.3, 26.3)	24.5 (21.7, 25.8)	0.931
Time since 1st live birth/index pregnancy (yrs)	34.5 (33.6, 36.7)	34.9 (32.9, 36.7)	0.564
Parity	3.0 (2.0, 3.0)	3.0 (2.0, 3.0)	0.967
Education:			0.219
High school or less	3 (8%)	6 (15%)
Some college/tech/voc	21 (53%)	22 (55%)
College graduate or higher	16 (40%)	12 (30%)
BMI (kg/m2)	25.3 (23.1, 32.0)	29.8 (25.9, 33.7)	0.023
Diastolic blood pressure (mm Hg)	75.2 (69.7, 84.0)	79.7 (69.3, 83.3)	0.368
Systolic blood pressure (mm Hg)	128.7 (116.5, 145.7)	131.7 (119.7, 140.2)	0.613
LDL cholesterol (mg/dL)	123.0 (99.7, 136.4)	106.1 (87.9, 124.3)	0.087
HDL cholesterol (mg/dL)	64.0 (50.5, 76.5)	54.5 (41.0, 69.5)	0.054
Triglycerides (mg/dL)	97.5 (72.0, 123.5)	108.0 (85.0, 163.0)	0.078
Fasting glucose (mg/dL)	95.5 (91.0, 101.5)	98.0 (91.5, 109.5)	0.151
Diabetes	2 (5%)	4 (10%)	0.414
Albumin/creatinine ratio (mg/mmol)	2.0 (0.00, 6.1)	2.4 (0.00, 5.1)	0.992
Past or current hormone therapy	17 (43%)	17 (43%)	1.000
Ongoing hormone therapy	8 (20%)	6 (15%)	0.556
17β-estradiol (pg/mL)	3.5 (2.1, 9.5)	5.4 (2.4, 7.8)	0.495
Estrone (pg/mL)	22.0 (14.0, 32.0)	26.0 (14.5, 32.5)	0.956
Coronary artery calcification: (AU)	0.0 (0.0, 0.3)	0.0 (0.0, 28.0)	0.007
ApoE-4 polymorphism	9 (23%)	11 (28%)	0.606
Hypertension	8 (20%)	24 (60%)	<.001
Medication with potential cognitive side effects	16 (40%)	29 (73%)	0.003
Obstructive sleep apnea	7 (18%)	12 (30%)	0.189
Family history of dementia	13 (33%)	12 (30%)	0.809

Continuous variables are reported as median (25^th, 75^th percentiles) whereas discrete variables are presented as count (%).

AU = Agatston Unit; BMI = body mass index.

After correction for multiple comparisons, there were no significant differences in women with hNTP or hPE on any measure of cognition or mood. Test scores for each cognitive and mood variable are presented in Table 3. Cohen’s d for magnitude of effect between scores from women with hNTP or hPE indicated moderate effect sizes for Logical Memory I (d = 0.52) and Logical Memory II (d = 0.65), with lower scores in the hPE group. When examining clinical consensus diagnosis, in which impairment was rated on a scale from none to dementia and secondly as a count (observed range, 0–4) of affected domains (Table 4), there was a more widespread pattern of cognitive impairment in women with hPE compared to women with hNTP (p = 0.03). Using a binary measure in which all classifications of cognitive impairment are grouped together, there was a modest yet non-significant difference (p = 0.10) in the frequency of cognitive impairment among women with hPE (n=8; 20%) compared to women with hNTP (n=3; 8%). Further, two of the three women with hNTP had single-domain (memory) and one had multi-domain MCI, while all of the eight women with hPE and cognitive impairment had multiple domains affected, including seven with MCI and one with dementia. None of the women with cognitive impairment reported depression or anxiety sufficient to explain cognitive scores (i.e., none reported depression and one with hPE reported marginal mild anxiety). Comparing women with hPE with cognitive impairment to hPE without, the largest effect sizes were observed for Trail Making Test B—a test of cognitive speed and flexibility used to assess executive functioning (d = 1.96), followed by verbal learning (d = 1.93), visual memory (d = 1.87), and auditory attention (d = 1.69) (Table 5).

Table 3.

Cognitive and mood comparisons (raw scores) by hypertensive pregnancy status

Cognitive Domain	Variable	Normotensive (n=40)	Preeclampsia (n=40)	P-value	Cohen’s d
Attention	Trail Making Test A (time/secs)†	24.0 (20.0, 28.0)	25.5 (20.5, 31.0)	0.643	0.39
	Digit Span	16.0 (13.5, 18.0)	15.5 (13.5, 18.0)	0.887	0.12
Working Memory	Letter-Number Sequencing	10.0 (9.0, 11.0)	9.0 (8.0, 11.0)	0.778	0.07
Psychomotor Speed	Digit Symbol Coding	60.5 (55.0, 66.5)	59.0 (52.0, 64.0)	0.778	0.29
Executive Functioning	Trail Making Test B (time/secs)†	56.5 (51.5, 66.0)	64.0 (50.5, 77.5)	0.643	0.37
Language	Letter Fluency	39.0 (32.5, 46.0)	41.0 (35.5, 45.5)	0.887	0.00
	Category Fluency	52.0 (46.5, 60.5)	50.5 (42.5, 61.0)	0.778	0.21
	Boston Naming Test	57.0 (55.5, 59.0)	57.0 (55.0, 58.5)	0.778	0.24
Visuospatial	Picture Completion	15.0 (14.0, 16.0)	15.0 (14.0, 16.0)	0.981	0.07
	Block Design	27.0 (24.0, 35.5)	27.5 (22.0, 32.0)	0.778	0.21
Learning/Immediate Memory	AVLT Trials 1–5	52.5 (46.0, 59.0)	50.0 (47.0, 55.5)	0.738	0.30
	Logical Memory I	27.0 (23.0, 30.0)	24.0 (20.0, 28.0)	0.333	0.52
	Visual Reproduction I	32.0 (29.0, 36.0)	34.0 (31.0, 35.5)	0.778	0.13
Delayed Memory	AVLT Delay	10.5 (9.0, 12.5)	10.5 (8.0, 12.0)	0.778	0.22
	AVLT % Retention	83.0 (64.0, 100.0)	84.0 (68.0, 93.0)	0.915	0.11
	Logical Memory II	23.0 (19.0, 26.5)	19.0 (14.5, 23.0)	0.161	0.65
	Logical Memory % Retention	87.5 (76.5, 94.0)	79.0 (66.0, 88.5)	0.309	0.48
	Visual Reproduction II	26.5 (24.0, 32.0)	30.0 (27.0, 33.0)	0.778	0.04
	Visual Reproduction % Ret.	83.5 (75.5, 97.0)	92.0 (79.0, 96.5)	0.778	0.03
Mood	Beck Depression Inventory,†	2.0 (0.0, 5.5)	4.0 (1.0, 7.5)	0.643	0.14
	Beck Anxiety Inventory,†	1.5 (0.0, 4.0)	3.0 (1.0, 6.0)	0.580	0.07
	POMS Anger,†	0.0 (0.0, 1.0)	0.0 (0.0, 2.5)	0.643	0.23
	POMS Confusion†	5.0 (4.0, 7.0)	5.0 (4.0, 7.5)	0.887	0.02
	POMS Depression Score,†	1.0 (0.0, 2.5)	1.0 (0.0, 5.0)	0.778	0.02
	POMS Fatigue Score,†	1.0 (0.0, 4.0)	2.5 (0.0, 4.5)	0.643	0.36
	POMS Tension Score,†	2.0 (1.0, 4.5)	2.0 (1.0, 4.5)	0.981	0.09
	POMS Vigor Score	18.5 (13.5, 23.5)	16.5 (11.0, 21.5)	0.643	0.32

Scores are presented as median (25^th, 75^th percentiles). No significant differences were found after correction for multiple comparisons.

^†Higher score is worse. Scores are total raw scores. AVLT = Auditory Verbal Learning Test; POMS = Profile of Mood States.

Table 4.

Consensus-based assessment of cognitive status

Variable	Normotensive (n=40) N (%)	Preeclampsia (n=40) N (%)	P-value
Cognitive Impairment			0.03~
None	37 (93%)	32 (80%)
MCI-single domain	2 (5%)	0 (0%)
MCI-multiple domains	1 (3%)	7 (18%)
Dementia	0 (0%)	1 (3%)
Number of Domains Affected			0.03~
0	37 (93%)	32 (80%)
1	2 (5%)	0 (0%)
2	1 (3%)	5 (13%)
3	0 (0%)	1 (3%)
4	0 (0%)	2 (5%)
MCI/Dementia			0.10
No	37 (93%)	32 (80%)
Yes	3 (8%)	8 (20%)

^~Measure of impairment analyzed as an ordinal variable with the Cochran-Armitage trend test.

MCI = mild cognitive impairment.

Table 5.

Cognitive and mood comparisons (raw scores) by cognitive status in women with preeclampsia

Cognitive Domain	Variable	No Impairment (n=32)	Impairment (n=8)	P-value	Cohen’s d
Attention	Trail Making Test A (time/secs)†	25.0 (20.5, 31.0)	27.0 (21.0, 43.0)	0.753	0.45
	Digit Span	17.0 (14.0, 19.0)	11.0 (11.0, 14.0)	0.016	1.69
Working Memory	Letter-Number Sequencing	10.0 (8.5, 11.0)	8.0 (6.5, 8.5)	0.018	1.32
Psychomotor Speed	Digit Symbol Coding	59.0 (55.0, 65.5)	54.5 (34.0, 64.0)	0.487	0.83
Executive Functioning	Trail Making Test B (time/secs)†	59.5 (48.5, 72.0)	101.0 (70.0, 157.0)	0.018	1.96
Language	Letter Fluency	42.0 (36.5, 47.5)	32.5 (23.0, 40.5)	0.034	1.25
	Category Fluency	54.5 (48.0, 62.5)	40.5 (31.0, 44.5)	0.018	1.40
	Boston Naming Test	57.0 (55.0, 59.0)	54.5 (52.0, 58.0)	0.243	0.72
Visuospatial	Picture Completion	15.0 (14.0, 16.0)	14.0 (12.0, 15.0)	0.178	0.85
	Block Design	28.0 (25.0, 32.0)	22.5 (16.0, 26.0)	0.108	0.95
Learning/Immediate Memory	AVLT Trials 1–5	53.0 (47.0, 56.0)	41.5 (29.5, 47.0)	0.016	1.93
	Logical Memory I	25.0 (22.5, 29.0)	18.5 (16.5, 23.0)	0.019	1.40
	Visual Reproduction I	34.5 (32.0, 36.0)	31.5 (28.5, 34.0)	0.134	0.69
Delayed Memory	AVLT Delay	11.0 (9.0, 12.0)	7.0 (4.0, 9.0)	0.018	1.44
	AVLT % Retention	87.5 (69.0, 93.0)	76.5 (46.0, 85.0)	0.228	0.81
	Logical Memory II	20.0 (15.0, 24.5)	15.5 (10.0, 19.5)	0.116	0.92
	Logical Memory % Retention	79.0 (69.0, 88.5)	78.0 (55.0, 89.0)	0.897	0.26
	Visual Reproduction II	30.0 (28.0, 33.5)	16.0 (11.5, 27.0)	0.026	1.87
	Visual Reproduction % Ret.	93.0 (81.5, 96.5)	64.5 (33.5, 91.0)	0.134	1.72
Mood	Beck Depression Inventory,†	4.0 (1.0, 6.5)	3.5 (1.0, 9.0)	0.933	0.08
	Beck Anxiety Inventory,†	3.0 (1.0, 6.0)	3.5 (0.5, 6.0)	0.922	0.15
	POMS Anger,†	0.0 (0.0, 2.5)	0.5 (0.0, 4.0)	0.854	0.02
	POMS Confusion†	5.0 (3.5, 7.5)	7.0 (5.0, 7.5)	0.409	0.39
	POMS Depression Score,†	1.0 (0.0, 5.0)	0.0 (0.0, 4.5)	0.659	0.14
	POMS Fatigue Score,†	2.0 (0.0, 4.5)	3.0 (0.0, 8.0)	0.895	0.33
	POMS Tension Score,†	2.0 (1.0, 4.5)	1.5 (0.5, 4.5)	0.640	0.13
	POMS Vigor Score	16.0 (11.0, 21.5)	18.0 (13.5, 20.5)	0.753	0.19

Scores are presented as median (25^th, 75^th percentiles).

^†Higher score is worse. Scores are total raw scores. Significant group differences are corrected for multiple comparisons. AVLT = Auditory Verbal Learning Test; POMS = Profile of Mood States.

In women with hPE, the amount of CAC was greater in those who had cognitive impairment versus those who did not (67.5 AU [IQR 6.0–180.0] vs 0.0 AU [IQR 0.0–25.0], p = 0.043). There was no significant difference in carriers of ApoE-4 polymorphism between hPE women with and without cognitive impairment nor was there any difference in use of hormone replacement therapy, BMI, frequency of hypertension, or use of medications with cognitive side effects (Table 6).

Table 6.

Demographics and clinical characteristics of women with a history of preeclampsia by cognitive status

Variable	No Impairment (n=32)	Impairment (n=8)	P-value
Age at study consent	58.3 (55.6, 61.2)	63.2 (59.3, 65.4)	0.063
Age at 1st live birth	24.4 (21.7, 25.2)	26.4 (22.1, 29.9)	0.166
Time since 1st live birth/index pregnancy (yrs)	34.9 (32.9, 36.7)	35.2 (32.7, 37.0)	0.892
Parity	3.0 (2.0, 3.5)	2.0 (2.0, 2.5)	0.055
Education:			0.053
High school or less	3 (9%)	3 (38%)
Some college/tech/voc	18 (56%)	4 (50%)
College graduate or higher	11 (34%)	1 (13%)
BMI (kg/m2)	29.4 (25.7, 33.3)	32.5 (27.8, 34.1)	0.398
Diastolic blood pressure (mm Hg)	78.7 (71.0, 82.2)	83.0 (66.5, 94.8)	0.407
Systolic blood pressure (mm Hg)	130.8 (119.7, 139.2)	136.5 (124.3, 144.7)	0.398
LDL cholesterol (mg/dL)	106.1 (90.7, 124.3)	93.1 (70.6, 131.1)	0.447
HDL cholesterol (mg/dL)	49.0 (37.5, 68.5)	60.0 (48.5, 84.5)	0.171
Triglycerides (mg/dL)	116.0 (91.0, 178.0)	97.5 (77.0, 114.5)	0.223
Fasting glucose (mg/dL)	101.0 (91.5, 112.0)	97.5 (90.0, 98.5)	0.457
Diabetes	3 (9%)	1 (13%)	1.000
Albumin/creatinine ratio (mg/mmol)	2.6 (0.0, 5.1)	2.3 (0.0, 7.2)	0.901
Past or current hormone therapy	13 (41%)	4 (50%)	0.631
Ongoing hormone therapy	5 (16%)	1 (13%)	1.000
17β-estradiol (pg/mL)	5.5 (2.4, 8.0)	4/0 (2.5, 6.4)	0.447
Estrone (pg/mL)	26.5 (15.0, 34.0)	22.5 (8.0, 29.5)	0.302
Coronary artery calcification: (AU)	0.0 (0.0, 25.0)	67.5 (6.0, 180.0)	0.043
ApoE-4 polymorphism	8 (25%)	3 (38%)	0.479
Hypertension	18 (56%)	6 (75%)	0.333
Medication with potential cognitive side effects	25 (78%)	4 (50%)	0.111
Obstructive sleep apnea	8 (25%)	4 (50%)	0.168
Family History of Dementia	8 (25%)	4 (50%)	0.168

Continuous variables are reported as median (25^th, 75^th percentiles) whereas discrete variables are presented as count (percentage).

AU = Agatston Unit; BMI = body mass index.

Comment

The first major finding from this study was a trend towards cognitive impairment being more frequently clinically diagnosed in women with hPE than in women with hNTP. Second, women with hPE showed a more diffuse range (i.e., multiple domains) of cognitive impairment, most prominently affecting abilities commonly ascribed to frontal subcortical brain processing, such as executive functioning, verbal learning, and attention.

Previous studies show that women with hPE exhibit variable neurocognitive changes in the first decade following the index pregnancy.^8,13 Results of the present study extend the literature by providing long-term objective and clinical assessment of women with hPE 35 years after the affected pregnancy and are consistent with prior studies showing no differences in scores on objective cognitive measures between women with and without hPE. However, using a clinical approach where women were diagnosed with MCI or dementia according to standard criteria, more women with hPE than hNTP met such criteria. Differences in outcomes based on individual clinical characterization and effect sizes versus statistical group comparisons that obscure important individual differences may help explain disparate results in the literature, for example, frequent subjective cognitive complaints reported by women with hPE yet no objective psychometric evidence.

Factors known to increase brain vulnerability and associate with CVD and cognitive dysfunction include hypertension,^4,5,21 diabetes,²² dyslipidemia,²³ obesity and BMI,^24,25 carotid intima-media thickness,²⁶ CAC,^27,28 and genetic polymorphisms (e.g., ApoE-4). ^29,30 Many of these factors also share association with hypertensive pregnancy disorders.^1,31–35 Our study is consistent with the literature in that women with hPE had higher BMI, higher CAC, and were more frequently hypertensive than women with hNTP. In the women with hPE, those with cognitive impairment had more CAC than those without cognitive impairment.

In preeclampsia, pathophysiological mechanisms associated with vascular disease may exist before, and persist long after, the affected pregnancy.^36–39 It is unclear whether hypertensive pregnancies induce vascular changes or whether they further stimulate a cascade of already evolving changes. Vascular pathology is present in 29% to 41% of dementia cases that come to autopsy.^40–42 Micro- and macro-vascular changes that disrupt blood flow integrity can cause structural and functional brain changes,⁴³ which can lead to vascular cognitive impairment directly⁴⁴ or indirectly by disrupting white matter pathways.^45–47 White matter hyperintensities on imaging associate with decreased performance on tests of executive functioning and psychomotor speed and processing with a fair amount of consistency, and more variably to diminished learning, episodic memory, and visual memory and organization.^48,49 Although most of these studies have focused on persons over the age of 65, findings were similar in a large cohort where the average age was 61 (range 34–88).⁴⁸ This suggests that vascular changes associated with cognitive changes may not be purely age-related and lend support to changes observed in the current sample of younger women (age 59, range 52–72).

The association of white matter hyperintensities and decreased cognitive performance on tasks of executive functioning and psychomotor processing^48,55 raises speculation that compromised white matter tracts result in the disruption of cortical-subcortical pathways that subserve these functions.^47,54,59,66 Indeed, in women with hPE examined in their late 30s, approximately 5 years from index pregnancy, white matter lesions were greater compared to women with hNTP.⁵⁰ In further support that hypertensive pregnancy is an independent predictor of change in cognition and brain structure, women with a history of hypertensive pregnancy disorders have been shown to have smaller brain volumes than women with normotensive pregnancies decades later, even after adjusting for traditional cardiovascular risk factors,⁵¹ in addition to increased risk of CAC.¹⁴ A recent study found no relationship between white matter hyperintensities, objective cognitive performance, or subjective cognitive complaints in formerly preeclamptic women 40 years of age 6 years after pregnancy,⁵² and we postulate that these women have not yet reached an age threshold that challenges cognitive reserve.

The fact that 25% of women with normal cognition and 38% with impaired cognition in our preeclampsia group were found to have an ApoE-4 polymorphism suggests that this gene may not independently increase risk of cognitive decline, but rather, interact with other underlying disease pathology, including cerebrovascular disease.⁵³ Hormone replacement therapy, too, has been linked to negative cognitive function, and in particular, conjugated equine estrogen (CEE).⁵⁴ In our study, we do not have information on type of hormone treatments, but current hormone levels (17β-estradiol and estrone) were measured in all women and did not differ between groups (see Tables 2 and 6).

A goal of the study was to assess the subclinical effect of hPE on cognitive functioning. A strength of our study is our extensive medical record data that allowed us to closely match women with and without hPE and to exclude women with potential neurologic confounding comorbidities.

Limitations of this study include the small sample size and potential response and selection biases. If women with hPE experience more cognitive decline and are more self-aware of cognitive inefficiencies, it may be that some were less likely to participate for fear of “confirming” their subjective experience of cognitive loss. In addition, a reported history of dementia was exclusionary. If this study captured a “more normal than not” sample, it might explain the lack of significant cognitive differences in comparisons of test scores between women with and without hPE. Results may also be biased towards “less physically healthy” women since women per inclusion criteria who did not have a documented clinical visit within the last two years, perhaps because they were healthier, were not contacted. Lastly, this study reflects Olmsted County, Minnesota, which is primarily white, non-Hispanic, and fairly highly educated. Higher levels of education and cognitive reserve^55–57 have been associated with reduced risk of cognitive decline and dementia. Both groups were comparably educated, which could limit our ability to detect subtle cognitive changes. Women with hPE and cognitive impairment were less highly educated than those without cognitive impairment, although the sample size is too small for this to be a meaningful finding. In addition, 23 of the 40 hNTP and 26 of the 40 hPE women reported ethnicity, and all identified as white/Caucasian. Therefore, these findings may not generalize to women with lower education or of other races and ethnicities.

In summary, women with hPE more frequently have a higher BMI, hypertension, and metabolic dysregulation, exacerbating an increased risk of cardiovascular morbidity and mortality over the life course. Cardiovascular disease is associated with cognitive decline and dementia. Results of this study suggest a trend for women with a history of preeclampsia to exhibit more cognitive impairment 35 years later than women with similar demographics but who experienced a normotensive pregnancy. The mechanisms underlying this difference are unclear, but could be reflect common mechanisms contributing to CAC and brain changes, such as white matter lesions. White matter lesions are common even in the early years following index pregnancy, and the pattern of cognitive impairment observed in the present study appears to reflect disruption in frontal subcortical white matter tracts, although a larger sample size will be needed to delineate this more clearly. The broader implications are that many cardiovascular risk factors are modifiable, and lifestyle interventions, particularly in women with hPE, may help prevent cognitive impairment. OB/GYNs are often the only care provider women see regularly throughout their menopausal years, and as such are in a unique position to integrate pregnancy history into risk assessment for future neurologic morbidity, recognize often missed cognitive impairment, and initiate individualized prevention and treatment plans.

Condensation.

Cognitive impairment tends to be more common and more diffuse in women with a history of preeclampsia versus history of normotensive pregnancy later in life.