Maternal hypertensive disorders during pregnancy: adaptive functioning and psychiatric and psychological problems of the older offspring

Authors


Abstract

Objective

To study whether pre-eclampsia and hypertension without proteinuria during pregnancy are associated with adaptive functioning, and psychiatric and psychological problems, of older offspring.

Design

Retrospective longitudinal cohort study.

Setting

Participants in the Helsinki Birth Cohort 1934–44 Study.

Population

A cohort of 778 participants born after normotensive, pre-eclamptic, or hypertensive pregnancies, defined based on the mother's blood pressure and urinary protein measurements at maternity clinics and birth hospitals.

Methods

Pearson's chi-squared tests and multivariable logistic regression.

Main outcome measures

Achenbach System of Empirically Based Assessment Older Adult Self-Report scores, completed at age 69.3 years (SD 3.1 years).

Results

Compared with offspring born after normotensive pregnancies, offspring born after pre-eclamptic pregnancies had increased odds of reporting total problems (aOR 4.00, 95%CI 1.64–9.77) and problems of particular concern to clinicians (critical items; aOR 5.28, 95%CI 1.87–14.96), as well as: anxious/depressed, functional impairment, memory, thought, and irritable/disinhibited problems on syndrome scales; depressive, somatic, and psychotic problems on Diagnostic and Statistical Manual of Mental Disorders scales; and adjustment problems in relationship satisfaction with spouse/partner. Maternal hypertension without proteinuria was not consistently associated with adjustment and problems (total problems, aOR 1.08, 95%CI 0.75–1.57; critical items, aOR 1.58, 95%CI 0.91–2.72).

Conclusions

Maternal hypertensive disorders in pregnancy, during a period of expectant treatment, carry an increased risk of problems in adaptive functioning and mental wellbeing in the offspring seven decades later. Being the longest follow-up on transgenerational consequences of maternal hypertensive disorders reported thus far, our study points to the life-time increased risk of an adverse intrauterine environment.

Introduction

Hypertensive pregnancy disorders complicate 10% of all pregnancies.[1] Pre-eclampsia, a severe form of these disorders, accounts for up to 4%. These disorders are characterised by new-onset hypertension after 20 weeks of gestation, with proteinuria being an additional characteristic in pre-eclampsia.[2] The etiology of hypertensive pregnancy disorders remains unknown. Hypertensive disorders not only threaten the health and wellbeing of the mother, but may also compromise fetal development and cause severe pre- and postnatal complications in the offspring.

Growing evidence shows that prematurity and small body size at birth are associated with an increased risk of a range of mental disorders and psychiatric symptoms.[3-9] Hypertensive pregnancy disorders are among the key causes of both prematurity and restricted fetal growth,[10, 11] and may offer insight into the mechanisms that underlie these associations. Yet, only a handful of studies have examined relationships between maternal hypertensive pregnancy disorders and mental health outcomes of the offspring. The existing evidence suggests that maternal hypertension and/or pre-eclampsia during pregnancy are associated with internalising behaviours in children/adolescents,[12] and with increased risks of any mental disorder,[13] mood and anxiety disorders,[13, 14] personality disorders,[15] and schizophrenia in the offspring in adulthood.[16-20] The findings remain inconclusive, however.[12, 13, 20-23] It is not fully clear whether any of the harmful effects of maternal hypertensive pregnancy disorders persist into old age and extend to risks of poorer adaptive functioning and psychiatric and psychological problems that may compromise everyday life.

We have previously shown that maternal hypertensive disorders during pregnancy are associated with depressive symptoms in primiparous offspring at 63 years of age,[24] with self-reported complaints of cognitive failures in the offspring at 69 years of age,[25] and with cognitive decline in male offspring from 20 to 69 years.[26] We extend these analyses here and test whether maternal hypertensive disorders during pregnancy predict poorer adaptive functioning and a range of psychiatric and psychological problems in old age in participants of the Helsinki Birth Cohort Study. We also explore whether the effects of hypertensive disorders vary according to sex, prematurity, childhood socio-economic status and parity. This is relevant, as the well-known sex differences in longevity may be reflected in the measures of functioning and problems in old age, and hypertensive disorders, and pre-eclampsia in particular, may differ in quality and/or in etiology if it occurs in preterm versus term pregnancy,[27, 28] and in primiparous versus multiparous pregnancy,[28, 29] and the occurrence of hypertensive disorders may vary according to socio-economic status.[30, 31]

Methods

Participants

The Helsinki Birth Cohort Study (HBCS) comprises 13 345 men and women who were born as singletons between 1934 and 1944 in one of the two maternity hospitals in Helsinki.[32, 33] 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.

In 2009–2010 a psychological questionnaire, including questions on adaptive functioning, and psychiatric and psychological problems, was administered to: (1) a subsample of women and men (n = 2003) randomly selected from those born in one of the two birth hospitals and who had participated in a detailed clinical examination in 2001–2004;[34] and (2) a subsample of men only (n = 2786; 642 of whom also belonged to the randomly selected clinical subsample) who had participated in a test of cognitive ability during their compulsory military service in 1952–1972.[35] Altogether, these subsamples comprised 3072 men and 1075 women. In 2009–2010, 1981 men and 954 women were still traceable; 709 had died, 312 had declined participation in a subsequent follow-up, and 193 lived abroad or had an unknown address. Of the traceable participants, 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 (for the definition of hypertensive disorders during pregnancy, see below) were available on 511 men and 387 women; 434 men and 344 women had adequate data on gestational age based on last menstrual period and other covariates and moderating variables, and were included in this study sample. Our previous publications have addressed the 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 HBCS cohort.[34-37] The current study sample did not differ from the sample including those who were still traceable in 2009–2010 but who did not return the questionnaire, in maternal age, weight, height, parity, and birthweight; the participants included were more often 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, versus 63, 23, and 14% of the participants who did not return the questionnaire; P = 0.01).

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

Measures

Maternal hypertensive disorders during pregnancy

Maternal blood pressure readings and results of urinary protein tests were used to define pre-eclampsia and hypertension without proteinuria.[36] We defined four groups: (1) mothers with severe pre-eclampsia, with a 1 +  proteinuria reading on dipstick in a random urine sample, and a systolic blood pressure of ≥160 mmHg or a diastolic pressure of ≥110 mmHg occurring after 20 weeks of gestation; (2) mothers with non-severe pre-eclampsia, with a 1 +  proteinuria reading on dipstick in a random urine sample, and a systolic blood pressure of ≥140 mmHg or a diastolic pressure of ≥90 mmHg occurring after 20 weeks of gestation; (3) mothers with gestational hypertension or chronic hypertension, with hypertension as described in (2), but with no proteinuria or with any systolic blood pressure ≥140 mmHg or any diastolic blood pressure ≥90 mmHg before 20 weeks of gestation; (4) normotensive mothers with neither systolic pressure attaining 140 mmHg nor diastolic pressure attaining 90 mmHg during pregnancy. The two groups of mothers with severe and non-severe pre-eclampsia were combined for the purposes of this study.

These definitions are consistent with the criteria of the National High Blood Pressure Education Program Working Group on High Blood Pressure in Pregnancy (NHBPEP; 2000),[2, 36] with two exceptions: first, we considered one high blood pressure measurement to be sufficient for diagnosis, because our data did not allow us to acquire two separate measurements; second, our data included only a qualitative measurement of protein – the 1 +  proteinuria reading approximates to 1 mg/ml of albumin.[2, 38]

Adaptive functioning, and psychiatric and psychological problems

Adaptive functioning, and psychiatric and psychological problems were assessed with the Achenbach System of Empirically Based Assessment (ASEBA) Older Adult Self-Report (OASR).[39] The OASR is a 113-item standardised questionnaire on adaptive functioning, strengths, and problems in a population aged 60–75 and >75 years. Items are self-rated as 0 (not true, as far as you know), 1 (somewhat or sometimes true), and 2 (very true or often true), based on the preceding 2 months. Three adaptive functioning scales measure ‘relationships and contacts with friends’, ‘relationship and satisfaction with spouse/partner’, and ‘personal strengths’, encompassing self-care, relationships, performance of tasks, and self-confidence. Two scales tap problems across all scales, namely the ‘total problems’ scale and the ‘critical items’ scale that measure problems of particular concern to clinicians. Seven scales measure empirically based syndromes, namely anxiousness/depression, worries, somatic complaints, functional impairment, memory/cognition problems, thought problems, and irritableness/disinhibition. Diagnostic and Statistical Manual of Mental Disorders (DSM)-oriented scales consist of items that experts from ten cultures have identified as being very consistent with DSM-IV categories. They comprise depressive, anxiety, somatic, dementia, psychotic, and antisocial personality problems. We used cut-offs to discriminate borderline deviant and non-deviant functioning and problems (cut-off scores: 35 for adaptive functioning; 65 for critical items, and for syndrome and DSM-oriented scales; and 60 for total problem scales).[39]

Covariates and moderating variables

Offspring's date of birth (year), and weight (g) and head circumference (cm) at birth, placental weight (g), mother's age, weight (kg), and height (cm) at delivery, parity, and date of last menstruation were obtained from hospital birth records. The mother's body mass index (BMI) was calculated as weight divided by height2 (kg/m2). The father's occupational status (manual worker, junior clerical, senior clerical) was extracted from the hospital, child welfare clinic, and school healthcare records, with the highest occupational status used as the variable, and breastfeeding (yes/no) was extracted from the child welfare clinic records. Adult socio-economic status was indicated by the highest level of education achieved from census data taken at 5-year intervals between 1970 and 2000 by Statistics Finland.

Statistical analyses

We used Pearson's chi-square tests and logistic regression analyses with odds ratios (ORs) and 95% confidence intervals (95%CIs) to test the associations between pre-eclampsia and maternal hypertension without proteinuria and borderline deviant scores of adjustment and problems in old age. To account for type-1 error, we conducted the analyses with problems in two steps. First, we focused on the total problems and critical items scales that assess problems across all scales. Second, we made further analyses focusing on the specific empirically based syndromes and DSM-oriented scales. We made adjustments for sex, year of birth (1934–38 versus 1939–44), gestational age, weight for gestational age, and head circumference at birth, placental weight, father's occupational status in childhood, parity, mother's age and BMI at delivery, breastfeeding, own maximum level of education, and age at completion of the questionnaire. Our secondary aim was to test whether sex, prematurity, parity, or childhood socio-economic status moderated the associations by including ‘sex, prematurity, parity, father's occupational status (grouped into manual workers and junior/senior clericals) × hypertensive disorder during pregnancy’ interactions in the regression equation, followed by their main effects.

Results

Table 1 presents descriptive data of the study population according to the status of mothers' hypertension disorders during pregnancy. There were 494 normotensive pregnancies, 260 pregnancies complicated by hypertension without proteinuria, and 24 pregnancies complicated by pre-eclampsia. Of the pre-eclamptic pregnancies 12 were severe and 12 non-severe. In comparison with normotensive mothers, mothers with hypertension without proteinuria and pre-eclampsia had higher BMIs. Pre-eclampsia was also associated with primiparity, shorter length of gestation, prematurity, lower weight, and smaller head circumference at birth, lower placental weight, and older age at testing of adjustment and problems. Hypertension without proteinuria was associated with older maternal age at birth. Hypertensive disorders were not associated with other neonatal, parental, or adult characteristics. Tables S1 and S2 show associations between covariates and moderating variables with the borderline clinically significant adaptive functioning, and psychiatric and psychological problem scales.

Table 1. Characteristic of the study sample according to mother's hypertension status during pregnancy
 Normotension n = 494 (63%)Hypertension without proteinuria = 260 (33%)Pre-eclampsia n = 24 (3%)
Mean (SD)/N (%)Mean (SD)/N (%) t χ2 P Mean (SD)/N (%) t χ2 P
Maternal characteristics
Mother's age at delivery (years)28.2 (5.2)29.1 (5.9)−2.07 0.0426.8 (4.9)1.28 0.20
Mother's BMI at delivery (kg/m2)26.5 (2.8)27.8 (2.2)−1.93 0.0526.9 (3.2)−2.40 0.02
Parity   0.0010.98  8.790.003
Primipara238 (48%)125 (48%)   19 (79%)   
Multipara256 (52%)135 (52%)   5 (21%)   
Offspring's characteristics
Sex   0.020.89  1.010.31
Men278 (56%)145 (56%)   11 (46%)   
Women216 (44%)115 (44%)   13 (54%)   
Birth year   0.140.15    
1934–38153 (31%)67 (26%)   11 (46%) 1.260.18
1939–44341 (69%)193 (74%)   13 (54%)   
Length of gestation (days)279.6 (11.3)278.9 (12.5)0.68 0.50273.4 (16.0)2.54 0.01
Preterm birth (<37 weeks)20 (4%)14 (5%) 0.710.403 (13%) 3.850.05
Birthweight (g)3477.0 (454.4)3414.1 (470.2)1.78 0.082906.5 (410.7)6.03 <0.001
Head circumference (cm)35.2 (1.6)35.3 (1.5)−0.69 0.4934.4 (1.4)2.34 0.02
Placental weight (g)655.17 (121.7)643.1 (124.8)1.28 0.20573.5 (86.9)3.25 0.001
Breastfed (yes)409 (83%)220 (85%) 0.650.4221 (88%) 0.480.49
Father's occupation in subject's childhood   4.530.10  0.060.97
Manual worker300 (61%)174 (67%)   14 (58%)   
Junior clerical119 (24%)60 (23%)   6 (25%)   
Senior Clerical75 (15%)26 (10%)   4 (17%)   
Own maximum level of education in adulthood   2.060.56  1.780.62
Basic or less153 (31%)90 (35%)   8 (33%)   
Upper secondary135 (27%)60 (23%)   9 (38%)   
Lower tertiary (polytechnic, vocational, bachelors)143 (29%)74 (28%)   5 (21%)   
Upper tertiary (masters or higher)63 (13%)36 (14%)   2 (8%)   
Age at completing the questionnaire (years)69.4 (3.2)69.0 (2.9)1.60 0.1170.7 (2.7)−2.00 0.02

Maternal hypertensive pregnancy disorders and adjustment and problems

Figure 1 shows the unadjusted percentages of individuals with borderline clinically significant adaptive functioning, and psychiatric and psychological problems, according to maternal hypertension status during pregnancy. Table 2 shows ORs and 95%CIs when these associations were adjusted for covariates and moderating variables. In comparison with offspring born after normotensive pregnancies, offspring born after pregnancies complicated by pre-eclampsia (in both unadjusted and adjusted models) had an increased risk of reporting the following difficulties: adjustment problems in relationship satisfaction with spouse/partner, total problems, and problems on the critical items scale; anxious/depressed, functional impairment, memory, thought, and irritable/disinhibited problems on syndrome scales; and depressive and psychotic problems on DSM-oriented scales.

Table 2. Adjusted odds ratios (aORs) and 95% confidence intervals (95%CIs) of borderline deviant problems in adaptive functioning and psychiatric and psychological problems in older offspring born after normotensive versus hypertensive/pre-eclamptic pregnancies
Adaptive functioning and psychiatric and psychological problems scalesn 778Hypertension without proteinuria versus normotension (referent)Pre-eclampsia versus normotension (referent)
aORa (95%CI) P aORa (95%CI) P
  1. a

    Adjustments were made for sex, year of birth (1934–38 versus 1939–44), gestational age, weight for gestational age, head circumference at birth, placental weight, father's occupational status in subject's childhood, parity, mother's age, BMI at delivery, breastfeeding, own maximum level of education in adulthood, and age at completion of the questionnaire.

  2. b

    Sufficient data to compute score on relationships and contacts with friends were available for 771 participants.

  3. c

    Sufficient data to compute score on relationship and satisfaction with spouse/partner were available for 585 participants. Note that these items are given only for participants cohabiting in the preceding 2 months.

Problems in adaptive functioning
Friendsb1081.35 (0.87, 2.10)0.180.81 (0.18, 3.72)0.79
Spouse/partnerc920.98 (0.58, 1.64)0.934.12 (1.35, 12.96)0.01
Personal strengths930.88 (0.53, 1.46)0.632.08 (0.71, 6.09)0.18
Any problems
Total problems1861.08 (0.75, 1.57)0.684.00 (1.64, 9.77)0.002
Critical items721.58 (0.91, 2.72)0.105.28 (1.87, 14.96)0.002
Problems on empirically based syndrome scales
Anxious/depressed811.55 (0.93, 2.59)0.093.17 (1.09, 9.23)0.03
Worries230.82 (0.30, 2.23)0.703.39 (0.54, 21.07)0.19
Somatic complaints891.24 (0.76, 2.02)0.391.99 (0.65, 6.11)0.23
Functional impairment921.16 (0.71, 1.89)0.552.99 (1.08, 8.24)0.03
Memory/cognition791.20 (0.71, 2.03)0.513.92 (1.39, 11.04)0.01
Thought751.66 (0.98, 2.83)0.067.07 (2.60, 19.23)<0.001
Irritable/disinhibited921.24 (0.76, 2.02)0.395.24 (2.01, 13.67)0.001
Problems on diagnostic and Statistical Manual of Mental Disorders oriented scales
Depressive771.71 (1.01, 2.89)0.046.79 (2.41, 19.08)<0.001
Anxiety941.44 (0.89, 2.33)0.142.62 (0.91, 7.56)0.08
Somatic591.07 (0.58, 1.96)0.823.21 (0.99, 10.39)0.05
Dementia501.02 (0.53, 1.98)0.951.66 (0.42, 6.63)0.47
Psychotic611.06 (0.58, 1.94)0.843.82 (1.26, 11.58)0.02
Antisocial personality600.87 (0.47, 1.59)0.652.91 (0.93, 9.07)0.07
Figure 1.

Unadjusted percentages of individuals with borderline deviant problems in adaptive functioning and in psychiatric and psychological problems according to maternal hypertensive disorders during pregnancy (normotensive, n = 494; hypertensive, n = 260; pre-eclamptic, n = 24). Note: Sufficient data to compute scale score on relationships and contacts with friends were available on 771 participants. Sufficient data to compute scale score on relationship and satisfaction with spouse/partner were available on 585 participants. These data are given only for participants cohabiting in the preceding 2 month.

Figure 1 and Table 2 show that offspring born after hypertensive pregnancies without proteinuria and normotensive pregnancies did not differ from each other on total problems or on the critical items scales. Nor did they differ from one another on specific empirically based syndromes and problems on DSM-oriented scales in unadjusted models (Figure 1). They did have an increased risk of reporting depressive problems on DSM-oriented scales in the adjusted model, however (Table 2).

When we explored an alternative model in which we replaced gestational age at birth with preterm, term, and post-term status, and replaced birthweights for gestational age, with small, appropriate, and large for gestational age as variables, the significant findings remained virtually identical or were even more pronounced (data not shown).

Moderation by sex, prematurity, parity, and father's occupational status in childhood

The following interactions were significant. In comparison with men who were born after normotensive pregnancies, men who were born after pre-eclamptic pregnancies had an increased risk of reporting problems on the critical items scale (OR 10.94, 95%CI 2.68–44.59, P = 0.001) and thought problems on syndrome scales (OR 15.84, 95%CI 3.82–65.63, P < 0.001) (P > 0.24 for women; P < 0.003 for sex × pre-eclampsia interactions).

In comparison with offspring born to manual working fathers after normotensive pregnancies, offspring born to manual working fathers after pregnancies complicated by pre-eclampsia had an increased risk of: reporting problems on the critical items scale (OR 12.12, 95%CI 3.04–48.37, P < 0.001); reporting somatic problems on syndrome scales (OR 4.34, 95%CI 1.18–15.98, P = 0.03); and reporting depressive (OR 13.92, 95%CI 3.53–54.87, P < 0.001), psychotic (OR 8.22, 95%CI 1.95–34.63, P = 0.004), and antisocial problems on DSM-oriented scales (OR 7.52, 95%CI 1.73–32.72, P = 0.01) [P > 0.41 for offspring of junior/senior clerical fathers; P < 0.04 for father's occupational status (workers versus clericals) × pre-eclampsia interaction].

Finally, in comparison with primiparous offspring born after normotensive pregnancies, primiparous offspring born after pregnancies complicated by pre-eclampsia had an increased risk of reporting total problems (OR 4.40, 95%CI 1.44–13.41, P = 0.01; P = 0.88 for multipara offspring; P = 0.03 for parity × pre-eclampsia interaction).

Discussion

Main findings

We found that hypertensive disorders during pregnancy carry an increased risk of a wide spectrum of problems in adaptive functioning and mental wellbeing in offspring seven decades later. Maternal pre-eclampsia increased the odds in the offspring for maladaptive functioning pertaining to relationship satisfaction with spouse/partner, and for total problems, capturing overall problems in behavioural, emotional, social, and cognitive functioning, and for problems in these functioning/domains that have been judged by clinicians to be of particular concern and labelled as critical items. The wide spectrum of problems in the offspring related to maternal pre-eclampsia was also evident in their increased odds for specific problems related to anxiousness, depression, memory, cognition, thought, and irritable/disinhibited behaviour, functional impairment on syndrome-level scales, and depression and psychotic problems on DSM-IV-oriented scales. These associations were not confounded by factors that may increase the risk of hypertensive disorders during pregnancy and/or problems in adaptive functioning and mental wellbeing. The increased risk was identified even after accounting for birthweight for gestational age (or small-for-gestational-age status) and gestational age (or prematurity), suggesting that an increased risk of these problems related to maternal pre-eclampsia is not likely to be explained solely by immaturity or small body size at birth.

Previous studies have shown that factors reflecting intrauterine growth restriction pose a risk for mental disorders and psychiatric symptoms.[4-9] Our findings are compatible with these findings and suggest that pre-eclampsia and maternal hypertension without proteinuria may provide insight into the underlying mechanisms. By being the longest follow-up on the transgenerational consequences of maternal hypertensive disorders reported thus far, our findings illustrate the lifetime increased risk of an adverse intrauterine environment. This interpretation of the effects of an adverse intrauterine environment is supported by Hill's well-known features of a causal relationship, including the strength, consistency, specificity, and temporality of the observed association.[40] Our findings also showed that some of these associations were moderated by sex, childhood socio-economic position, and parity; however, because of the small cell sizes, these group-specific effects ought to be interpreted with caution.

Strengths and limitations

The strength of our study is the large and well-characterised birth cohort. Yet, only a subpopulation of this cohort had data available on maternal hypertension and proteinuria. The representativeness of the subpopulation is addressed in our previous publications.[36, 37] Sample attrition may limit the generalisability of our findings if the associations between maternal hypertensive disorders and adjustment and problems of the offspring were different in those with data available and those without. Moreover, to define pre-eclampsia or hypertension without proteinuria we required only one high blood pressure reading during pregnancy. It is of note that there were on average 2.0 blood pressure measurements recorded in each pregnancy. Consequently, the prevalence of hypertensive disorders was higher than that reported in the literature. Only qualitative measurements of proteinuria were available to diagnose pre-eclampsia. All the same, the prevalence of maternal pre-eclampsia of 3% in our sample is in line with the rates shown in an international comparative study.[1] We had no data on eclampsia itself, which, when our study subjects were born, was common, with rates of 0.6% at the Helsinki University Central Hospital.[41] We have no data on medication use for individual mothers; however, at that time, the care given was mainly expectant management. Glucocorticoid treatment was not known; chloral hydrate was administered to patients at risk of convulsions. A small number of mothers, if any, may have received magnesium sulphate, as the first treatment was given in Helsinki in 1943.[42] We do not have data on the treatment that the mothers or their babies obtained. Limited neonatal care, in addition to the limited availability of medication, at that time may restrict the generalisability of our findings to babies born in high-resource settings more recently.

An obvious study limitation is that self-ratings cannot reflect absolute levels of adaptive functioning and psychiatric and psychological problems. Furthermore, we used cut-offs of borderline deviant ranges. Yet, borderline cut-offs have been shown to discriminate between older adults who were referred to mental health services for psychiatric and psychological problems and demographically similar people who were not referred.[39]

In addition, complications around the time of birth may increase the risk of postpartum depression.[43] Postpartum depression may compromise maternal sensitivity to the infant's needs, influence the developing mother–child attachment relationship, and thereby increase the risk of mental disorders in the offspring. We do not have data on maternal postpartum psychopathology. We do not have data on psychological functioning, smoking, and alcohol consumption during pregnancy either. Some evidence suggests that prenatal job stress, depression, and anxiety may increase the risk of maternal hypertensive pregnancy disorders.[44, 45] It is of note that smoking during pregnancy has been shown to be associated with a decreased risk of pre-eclampsia and pregnancy hypertension.[46] All of these factors are shown to increase the risk of mental disorders in the offspring.[47-54] We cannot rule out factors, such as paternal psychopathology, that may increase the risk of mental disorders in the offspring. Nor can we rule out that the strain of war during the period 1939–1944, when part of our cohort was born, and when many of the cohort were young children, may in some ways influence our findings, even though adjustments for year of birth made no alterations to our findings. It is possible that these factors to some extent explain our findings. Finally, we can't rule out the possibility of residual confounding, even though our data allowed us to adjust for a number of covariates and confounding factors.

Interpretation

In agreement with our findings, pre-eclampsia has been associated with an increased risk of schizophrenia,[16-19] personality disorders,[15] and depressive symptoms in adult offspring,[24] and with complaints of cognitive failures in older offspring and cognitive decline in offspring up to old age.[25, 26]

In disagreement with our findings, null associations have been reported between pre-eclampsia and schizophrenia, anxiety disorder, and/or depression in adult offspring, and non-clinical psychosis-like symptoms in adolescent offspring.[20-23] Pre-eclampsia has also been associated with a lower risk of internalising behaviors in children/young adults,[12] and with any mental and substance-use disorders in adult male offspring;[13] however, most of the previous studies have examined the effects of pre-eclampsia on severe mental disorders, and all among people much younger in age than in our study.

Although our findings may point to mechanisms by which prenatal adversity is associated with these problems in subsequent life, the exact mechanisms linking maternal pre-eclampsia with higher risk of poor adjustment and problems in subsequent life remain to be determined. Hypertensive disorders in pregnancy may induce fetal malnutrition and oxidative distress,[55, 56] and activate similar sympathetic nervous system responses in the mother that are often seen under psychosocial stress,[57, 58] leading to adverse fetal development, especially brain development. Pre-eclampsia is also associated with reduced function of placental 11β-hydroxysteroid dehydrogenase type-2 (11βHSD-2),[59, 60] an enzyme that catalyses the conversion of maternal circulating cortisol to inactive cortisone.[61] All of these influences have the potential to cause lifelong changes in the offspring at epigenomic and transcriptomic levels, and in the organ structure and function of the body.[35, 47, 48, 54, 62] Furthermore, we cannot exclude that a common genetic background underlies pre-eclampsia and poor adjustment and problems: both conditions are probably genetically heterogeneous, and their genetic architecture remains unclear.

Although our results in people born 70–80 years ago cannot be directly translated into clinical recommendations, they highlight the role of prenatal events as one of the factors that may help in identifying high-risk children and families who could benefit from targeted interventions early in life. The impact of preventive interventions should be addressed in future studies.

Conclusion

Maternal hypertensive disorders during pregnancy carry an increased risk of a wide spectrum of problems in adaptive functioning and mental wellbeing in the offspring seven decades later. By being the longest follow-up on the transgenerational consequences of maternal hypertensive disorders reported so far, our findings highlight the lifetime increased risk of an adverse intrauterine environment.

Disclosure of interests

None of the authors have any conflicts of interest.

Contribution to authorship

Conception and design of the study, acquisition of data, or analysis and interpretation of data: ST, TA-V, JGE, EK, JL, A-KP, KH, ML, CO, DJPB, and KR. Drafting the article or revising it critically for important intellectual content: ST, TA-V, JGE, EK, JL, A-KP, KH, ML, CO, DJPB, and KR. Final approval of the version to be published: ST, TA-V, JGE, EK, JL, A-KP, KH, ML, CO, DJPB, and KR.

Details of ethics approval

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

Funding

This study was supported by grants from the Academy of Finland, University of Helsinki, the British Heart Foundation, the Finnish Foundation of Cardiovascular Research, the Finnish Diabetes Research Foundation, the Finnish Medical Society (Duodecim), Finska Läkaresällskapet, the National Doctoral Programme of Psychology, the Päivikki and Sakari Sohlberg Foundation, the Juho Vainio Foundation, the Yrjö Jahnsson Foundation, the Signe and Ane Gyllenberg Foundation, the Jalmari and Rauha Ahokas Foundation, the Emil Aaltonen Foundation, the Finnish Ministry of Education, and the Finnish Foundation for Paediatric Research.

Ancillary