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1 OBSTETRICS 56
2 57
3 Preeclampsia and cognitive impairment later in life 58
4 Q10 Julie A. Fields, PhD; Vesna D. Garovic, MD; Michelle M. Mielke, PhD; Kejal Kantarci, MD; Muthuvel Jayachandran, PhD; 59
5 Wendy M. White, MD; Alissa M. Butts, PhD; Jonathan Graff-Radford, MD; Brian D. Lahr, MS; Kent R. Bailey, PhD; 60
6 Q1 Virginia M. Miller, PhD 61
7 62
8 63
9 BACKGROUND: Hypertension is a risk factor for cerebrovascular RESULTS: Age at time of consent did not differ between preeclampsia 64
10 disease and cognitive impairment. Women with hypertensive episodes (59.2 [range 50.9-71.5] years) and normotensive (59.6 [range 52.1-72.2] 65
11 during pregnancy report variable neurocognitive changes within the first years) groups, nor did time from index pregnancy (34.9 [range 32.0-47.2] vs 66
12 decade following the affected pregnancy. However, long-term follow-up 34.5 [range 32.0-46.4] years, respectively). There were no statistically 67
13 of these women into their postmenopausal years has not been significant differences in raw scores on tests of cognition and mood between 68
14 conducted. women with histories of preeclampsia compared to women with histories of 69
15 OBJECTIVE: The aim of this study was to examine whether women with normotensive pregnancy. However, a consensus diagnosis of mild cognitive 70
16 a history of preeclampsia were at increased risk of cognitive decline 35-40 impairment or dementia trended toward greater frequency in women with 71
17 years after the affected pregnancy. histories of preeclampsia compared to those with normotensive pregnancies 72
18 STUDY DESIGN: Women were identified and recruited through the (20% vs 8%, P .10) and affected more domains among the preeclampsia 73
19 medical linkage, population-based Rochester Epidemiologic Project. group (P .03), most strongly related to executive dysfunction (d 1.96) 74
20 Forty women with a history of preeclampsia were age- and parity- and verbal list learning impairment (d 1.93). 75
21 matched to 40 women with a history of normotensive pregnancy. CONCLUSION: These findings suggest a trend for women with a 76
22 All women underwent comprehensive neuropsychological assess- history of preeclampsia to exhibit more cognitive impairment later in life 77
23 ment and completed self-report inventories measuring mood, ie, than those with a history of normotensive pregnancy. Furthermore, the 78
24 depression, anxiety, and other symptoms related to emotional state. pattern of cognitive changes is consistent with that observed with vascular 79
25 Scores were compared between groups. In addition, individual disease/white matter pathology. 80
cognitive scores were examined by neuropsychologists and a 81
26
neurologist blinded to pregnancy status, and a clinical consensus Key words: cardiovascular disease, cerebrovascular disease, cognition,
27 82
diagnosis of normal, mild cognitive impairment, or dementia for each dementia, hypertensive pregnancy, mild cognitive impairment,
28 83
participant was conferred. preeclampsia
29 84
30 85
31 Introduction subjective cognitive symptoms and these women into their postmenopausal 86
32 Hypertensive disorders of pregnancy, endorse more physical and psychological years has not been conducted. 87
33 including preeclampsia, confer increased symptoms that negatively impact phys- Therefore, in the current study, cognition 88
34 risk of cardiovascular disease (CVD) ical, social, and emotional well-being and mood were evaluated in women 89
35 morbidity and mortality.1 Preeclampsia and quality of life than women with approximately 35 years after preeclamptic 90
36 occurs in about 3% of pregnancies,2 and a history of normotensive pregnancy or normotensive pregnancy. We hypoth- 91
37 is associated with an approximate 2-fold (hNTP).8-10 In addition, reported changes esized that women with a history of 92
38 increased risk of CVD and cerebrovas- in cognition associate with the severity preeclampsia (hPE) would be more 93
39 cular disease.3 Some risk factors associ- of preeclampsia11 or posttraumatic stress likely than women with a hNTP to 94
40 ated with preeclampsia are shared with symptoms of preeclampsia.12 However, have cognitive impairment and that 95
41 those for CVD and cognitive decline, studies examining the impact of hyper- the pattern would resemble changes 96
42 including hypertension, metabolic syn- tensive pregnancy on cognitive perfor- characteristic of vascular/white matter 97
43 drome, and insulin resistance.4-7 mance report mixed results. For example, disease. 98
44 Women with a history of hypertensive no differences in sustained attention or 99
45 pregnancy more frequently report executive functioning were reported Materials and Methods 100
46 in women in their late 30s to early 40s, Participants 101
47 up to a decade following an index preg- Recruitment details have been previously 102
48 nancy of preeclampsia or eclampsia, reported.14 In brief, hospital adaptation Q3 103
Cite this article as: Fields JA, Garovic VD, Mielke MM,
49 et al. Preeclampsia and cognitive impairment later in life. compared to age-matched women of the International Classication of Dis- 104
50 Am J Obstet Gynecol 2017;volume:x.ex-x.ex. with normotensive pregnancies.13 In eases adapted codes and the population- 105
51 contrast, others have found slower based Rochester Epidemiology Project 106
0002-9378
52 2017 The Authors. Published by Elsevier Inc. This is an motor speed,8 poorer attention,12 or medical records linkage system15 were 107
53 open access article under the CC BY-NC-ND license (http:// poorer learning and memory11 in used to identify 40 women with hPE and 108
54 creativecommons.org/licenses/by-nc-nd/4.0/).
women with a history of hypertensive 40 women with hNTP. Sample size was 109
http://dx.doi.org/10.1016/j.ajog.2017.03.008
55 pregnancy. Long-term follow-up of based on power calculation to detect 110

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111 167
112 TABLE 1 168
113 Measures of cognition and mood 169
114 170
115 Attention Wechsler Adult Intelligence Scale-III digit span measures auditory attention and working memory capacity. This test 171
116 involves repetition of oral sequences of numbers of increasing length exactly as they are presented in forward 172
condition and then in reverse in backward condition. Digit span forward measures simple auditory attention capacity
117 and digit span backward measures working memory capacity. Score is total number of forward and backward 173
118 sequences repeated correctly. 174
119 Trail Making Test A measures visual attention and processing speed. It is paper-and-pencil test requiring rapid 175
120 connection of consecutively numbered circles. Score is time (in seconds) to complete trial, with higher score reflecting 176
121 poorer performance. 177
122 Working memory Wechsler Adult Intelligence Scale-III letter-number sequencing measures auditory working memory. Letters and 178
123 numbers of increasing length are orally presented in random order. Mental manipulation is required to rearrange 179
numbers and letters and then repeat in ascending order. Score is total number of correct sequences.
124 180
125 Psychomotor processing Wechsler Adult Intelligence Scale-III digit symbol coding measures visual scanning, motor persistence, sustained 181
126 attention, response speed, and visuomotor coordination. It involves quickly transcribing symbols into blank spaces 182
below numbers that correspond to symbol-number pairs presented in key above. Score is total number of symbols
127 correctly transcribed within specified amount of time. 183
128 184
129 Executive functioning Trail Making Test B measures visuomotor speed, divided attention, and cognitive flexibility. It increases demands of 185
Trail Making Test A by requiring rapid connection of not only consecutively numbered circles but also lettered circles
130 and alternating between them. Score is time (in seconds) to complete trial, with higher score reflecting poorer 186
131 performance. 187
132 188
Language Phonemic (C, F, L) and semantic (animals, fruits, vegetables) verbal fluency measure ability to produce fluent speech.
133 It has also been used to assess ability to think flexibly and gauge how efficiently one uses search and retrieval 189
134 strategies to organize thoughts. Objective is to rapidly generate as many words as possible within certain amount of 190
135 time that begin with specified letters and belong to specified categories. Scores are total number of words generated 191
136 for 3 letters and 3 categories. 192
Boston Naming Test measures ease and accuracy of word retrieval and how intact semantic networks are. It also
137 193
gives some indication of vocabulary level. This test requires providing name for common objects presented in black
138 and white drawings. Score is total number of objects correctly named. 194
139 195
Visuospatial processing Wechsler Adult Intelligence Scale-III picture completion measures ability to measure attention to visual detail. Pictures
140 of common objects and scenes with detail missing from them are presented, and examinee is asked to identify what is 196
141 missing. Score is total number of correct responses. 197
142 Wechsler Adult Intelligence Scale-III block design measures visual problem-solving and understanding of part-to- 198
143 whole relationships. It involves manual manipulation of 3-dimensional blocks to match 2-dimensional line drawings. 199
144 Score is total number of correct designs. 200
145 Learning and memory Auditory Verbal Learning Test measures learning efficiency, immediate memory span, sensitivity to interference with 201
146 learning and recall, and rates of forgetting and retention. List of unrelated words is serially presented. Object is to learn 202
147 as many words as possible over repeated trials, recall them after being presented distractor list, and recall them again 203
after 30-min delay. Several scores are derived: learning score is sum of number of words recalled immediately on
148 each trial, delay score is number of words recalled after long delay, and percent retention score is number of words on 204
149 delayed recall trial divided by number of words recalled on last learning trial. 205
150 Wechsler Memory Scale-Revised logical memory I and II measure learning, recall, and retention of logically organized 206
151 verbal information. Paragraph-length prose passages are read out loud to examinee, who is to recall as much 207
152 information from stories as possible immediately following presentation and again after 25- to 35-min delay. Logical 208
memory I score is total number of story details recalled immediately following presentation, logical memory II is total
153 number of story details recalled after longer delay, and percent retention is number of story details on delayed recall 209
154 divided by immediate recall. 210
155 Wechsler Memory Scale-Revised visual reproduction I and II measure visual learning, memory, and retention of 211
156 geometric designs. Cards with line drawings are presented for brief amount of time, taken away, and then examinee is 212
157 asked to reproduce designs as accurately as possible. After 25- to 35-min delay, examinee is asked to again 213
reproduce as many of designs as possible, but this time without being shown cards. Visual reproduction I score is total
158 number of design details recalled immediately following presentation, visual reproduction II is total number of design 214
159 details recalled after longer delay, and percent retention is number of design details on delayed recall divided by 215
160 immediate recall. 216
161 Fields et al. Cognitive impairment following preeclampsia. Am J Obstet Gynecol 2017. (continued) 217
162 218
163 219
164 220
165 differences in cardiovascular parameters. Minnesota, when delivering a baby from 31, 1982; had to have had a documented 221
166 To be eligible for the study, a woman had a pregnancy lasting >20 weeks (live birth clinical visit within the last 2 years to 222
to be a resident of Olmsted County, or stillbirth) from Jan. 1, 1976, and Dec. conrm that women did not have

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223 279
224 TABLE 1 280
225 Measures of cognition and mood (continued) 281
226 282
227 Mood state Beck Depression Inventory-II is 21-item self-report scale measuring range of affective, cognitive, and physiologic 283
228 symptoms of depression (eg, sense of failure, loss of interest, indecisiveness, appetite, libido). Each item contains 4 284
statements of graded severity expressing how person might feel or think about aspect of depression under
229 consideration, with scores ranging from 0 for absence of problems in that area to 3 for most severe level of that
285
230 problem. Score is sum of all statements endorsed, with higher score representing greater severity. 286
231 Beck Anxiety Inventory is 21-item self-report scale measuring range of subjective, physiologic, autonomic, and panic- 287
232 related symptoms of anxiety (eg, unable to relax, hands trembling, heart pounding or racing, fear of worst happening). 288
233 Each item contains 4 statements of graded severity expressing how person might feel or think about aspect of 289
depression under consideration, with scores ranging from 0 for absence of problems in that area to 3 for most severe
234 level of that problem. Score is sum of all statements endorsed, with higher score representing greater severity.
290
235 Profile of Mood States is 65-item self-report measure of 6 mood states: tension-anxiety, depression-dejection, anger- 291
236 hostility, vigor-activity, fatigue-inertia, and confusion-bewilderment. It contains adjectives that describe how person 292
237 may be feeling (eg, unhappy, relaxed, exhausted, rebellious, efficient), and individuals are asked to rate how much 293
238 during past week they have had that feeling. Scores range from 0e4, with 0 being not at all and 4 being extremely. 294
Subscale score is derived for each of 6 mood states, with higher score representing greater difficulty in all but vigor-
239 activity state, where higher score is better.
295
240 296
Fields et al. Cognitive impairment following preeclampsia. Am J Obstet Gynecol 2017.
241 297
242 298
243 299
244 a cardiovascular or other neurological (17%) refused, 41 (39%) did not record review, or if SBP 140 mm Hg or 300
245 event that could potentially confound respond, and 5 (5%) wanted to partici- DBP 90 mm Hg was documented in 301
246 results; and had to live within 120 miles pate but another matched control had the medical records on 2 separate occa- 302
247 of Olmsted County to be available for in- already agreed. sions. The diagnosis of dyslipidemia was 303
248 person visits. As the primary focus of this study was conrmed if 1 of the following criteria 304
249 The medical records of all women to understand the potential mechanisms were met: use of lipid-lowering drugs or 305
250 were fully abstracted for demographic that place women with hPE at risk for laboratory measurements revealing a 306
251 and clinical information. A potential subclinical CVD and cognitive decline, total cholesterol 200 mg/dL, tri- 307
252 exposure was conrmed as preeclampsia women were excluded with a medical- glycerides 150 mg/dL, or high-density 308
253 if a woman had at least 1 preeclamptic record conrmed clinical diagnosis of lipoprotein 50 mg/dL. Diabetes melli- Q4 309
254 pregnancy from 1976 through 1982 that myocardial infarction, congestive heart tus was diagnosed by HgA1c 6.5%, 310
255 met the standard denition: (1) 2 failure, stroke, dementia, cancer fasting glucose >126 mg/dL, or a 311
256 blood pressure readings of a systolic (excluding nonmelanoma skin cancer), physician diagnosis in the past, with or 312
257 blood pressure (SBP) >140 mm Hg or a autoimmune disease (eg, multiple scle- without current glucose-lowering 313
258 diastolic blood pressure (DBP) >90 mm rosis, lupus), and neurological condi- agents. Coronary artery calcication 314
259 Hg at least 4 hours apart >20 weeks tions (eg, epilepsy). All protocols were (CAC) is a measurement of the amount 315
260 gestation; and (2) new-onset protein- approved by Mayo Clinic and Olmsted of calcium in the walls of the arteries that 316
261 uria, as dened by a urine dipstick 1, or Medical Center Institutional Review supply the heart muscle and is recorded 317
262 proteinuria 0.300 g/24 h, or a protein/ Boards (PR10-005198-05) and all par- in Agatston units (AU). The higher the 318
263 creatinine ratio equivalent to 0.300 g/ ticipants gave written informed consent. number, the greater the amount of pla- 319
264 24 h. Emergency room visits were not que. CAC was evaluated by computed 320
265 included. Women were sequentially Clinical assessment of tomography and was previously 321
266 contacted and recruited. Each of the 40 cardiovascular risk reported.14 322
267 women with hPE was age- and parity- Demographic and clinical data obtained 323
268 matched to a woman with hNTP. All from medical records and patient in- Cognitive assessment 324
269 women were postmenopausal and index terviews at the time of the in-clinic Women underwent comprehensive 325
270 pregnancies were rst pregnancies. assessment included age, body mass cognitive testing administered by an 326
271 Eligible women were sent a letter index (BMI), SBP, DBP, antihy- experienced psychometrist under the 327
272 describing the study, given contact in- pertensive and lipid-lowering medica- supervision of a neuropsychologist. The 328
273 formation, and if no response within 2 tions, and chart-abstracted and 2.5-hour battery included standardized 329
274 weeks, contacted by telephone. Of the 77 physician-conrmed diagnoses of hy- and validated tests of attention, working 330
275 women with conrmed hPE, 25 (32%) pertension, hyperlipidemia, and diabetes memory, psychomotor processing 331
276 refused and 7 (9%) did not respond. Five mellitus. The diagnosis of hypertension speed, executive functioning, language, 332
277 (6%) were found to be ineligible after was conrmed if a prior diagnosis and/or perceptual processing, learning, and 333
278 further screening. For women with use of prescription antihypertensive memory administered in a xed order. 334
hNTP, 104 women were contacted, 18 medication was conrmed upon medical Women also completed self-report

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335 391
336 TABLE 2 392
337 Q9 Demographics and clinical characteristics by hypertensive pregnancy status 393
338 394
339 Variable Normotensive, n 40 Preeclampsia, n 40 P value 395
340 Age at study consent, y 59.6 (56.2, 62.5) 59.2 (56.3, 62.5) .814 396
341 Age at first live birth, y 24.0 (22.3, 26.3) 24.5 (21.7, 25.8) .931 397
342 398
Time since first live birth/index pregnancy, y 34.5 (33.6, 36.7) 34.9 (32.9, 36.7) .564
343 399
344 Parity 3.0 (2.0, 3.0) 3.0 (2.0, 3.0) .967 400
345 Education .219 401
346 High school 3 (8%) 6 (15%) 402
347 403
Some college/technical/vocational 21 (53%) 22 (55%)
348 404
349 College graduate 16 (40%) 12 (30%) 405
2
350 BMI, kg/m 25.3 (23.1, 32.0) 29.8 (25.9, 33.7) .023 406
351 Diastolic blood pressure, mm Hg 75.2 (69.7, 84.0) 79.7 (69.3, 83.3) .368 407
352 408
353 Systolic blood pressure, mm Hg 128.7 (116.5, 145.7) 131.7 (119.7, 140.2) .613 409
354 LDL cholesterol, mg/dL 123.0 (99.7, 136.4) 106.1 (87.9, 124.3) .087 410
355 HDL cholesterol, mg/dL 64.0 (50.5, 76.5) 54.5 (41.0, 69.5) .054 411
356 412
Triglycerides, mg/dL 97.5 (72.0, 123.5) 108.0 (85.0, 163.0) .078
357 413
358 Fasting glucose, mg/dL 95.5 (91.0, 101.5) 98.0 (91.5, 109.5) .151 414
359 Diabetes 2 (5%) 4 (10%) .414 415
360 Albumin/creatinine ratio, mg/mmol 2.0 (0.00, 6.1) 2.4 (0.00, 5.1) .992 416
361 417
Past or current hormone therapy 17 (43%) 17 (43%) 1.000
362 418
363 Ongoing hormone therapy 8 (20%) 6 (15%) .556 419
364 17b-Estradiol, pg/mL 3.5 (2.1, 9.5) 5.4 (2.4, 7.8) .495 420
365 Estrone, pg/mL 22.0 (14.0, 32.0) 26.0 (14.5, 32.5) .956 421
366 422
Coronary artery calcification, AU 0.0 (0.0, 0.3) 0.0 (0.0, 28.0) .007
367 423
368 ApoE-4 polymorphism 9 (23%) 11 (28%) .606 424
369 Hypertension 8 (20%) 24 (60%) <.001 425
370 426
Medication with potential cognitive side effects 16 (40%) 29 (73%) .003
371 427
372 Obstructive sleep apnea 7 (18%) 12 (30%) .189 428
373 Family history of dementia 13 (33%) 12 (30%) .809 429
374 Continuous variables are reported as median (25th, 75th percentiles) whereas discrete variables are presented as count (%). 430
375 AU, Agatston unit; BMI, body mass index; HDL, high-density lipoprotein; LDL, low-density lipoprotein. 431
376 Fields et al. Cognitive impairment following preeclampsia. Am J Obstet Gynecol 2017. 432
377 433
378 434
379 mood questionnaires 1 week prior to or impairment (MCI), multiple-domain mild impairment on 1 measures 435
at the same time as cognitive testing. (See MCI, or dementia. A consensus diag- within at least 2 domains. A diagnosis
380 436
T1 Table 1 for complete description of nosis was determined based on agree- of dementia was considered if there
381 437
cognitive and mood measures.) ment of at least 3 raters. were cognitive decits 2 SD below
382 438
Most diagnostic criteria require the mean in 2 domains. Education
383 439
384
Clinical assessment of cognitive objective evidence of mild impairment was used to estimate baseline 440
385 impairment (typically 1-1.5 SD below the norma- functioning. 441
386 Three experienced neuropsychologists tive mean and a decline from baseline 442
387 and a behavioral neurologist blinded to functioning) in 1 cognitive domains. Statistical analyses 443
pregnancy status independently exam- For this study, incorporating published Demographic, clinical, and cognitive test
388 444
ined age-corrected scaled scores for each guidelines and criteria,16-18 MCI was data were summarized with descriptive
389 445
of the 80 women and assigned ratings of dened as mild impairment on 2 statistics, including percentages for
390 446
normal, single-domain mild cognitive measures within a single domain, or discrete variables and quartiles (median,

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447 503
448 TABLE 3 504
449 Cognitive and mood comparisons (raw scores) by hypertensive pregnancy status 505
450 506
451 Cognitive domain Variable Normotensive n 40 Preeclampsia n 40 P value Cohen d 507
452 Attention Trail Making Test A, time/seca 24.0 (20.0, 28.0) 25.5 (20.5, 31.0) .643 0.39 508
453 Digit span 16.0 (13.5, 18.0) 15.5 (13.5, 18.0) .887 0.12 509
454 510
Working memory Letter-number sequencing 10.0 (9.0, 11.0) 9.0 (8.0, 11.0) .778 0.07
455 511
456 Psychomotor speed Digit symbol coding 60.5 (55.0, 66.5) 59.0 (52.0, 64.0) .778 0.29 512
a
457 Executive functioning Trail Making Test B, time/sec 56.5 (51.5, 66.0) 64.0 (50.5, 77.5) .643 0.37 513
458 Language Letter fluency 39.0 (32.5, 46.0) 41.0 (35.5, 45.5) .887 0.00 514
459 515
Category fluency 52.0 (46.5, 60.5) 50.5 (42.5, 61.0) .778 0.21
460 516
461 Boston Naming Test 57.0 (55.5, 59.0) 57.0 (55.0, 58.5) .778 0.24 517
462 Visuospatial Picture completion 15.0 (14.0, 16.0) 15.0 (14.0, 16.0) .981 0.07 518
463 Block design 27.0 (24.0, 35.5) 27.5 (22.0, 32.0) .778 0.21
519
464 520
465 Learning/immediate AVLT trials 1e5 52.5 (46.0, 59.0) 50.0 (47.0, 55.5) .738 0.30 521
memory
466 522
467 Logical memory I 27.0 (23.0, 30.0) 24.0 (20.0, 28.0) .333 0.52 523
468 Visual reproduction I 32.0 (29.0, 36.0) 34.0 (31.0, 35.5) .778 0.13 524
469 Delayed memory AVLT delay 10.5 (9.0, 12.5) 10.5 (8.0, 12.0) .778 0.22 525
470 526
AVLT percent retention 83.0 (64.0, 100.0) 84.0 (68.0, 93.0) .915 0.11
471 527
472 Logical memory II 23.0 (19.0, 26.5) 19.0 (14.5, 23.0) .161 0.65 528
473 Logical memory percent retention 87.5 (76.5, 94.0) 79.0 (66.0, 88.5) .309 0.48 529
474 Visual reproduction II 26.5 (24.0, 32.0) 30.0 (27.0, 33.0) .778 0.04
530
475 531
476 Visual reproduction percent retention 83.5 (75.5, 97.0) 92.0 (79.0, 96.5) .778 0.03 532
477 Mood Beck Depression Inventorya 2.0 (0.0, 5.5) 4.0 (1.0, 7.5) .643 0.14 533
478 Beck Anxiety Inventory a
1.5 (0.0, 4.0) 3.0 (1.0, 6.0) .580 0.07 534
479 535
POMS angera 0.0 (0.0, 1.0) 0.0 (0.0, 2.5) .643 0.23
480 536
481 POMS confusiona 5.0 (4.0, 7.0) 5.0 (4.0, 7.5) .887 0.02 537
482 POMS depressiona 1.0 (0.0, 2.5) 1.0 (0.0, 5.0) .778 0.02 538
483 POMS fatigue a
1.0 (0.0, 4.0) 2.5 (0.0, 4.5) .643 0.36 539
484 540
POMS tensiona 2.0 (1.0, 4.5) 2.0 (1.0, 4.5) .981 0.09
485 541
486 POMS vigor 18.5 (13.5, 23.5) 16.5 (11.0, 21.5) .643 0.32 542
487 Scores are presented as median (25th, 75th percentiles). No significant differences were found after correction for multiple comparisons. 543
488 AVLT, Auditory Verbal Learning Test; POMS, Profile of Mood States. 544
489 a
Higher score is worseescores are total raw scores. 545
490 Fields et al. Cognitive impairment following preeclampsia. Am J Obstet Gynecol 2017. 546
491 547
492 548
493 549
494 25th and 75th percentiles) for contin- method described by Benjamini and Version 9.4; SAS Institute Inc, Cary, 550
495 uous variables. Bivariate comparisons Hochberg.19 The magnitude of effect on NC). 551
496 between groups with hPE or hNTP were measures of cognitive functioning was 552
497 performed using the c2 test or Wilcoxon estimated with Cohen d standardized Results 553
498 rank sum test, or with a Cochran- effect size.20 Convention suggests .2 is a Demographics and current clinical 554
499 Armitage trend test for ordinal mea- small effect size, .5 moderate, and .8 characteristics by pregnancy status are 555
500 sures of cognitive impairment. To large. All data were recorded and presented in Table 2. Compared to T2 556
501 correct for multiple comparisons among managed in a secure database (Medidata women with hNTP, women with hPE 557
502 all cognitive tests that were included, P Rave, Medidata Solutions Inc), and were had higher BMI (29.8 kg/m2 [inter- Q5 558
values were adjusted according to the analyzed using statistical software (SAS, quartile range {IQR} 25.9-33.7] vs 25.3

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559 615
560 and exibility used to assess executive 616
TABLE 4
561 functioning (d 1.96), followed by 617
Consensus-based assessment of cognitive status
562 verbal learning (d 1.93), visual mem- 618
563 Normotensive n 40 Preeclampsia n 40 ory (d 1.87), and auditory attention 619
564
Variable N (%) N (%) P value (d 1.69) (Table 5). T5
620
565 Cognitive impairment .03a In women with hPE, the amount of 621
566 CAC was greater in those who had 622
None 37 (93) 32 (80)
567 cognitive impairment vs those who did 623
MCI single domain 2 (5) 0 (0) not (67.5 AU [IQR 6.0-180.0] vs 0.0 AU
568 624
569
MCI multiple domains 1 (3) 7 (18) [IQR 0.0-25.0], P .043). There was no 625
570 Dementia 0 (0) 1 (3) signicant difference in carriers of 626
ApoE-4 polymorphism between hPE
571 No. of domains affected .03a 627
572 women with and without cognitive 628
0 37 (93) 32 (80) impairment nor was there any difference
573 629
574
1 2 (5) 0 (0) in use of hormone replacement therapy, 630
575 2 1 (3) 5 (13) BMI, frequency of hypertension, or use 631
576 of medications with cognitive side effects 632
3 0 (0) 1 (3)
(Table 6). T6
577 4 0 (0) 2 (5) 633
578 634
579
MCI/dementia .10 Comment 635
580 No 37 (93) 32 (80) The rst major nding from this study 636
581 was a trend toward cognitive impair- 637
Yes 3 (8) 8 (20)
582 ment being more frequently clinically 638
MCI, mild cognitive impairment.
583 a
diagnosed in women with hPE than in 639
Measure of impairment analyzed as ordinal variable with Cochran-Armitage trend test.
584 women with hNTP. Second, women with 640
Fields et al. Cognitive impairment following preeclampsia. Am J Obstet Gynecol 2017.
585 hPE showed a more diffuse range (ie, 641
586 multiple domains) of cognitive impair- 642
587 ment, most prominently affecting abili- 643
588 kg/m2 [IQR 23.1-32.0], P .004), had (observed range 0-4) of affected do- ties commonly ascribed to frontal 644
589 more CAC (0.0 AU [IQR 0.0-28.0] vs 0.0 mains (Table 4), there was a more subcortical brain processing, such as T4 645
590 AU [IQR 0.0-0.3], P .007), and were widespread pattern of cognitive impair- executive functioning, verbal learning, 646
591 more frequently diagnosed with hyper- ment in women with hPE compared to and attention. 647
592 tension (60% vs 20%, P < .001). More women with hNTP (P .03). Using a Previous studies show that women 648
593 women with hPE than with hNTP were binary measure in which all classica- with hPE exhibit variable neuro- 649
594 taking medications that could poten- tions of cognitive impairment are cognitive changes in the rst decade 650
595 tially affect cognition (73% vs 40%, P grouped together, there was a modest yet following the index pregnancy.8,13 Re- 651
596 .003). In the hNTP group, none of the nonsignicant difference (P .10) in the sults of the current study extend the 652
597 women with MCI were taking them. In frequency of cognitive impairment literature by providing long-term 653
598 the hPE group, 3 of the women with MCI among women with hPE (n 8; 20%) objective and clinical assessment of 654
599 were taking them but not the 1 with compared to women with hNTP (n 3; women with hPE 35 years after the 655
600 dementia. 8%). Further, 2 of the 3 women with affected pregnancy and are consistent 656
601 After correction for multiple com- hNTP had single-domain (memory) and with prior studies showing no differ- 657
602 parisons, there were no signicant dif- 1 had multidomain MCI, while all of the ences in scores on objective cognitive 658
603 ferences in women with hNTP or hPE on 8 women with hPE and cognitive measures between women with and 659
604 any measure of cognition or mood. Test impairment had multiple domains without hPE. However, using a clinical 660
605 scores for each cognitive and mood affected, including 7 with MCI and 1 approach where women were diagnosed 661
606T3 variable are presented in Table 3. Cohen with dementia. None of the women with with MCI or dementia according to 662
607 d for magnitude of effect between scores cognitive impairment reported depres- standard criteria, more women with 663
608 from women with hNTP or hPE indi- sion or anxiety sufcient to explain hPE than hNTP met such criteria. 664
609 cated moderate effect sizes for logical cognitive scores (ie, none reported Differences in outcomes based on in- 665
610 memory I (d 0.52) and logical mem- depression and 1 with hPE reported dividual clinical characterization and 666
611 ory II (d 0.65), with lower scores in the marginal mild anxiety). Comparing effect sizes vs statistical group compar- 667
612 hPE group. When examining clinical women with hPE with cognitive isons that obscure important individual 668
613 consensus diagnosis, in which impair- impairment to hPE without, the largest differences may help explain disparate 669
614 ment was rated on a scale from none to effect sizes were observed for Trail results in the literature, for example, 670
dementia and secondly as a count Making Test Bea test of cognitive speed frequent subjective cognitive symptoms

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671 727
672 TABLE 5 728
673 Cognitive and mood comparisons (raw scores) by cognitive status in women with preeclampsia 729
674 730
675 Cognitive domain Variable No impairment n 32 Impairment n 8 P value Cohen d 731
676 Attention Trail Making Test A, time/seca 25.0 (20.5, 31.0) 27.0 (21.0, 43.0) .753 0.45 732
677 Digit span 17.0 (14.0, 19.0) 11.0 (11.0, 14.0) .016 1.69 733
678 734
Working memory Letter-number sequencing 10.0 (8.5, 11.0) 8.0 (6.5, 8.5) .018 1.32
679 735
680 Psychomotor speed Digit symbol coding 59.0 (55.0, 65.5) 54.5 (34.0, 64.0) .487 0.83 736
a
681 Executive functioning Trail Making Test B, time/sec 59.5 (48.5, 72.0) 101.0 (70.0, 157.0) .018 1.96 737
682 Language Letter fluency 42.0 (36.5, 47.5) 32.5 (23.0, 40.5) .034 1.25 738
683 739
Category fluency 54.5 (48.0, 62.5) 40.5 (31.0, 44.5) .018 1.40
684 740
685 Boston Naming Test 57.0 (55.0, 59.0) 54.5 (52.0, 58.0) .243 0.72 741
686 Visuospatial Picture completion 15.0 (14.0, 16.0) 14.0 (12.0, 15.0) .178 0.85 742
687 Block design 28.0 (25.0, 32.0) 22.5 (16.0, 26.0) .108 0.95
743
688 744
689 Learning/immediate memory AVLT trials 1e5 53.0 (47.0, 56.0) 41.5 (29.5, 47.0) .016 1.93 745
690 Logical memory I 25.0 (22.5, 29.0) 18.5 (16.5, 23.0) .019 1.40 746
691 Visual reproduction I 34.5 (32.0, 36.0) 31.5 (28.5, 34.0) .134 0.69 747
692 748
Delayed memory AVLT delay 11.0 (9.0, 12.0) 7.0 (4.0, 9.0) .018 1.44
693 749
694 AVLT percent retention 87.5 (69.0, 93.0) 76.5 (46.0, 85.0) .228 0.81 750
695 Logical memory II 20.0 (15.0, 24.5) 15.5 (10.0, 19.5) .116 0.92 751
696 Logical memory percent retention 79.0 (69.0, 88.5) 78.0 (55.0, 89.0) .897 0.26 752
697 753
Visual reproduction II 30.0 (28.0, 33.5) 16.0 (11.5, 27.0) .026 1.87
698 754
699 Visual reproduction percent retention 93.0 (81.5, 96.5) 64.5 (33.5, 91.0) .134 1.72 755
700 Mood Beck Depression Inventory a
4.0 (1.0, 6.5) 3.5 (1.0, 9.0) .933 0.08 756
701 Beck Anxiety Inventorya 3.0 (1.0, 6.0) 3.5 (0.5, 6.0) .922 0.15
757
702 a
758
703 POMS anger 0.0 (0.0, 2.5) 0.5 (0.0, 4.0) .854 0.02 759
a
704 POMS confusion 5.0 (3.5, 7.5) 7.0 (5.0, 7.5) .409 0.39 760
705 POMS depression a
1.0 (0.0, 5.0) 0.0 (0.0, 4.5) .659 0.14 761
706 a 762
POMS fatigue 2.0 (0.0, 4.5) 3.0 (0.0, 8.0) .895 0.33
707 763
708 POMS tensiona 2.0 (1.0, 4.5) 1.5 (0.5, 4.5) .640 0.13 764
709 POMS vigor 16.0 (11.0, 21.5) 18.0 (13.5, 20.5) .753 0.19 765
710 Scores are presented as median (25th, 75th percentiles). 766
711 AVLT, Auditory Verbal Learning Test; POMS, Profile of Mood States. 767
712 a
Higher score is worseescores are total raw scores. Significant group differences are corrected for multiple comparisons. 768
713 Fields et al. Cognitive impairment following preeclampsia. Am J Obstet Gynecol 2017. 769
714 770
715 771
716 772
717 reported by women with hPE yet no disorders.1,31-35 Our study is consistent after, the affected pregnancy.36-39 It is 773
718 objective psychometric evidence. with the literature in that women with unclear whether hypertensive pregnan- 774
719 Factors known to increase brain hPE had higher BMI, had higher CAC, cies induce vascular changes or whether 775
720 vulnerability and associate with CVD and were more frequently hypertensive they further stimulate a cascade of 776
721 and cognitive dysfunction include hy- than women with hNTP. In the women already evolving changes. Vascular pa- 777
722 pertension,4,5,21 diabetes,22 dyslipide- with hPE, those with cognitive impair- thology is present in 29-41% of demen- 778
723 mia,23 obesity and BMI,24,25 carotid ment had more CAC than those without tia cases that come to autopsy.40-42 779
724 intima-media thickness,26 CAC,27,28 and cognitive impairment. Microvascular and macrovascular 780
725 genetic polymorphisms (eg, ApoE- In preeclampsia, pathophysiological changes that disrupt blood ow integrity 781
726 4).29,30 Many of these factors also share mechanisms associated with vascular can cause structural and functional brain 782
association with hypertensive pregnancy disease may exist before, and persist long changes,43 which can lead to vascular

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783 839
784 TABLE 6 840
785 Demographics and clinical characteristics of women with history of preeclampsia by cognitive status 841
786 842
787 Variable No impairment, n 32 Impairment, n 8 P value 843
788 Age at study consent, y 58.3 (55.6, 61.2) 63.2 (59.3, 65.4) .063 844
789 Age at first live birth, y 24.4 (21.7, 25.2) 26.4 (22.1, 29.9) .166 845
790 846
Time since first live birth/index pregnancy, y 34.9 (32.9, 36.7) 35.2 (32.7, 37.0) .892
791 847
792 Parity 3.0 (2.0, 3.5) 2.0 (2.0, 2.5) .055 848
793 Education .053 849
794 High school 3 (9%) 3 (38%) 850
795 851
Some college/technical/vocational 18 (56%) 4 (50%)
796 852
797 College graduate 11 (34%) 1 (13%) 853
2
798 BMI, kg/m 29.4 (25.7, 33.3) 32.5 (27.8, 34.1) .398 854
799 Diastolic blood pressure, mm Hg 78.7 (71.0, 82.2) 83.0 (66.5, 94.8) .407 855
800 856
801 Systolic blood pressure, mm Hg 130.8 (119.7, 139.2) 136.5 (124.3, 144.7) .398 857
802 LDL cholesterol, mg/dL 106.1 (90.7, 124.3) 93.1 (70.6, 131.1) .447 858
803 HDL cholesterol, mg/dL 49.0 (37.5, 68.5) 60.0 (48.5, 84.5) .171 859
804 860
Triglycerides, mg/dL 116.0 (91.0, 178.0) 97.5 (77.0, 114.5) .223
805 861
806 Fasting glucose, mg/dL 101.0 (91.5, 112.0) 97.5 (90.0, 98.5) .457 862
807 Diabetes 3 (9%) 1 (13%) 1.000 863
808 Albumin/creatinine ratio, mg/mmol 2.6 (0.0, 5.1) 2.3 (0.0, 7.2) .901 864
809 865
Past or current hormone therapy 13 (41%) 4 (50%) .631
810 866
811 Ongoing hormone therapy 5 (16%) 1 (13%) 1.000 867
812 17b-Estradiol, pg/mL 5.5 (2.4, 8.0) 4/0 (2.5, 6.4) .447 868
813 Estrone, pg/mL 26.5 (15.0, 34.0) 22.5 (8.0, 29.5) .302 869
814 870
Coronary artery calcification, AU 0.0 (0.0, 25.0) 67.5 (6.0, 180.0) .043
815 871
816 ApoE-4 polymorphism 8 (25%) 3 (38%) .479 872
817 Hypertension 18 (56%) 6 (75%) .333 873
818 874
Medication with potential cognitive side effects 25 (78%) 4 (50%) .111
819 875
820 Obstructive sleep apnea 8 (25%) 4 (50%) .168 876
821 Family history of dementia 8 (25%) 4 (50%) .168 877
822 Continuous variables are reported as median (25th, 75th percentiles) whereas discrete variables are presented as count (percentage). 878
823 AU, Agatston unit; BMI, body mass index; HDL, high-density lipoprotein; LDL, low-density lipoprotein. 879
824 Fields et al. Cognitive impairment following preeclampsia. Am J Obstet Gynecol 2017. 880
825 881
826 882
827 883
828 cognitive impairment directly44 or indi- ndings were similar in a large cohort raises speculation that compromised 884
829 rectly by disrupting white matter path- where the average age was 61 (range 34- white matter tracts result in the disrup- 885
830 ways.45-47 White matter hyperintensities 88) years.48 This suggests that vascular tion of cortical-subcortical pathways 886
831 on imaging associate with decreased changes associated with cognitive that subserve these functions.47,54,59,66 887
832 performance on tests of executive func- changes may not be purely age-related Indeed, in women with hPE examined in 888
833 tioning and psychomotor speed and and lend support to changes observed their late 30s, approximately 5 years from 889
834 processing with a fair amount of con- in the current sample of younger women index pregnancy, white matter lesions 890
835 sistency, and more variably to dimin- (age 59 [range 52-72] years). were greater compared to women with 891
836 ished learning, episodic memory, and The association of white matter hNTP.50 In further support that hyper- 892
837 visual memory and organization.48,49 hyperintensities and decreased cognitive tensive pregnancy is an independent 893
838 Although most of these studies have performance on tasks of executive func- predictor of change in cognition and 894
focused on persons age >65 years, tioning and psychomotor processing48,55 brain structure, women with a history of

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895 951
896 hypertensive pregnancy disorders have with and without hPE. Results may also Obstetricians/gynecologists are often the 952
897 been shown to have smaller brain vol- be biased toward less physically healthy only care provider women see regularly 953
898 umes than women with normotensive women since women per inclusion throughout their menopausal years, and 954
899 pregnancies decades later, even after criteria who did not have a documented as such are in a unique position to inte- 955
900 adjusting for traditional cardiovascular clinical visit within the last 2 years, grate pregnancy history into risk assess- 956
901 risk factors,51 in addition to increased perhaps because they were healthier, ment for future neurologic morbidity, 957
902 risk of CAC.14 A recent study found no were not contacted. Lastly, this study recognize often missed cognitive 958
903 relationship between white matter reects Olmsted County, Minnesota, impairment, and initiate individualized 959
904 hyperintensities, objective cognitive which is primarily white, non-Hispanic, prevention and treatment plans. n 960
905 performance, or subjective cognitive and fairly highly educated. Higher levels 961
906 symptoms in formerly preeclamptic of education and cognitive reserve55-57 Acknowledgment
962
907 women 40 years of age 6 years after have been associated with reduced risk We acknowledge the participants for their in-
963
908 pregnancy,52 and we postulate that these of cognitive decline and dementia. Both terest, time, and dedication to our research.
964
909 women have not yet reached an age groups were comparably educated, 965
threshold that challenges cognitive which could limit our ability to detect References
910 Q7 966
911 reserve. subtle cognitive changes. Women with 1. Wenger NK. Recognizing pregnancy-
967
The fact that 25% of women with hPE and cognitive impairment were less associated cardiovascular risk factors. Am J
912 Cardiol 2014;113:406-9. 968
913 normal cognition and 38% with highly educated than those without 969
2. Roberts JM, Hubel CA. Pregnancy: a
914 impaired cognition in our preeclampsia cognitive impairment, although the screening test for later life cardiovascular dis- 970
915 group were found to have an ApoE-4 sample size is too small for this to be a ease. Womens Health Issues 2010;20:304-7. 971
916 polymorphism suggests that this gene meaningful nding. In addition, 23 of 3. Brown MC, Best KE, Pearce MS, Waugh J,
972
may not independently increase risk of the 40 hNTP and 26 of the 40 hPE Robson SC, Bell R. Cardiovascular disease risk
917 in women with pre-eclampsia: systematic review 973
918 cognitive decline, but rather, interact women reported ethnicity, and all iden- 974
and meta-analysis. Eur J Epidemiol 2013;28: Q6
919 with other underlying disease pathology, tied as white/Caucasian. Therefore, 1-19. 975
920 including cerebrovascular disease.53 these ndings may not generalize to 4. Debette S, Seshadri S, Beiser A, et al. Midlife 976
921 Hormone replacement therapy, too, has women with lower education or of other vascular risk factor exposure accelerates struc-
977
been linked to negative cognitive func- races and ethnicities. tural brain aging and cognitive decline.
922 Neurology 2011;77:461-8. 978
923 tion, and in particular, conjugated In summary, women with hPE more 979
5. Knopman DS, Roberts R. Vascular risk fac-
924 equine estrogen.54 In our study, we do frequently have a higher BMI, hyper- tors: imaging and neuropathologic correlates. 980
925 not have information on type of hor- tension, and metabolic dysregulation, J Alzheimers Dis 2010;20:699-709. 981
926 mone treatments, but current hormone exacerbating an increased risk of car- 6. Rapp SR, Espeland MA, Shumaker SA, et al.
982
927 levels (17b-estradiol and estrone) were diovascular morbidity and mortality Effect of estrogen plus progestin on global
983
measured in all women and did not over the life course. CVD is associated cognitive function in postmenopausal women:
928 the Womens Health Initiative Memory Study: a 984
929 differ between groups (Tables 2 and 6). with cognitive decline and dementia. randomized controlled trial. JAMA 2003;289: 985
930 A goal of the study was to assess the Results of this study suggest a trend for 2663-72. 986
931 subclinical effect of hPE on cognitive women with hPE to exhibit more 7. Rawlings AM, Sharrett AR, Schneider AL,
987
functioning. A strength of our study is cognitive impairment 35 years later than et al. Diabetes in midlife and cognitive change
932 over 20 years: a cohort study. Ann Intern Med 988
933 our extensive medical record data that women with similar demographics but 989
2014;161:785-93.
934 allowed us to closely match women with who experienced a normotensive preg- 8. Postma IR, Bouma A, Ankersmit IF, 990
935 and without hPE and to exclude women nancy. The mechanisms underlying this Zeeman GG. Neurocognitive functioning 991
936 with potential neurologic confounding difference are unclear, but could be following preeclampsia and eclampsia: a long-
992
comorbidities. reect common mechanisms contrib- term follow-up study. Am J Obstet Gynecol
937 2014;211:37.e1-9. 993
938 Limitations of this study include the uting to CAC and brain changes, such as 994
9. Postma IR, Groen H, Easterling TR, et al. The
939 small sample size and potential response white matter lesions. White matter le- brain study: cognition, quality of life and social 995
940 and selection biases. If women with hPE sions are common even in the early years functioning following preeclampsia; an obser- 996
941 experience more cognitive decline and following index pregnancy, and the vational study. Pregnancy Hypertens 2013;3:
997
are more self-aware of cognitive in- pattern of cognitive impairment 227-34.
942 10. Roes EM, Raijmakers MT, 998
943 efciencies, it may be that some were less observed in this study appears to reect 999
Schoonenberg M, Wanner N, Peters WH,
944 likely to participate for fear of conrm- disruption in frontal subcortical white Steegers EA. Physical well-being in women with 1000
945 ing their subjective experience of cogni- matter tracts, although a larger sample a history of severe preeclampsia. J Matern Fetal 1001
946 tive loss. In addition, a reported history size will be needed to delineate this more Neonatal Med 2005;18:39-45.
1002
of dementia was exclusionary. If this clearly. The broader implications are that 11. Brusse I, Duvekot J, Jongerling J,
947 Steegers E, De Koning I. Impaired maternal 1003
948 study captured a more normal than many cardiovascular risk factors are 1004
cognitive functioning after pregnancies compli-
949 not sample, it might explain the lack of modiable, and lifestyle interventions, cated by severe pre-eclampsia: a pilot case- 1005
950 signicant cognitive differences in com- particularly in women with hPE, may control study. Acta Obstet Gynecol Scand 1006
parisons of test scores between women help prevent cognitive impairment. 2008;87:408-12.

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1007 1063
12. Baecke M, Spaanderman ME, van der 27. Reis JP, Launer LJ, Terry JG, et al. Sub- disease in a community-based case series.
1008 Werf SP. Cognitive function after pre-eclampsia: clinical atherosclerotic calcication and cognitive J Am Geriatr Soc 1999;47:564-9. 1064
1009 an explorative study. J Psychosom Obstet functioning in middle-aged adults: the CARDIA 43. Honjo K, Black SE, Verhoeff NP. Alzheimers 1065
1010 Gynaecol 2009;30:58-64. study. Atherosclerosis 2013;231:72-7. disease, cerebrovascular disease, and the beta- 1066
1011 13. Postma IR, Wessel I, Aarnoudse JG, 28. Vidal JS, Sigurdsson S, Jonsdottir MK, et al. amyloid cascade. Can J Neurol Sci 2012;39: 1067
1012 Zeeman GG. Neurocognitive functioning in Coronary artery calcium, brain function and 712-28.
1068
women with a history of eclampsia: executive structure: the AGES-Reykjavik Study. Stroke 44. Arvanitakis Z, Leurgans SE, Barnes LL,
1013 functioning and sustained attention. Am J Peri- 2010;41:891-7. Bennett DA, Schneider JA. Microinfarct pathol- 1069
1014 natol 2010;27:685-90. 29. Corder EH, Saunders AM, Strittmatter WJ, ogy, dementia, and cognitive systems. Stroke 1070
1015 14. White WM, Mielke MM, Araoz PA, et al. et al. Gene dose of apolipoprotein E type 4 allele 2011;42:722-7. 1071
1016 A history of preeclampsia is associated with a and the risk of Alzheimers disease in late onset 45. Knopman DS, Griswold ME, Lirette ST, et al. 1072
1017 risk for coronary artery calcication 3 decades families. Science 1993;261:921-3. Vascular imaging abnormalities and cognition:
1073
later. Am J Obstet Gynecol 2016;214:519.e1-8. 30. Dube JB, Johansen CT, Robinson JF, mediation by cortical volume in nondemented
1018 15. St Sauver JL, Grossardt BR, Yawn BP, et al. Lindsay J, Hachinski V, Hegele RA. Genetic individuals: atherosclerosis risk in communitiese 1074
1019 Data resource prole: the Rochester Epidemi- determinants of cognitive impairment, no de- neurocognitive study. Stroke 2015;46:433-40. 1075
1020 ology Project (REP) medical records-linkage mentia. J Alzheimers Dis 2013;33:831-40. 46. Lawrence AJ, Chung AW, Morris RG, 1076
1021 system. Int J Epidemiol 2012;41:1614-24. 31. Ahmed R, Dunford J, Mehran R, Robson S, Markus HS, Barrick TR. Structural network ef- 1077
1022 16. Albert MS, DeKosky ST, Dickson D, et al. Kunadian V. Pre-eclampsia and future cardio- ciency is associated with cognitive impairment in
1078
The diagnosis of mild cognitive impairment due vascular risk among women: a review. J Am Coll small-vessel disease. Neurology 2014;83:
1023 to Alzheimers disease: recommendations from Cardiol 2014;63:1815-22. 304-11. 1079
1024 the National Institute on Aging-Alzheimers As- 32. Breetveld NM, Ghossein-Doha C, van 47. Tuladhar AM, Reid AT, Shumskaya E, et al. 1080
1025 sociation workgroups on diagnostic guidelines Kuijk S, et al. Cardiovascular disease risk is only Relationship between white matter hyper- 1081
1026 for Alzheimers disease. Alzheimers Dement elevated in hypertensive, formerly preeclamptic intensities, cortical thickness, and cognition. 1082
1027 2011;7:270-9. women. BJOG 2015;122:1092-100. Stroke 2015;46:425-32.
1083
17. American Psychiatric Association. Diag- 33. Drost JT, Arpaci G, Ottervanger JP, et al. 48. Au R, Massaro JM, Wolf PA, et al. As-
1028 nostic and statistical manual of mental disorders, Cardiovascular risk factors in women 10 years sociation of white matter hyperintensity vol- 1084
1029 5th ed. Arlington (VA): American Psychiatric post early preeclampsia: the Preeclampsia Risk ume with decreased cognitive functioning: the 1085
1030 Publishing; 2013. EValuation in FEMales study (PREVFEM). Eur J Framingham Heart Study. Arch Neurol 1086
1031 18. Winblad B, Palmer K, Kivipelto M, et al. Mild Prev Cardiol 2012;19:1138-44. 2006;63:246-50. 1087
1032 cognitive impairmentebeyond controversies, 34. McDonald SD, Ray J, Teo K, et al. Measures 49. Smith EE, Salat DH, Jeng J, et al. Correla-
1088
towards a consensus: report of the International of cardiovascular risk and subclinical athero- tions between MRI white matter lesion location
1033 Working Group on Mild Cognitive Impairment. sclerosis in a cohort of women with a remote and executive function and episodic memory. 1089
1034 J Intern Med 2004;256:240-6. history of preeclampsia. Atherosclerosis Neurology 2011;76:1492-9. 1090
1035 19. Benjamini Y, Hochberg Y. Controlling the 2013;229:234-9. 50. Aukes AM, De Groot JC, Wiegman MJ, 1091
1036 false discovery rate: a practical and powerful 35. Ray JG, Vermeulen MJ, Schull MJ, Aarnoudse JG, Sanwikarja GS, Zeeman GG. 1092
1037 Q8 approach to multiple testing. J R Stat Soc Series Redelmeier DA. Cardiovascular health after Long-term cerebral imaging after pre-
1093
B Stat Methodol 1995;57:289-300. maternal placental syndromes (CHAMPS): eclampsia. BJOG 2012;119:1117-22.
1038 20. Cohen J. Statistical power analysis for the population-based retrospective cohort study. 51. Mielke MM, Milic NM, Weissgerber TL, et al. 1094
1039 behavioral sciences, 2nd ed. Hillsdale (NJ): Lancet 2005;366:1797-803. Impaired cognition and brain atrophy decades 1095
1040 Lawrence Earlbaum Associates; 1988. 36. Amaral LM, Cunningham MW Jr, after hypertensive pregnancy disorders. Circ 1096
1041 21. Gottesman RF, Schneider AL, Albert M, Cornelius DC, LaMarca B. Preeclampsia: long- Cardiovasc Qual Outcomes 2016;9:S70-6. 1097
1042 et al. Midlife hypertension and 20-year cognitive term consequences for vascular health. Vasc 52. Postma IR, Bouma A, de Groot JC,
1098
change: the atherosclerosis risk in communities Health Risk Manag 2015;11:403-15. Aukes AM, Aarnoudse JG, Zeeman GG. Cere-
1043 neurocognitive study. JAMA Neurol 2014;71: 37. Aykas F, Solak Y, Erden A, et al. Persistence bral white matter lesions, subjective cognitive 1099
1044 1218-27. of cardiovascular risk factors in women with failures, and objective neurocognitive func- 1100
1045 22. Biessels GJ, Staekenborg S, Brunner E, previous preeclampsia: a long-term follow-up tioning: a follow-up study in women after hy- 1101
1046 Brayne C, Scheltens P. Risk of dementia in study. J Investig Med 2015;63:641-5. pertensive disorders of pregnancy. J Clin Exp 1102
1047 diabetes mellitus: a systematic review. Lancet 38. Mangos GJ, Spaan JJ, Pirabhahar S, Neuropsychol 2016;38:585-98.
1103
Neurol 2006;5:64-74. Brown MA. Markers of cardiovascular disease 53. Yu L, Boyle PA, Leurgans S, Schneider JA,
1048 23. Solomon A, Kareholt I, Ngandu T, et al. risk after hypertension in pregnancy. Bennett DA. Disentangling the effects of age 1104
1049 Serum cholesterol changes after midlife and J Hypertens 2012;30:351-8. and APOE on neuropathology and late life 1105
1050 late-life cognition: twenty-one-year follow-up 39. Savitz DA, Danilack VA, Elston B, cognitive decline. Neurobiol Aging 2014;35: 1106
1051 study. Neurology 2007;68:751-6. Lipkind HS. Pregnancy-induced hypertension 819-26. 1107
1052 24. Cournot M, Marquie JC, Ansiau D, et al. and diabetes and the risk of cardiovascular 54. Shumaker SA, Legault C, Kuller L, et al.
1108
Relation between body mass index and cogni- disease, stroke, and diabetes hospitalization in Conjugated equine estrogens and incidence of
1053 tive function in healthy middle-aged men and the year following delivery. Am J Epidemiol probable dementia and mild cognitive impair- 1109
1054 women. Neurology 2006;67:1208-14. 2014;180:41-4. ment in postmenopausal women: Womens 1110
1055 25. Whitmer RA, Gunderson EP, Barrett- 40. Holmes C, Cairns N, Lantos P, Mann A. Health Initiative Memory Study. JAMA 1111
1056 Connor E, Quesenberry CP Jr, Yaffe K. Obesity Validity of current clinical criteria for Alz- 2004;291:2947-58. 1112
1057 in middle age and future risk of dementia: a 27 heimers disease, vascular dementia and de- 55. Prince M, Acosta D, Ferri CP, et al. Dementia
1113
year longitudinal population based study. BMJ mentia with Lewy bodies. Br J Psychiatry incidence and mortality in middle-income
1058 2005;330:1360. 1999;174:45-50. countries, and associations with indicators of 1114
1059 26. Wendell CR, Zonderman AB, Metter EJ, 41. Knopman DS, Parisi JE, Boeve BF, et al. cognitive reserve: a 10/66 Dementia Research 1115
1060 Najjar SS, Waldstein SR. Carotid intimal medial Vascular dementia in a population-based au- Group population-based cohort study. Lancet 1116
1061 thickness predicts cognitive decline among topsy study. Arch Neurol 2003;60:569-75. 2012;380:50-8. 1117
1062 adults without clinical vascular disease. Stroke 42. Lim A, Tsuang D, Kukull W, et al. Clinico- 56. Stern Y, Gurland B, Tatemichi TK, Tang MX,
1118
2009;40:3180-5. neuropathological correlation of Alzheimers Wilder D, Mayeux R. Inuence of education and

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occupation on the incidence of Alzheimers Internal Medicine (Dr Garovic); Division of Maternal Fetal AG034676); the National Center for Advancing Trans-
1120 disease. JAMA 1994;271:1004-10. Medicine, Department of Obstetrics and Gynecology (Drs lational Sciences (a component of the NIH; UL1 1176
1121 57. Vemuri P, Lesnick TG, Przybelski SA, et al. Garovic and White); and Departments of Health Sciences TR000135); the Department of Surgery, Mayo Clinic; and 1177
1122 Vascular and amyloid pathologies are indepen- Research (Drs Mielke and Bailey, and Mr Lahr), Neurology the Mayo Foundation. Its contents are solely the re- 1178
1123 dent predictors of cognitive decline in normal (Drs Mielke and Graff-Radford), Radiology (Dr Kantarci), sponsibility of the authors and do not necessarily repre- 1179
elderly. Brain 2015;138:761-71. Physiology and Biomedical Engineering (Drs Jayachan- sent the official views of NIH. Funding sources had no role
1124 1180
dran and Miller), and Surgery (Dr Miller), Mayo Clinic, in study design, analysis and interpretation of data,
1125 Rochester, MN. manuscript preparation, or decision to submit this article 1181
1126 Author and article information Received Aug. 15, 2016; revised Dec. 7, 2016; for publication. Q2 1182
1127 From the Division of Neurocognitive Disorders, Depart- accepted March 10, 2017. The authors report no conflict of interest. 1183
1128 ment of Psychiatry and Psychology (Drs Fields and Butts); This work was funded by grants from the National Corresponding author: Julie A. Fields, PhD. fields. 1184
Division of Nephrology and Hypertension, Department of Institutes of Health (NIH) (P50 AG44170, R01 julie@mayo.edu
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