Maternal hypertensive disorders in pregnancy and self-reported cognitive impairment of the offspring 70 years later: the Helsinki Birth Cohort Study




Objective


We tested whether maternal hypertensive disorders during pregnancy predict self-reported cognitive impairment, which is one of the earliest behavioral markers of dementia, of the offspring 70 years later.


Study Design


We included 876 participants of the Helsinki Birth Cohort Study 1934-44 who were born after normotensive, preeclamptic, or hypertensive pregnancies that were defined by the use of the mother’s blood pressure and urinary protein measurements at maternity clinics and birth hospitals. The participants completed a psychological questionnaire that included questions on cognitive failures and dysexecutive functioning at an average age of 69.3 ± 3.1 (SD) years.


Results


In comparison with the offspring who were born after normotensive pregnancies, the offspring who were born after preeclamptic pregnancies reported more frequent complaints of cognitive failures, distractibility, and false triggering. Further, among women we found maternal hypertension without proteinuria that was associated with more frequent complaints of cognitive failures, forgetfulness, and false triggering.


Conclusion


Hypertensive disorders during pregnancy are associated with more frequent subjective complaints of cognitive failures of the offspring in old age.


Empiric evidence suggests that a suboptimal prenatal environment, which is reflected in prematurity and smaller body size at birth, is associated with lower cognitive and executive function in childhood, adolescence, and adulthood and with cognitive decline up to old age. Hypertensive disorders (which include chronic hypertension, gestational hypertension, and [pre]eclampsia) complicate approximately 10% of all pregnancies. These disorders threaten the health and well-being of both the mother and the fetus and are among the key underlying causes of prematurity and intrauterine growth restriction. Thus, by affecting the fetal developmental milieu, hypertensive disorders may point to the mechanisms by which prenatal adversity associates with cognitive function in subsequent life.


The literature that reports associations between maternal hypertensive disorders in pregnancy and cognitive ability of the offspring is, however, scanty. The existing evidence shows that maternal hypertensive disorders are associated with poorer cognitive ability of the offspring in childhood and young adulthood. Although some studies have reported null associations and even that maternal hypertensive disorders are associated with better cognitive ability of the offspring, the findings tip in the direction of a negative association. Yet, it remains uncertain whether maternal hypertensive disorders continue to affect cognitive function in old age. We recently demonstrated that men who had been born after pregnancies that were complicated by a hypertensive disorder, in comparison with men who had been born after normotensive pregnancies, had lower cognitive ability at an average age of 68 years and displayed a greater decline in cognitive ability after age 20 years. Here our primary aim was to extend these analyses by testing whether maternal hypertensive disorders during pregnancy are associated with self-reported cognitive impairment, namely subjective complaints of cognitive failures and dysexecutive functioning, which are among the earliest behavioral markers of dementia, in elderly men and women who participated in the Helsinki Birth Cohort study.


Our secondary aim was to test whether any potential associations between hypertensive disorders in pregnancy and self-reported cognitive impairment differ according to sex, childhood socioeconomic status, length of gestation, and parity. The rationale for testing modulation by these factors was motivated by studies that point to sex differences in cognitive aging. Further, the occurrence of hypertensive disorders in pregnancy may vary according to social class and hypertensive disorders, especially preeclampsia, that occur in preterm pregnancy are on average more severe and may be different in cause from disorders that occur at term. Finally, hypertensive disorders appear to occur more frequently and may be qualitatively different in primi- than in multiparous pregnancies.


Methods


Participants


The Helsinki Birth Cohort Study comprises 13,345 men and women who were born as singletons between 1934 and 1944 in 1 of the 2 maternity hospitals in Helsinki, Finland. These men and women attended child welfare clinics during childhood and were still living in Finland in 1971, by which time a unique personal identification number had been assigned to each resident of the country. The study population has been described in detail previously.


From 2009-2010, a psychologic questionnaire that included questions on cognitive failures and executive function was administered to (1) a randomly selected subsample of women and men (n = 2003) who had from 2001-2004 participated in a detailed clinical examination and (2) a subsample of men only (n = 2786; 642 of whom belonged also to the randomly selected clinical subsample) who participated in a testing of cognitive ability during their compulsory military service from 1952-1972. Altogether these subsamples comprised 3072 men and 1075 women. From 2009-2010, 1981 men and 954 women were still traceable: 709 had died; 312 had declined participation in subsequent follow-up evaluation; and 193 lived abroad or had an unknown address. Of the traceable subjects, 1095 men and 798 women (64.5%) returned the questionnaire. Of these, data on maternal blood pressure and protein tests during pregnancy to diagnose hypertensive pregnancy disorders were available on 511 men and 387 women; 499 men and 377 women had adequate data on gestational age based on last menstrual period and were included in this study sample. Our previous publications have addressed representativeness of the randomly selected subsample, the subset of military conscripts, and the subpopulation with data available on maternal hypertension and proteinuria in relation to the entire Helsinki Birth Cohort study cohort. The current study sample did not differ in maternal age, weight, height, parity, and birthweight from those who were still traceable from 2009-2010 but who did not return the questionnaire. The included participants more often were born to lower social classes (69%, 21%, and 10% of the included participants were born to manual working, junior clerical and senior clerical fathers, respectively, vs 63%, 23%, and 14% of the participants who did not return the questionnaire; P = .002).


The Ethics Committee of the Helsinki and Uusimaa Hospital District approved the study, and all participants signed written informed consent.


Measures


Hypertensive disorders


To identify pregnancy-related hypertensive disorders, we used the mother’s blood pressure and urinary protein measurements that were recorded at antenatal clinics or at birth hospital. These data and definitions of hypertensive pregnancy disorders have been described in detail. Briefly, all pregnant women were encouraged to attend the antenatal clinics, which were introduced in Helsinki in 1928. Of the 13,345 participants in the original cohort, maternal antenatal clinics data were available for 6410 participants (48.0%) and included, on average, 2.0 blood pressure and 2.5 urinary protein measurements in each pregnancy. Based on this information, we defined 3 groups of mothers: (1) mothers with severe and nonsevere preeclampsia, with proteinuria (approximately, 1 mg/mL of albumin) and a systolic blood pressure of ≥140 mm Hg or a diastolic pressure of ≥90 mm Hg; (2) mothers with gestational and chronic hypertension, with hypertension as in (1) but no proteinuria and with any systolic blood pressure ≥140 mm Hg or any diastolic blood pressure ≥90 mm Hg at <20 weeks gestation; and (3) normotensive mothers with neither systolic pressure of 140 mm Hg nor diastolic pressure of 90 mm Hg during pregnancy. These definitions are consistent with the National High Blood Pressure Education Program Working Group on High Blood Pressure in Pregnancy 2000 criteria, with 2 exceptions: first, we considered 1 high blood pressure measurement to be sufficient for diagnosis because our data did not allow us to require 2 separate measurements according to the National High Blood Pressure Education Program Working Group on High Blood Pressure in Pregnancy criteria; second, our data included only a qualitative measurement of proteinuria.


Other neonatal, maternal and adult characteristics


Data on offspring date of birth, weight (grams) and head circumference (centimeters) at birth; mother’s height (centimeters), weight (kilograms), and age at delivery; parity, and date of last menstrual period were extracted from birth records. Birth, child welfare clinic, and school health care records included data on fathers’ occupations, a marker of the family’s socioeconomic status, which were grouped into manual workers and junior and senior clerical workers. Highest attained level of education in adulthood recorded at 5-year intervals from 1970-1995 was extracted from Statistics Finland. Diagnoses of stroke (international classification of disease codes 430-434 and 436-437 from ICD-8 and 9; 438 from ICD-9; I60-I69 from ICD-10), coronary heart disease (codes 410-414 from ICD-8 and ICD-9; I21-I25 from ICD-10), mood disorders (codes 296, 298.00, 300.40, 300.41, and 301.10 from ICD-8; 296, 3004A, and 3011D from ICD-9; F30-F39 from ICD-10), and anxiety disorders (codes 300.00-300.30, 300.50-300.99, 305, 306.80, and 307.99 from ICD-8; 3000A-3003A, 3006A-3009X, 3078A, and 309 from ICD-9; F40-F48 from ICD-10 ) that were recorded between 1969 and 2004 were extracted from the Finnish Hospital Discharge Register.


Self-reported cognitive impairment


The Cognitive Failures Questionnaire (CFQ) is composed of 25 questions that inquire about basic cognitive problems that people may have had in everyday activities in the past 6 months. The CFQ items are self-rated on a scale that ranges from 0 (never) to 4 (very often). Sample items include “Do you fail to notice signposts on the road?” and “Do you find you forget whether you’ve turned off a light or a fire or locked the door?” The scale yields a total score and 3 subscale scores that measure forgetfulness, distractibility, and false triggering. Higher scores reflect more frequent complaints. The reliabilities (Cronbach’s alpha) of the CFQ total score and subscale scores were 0.92, 0.84, 0.79, and 0.79 for total score of forgetfulness, distractibility, and false triggering, respectively.


The Dysexecutive Questionnaire (DEX), which was derived from the Behavioral Assessment of Dysexecutive Syndrome, is a 20-item scale that was designed to screen for changes in observable everyday manifestations of executive function, such as abstract thinking, impulsivity, confabulation, and planning problems. The DEX items are self-rated on a scale that ranges from 0 (never) to 4 (very often). Sample items include “I have problems in understanding what other people mean unless they keep things simple and straightforward,” “I have difficulties in planning for the future,” and “I talk in one way but act in another.” The scale yields a total score and 3 subscale scores that measure behavioral-emotional self-regulation, metacognition, and executive cognition. Higher scores reflect more frequent complaints. The reliabilities (Cronbach’s alpha) of the DEX total score and subscale scores were 0.90, 0.78, 0.72, and 0.73 for total score, behavioral-emotional self-regulation, metacognition, and executive cognition, respectively.


Statistical analysis


Multiple linear regression analyses were used to test associations between maternal hypertensive disorders and subjective complaints of cognitive failures and executive function. To attain normality, the skewed DEX and CFQ total and subscale scores were transformed into normalized z-scores. The z-score represents the difference from the mean value for the entire cohort and is expressed in standard deviation (SD) units. We made adjustments for the neonatal, maternal, and adult characteristics that may increase the risk for hypertensive pregnancy disorders and/or cognitive impairment in old age. These included offspring’s sex, length of gestation, weight and head circumference at birth, age at completion of the questionnaire, mother’s body mass index (calculated from weight in kg divided by height in meters squared) and age at delivery, parity, and father’s occupational status in childhood. A further model that was adjusted for the highest attained level of education in adulthood.


We also tested whether sex, prematurity, parity, or childhood socioeconomic status modified any potential associations between maternal hypertensive pregnancy disorders and complaints of cognitive failures/dysexecutive function. For these analyses, interaction terms such as sex, prematurity, parity, father’s occupational status in childhood x hypertensive disorders during pregnancy were entered into the regression equation and were followed by the main effects of these variables.




Results


Table 1 presents characteristics of the sample according to maternal hypertensive pregnancy disorders. Preeclampsia and hypertension without proteinuria were associated with higher body mass index of the mothers and lower birthweight of the babies ( P < .05). Preeclampsia was also associated with primiparity and shorter length of gestation; hypertension without proteinuria was associated with older age of the mothers ( P < .05). In this sample, hypertensive disorders did not associate with the other neonatal, maternal, or adult characteristics ( P > .08).



TABLE 1

Characteristic of the study sample according to maternal hypertension status during pregnancy
























































































































































































































































































































Characteristic Normotension (n = 553) Preeclampsia (n = 31) t χ 2 P value Hypertension without proteinuria (n = 292) t χ 2 P value
Maternal
Mother’s age at delivery, y a 28.1 ± 5.1 26.7 ± 4.9 1.48 .14 29.2 ± 5.9 −2.71 .007
Mother’s body mass index at delivery, kg/m 2 a 26.5 ± 2.8 27.8 ± 2.2 −2.37 .02 26.9 ± 3.2 −2.15 .03
Parity, n (%) 12.44 < .001 0.002 .97
Primiparity 266 (48) 25 (81) 140 (48)
Multiparity 287 (52) 6 (19) 152 (52)
Offspring
Sex, n (%) 0.05 .82 0.004 .95
Male 315 (57) 17 (55) 167 (57)
Female 238 (43) 14 (45) 125 (43)
Length of gestation, d a 279.0 ± 12.1 274.1 ± 16.2 2.16 .03 278.5 ± 12.9 0.53 .60
Preterm birth at <37 weeks gestation, n (%) 31 (6) 4 (13) 2.78 .10 19 (7) 0.28 .60
Birthweight, g a 3463.2 ± 471.7 2978.6 ± 477.9 5.56 < .001 3393.0 ± 484.0 2.04 .04
Head circumference, cm a 35.2 ± 1.6 35.1 ± 1.5 35.2 ± 1.5 −0.40 .69
Father’s occupation in subject’s childhood, n (%) 0.07 .97 5.05 .08
Manual worker 362 (67) 19 (66) 212 (74)
Junior clerical 120 (22) 7 (24) 54 (19)
Senior clerical 60 (11) 3 (10) 21 (7)
General
Highest achieved level of education, n (%) 1.32 .73 2.84 .42
Basic or less 169 (31) 11 (35) 104 (36)
Upper secondary 148 (27) 10 (32) 67 (23)
Lower tertiary (polytechnic, vocational, bachelors) 163 (29) 7 (23) 81 (28)
Upper tertiary (masters or higher) 73 (13) 3 (10) 40 (14)
Age at completing the questionnaires, y a 69.4 ± 3.2 70.4 ± 2.8 −1.70 .08 69.1 ± 2.9 1.47 .14
Hospitalization for coronary heart disease and/or stroke, n (%) 52 (9) 4 (13) 33 (11)
Hospitalization for mood and/or anxiety disorder,n (%) 13 (2) 1 (3) 7 (2)

Tuovinen. Hypertensive disorders in pregnancy and cognitive impairment of offspring. Am J Obstet Gynecol 2013.

a Data are given as mean ± SD.



Men and women did not differ in complaints of cognitive failures and dysexecutive functioning. Prematurity, weight, and head circumference at birth; mother’s body mass index, age at delivery, and parity; and father’s occupational status did not associate with complaints of cognitive failures or dysexecutive functioning ( P > .06). Older age at completion of the questionnaire was associated with more frequent complaints of cognitive failures (unstandardized regression coefficient [B] = 0.03; 95% confidence interval [CI], 0.01–0.06; P = .002), forgetfulness (unstandardized regression coefficient [B] = 0.04; 95% CI, 0.02−0.06; P < .001), and distractibility (unstandardized regression coefficient [B] = 0.03; 95% CI, 0.01–0.05; P = .02) and the more frequent complaints of dysexecutive functioning (unstandardized regression coefficient [B] = 0.03; 95% CI, 0.004–0.05; P = .02), behavioral-emotional self-regulation (unstandardized regression coefficient [B] = 0.02; 95% CI, 0.001–0.04; P = .04), and executive cognition (unstandardized regression coefficient [B] = 0.04; 95% CI, 0.02–0.06; P < .001). Higher attained level of education in adulthood was associated inversely with complaints of distractibility (unstandardized regression coefficient [B] = −0.09; 95% CI, −0.15 to −0.03; P = .01), complaints of dysexecutive functioning (unstandardized regression coefficient [B] = −0.14; 95% CI, −0.20 to −0.07; P < .001), behavioral-emotional self-regulation (unstandardized regression coefficient [B] = −0.12; 05% CI, −0.18 to −0.06; P < .001), metacognition (unstandardized regression coefficient [B] = −0.09; 95% CI, −0.15 to −0.03; P = .002), and executive cognition (unstandardized regression coefficient [B] = −0.14; 95% CI, −0.20 to 0.09; P < .001). Frequencies of hospitalizations for stroke or coronary heart disease and mood or anxiety disorders are shown in Table 1 . However, no analyses were pursued with these variables because the numbers of hospitalizations were too small to include.


Preeclampsia and self-reported cognitive impairment


Unadjusted univariate statistics for cognitive failures and dysexecutive functioning according to maternal hypertension status during pregnancy are given in Table 2 . Table 3 shows that, in comparison with participants who were born after normotensive pregnancies, participants who were born after pregnancies that were complicated by preeclampsia reported more frequent complaints of cognitive failures, distractibility, and false triggering. These associations remained significant in the unadjusted and adjusted models ( Table 3 ).



TABLE 2

Unadjusted univariate statistics for CFQ and DEX scores according to maternal hypertension status during pregnancy







































































































Variable Normotension (n = 553) a Preeclampsia (n = 31) a F P value Hypertension without proteinuria (n = 292) a F P value
CFQ
Total score −0.05 ± 1.00 0.43 ± 0.86 6.72 .01 0.04 ± 0.98 1.51 .22
Forgetfulness −0.04 ± 0.99 0.28 ± 0.90 3.14 .08 0.04 ± 1.00 1.25 .26
Distractibility −0.04 ± 1.02 0.42 ± 0.79 6.20 .01 0.03 ± 0.94 1.03 .31
False triggering 0.05 ± 1.00 0.37 ± 0.86 5.22 .02 0.06 ± 0.96 2.66 .10
DEX
Total score −0.04 ± 0.98 0.32 ± 0.93 3.93 .05 0.05 ± 0.97 1.80 .22
Behavioral-emotional self-regulation −0.01 ± 0.92 0.27 ± 0.98 2.72 .10 0.08 ± 0.91 1.50 .22
Metacognition −0.01 ± 0.92 0.33 ± 0.88 3.96 .05 0.04 ± 0.97 0.52 .47
Executive cognition −0.01 ± 0.92 0.34 ± 0.78 4.21 .04 0.06 ± 0.92 1.05 .31

CFQ, Cognitive Failure Questionnaire; DEX, Dysexecutive Questionnaire.

Tuovinen. Hypertensive disorders in pregnancy and cognitive impairment of offspring. Am J Obstet Gynecol 2013.

a Data are given as mean ± SD.



TABLE 3

Comparison of CFQ and DEX scores according to maternal hypertension status during pregnancy


























































































































Variable Normotension vs preeclampsia Normotension vs hypertension without proteinuria
Unadjusted model Adjusted model a Unadjusted model Adjusted model a
Mean difference in SD units (95% CI) P value Mean difference in SD units (95% CI) P value Mean difference in SD units (95% CI) P value Mean difference in SD units (95% CI) P value
CFQ
Total score 0.48 (0.12–0.84) .01 0.45 (0.02–0.87) .04 0.09 (−0.05 to 0.23) .22 0.12 (−0.04 to 0.27) .14
Forgetfulness 0.32 (−0.04 to 0.68) .08 0.18 (−0.25 to 0.60) .41 0.08 (−0.06 to 0.22) .26 0.13 (−0.02 to 0.28) .10
Distractibility 0.46 (0.11–0.82) .01 0.51 (0.08–0.93) .02 0.07 (−0.07 to 0.21) .31 0.09 (−0.06 to 0.24) .16
False triggering 0.42 (0.06–0.78) .02 0.48 (0.06–0.90) .03 0.12 (−0.02 to 0.26) .10 0.13 (−0.02 to 0.29) .08
DEX
Total score 0.36 (0.004–0.71) .05 0.31 (−0.11 to 0.73) .15 0.09 (−0.05 to 0.23) .22 0.07 (−0.08 to 0.22) .37
Behavioral-emotional self-regulation 0.28 (−0.05 to 0.61) .10 0.31 (−0.08 to 0.70) .12 0.08 (−0.05 to 0.21) .22 0.06 (−0.08 to 0.20) .40
Metacognition 0.34 (−0.002 to 0.67) .05 0.23 (−0.17 to 0.63) .25 0.05 (−0.08 to 0.18) .47 0.04 (−0.10 to 0.19) .56
Executive cognition 0.35 (0.01–0.68) .04 0.37 (−0.02 to 0.76) .06 0.07 (−0.06 to 0.20) .30 0.06 (−0.08 to 0.20) .40

Comparison of the CFQ and the DEX scores of offspring who were born after pregnancies that were complicated by preeclampsia (n = 31) or by hypertension without proteinuria (n = 292) compared with offspring who were born after normotensive pregnancies (n = 553). Referent: Normotensive (0.00).

CFQ, Cognitive Failure Questionnaire; DEX, Dysexecutive Questionnaire.

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May 13, 2017 | Posted by in GYNECOLOGY | Comments Off on Maternal hypertensive disorders in pregnancy and self-reported cognitive impairment of the offspring 70 years later: the Helsinki Birth Cohort Study

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