Journal of the American Society of Hypertension 8(11) (2014) 832–847
Review Article
Maternal hypertensive pregnancy disorders and cognitive functioning of the offspring: a systematic review Soile Tuovinen, MAa,*, Johan G. Eriksson, MD, DMSCb,c,d,e,f, Eero Kajantie, MD, DMSCb,g,h, and Katri R€aikk€ onen, PhDa a
Institute of Behavioral Sciences, University of Helsinki, Helsinki, Finland; Department of Chronic Disease Prevention, National Institute for Health and Welfare, Helsinki, Finland; c Department of General Practice and Primary Health Care, University of Helsinki, Helsinki, Finland; d Helsinki University Central Hospital, Unit of General Practice, Helsinki, Finland; e Folkh€alsan Research Centre, Helsinki, Finland; f Vasa Central Hospital, Vasa, Finland; g Hospital for Children and Adolescents, Institute of Clinical Medicine, University of Helsinki, Helsinki, Finland; and h Department of Obstetrics and Gynecology, Oulu University Hospital and University of Oulu, Oulu, Finland Manuscript received June 12, 2014 and accepted September 1, 2014 b
Abstract Hypertensive pregnancy disorders may affect the fetal developmental milieu and thus hint at mechanisms that link prenatal conditions with later developmental outcomes of the offspring. Here, we systematically review studies that have tested whether maternal pre–eclampsia, gestational hypertension, and hypertensive pregnancy disorders as a single diagnostic entity are associated with cognitive functioning of the offspring. Twenty–six studies were eligible for this review. Of them, 19 provided detailed methodological information deemed necessary to be included for a more detailed review. An overall conclusion is that, in the general population, maternal hypertensive disorders may be associated with lower cognitive ability of the offspring. Studies that extend to adulthood show the most consistent pattern of findings. It is possible that the associations arise during the lifetime or that the findings reflect improvements in management of these disorders. Evidence is, however, insufficient to conclude whether these associations are dissimilar in the offspring exposed to maternal pre–eclampsia and gestational hypertension, due to the varied criteria used across the different studies to distinguish between these conditions. The existing studies also vary in the definition of control groups, and very few have taken into account important confounding factors, including maternal pre–pregnancy obesity and lifestyle behaviors. Given the mixed pattern of findings and limitations related to internal and external validity, further studies are clearly warranted to clarify the associations. J Am Soc Hypertens 2014;8(11):832–847. Ó 2014 American Society of Hypertension. All rights reserved. Keywords: Gestational hypertension; intelligence; mental development; pre–eclampsia.
Introduction Children and adults born preterm or with a small body size at birth have poorer cognitive and executive The authors declare no conflict of interest. Part of this review will be published in Tuovinen’s dissertation thesis. *Corresponding author: Soile Tuovinen, MA, University of Helsinki, PO Box 9, 00140 University of Helsinki, Finland. Tel.: þ358-9-191 29524; Fax: þ358 9 191 2952. E-mail: [email protected]
functioning than their peers born at term or at normal birth weight.1–12 Recent evidence suggests that those born small in addition show a greater cognitive decline up to old age.13 Although there are some contradictory findings, a majority of the existing findings lend credence to the developmental origins of health and disease (DOHaD) concept.14 While prematurity and small body size at birth have been extensively studied as proxies of prenatal environmental adversities, they do not inform what the specific adversities underlying preterm birth and suboptimal fetal growth are. A key factor that may underlie prematurity and restricted fetal
1933-1711/$ - see front matter Ó 2014 American Society of Hypertension. All rights reserved. http://dx.doi.org/10.1016/j.jash.2014.09.005
S. Tuovinen et al. / Journal of the American Society of Hypertension 8(11) (2014) 832–847
growth is maternal hypertensive pregnancy disorders.15,16 Even though they may not always result in prematurity or small body size at birth, they may have a major impact on fetal development with consequences that may persist into later life. These disorders include chronic hypertension, gestational hypertension, and (pre)eclampsia. Together, they complicate approximately up to 10% of all pregnancies.17 Pre–eclampsia, which is a severe form of these disorders, comprises up to 4% of maternal hypertensive pregnancy disorders. These disorders are characterized by elevated blood pressure, with proteinuria being an additional characteristic in pre–eclampsia. Table 1 describes the diagnostic criteria according to the National High Blood Pressure Education Program Working Group on High Blood Pressure in Pregnancy18 and the American College of Obstetricians and Gynecologists and Task Force on Hypertension in Pregnancy.19 While the etiology of maternal hypertensive disorders remains unknown, risk factors are multiple. These include older maternal age, primiparity, previous pre–eclampsia and family history of pre–eclampsia, multi–fetal gestation, pre–existing medical conditions including type 1 diabetes, hypertension, renal disease, and chronic autoimmune disease, longer time–interval between pregnancies, changing paternity, overweight and obesity, and African ethnicity.20,21 In addition, psychological risk factors, such as stress, depression, and anxiety, seem to be positively associated with higher risk.22,23 Interestingly, smoking during pregnancy has been associated with a decreased risk for pre–eclampsia.17 Some of these risk and protective factors are per se associated with offspring cognitive outcomes. Yet, to date, it remains unclear whether and to what extent such confounding factors explain the associations between maternal hypertensive disorders during pregnancy and offspring cognitive outcomes. Maternal hypertensive pregnancy disorders may result in inadequate fetal nutrition, hypoxia,24 systemic inflammation,25 or overexposure to maternal glucocorticoids.26–29 It is therefore highly plausible that at least part of the associations reflect causal effects of maternal hypertension in pregnancy. It is therefore somewhat surprising that they have attracted relatively little research attention in relation
833
to cognitive outcomes of the offspring. Here we provide a systematic review and evaluate the available evidence from human studies that have tested the effects of maternal hypertensive disorders during pregnancy on cognitive functioning of the offspring later in life.
Methods Data Collection Search Strategy We searched the database MEDLINE in February 2013 and February 2014 and evaluated the results systematically. We looked for articles whose main focus was maternal hypertensive disorders but also mentioned cognition (or any of its synonyms) or cognitive tests (or any of its synonyms) or whose main focus was on cognition (or any of its synonyms) or cognitive tests (or any of its synonyms) but also mentioned maternal hypertensive disorders. For specific search items see Table 3, Appendix. This search strategy had high sensitivity but low specificity. We read through a large number of article titles of which a large proportion turned out to be irrelevant. This was necessary owing to the lack of a specific search term to identify relevant studies. Also, we used Web of Knowledge – Citation information to find any additional studies citing primary articles. Further, we checked that we included relevant studies cited by primary articles.
Study Selection The database searches produced 1040 article titles (Figure 1). Several publications were rejected at the first stage after reading the title. After retrieving 49 of these articles, we ended up with 26 articles that met our selection criteria. Twenty-three articles were rejected, two because the article was a review or summary, 10 because the outcome variables fell out of the scope of this review, two because the independent variable lacked clear specificity, eight because a control group was lacking or its characteristics remained unclear, and one because it was published in other languages than English. We double– checked the performance of our search strategy. We also
Table 1 Classification of hypertensive pregnancy disorders18,19 Category
Definition
Chronic hypertension
HT 140/90 mm Hg present before pregnancy or diagnosed before 20th week of gestation or does not resolve postpartum HT 140/90 mm Hg on 2 occasions at least 4 h apart in a women who was normotensive before 20th week of gestation and whose blood pressure returns to normal postpartum HT 140/90 mm Hg on 2 occasions at least 4 h apart in a women who was normotensive before 20th week of gestation with proteinuria 300 mg/24 h HT 140/90 mm Hg present before pregnancy or diagnosed before 20th week of gestation with (new–onset) proteinuria 300 mg/24 h
Gestational hypertension Pre–eclampsia–eclampsia Pre–eclampsia superimposed on chronic hypertension
834
S. Tuovinen et al. / Journal of the American Society of Hypertension 8(11) (2014) 832–847
Figure 1. Selection of studies focusing of maternal hypertensive pregnancy disorders and cognitive functioning of the offspring.
ensured that our strategy resulted in a collection of the most important published articles that we were aware of beforehand.
Results Our literature search for this systematic review resulted in 26 studies testing associations between maternal hypertensive pregnancy disorders and cognitive functioning of the offspring. The eldest study examining the associations between maternal hypertensive disorders and cognitive functioning of the offspring is that of Barker and Edwards.30 In this population–based study, 3321 children born after toxemic pregnancies and 46,735 children born after non–toxemic pregnancies were followed to 11 years of age. Verbal reasoning test score of those children born after toxemic pregnancies was above the population mean. This was consistent across the birth ranks when compared with the mean of all children in the same birth rank. However, in further analyses using the same dataset, the authors compared siblings born to the same mother after a pregnancy that was complicated with toxemia and after a pregnancy that was not. The affected siblings scored lower on verbal reasoning when compared with their unaffected sibs. This difference was most obvious among those born at term. The authors did not report the diagnostic criteria for toxemia. However, in cohorts born before late 1990s, the diagnostic criteria for pre–eclampsia and hypertension do not follow the current diagnostic criteria. After the study by Barker and Edwards, 25 other studies have been published where associations between maternal hypertensive pregnancy disorders and cognitive functioning of the offspring in later life have been studied. Of these studies, only three have used the current diagnostic criteria described in Table 1, while in the remaining studies, the criteria have varied or have not been reported at all. The findings have also varied: some of the studies have shown
that maternal hypertensive pregnancy disorders are associated with poorer cognitive functioning of the offspring later in life, while some of the studies have reported null and some even positive associations. Table 2 summarizes findings from these studies. Table 2 is organized according to the year of birth of the sample, reflecting changes in disease classification between past and present and within two major categories, namely whether the offspring have been followed–up to (a) childhood or (b) adulthood, and whether the childhood and adulthood follow–up studies have been conducted in (a) a general population or (b) in samples born preterm or with small body size. Seven of these studies did not provide detailed methodological information deemed necessary to be included in this review; namely, the number of exposed offspring was not reported31 or the exact diagnostic criteria for maternal hypertensive pregnancy disorders was not reported,30,32–34 or they turned out to be hypertensive medication treatment trials mainly comparing offspring born to hypertensive mothers who did and who did not receive hypertensive medication during pregnancy.35,36 Findings from these studies are therefore not presented in any further detail. Fifteen studies, the majority included in this systematic review, focused on maternal pre–eclampsia. Six reported findings relating to gestational hypertension, and four did not differentiate between the different diagnostic entities. According to the categorization of hypertensive pregnancy disorders used in the literature, we first review studies that have focused on pre–eclampsia. We then describe studies that have focused on gestational hypertension without proteinuria. Finally, we review studies that have treated maternal hypertensive pregnancy disorders as a single diagnostic entity. As the studies vary in what covariates and confounders are being accounted for, we present in Table 4 in Appendix a detailed list what covariates and confounders the studies did take into account.
Pre–eclampsia Follow–up Studies to Childhood Thirteen studies have examined whether maternal pre– eclampsia is associated with poorer cognitive functioning or mental/cognitive development of the offspring in childhood. Three of them have been conducted in general populations and the rest in clinical study populations. Table 2 shows the varied criteria used to define pre–eclampsia in these studies. Three of them have used criteria as described in Table 1, while the rest have applied criteria of pre– eclampsia that differ from this definition. Of the studies, six reported that maternal pre–eclampsia is associated with poorer cognitive functioning of the offspring, while six found no associations or the associations were rendered non–significant when adjustments were made for important covariates and confounders, and one reported that maternal
Country and Birth Year
Study Design
Follow-up of 34 PE, 1076 NT the Western Australian Pregnancy Cohort Study
Whitehouse Australia et al., 2012 1989–1992
35 PE, 35 non–PE
258 PE, 6761 NT Follow–up of the Northern Finland Birth Cohort
Heikura et al., Finland, 2012 1985–1986
Studies in clinical populations Szymonowicz Australia Case–control & Yu, 1987 1982–1984
428 PE 33117 Follow–up of the Jerusalem non–PE Perinatal Study
3321 PE, 50,046 non–PE
Sample Size
Seidman Israel et al., 1991 1964–1971
Pre-eclampsia Follow-up to childhood Population-based cohort studies UK Population– Barker & based study Edwards, 1950–1954 1967
First Author, Publishing year/ Reference
BP 140/90 mm Hg, persistent proteinuria with urinary tract infection and generalized edema before 32 weeks of gestationy
BP 140/90 mm Hg after 24th week of gestation in women whose BP had previously been normal plus proteinuria 300 mg/dz
2 y CA
10 y
11.5 y
17 y
BP 140/90 mm Hg or rise in BP 30/15 mm Hg (two readings, 6 hour apart) or significant proteinuria or edema or any combination of two or more after 24th week of gestationy BP 140/90 mm Hg after 20th weeks of gestation twice after a 5 min rest plus proteinuria 300 mg/Lz
Offspring Age at Follow-up
11 y
VLBW
Offspring Characteristics at Birth
N/A (Birth records)
Definition of Hypertensive Spectrum Disorders (Obtained From)
Table 2 Cognitive functioning of the offspring born after pregnancies complicated by hypertensive disorders Main Findings on Maternal Hypertensive Disorders and Cognitive Outcome (95% CI/SD)
(continued)
PE associated with lower mean mental developmental index; Mean 94 (25) vs. 106 (21)
Psychological No associations; Crude OR 1.7 (0.9, 3.4), OR tests adjusted for parental (WISC-R characteristics 1.2 for 78%) in (0.5, 2.8) routine clinical care, individual data reviewed by study authors PPVT-R, RCPM No associations; MD for verbal ability 3.53 (8.41, 1.35), for non–verbal ability 1.82 (12.59, 8.95)
Toxemia/PE associated with lower verbal reasoning within sibpairs Verbal Otis test, No associations; Mean matrices test 109.3 (1.2) vs. 110.9 (0.1)/females, 101.9 (1.0) vs. 103.1 (0.1)/males
N/A (Eleven– plus)
Outcome Measure
Mental BSID developmental index (normative mean 100, SD 15)
Verbal (mean 100, SD 15) and non–verbal (range 0–60) ability
Mild cognitive limitations (IQ 50–85)
IQ (mean 100, SD 15)
Verbal reasoning
Cognitive Outcome
S. Tuovinen et al. / Journal of the American Society of Hypertension 8(11) (2014) 832–847 835
Cohort follow–up
Cohort follow–up
Cohort follow–up
Follow–up
Case–control
Cohort follow–up
Spinillo et al., Italy 2009 1990–2004
Israel 1992–1993
Leitner et al., Israel 2012 1992–1993
Taiwan 1997–1999
Sweden, 1998–2004
Many et al., 2003
Cheng et al., 2004
Morsing & Marsal, 2014
Leversen Norway et al., 2011 1999–2000
Study Design
Case–control
Country and Birth Year
Spinillo et al., Italy 1994 1986–1990
First Author, Publishing year/ Reference
Table 2 (continued ) Definition of Hypertensive Spectrum Disorders (Obtained From)
68 PE, 184 non–PIH Diastolic BP 110 mm Hg or in 2 consecutive measures 90 mm Hg plus proteinuria 300 mg/dy 185 PE, 569 NT Diastolic BP 110 mm Hg or in 2 consecutive measures 90 mm Hg at any time during pregnancy plus proteinuria 300 mg/dy 11 PE, 64 non–PE Persistent BP 140/90 mm Hg with proteinuria of either 100 mg/dL or >500 mg/dy 17 PE, 78 NT BP 140/90 mm Hg after 20th weeks of gestation in women whose BP had previously been normal plus proteinuria 300 mg/d or þ2y 28 PE, 61 NT Diastolic BP 110 mm Hg or in two consecutive measures 90 mm Hg at any time during pregnancy plus proteinuria 300 mg/dy 11 PE–IUGR, 23 Diastolic BP 90 mm non-PE–IUGR, Hg in 2 measures 34 non–PE AGA plus proteinuria 300 ml/Ly 73 PE, 233 non–PE Current clinical criteria/Medical Birth Registerx
Sample Size
Outcome Measure
GL 22–27 weeks
5 y 10 m
5–8 y
GA
Review Article
Maternal hypertensive pregnancy disorders and cognitive functioning of the offspring: a systematic review Soile Tuovinen, MAa,*, Johan G. Eriksson, MD, DMSCb,c,d,e,f, Eero Kajantie, MD, DMSCb,g,h, and Katri R€aikk€ onen, PhDa a
Institute of Behavioral Sciences, University of Helsinki, Helsinki, Finland; Department of Chronic Disease Prevention, National Institute for Health and Welfare, Helsinki, Finland; c Department of General Practice and Primary Health Care, University of Helsinki, Helsinki, Finland; d Helsinki University Central Hospital, Unit of General Practice, Helsinki, Finland; e Folkh€alsan Research Centre, Helsinki, Finland; f Vasa Central Hospital, Vasa, Finland; g Hospital for Children and Adolescents, Institute of Clinical Medicine, University of Helsinki, Helsinki, Finland; and h Department of Obstetrics and Gynecology, Oulu University Hospital and University of Oulu, Oulu, Finland Manuscript received June 12, 2014 and accepted September 1, 2014 b
Abstract Hypertensive pregnancy disorders may affect the fetal developmental milieu and thus hint at mechanisms that link prenatal conditions with later developmental outcomes of the offspring. Here, we systematically review studies that have tested whether maternal pre–eclampsia, gestational hypertension, and hypertensive pregnancy disorders as a single diagnostic entity are associated with cognitive functioning of the offspring. Twenty–six studies were eligible for this review. Of them, 19 provided detailed methodological information deemed necessary to be included for a more detailed review. An overall conclusion is that, in the general population, maternal hypertensive disorders may be associated with lower cognitive ability of the offspring. Studies that extend to adulthood show the most consistent pattern of findings. It is possible that the associations arise during the lifetime or that the findings reflect improvements in management of these disorders. Evidence is, however, insufficient to conclude whether these associations are dissimilar in the offspring exposed to maternal pre–eclampsia and gestational hypertension, due to the varied criteria used across the different studies to distinguish between these conditions. The existing studies also vary in the definition of control groups, and very few have taken into account important confounding factors, including maternal pre–pregnancy obesity and lifestyle behaviors. Given the mixed pattern of findings and limitations related to internal and external validity, further studies are clearly warranted to clarify the associations. J Am Soc Hypertens 2014;8(11):832–847. Ó 2014 American Society of Hypertension. All rights reserved. Keywords: Gestational hypertension; intelligence; mental development; pre–eclampsia.
Introduction Children and adults born preterm or with a small body size at birth have poorer cognitive and executive The authors declare no conflict of interest. Part of this review will be published in Tuovinen’s dissertation thesis. *Corresponding author: Soile Tuovinen, MA, University of Helsinki, PO Box 9, 00140 University of Helsinki, Finland. Tel.: þ358-9-191 29524; Fax: þ358 9 191 2952. E-mail: [email protected]
functioning than their peers born at term or at normal birth weight.1–12 Recent evidence suggests that those born small in addition show a greater cognitive decline up to old age.13 Although there are some contradictory findings, a majority of the existing findings lend credence to the developmental origins of health and disease (DOHaD) concept.14 While prematurity and small body size at birth have been extensively studied as proxies of prenatal environmental adversities, they do not inform what the specific adversities underlying preterm birth and suboptimal fetal growth are. A key factor that may underlie prematurity and restricted fetal
1933-1711/$ - see front matter Ó 2014 American Society of Hypertension. All rights reserved. http://dx.doi.org/10.1016/j.jash.2014.09.005
S. Tuovinen et al. / Journal of the American Society of Hypertension 8(11) (2014) 832–847
growth is maternal hypertensive pregnancy disorders.15,16 Even though they may not always result in prematurity or small body size at birth, they may have a major impact on fetal development with consequences that may persist into later life. These disorders include chronic hypertension, gestational hypertension, and (pre)eclampsia. Together, they complicate approximately up to 10% of all pregnancies.17 Pre–eclampsia, which is a severe form of these disorders, comprises up to 4% of maternal hypertensive pregnancy disorders. These disorders are characterized by elevated blood pressure, with proteinuria being an additional characteristic in pre–eclampsia. Table 1 describes the diagnostic criteria according to the National High Blood Pressure Education Program Working Group on High Blood Pressure in Pregnancy18 and the American College of Obstetricians and Gynecologists and Task Force on Hypertension in Pregnancy.19 While the etiology of maternal hypertensive disorders remains unknown, risk factors are multiple. These include older maternal age, primiparity, previous pre–eclampsia and family history of pre–eclampsia, multi–fetal gestation, pre–existing medical conditions including type 1 diabetes, hypertension, renal disease, and chronic autoimmune disease, longer time–interval between pregnancies, changing paternity, overweight and obesity, and African ethnicity.20,21 In addition, psychological risk factors, such as stress, depression, and anxiety, seem to be positively associated with higher risk.22,23 Interestingly, smoking during pregnancy has been associated with a decreased risk for pre–eclampsia.17 Some of these risk and protective factors are per se associated with offspring cognitive outcomes. Yet, to date, it remains unclear whether and to what extent such confounding factors explain the associations between maternal hypertensive disorders during pregnancy and offspring cognitive outcomes. Maternal hypertensive pregnancy disorders may result in inadequate fetal nutrition, hypoxia,24 systemic inflammation,25 or overexposure to maternal glucocorticoids.26–29 It is therefore highly plausible that at least part of the associations reflect causal effects of maternal hypertension in pregnancy. It is therefore somewhat surprising that they have attracted relatively little research attention in relation
833
to cognitive outcomes of the offspring. Here we provide a systematic review and evaluate the available evidence from human studies that have tested the effects of maternal hypertensive disorders during pregnancy on cognitive functioning of the offspring later in life.
Methods Data Collection Search Strategy We searched the database MEDLINE in February 2013 and February 2014 and evaluated the results systematically. We looked for articles whose main focus was maternal hypertensive disorders but also mentioned cognition (or any of its synonyms) or cognitive tests (or any of its synonyms) or whose main focus was on cognition (or any of its synonyms) or cognitive tests (or any of its synonyms) but also mentioned maternal hypertensive disorders. For specific search items see Table 3, Appendix. This search strategy had high sensitivity but low specificity. We read through a large number of article titles of which a large proportion turned out to be irrelevant. This was necessary owing to the lack of a specific search term to identify relevant studies. Also, we used Web of Knowledge – Citation information to find any additional studies citing primary articles. Further, we checked that we included relevant studies cited by primary articles.
Study Selection The database searches produced 1040 article titles (Figure 1). Several publications were rejected at the first stage after reading the title. After retrieving 49 of these articles, we ended up with 26 articles that met our selection criteria. Twenty-three articles were rejected, two because the article was a review or summary, 10 because the outcome variables fell out of the scope of this review, two because the independent variable lacked clear specificity, eight because a control group was lacking or its characteristics remained unclear, and one because it was published in other languages than English. We double– checked the performance of our search strategy. We also
Table 1 Classification of hypertensive pregnancy disorders18,19 Category
Definition
Chronic hypertension
HT 140/90 mm Hg present before pregnancy or diagnosed before 20th week of gestation or does not resolve postpartum HT 140/90 mm Hg on 2 occasions at least 4 h apart in a women who was normotensive before 20th week of gestation and whose blood pressure returns to normal postpartum HT 140/90 mm Hg on 2 occasions at least 4 h apart in a women who was normotensive before 20th week of gestation with proteinuria 300 mg/24 h HT 140/90 mm Hg present before pregnancy or diagnosed before 20th week of gestation with (new–onset) proteinuria 300 mg/24 h
Gestational hypertension Pre–eclampsia–eclampsia Pre–eclampsia superimposed on chronic hypertension
834
S. Tuovinen et al. / Journal of the American Society of Hypertension 8(11) (2014) 832–847
Figure 1. Selection of studies focusing of maternal hypertensive pregnancy disorders and cognitive functioning of the offspring.
ensured that our strategy resulted in a collection of the most important published articles that we were aware of beforehand.
Results Our literature search for this systematic review resulted in 26 studies testing associations between maternal hypertensive pregnancy disorders and cognitive functioning of the offspring. The eldest study examining the associations between maternal hypertensive disorders and cognitive functioning of the offspring is that of Barker and Edwards.30 In this population–based study, 3321 children born after toxemic pregnancies and 46,735 children born after non–toxemic pregnancies were followed to 11 years of age. Verbal reasoning test score of those children born after toxemic pregnancies was above the population mean. This was consistent across the birth ranks when compared with the mean of all children in the same birth rank. However, in further analyses using the same dataset, the authors compared siblings born to the same mother after a pregnancy that was complicated with toxemia and after a pregnancy that was not. The affected siblings scored lower on verbal reasoning when compared with their unaffected sibs. This difference was most obvious among those born at term. The authors did not report the diagnostic criteria for toxemia. However, in cohorts born before late 1990s, the diagnostic criteria for pre–eclampsia and hypertension do not follow the current diagnostic criteria. After the study by Barker and Edwards, 25 other studies have been published where associations between maternal hypertensive pregnancy disorders and cognitive functioning of the offspring in later life have been studied. Of these studies, only three have used the current diagnostic criteria described in Table 1, while in the remaining studies, the criteria have varied or have not been reported at all. The findings have also varied: some of the studies have shown
that maternal hypertensive pregnancy disorders are associated with poorer cognitive functioning of the offspring later in life, while some of the studies have reported null and some even positive associations. Table 2 summarizes findings from these studies. Table 2 is organized according to the year of birth of the sample, reflecting changes in disease classification between past and present and within two major categories, namely whether the offspring have been followed–up to (a) childhood or (b) adulthood, and whether the childhood and adulthood follow–up studies have been conducted in (a) a general population or (b) in samples born preterm or with small body size. Seven of these studies did not provide detailed methodological information deemed necessary to be included in this review; namely, the number of exposed offspring was not reported31 or the exact diagnostic criteria for maternal hypertensive pregnancy disorders was not reported,30,32–34 or they turned out to be hypertensive medication treatment trials mainly comparing offspring born to hypertensive mothers who did and who did not receive hypertensive medication during pregnancy.35,36 Findings from these studies are therefore not presented in any further detail. Fifteen studies, the majority included in this systematic review, focused on maternal pre–eclampsia. Six reported findings relating to gestational hypertension, and four did not differentiate between the different diagnostic entities. According to the categorization of hypertensive pregnancy disorders used in the literature, we first review studies that have focused on pre–eclampsia. We then describe studies that have focused on gestational hypertension without proteinuria. Finally, we review studies that have treated maternal hypertensive pregnancy disorders as a single diagnostic entity. As the studies vary in what covariates and confounders are being accounted for, we present in Table 4 in Appendix a detailed list what covariates and confounders the studies did take into account.
Pre–eclampsia Follow–up Studies to Childhood Thirteen studies have examined whether maternal pre– eclampsia is associated with poorer cognitive functioning or mental/cognitive development of the offspring in childhood. Three of them have been conducted in general populations and the rest in clinical study populations. Table 2 shows the varied criteria used to define pre–eclampsia in these studies. Three of them have used criteria as described in Table 1, while the rest have applied criteria of pre– eclampsia that differ from this definition. Of the studies, six reported that maternal pre–eclampsia is associated with poorer cognitive functioning of the offspring, while six found no associations or the associations were rendered non–significant when adjustments were made for important covariates and confounders, and one reported that maternal
Country and Birth Year
Study Design
Follow-up of 34 PE, 1076 NT the Western Australian Pregnancy Cohort Study
Whitehouse Australia et al., 2012 1989–1992
35 PE, 35 non–PE
258 PE, 6761 NT Follow–up of the Northern Finland Birth Cohort
Heikura et al., Finland, 2012 1985–1986
Studies in clinical populations Szymonowicz Australia Case–control & Yu, 1987 1982–1984
428 PE 33117 Follow–up of the Jerusalem non–PE Perinatal Study
3321 PE, 50,046 non–PE
Sample Size
Seidman Israel et al., 1991 1964–1971
Pre-eclampsia Follow-up to childhood Population-based cohort studies UK Population– Barker & based study Edwards, 1950–1954 1967
First Author, Publishing year/ Reference
BP 140/90 mm Hg, persistent proteinuria with urinary tract infection and generalized edema before 32 weeks of gestationy
BP 140/90 mm Hg after 24th week of gestation in women whose BP had previously been normal plus proteinuria 300 mg/dz
2 y CA
10 y
11.5 y
17 y
BP 140/90 mm Hg or rise in BP 30/15 mm Hg (two readings, 6 hour apart) or significant proteinuria or edema or any combination of two or more after 24th week of gestationy BP 140/90 mm Hg after 20th weeks of gestation twice after a 5 min rest plus proteinuria 300 mg/Lz
Offspring Age at Follow-up
11 y
VLBW
Offspring Characteristics at Birth
N/A (Birth records)
Definition of Hypertensive Spectrum Disorders (Obtained From)
Table 2 Cognitive functioning of the offspring born after pregnancies complicated by hypertensive disorders Main Findings on Maternal Hypertensive Disorders and Cognitive Outcome (95% CI/SD)
(continued)
PE associated with lower mean mental developmental index; Mean 94 (25) vs. 106 (21)
Psychological No associations; Crude OR 1.7 (0.9, 3.4), OR tests adjusted for parental (WISC-R characteristics 1.2 for 78%) in (0.5, 2.8) routine clinical care, individual data reviewed by study authors PPVT-R, RCPM No associations; MD for verbal ability 3.53 (8.41, 1.35), for non–verbal ability 1.82 (12.59, 8.95)
Toxemia/PE associated with lower verbal reasoning within sibpairs Verbal Otis test, No associations; Mean matrices test 109.3 (1.2) vs. 110.9 (0.1)/females, 101.9 (1.0) vs. 103.1 (0.1)/males
N/A (Eleven– plus)
Outcome Measure
Mental BSID developmental index (normative mean 100, SD 15)
Verbal (mean 100, SD 15) and non–verbal (range 0–60) ability
Mild cognitive limitations (IQ 50–85)
IQ (mean 100, SD 15)
Verbal reasoning
Cognitive Outcome
S. Tuovinen et al. / Journal of the American Society of Hypertension 8(11) (2014) 832–847 835
Cohort follow–up
Cohort follow–up
Cohort follow–up
Follow–up
Case–control
Cohort follow–up
Spinillo et al., Italy 2009 1990–2004
Israel 1992–1993
Leitner et al., Israel 2012 1992–1993
Taiwan 1997–1999
Sweden, 1998–2004
Many et al., 2003
Cheng et al., 2004
Morsing & Marsal, 2014
Leversen Norway et al., 2011 1999–2000
Study Design
Case–control
Country and Birth Year
Spinillo et al., Italy 1994 1986–1990
First Author, Publishing year/ Reference
Table 2 (continued ) Definition of Hypertensive Spectrum Disorders (Obtained From)
68 PE, 184 non–PIH Diastolic BP 110 mm Hg or in 2 consecutive measures 90 mm Hg plus proteinuria 300 mg/dy 185 PE, 569 NT Diastolic BP 110 mm Hg or in 2 consecutive measures 90 mm Hg at any time during pregnancy plus proteinuria 300 mg/dy 11 PE, 64 non–PE Persistent BP 140/90 mm Hg with proteinuria of either 100 mg/dL or >500 mg/dy 17 PE, 78 NT BP 140/90 mm Hg after 20th weeks of gestation in women whose BP had previously been normal plus proteinuria 300 mg/d or þ2y 28 PE, 61 NT Diastolic BP 110 mm Hg or in two consecutive measures 90 mm Hg at any time during pregnancy plus proteinuria 300 mg/dy 11 PE–IUGR, 23 Diastolic BP 90 mm non-PE–IUGR, Hg in 2 measures 34 non–PE AGA plus proteinuria 300 ml/Ly 73 PE, 233 non–PE Current clinical criteria/Medical Birth Registerx
Sample Size
Outcome Measure
GL 22–27 weeks
5 y 10 m
5–8 y
GA
