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Pre-eclampsiaAn additional risk factor for cognitive impairment at

school age after intrauterine growth restriction and very preterm birth
E. Morsing
a,
, K. Marl
b
a
Department of Pediatrics, Clinical Sciences Lund, Lund University, Lund, Sweden
b
Departments of Obstetrics and Gynecology, Clinical Sciences Lund, Lund University, Lund, Sweden
a b s t r a c t a r t i c l e i n f o
Article history:
Received 1 May 2013
Received in revised form 4 December 2013
Accepted 10 December 2013
Keywords:
Cognitive outcome
Very preterm birth
Pre-eclampsia
Intrauterine growth restriction
Umbilical blood ow
Objective: To explore the possible inuence of pre-eclampsia on cognitive outcome inchildren born very preterm
after intrauterine growth restriction (IUGR) and abnormal umbilical artery blood ow.
Methods: Cognitive function was evaluated at 58 years of age with Wechsler scales in 34 children born before
30 gestational weeks after IUGR (PT-IUGR) (11 children were exposed to maternal pre-eclampsia, 23 non-
exposed) and in 34 children with no maternal pre-eclampsia and birth weight appropriate-for-gestational age
(PT-AGA) matched for gestational age at birth, gender and age at examination.
Results: The subjects in the PT-IUGR group exposed to maternal pre-eclampsia had lower mean verbal IQ (VIQ)
(mean SD 74 16) and lower full scale IQ (FSIQ) (70 19) in comparison with both the non-exposed
PT-IUGR (VIQ 89 15; p = 0.013; FSIQ 83 14, p = 0.029), and, the PT-AGA group (VIQ 96 15, p b 0.001;
FSIQ 90 14, p = 0.001). The differences remained signicant after adjustment for known confounders. VIQ
and FSIQ did not differ between the non-exposed IUGR and PT-AGA children.
Conclusion: Fetal exposure to maternal pre-eclampsia seems to have an additional negative impact to that of IUGR
on cognitive function in children born very preterm.
2013 Elsevier Ireland Ltd. All rights reserved.
1. Introduction
Intrauterine growth restriction (IUGR), dened as abnormal umbili-
cal artery blood ow in a fetus born small-for-gestational age (SGA),
resulting in very preterm birth has been previously described as a risk
factor for cognitive impairment in children [1,2]. Maternal complica-
tions such as hypertension, pre-eclampsia (PE) and systemic lupus
erythematosus are associated with IUGR [3]. Growth restriction with
abnormal fetal blood ow in children born preterm as well as in those
born at term has been shown to be a risk factor for adverse cognitive
outcome [4,5]. Intrauterine exposure to PE has been found to be associ-
ated with adverse cardiovascular health in the offspring [6,7]. However,
the inuence of maternal PE on cognitive development in the offspring
is less investigated [8,9].
The aim of this study was to explore the impact of maternal PE
on cognitive development in children born after IUGR with absent or
reversed end-diastolic (ARED) blood ow in the umbilical artery (UA).
2. Patients and methods
We performed a secondary analysis of data from a casecontrol pro-
spective study in34 childrenbornvery preterm(b30 gestational weeks)
after IUGR with AREDow(PT-IUGR) [1]. In that study we have reported
a cognitive impairment at early school age especially in boys. Eleven chil-
dren (6 girls and 5 boys) in the IUGR group were exposed to PE and 23
children (11 girls and 12 boys) were non-exposed. The control group
(PT-AGA) comprised 34 children with birth weight appropriate-for-
gestational age (AGA) who were matched for gender, gestational age at
birth and age at examination. The children were born between 1998
and 2004 at Lund University Hospital. Their demographics, birth charac-
teristics andneonatal data have beenreportedindetail earlier [1] andare
summarized in Table 1.
PE inthe mother was denedas diastolic bloodpressure N90 mm Hg
on two or more occasions and proteinuria N300 mg/L. Four pregnancies
were complicated by severe PE (diastolic blood pressure N110 mm Hg
on two or more occasions and proteinuria N300 ml/L). The mean (SD)
systolic and diastolic blood pressures were higher in mothers with PE,
166 (28) and 103 (14) mm Hg, than in those without PE, 126 (15) and
80 (13) mm Hg, p b 0.001 and b0.001, respectively. Four mothers with-
out PE had essential hypertension. In the PE-exposed group, 10 (91%)
fetuses had absent and 1 (9%) reversed end-diastolic ow in the UA
compared to the non-exposed fetuses, of which 16 (70%) had absent
and 7 (30%) had reversed end-diastolic ow in the UA. The median
(range) time from admission to delivery did not differ between
the PE-exposed (2 (014) days) and the non-exposed IUGR children
(4 (021) days). Cearean section was performed on fetal indication in
all but three cases in the PE-exposed IUGR group, where deterioration
of severe pre-eclampsia was a contributing factor for delivery.
Early Human Development 90 (2014) 99101
Corresponding author at: Department of Neonatology, Skane University Hospital
Lund, 22185 Lund, Sweden. Tel.: +46 7087 88442.
E-mail address: eva.morsing@med.lu.se (E. Morsing).
0378-3782/$ see front matter 2013 Elsevier Ireland Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.earlhumdev.2013.12.002
Contents lists available at ScienceDirect
Early Human Development
j our nal homepage: www. el sevi er . com/ l ocat e/ ear l humdev
Cognitive evaluation was performed at 5 to 8 years of age (range:
60105 months) with Wechsler scales (the Wechsler Preschool and
Primary Scale of Intelligence-III and the Wechsler Intelligence Scale for
Children-III, 1991 revision, British version). Both tests consist of two
IQ subscales, verbal IQ (VIQ) and performance IQ (PIQ), that form the
full-scale IQ (FSIQ). All scales have a mean of 100 points and SD of 15.
Cognitive impairment was dened as FSIQ b 70 (i.e. N2 SD below the
normative mean).
The study was approved by the Regional Research Ethics Committee
at Lund University and the parents of the children gave informed
consent.
Statistical analyses were performed by using SPSS 19.0 statistical
software (SPSS Inc., Chicago, IL). Categorical variables were compared
between the groups with the chi-square test. Group differences in con-
tinuous variables were assessed with analysis of variance with posthoc
Bonferroni correction. p values of b0.5 were considered statistically sig-
nicant. Confounders were explored by using linear regression analysis
as appropriate.
3. Results
Neonatal morbidity, such as chronic lung disease, neonatal brain
damage, and septicemia, and treatment with postnatal steroids did not
differ between the PE-exposed (n = 11) and non exposed (n = 23)
subjects in the PT-IUGR group. The gestational age at birth was lower
in the exposed (mean SD 184 9 days) than in the non-exposed
IUGR children (192 9 days; p b 0.05). The exposed IUGR children
were less growth-restricted at birth compared to the non-exposed
IUGR group (weight deviation 32 6% vs 42 11%; p b 0.01).
The PT-IUGR children exposed to PE had signicantly lower scores
in VIQ and FSIQ compared to the IUGR group without a history of PE
(p = 0.013 and p = 0.029, respectively) and also compared to the
control PT-AGA (p b 0.001 and p = 0.001, respectively) (Table 2). The
PIQ did not differ between the PE-exposed and non-exposed IUGR
subjects; the exposed PT-IUGR group had lower score in PIQ compared
to the PT-AGA group (p = 0.026). The non-exposed PT-IUGR group
did not differ in any of the IQ scores from those of the PT-AGA group.
Cognitive impairment, i.e. FSIQ b 70 was more prevalent in the
PE-exposed IUGR group (p = 0.006) (Table 1). Three IUGR children
with cognitive impairment had been exposed to severe PE. The differ-
ences in VIQand FSIQ remained signicant after adjustment for gender,
gestational age and weight deviation at birth (p = 0.013 and p = 0.01,
respectively).
4. Discussion
In this study we explored the inuence of maternal PE on cognitive
development in school age children born very preterm after IUGR and
ARED ow. The PE-exposed IUGR group had lower scores in VIQ and
FSIQ compared to the non-exposed IUGR children. Cognitive impair-
ment was present in almost half (45%) of the PE-exposed IUGR children,
and besides, the majority of them had been exposed to severe PE. Neo-
natal morbidity did not differ between the groups. Although the ex-
posed IUGR children were less mature at birth than the non-exposed
children, this difference had no impact on cognitive outcome according
to regression analysis. Further, PE remained a signicant risk factor for
cognitive impairment after adjustment for gender. This is important as
male PT-IUGR children had a considerably higher degree of cognitive
impairment as compared to their female counter-parts in our back-
ground study [1].
Neurodevelopmental studies addressing the inuence of PE and pre-
term birth on cognitive function at school-age are sparse. Some studies
have examined the inuence of PE at a younger age (1836 months) in
SGA children born preterm. At 18 months of age, cognitive function,
assessed by the Bayley Scales, was not associated with maternal PE.
The authors concluded that hypertension during gestation could even
be protective [10]. In agreement with our ndings, two studies have
described lower cognitive ability in childhood after PE: one study in
3-year old children born after PE and growth restriction at a median
of 34.7 gestational weeks [6] and another in 2-year old infants born
preterm before 32 gestational weeks to pre-eclamptic mothers [7].
The subjects in the former study were more mature at birth, thus, neo-
natal complications were less likely to confound the prenatal inuence
on the outcome. In the latter study, children in the index group were
Table 1
Characteristics at birth and neonatal morbidity in children born very preterm with IUGR with/without preeclampsia and very preterm with birthweight AGA.
Preterm-IUGR with
pre-eclampsia
N = 11
Preterm-IUGR without
pre-eclampsia
N = 23
Preterm-AGA
N = 34
Signicance of difference
Preterm-IUGR with
preeclampsia
vs Preterm-AGA
Preterm-IUGR with
preeclampsia vs
Preterm-AGA
Preterm-IUGR no
preeclampsia vs
Preterm-AGA
Gestational age, mean SD 184 9 192 9 190 11 p = 0.017 ns ns
Birthweight, g, mean SD 663 119 679 174 1084 300 ns p b 0.001 p b 0.001
Birthweight deviation, % mean SD 32.3 6.2 41.9 10.8 3.9 9.2 p = 0.01 p b 0.001 p b 0.001
Chronic lung disease, n (%) 7/11 (64) 17/23 (74) 10/34 (30) ns ns p = 0.001
Postnatal steroids, n (%) 5/11 (45) 7/23 (30) 8/34 (24) ns ns ns
Septicemia, n (%) 6/11 (54) 12/23 (52) 7/34 (21) ns ns p = 0.023
Neonatal brain damage, n (%) 1/11 (9) 2/23 (9) 5/34 (15) ns ns ns
Cerebral palsy, n (%) 3/11 (27) 1/23 (4) 5/34 (15) ns ns ns
IUGR: intrauterine growth restriction; AGA: appropriate for gestational age; ns: non-signicant.
Table 2
Cognitive evaluation at 58 years of age by WISC-III/WPSSI-III.
Preterm-IUGR
Preeclampsia
N = 11
Preterm-IUGR
No preeclampsia
N = 23
Preterm-AGA
n = 34
Signicance of difference
Preterm-IUGR with
vs no preeclampsia
Preterm-IUGR with
preeclampsia vs
Preterm-AGA
Preterm-IUGR no
preeclampsia vs
Preterm-AGA
Verbal IQ, mean SD 73.7 16 88.8 15 96.0 15 p = 0.013 p b 0.001 ns
Performance IQ, mean SD 73.1 19 82.4 14.0 87.2 17 ns p = 0.026 ns
Full-scale IQ, mean SD 70.1 19 83.3 14 90.1 14 p = 0.029 p = 0.001 ns
Full scale IQ (FSIQ) b 70, n (%) 5/11 (45) 5/23 (22) 2/34 (6) ns p = 0.006 ns
WISC: Wechsler Intelligence Scale for Children, 3rd edition. WPPSI: Wechsler Preschool and Primary Scale of Intelligence, 3rd edition.
100 E. Morsing, K. Marl / Early Human Development 90 (2014) 99101
more growth-restricted compared to the children in the control group.
Therefore, it might be difcult to estimate whether growth restriction
per se had an impact on the results. In our study, the index children
were all intrauterine growth restricted and the degree of weight devi-
ation at birth did not inuence the impact of PE on FSIQ at 7 years
of age.
Increased oxidative stress [11], reduced levels of angiogenic factors
[12], and lower levels of nerve growth factor in plasma [13] are found
in pre-eclamptic mothers. Associations between adverse respiratory
outcome in preterm infants and decreased cord blood angiogenic
progenitor cells have been described [14] Administration of angiogenic
factors protects the brain against ischemic injury and improves neuro-
behavioral outcome in mice [15]. Nerve growth factor is involved in
the neurogenesis and growth of neuronal cells. We speculate that de-
ciency in angiogenic and growth factors might contribute to adverse
brain development and to cognitive impairment in growth restricted
preterm infants affected by PE, as observed in our study.
In conclusion, our results indicate that maternal PE might be an
additional factor contributing to the adverse fetal environment in
IUGR resulting in an unfavorable postnatal neurodevelopment in the
offspring. It is of importance to discern the mechanisms resulting in
a damaging effect to the fetal brain during PE and IUGR in the very
preterm fetus.
Conicts of interest statement
None.
Acknowledgment
We acknowledge the help given by psychologists Malena sard, BSc,
Anette Carnemalm, BSc, and Professor Karin Stjernqvist, PhD, in the
cognitive evaluation of children.
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