Early Human Development 90 (2014) 99–101

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Pre-eclampsia—An additional risk factor for cognitive impairment at school age after intrauterine growth restriction and very preterm birth E. Morsing a,⁎, K. Maršál b a b

Department of Pediatrics, Clinical Sciences Lund, Lund University, Lund, Sweden Departments of Obstetrics and Gynecology, Clinical Sciences Lund, Lund University, Lund, Sweden

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 flow

a b s t r a c t Objective: To explore the possible influence of pre-eclampsia on cognitive outcome in children born very preterm after intrauterine growth restriction (IUGR) and abnormal umbilical artery blood flow. Methods: Cognitive function was evaluated at 5–8 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 nonexposed) 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 significant 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), defined as abnormal umbilical artery blood flow 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 complications such as hypertension, pre-eclampsia (PE) and systemic lupus erythematosus are associated with IUGR [3]. Growth restriction with abnormal fetal blood flow 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 associated with adverse cardiovascular health in the offspring [6,7]. However, the influence 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 flow in the umbilical artery (UA). 2. Patients and methods We performed a secondary analysis of data from a case–control prospective study in 34 children born very preterm (b30 gestational weeks) ⁎ Corresponding author at: Department of Neonatology, Skane University Hospital Lund, 22185 Lund, Sweden. Tel.: +46 7087 88442. E-mail address: [email protected] (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

after IUGR with ARED flow (PT-IUGR) [1]. In that study we have reported a cognitive impairment at early school age especially in boys. Eleven children (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-forgestational 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 characteristics and neonatal data have been reported in detail earlier [1] and are summarized in Table 1. PE in the mother was defined as diastolic blood pressure N 90 mm Hg on two or more occasions and proteinuria N300 mg/L. Four pregnancies were complicated by severe PE (diastolic blood pressure N 110 mm Hg on two or more occasions and proteinuria N 300 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 without PE had essential hypertension. In the PE-exposed group, 10 (91%) fetuses had absent and 1 (9%) reversed end-diastolic flow in the UA compared to the non-exposed fetuses, of which 16 (70%) had absent and 7 (30%) had reversed end-diastolic flow in the UA. The median (range) time from admission to delivery did not differ between the PE-exposed (2 (0–14) days) and the non-exposed IUGR children (4 (0–21) 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.

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E. Morsing, K. Maršál / Early Human Development 90 (2014) 99–101

Table 1 Characteristics at birth and neonatal morbidity in children born very preterm with IUGR with/without preeclampsia and very preterm with birthweight AGA.

Gestational age, mean ± SD Birthweight, g, mean ± SD Birthweight deviation, % mean ± SD Chronic lung disease, n (%) Postnatal steroids, n (%) Septicemia, n (%) Neonatal brain damage, n (%) Cerebral palsy, n (%)

Preterm-IUGR with pre-eclampsia N = 11

Preterm-IUGR without pre-eclampsia N = 23

Preterm-AGA N = 34

Significance of difference Preterm-IUGR with preeclampsia vs Preterm-AGA

Preterm-IUGR with preeclampsia vs Preterm-AGA

Preterm-IUGR no preeclampsia vs Preterm-AGA

184 ± 9 663 ± 119 −32.3 ± 6.2 7/11 (64) 5/11 (45) 6/11 (54) 1/11 (9) 3/11 (27)

192 ± 9 679 ± 174 −41.9 ± 10.8 17/23 (74) 7/23 (30) 12/23 (52) 2/23 (9) 1/23 (4)

190 ± 11 1084 ± 300 −3.9 ± 9.2 10/34 (30) 8/34 (24) 7/34 (21) 5/34 (15) 5/34 (15)

p = 0.017 ns p = 0.01 ns ns ns ns ns

ns p b 0.001 p b 0.001 ns ns ns ns ns

ns p b 0.001 p b 0.001 p = 0.001 ns p = 0.023 ns ns

IUGR: intrauterine growth restriction; AGA: appropriate for gestational age; ns: non-significant.

Cognitive evaluation was performed at 5 to 8 years of age (range: 60–105 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 defined 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 continuous variables were assessed with analysis of variance with posthoc Bonferroni correction. p values of b0.5 were considered statistically significant. 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 significantly 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 differences in VIQ and FSIQ remained significant 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 influence of maternal PE on cognitive development in school age children born very preterm after IUGR and ARED flow. The PE-exposed IUGR group had lower scores in VIQ and FSIQ compared to the non-exposed IUGR children. Cognitive impairment was present in almost half (45%) of the PE-exposed IUGR children, and besides, the majority of them had been exposed to severe PE. Neonatal morbidity did not differ between the groups. Although the exposed 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 significant 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 background study [1]. Neurodevelopmental studies addressing the influence of PE and preterm birth on cognitive function at school-age are sparse. Some studies have examined the influence of PE at a younger age (18–36 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 findings, 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, neonatal complications were less likely to confound the prenatal influence on the outcome. In the latter study, children in the index group were

Table 2 Cognitive evaluation at 5–8 years of age by WISC-III/WPSSI-III.

Verbal IQ, mean ± SD Performance IQ, mean ± SD Full-scale IQ, mean ± SD Full scale IQ (FSIQ) b 70, n (%)

Preterm-IUGR Preeclampsia N = 11

Preterm-IUGR No preeclampsia N = 23

Preterm-AGA n = 34

Significance of difference Preterm-IUGR with vs no preeclampsia

Preterm-IUGR with preeclampsia vs Preterm-AGA

73.7 ± 16 73.1 ± 19 70.1 ± 19 5/11 (45)

88.8 ± 15 82.4 ± 14.0 83.3 ± 14 5/23 (22)

96.0 ± 15 87.2 ± 17 90.1 ± 14 2/34 (6)

p = 0.013 ns p = 0.029 ns

p p p p

WISC: Wechsler Intelligence Scale for Children, 3rd edition. WPPSI: Wechsler Preschool and Primary Scale of Intelligence, 3rd edition.

b 0.001 = 0.026 = 0.001 = 0.006

Preterm-IUGR no preeclampsia vs Preterm-AGA ns ns ns ns

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more growth-restricted compared to the children in the control group. Therefore, it might be difficult 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 deviation at birth did not influence 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 neurobehavioral outcome in mice [15]. Nerve growth factor is involved in the neurogenesis and growth of neuronal cells. We speculate that deficiency 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. Conflicts of interest statement None. Acknowledgment We acknowledge the help given by psychologists Malena Åsard, BSc, Anette Carnemalm, BSc, and Professor Karin Stjernqvist, PhD, in the cognitive evaluation of children.

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