High postnatal oxidative stress in neonatal cystic periventricular leukomalacia

Brain & Development 31 (2009) 641–648 www.elsevier.com/locate/braindev

Original article

High postnatal oxidative stress in neonatal cystic periventricular leukomalacia Hiroki Kakita a,b,c,*, Mohamed Hamed Hussein a,d,e, Yasumasa Yamada c, Hayato Henmi c, Shin Kato a, Satoru Kobayashi a, Tetsuya Ito a, Ineko Kato a, Sumio Fukuda b, Satoshi Suzuki a, Hajime Togari a a

Department of Pediatrics and Neonatology, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya, 467-8601, Japan b Department of Pediatrics, Nagoya City Jyouhoku Hospital, Nagoya, Japan c Department of Neonatology, Aichi Human Service Center Central Hospital, Japan d Neonatal Intensive Care Unit, Pediatric Hospital, Cairo University, Cairo, Egypt e Maternal and Child Health Department, VACSERA, Giza, Egypt Received 18 September 2008; received in revised form 23 October 2008; accepted 27 October 2008

Abstract Oxidative stress plays an important role in cystic periventricular leukomalacia (PVL). We performed a case-control study of preterm infants delivered at <35 weeks of gestation between January 2003 and December 2006. Patients were stratified into three groups, according to age at which cysts were initially identified: 610 days old (early cystic PVL; n = 10), >10 days old (late cystic PVL; n = 12); and no cystic PVL (controls; n = 22). Serum total hydroperoxide, biological antioxidant potential and oxidative stress index (calculated as total hydroperoxide/biological antioxidant potential) were measured within 3 h after birth. Frequencies of preterm rupture of membrane and chorioamnionitis were significant higher in early cystic PVL than in late cystic PVL or controls. Duration of oxygen treatment and mechanical ventilation and frequency of apnea were significantly higher in late cystic PVL than in controls or early cystic PVL. Serum total hydroperoxide levels and oxidative stress index were significantly higher in early cystic PVL than in late cystic PVL or controls (p < 0.05, respectively). Postnatal duration until cyst identification displayed a significant negative correlation with oxidative stress index and total hydroperoxide level (r = 0.497, p < 0.05; r = 0.50, p < 0.05, respectively). These findings suggest that early onset of cystic PVL might be due to either antenatal or intrapartum factors, but late onset might be due to postnatal factors. In the pathophysiology and therapy of cystic PVL, oxidative stress and onset timing appear crucial. This is the first study to reveal that neonates experiencing much more oxidative stress at birth show earlier onset of cystic PVL. Crown copyright Ó 2008 Published by Elsevier B.V. All rights reserved. Keywords: Oxidative stress; Total hydroperoxide; Biological antioxidant potential; Cystic periventricular leukomalacia; Premature

1. Introduction

*

Corresponding author. Address: Department of Pediatrics and Neonatology, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya, 467-8601, Japan. Tel.: +81 52 853 8246; fax: +81 52 842 3449. E-mail address: [email protected] (H. Kakita).

Oxidative injury has been implicated as a causal factor in several complications of prematurity, including bronchopulmonary dysplasia, retinopathy of prematurity, necrotising enterocolitis, intraventricular haemorrhage and periventricular leukomalacia (PVL) [1,2]. Neonates, particularly preterm infants, are at high risk

0387-7604/$ - see front matter Crown copyright Ó 2008 Published by Elsevier B.V. All rights reserved. doi:10.1016/j.braindev.2008.10.008

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of oxidative stress and are extremely susceptible to oxidative damage from reactive oxygen species (ROS) [2]. Numerous markers of oxidative stress and brain damage have recently been identified [3–8]. Total hydroperoxide (TH) represents a group of ROS generated from lipids, peptides and amino acids. Determination of TH thus provides information on some of the fundamental mechanisms of oxidative stress involved in critically ill neonates [5,8–10]. Conversely, biological antioxidant potential (BAP) is used to represent overall antioxidant activity. Serum BAP provides a reliable measure of the power of the antioxidant barrier to oxidation, including enzymatic and non-enzymatic antioxidants, by measuring the ability to reduce ferric to ferrous ions [8,10,11]. Neonatal cerebral white matter injury, characterised by PVL and ventricular dilation, represents a major precursor for neurological impairment and cerebral palsy in later life. [12,13]. Prenatal and perinatal factors strongly influence brain damage in premature infants [13]. In the presence of inflammation, infection and oxidative stress, premature infants are subjected to severe brain damage, due to the underdeveloped status of the antioxidant enzymatic and non-enzymatic defence system [14–16]. Several recent reports have shown that oxidative injury is associated with neuronal damage in vitro [17–19] and in human infants [20–22]. We hypothesised that high postnatal TH and oxidative stress index (OSI) are associated with early onset of cystic PVL development. To test this hypothesis, the present retrospective case-control study examined the relationship between oxidative stress as indicated by TH, OSI, and onset of PVL. 2. Material and methods 2.1. Subjects This case-control study examined preterm infants delivered at <35 weeks of gestation who had been admitted to the neonatal intensive care unit at Aichi Human Service Center Central Hospital between January 2003 and December 2006. The inclusion criterion was diagnosis of cystic PVL by ultrasonography. Patients were stratified into two groups according to postnatal age at which cysts were initially identified: 610 days old (early cystic PVL); and >10 days old (late cystic PVL). These patients were matched with control infants who were selected based on the following criteria: gestational age differing by 61 week and birth weight differing by 6500 g from cystic PVL cases; and no appearance of cysts or diffuse white matter injury on ultrasonography and magnetic resonance imaging at discharge or 40 weeks corrected age. Exclusion criteria included congenital abnormalities and/or chromosomal disorder. Written informed

consent was obtained for each infant from their parents. All study protocols were approved by the ethics committee of Nagoya City University. 2.2. Antenatal and intrapartum factors Antenatal and intrapartum factors were recorded as follows: gestational age, birth weight; Apgar scores at 1 and 5 min, arterial blood gases, administration of bicarbonate, base excess, maximum fraction of inspired oxygen; mean blood pressure, haematocrit at birth; sex, preterm rupture; mode of delivery, small for gestational age (more than 2 standard deviations below body weight), multiple gestations, placental disruption, antenatal steroid therapy, preterm rupture of membrane (PROM), and chorioamnionitis (CAM). CAM was defined as infection/inflammation of the membrane diagnosed from P2 clinical, microbiological and histological examinations. Postnatal data included: duration of ventilation, duration of oxygen treatment; surfactant therapy, indomethacin therapy, duration of catecholamine administration, transfusion of red blood cells, mean oxygen saturation and fraction of inspired oxygen, mean and minimum arterial CO2 pressure within 24 h, from 24 h to 48 h, and from 48 h to 72 h after birth, erythropoietin therapy, total parental nutrition including lipid infusion, iron administration, steroid therapy, chronic lung disease, apnoea, sepsis; necrotising enterocolitis, retinopathy of prematurity, and intraventricular haemorrhage. Chronic lung disease was defined as continued need for supplemental oxygen or ventilatory assistance at a corrected age of 36 weeks. Apnea was defined as any complete cessation in breathing movements lasting >20 s. Sepsis was diagnosed by the presence of clinical signs of sepsis confirmed by positive blood culture. Retinopathy of prematurity was defined as a need for laser therapy. Necrotising enterocolitis was defined as stage 2 or 3 according to Bell’s criteria [23]. Intraventricular haemorrhage was defined as grade III or IV [24]. 2.3. Cranial ultrasonography and magnetic resonance imaging Cranial ultrasonography was routinely obtained in all cases on days 0, 3, 5 and 7, and thereafter once or twice a week. Ultrasonography was performed using an SSD-2200 system (Aloka, Tokyo, Japan) with a 7.5-MHz transducer, and multiple images were obtained in coronal and sagittal planes through the anterior fontanel. Cystic PVL was diagnosed when a cyst >3 mm in diameter was detected in the periventricular region. Magnetic resonance imaging was performed for all cases to confirm the diagnosis at discharge or 40 weeks corrected age.

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2.4. Blood samples Arterial blood samples were obtained from the radial artery at birth (63 h after birth). Arterial blood gases were analysed using a Rapid Lab 348 analyser (Chiron, Emeryville, Canada). Serum samples were obtained by centrifugation at 3000 rpm for 10 min. TH and BAP were measured, without knowing the diagnosis of each sample, using a d-ROMs kit and commercial assay kit, respectively (Diacron SRL, Parma, Italy), as previously described [5,8–11]. OSI was determined as the ratio of TH to BAP, since the shift of oxidative/antioxidative balance toward the oxidative side is considered to represent oxidative stress [25]. 2.5. Statistical analysis Statistical analyses were performed using SPSS for Windows version 13.0 software (SPSS, Chicago, IL, USA). Analysis of variance was used to compare continuous data, followed by Bonferroni post-hoc testing, with dichotomous outcomes compared using the v2 test or Fisher’s exact test. Coefficients of correlation were tested using the Pearson two-tailed test. If data were non-parametric, Spearman’s two-tailed test was used. Data are reported as mean ± standard error of the mean, unless mentioned otherwise. Values of p < 0.05 were considered statistically significant. 3. Results During the study period, 10 preterm infants were diagnosed with early cystic PVL (Fig 1A,B), 12 preterm infants diagnosed with late cystic PVL (Fig 1C,D), and 22 preterm infants developed normally and were considered as controls. There were no control cases who develop periventricular cysts, white matter atrophy, ventriculomegaly, and cortical underdevelopment on magnetic resonance imaging. Mean ages of diagnosis for early and late cystic PVL were 5.1 ± 1.3 days and 16.7 ± 2.3 days, respectively. All cases with the exception of 1 control case were intubated and received oxygen at birth. Neonatal and maternal characteristics for all PVL and control cases are presented in Table 1. Frequencies of PROM and CAM were significant higher in early cystic PVL than in late cystic PVL or controls (p < 0.05, p < 0.05, respectively), but did not differ between late cystic PVL and controls. Birth weight, gestational age, Apgar scores at 1 and 5 min, arterial pH, base excess, mean blood pressure, maximum fraction of inspired oxygen, PaO2, PaCO2 and haematocrit at birth did not differ significantly among any of the three groups. Likewise, frequencies of male gender, caesarean section, small for gestational age, multiple gestations, placental abruption, and antenatal steroid therapy did not differ significantly among the three groups.

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Postnatal characteristics and complications in early and late cystic PVL and control groups are presented in Table 2. Frequencies of apnea and durations of oxygen treatment and mechanical ventilation were significantly higher in late cystic PVL than in controls or early cystic PVL, but did not differ between early cystic PVL and controls. No significant differences were seen in mean and minimum PaCO2, mean oxygen saturation or fraction of inspired oxygen within 24 h, from 24 h to 48 h, or from 48 h to 72 h among the three groups. In addition, no significant differences in frequency of surfactant, indomethacin, transfusion, erythropoietin therapy, total parental nutrition, iron administration, steroid therapy, chronic lung disease, sepsis, retinopathy of prematurity, necrotising enterocolitis or intraventricular haemorrhage were seen among groups. Serum TH levels showed no significant differences between late cystic PVL and controls, but were significantly higher in early cystic PVL than in late cystic PVL or controls (early cystic PVL, 281.3 ± 51.6 Carr units; late cystic PVL, 97.3 ± 18.7 Carr units; controls, 107.5 ± 13.8 Carr units; early cystic PVL vs. late cystic PVL, p < 0.05; and early cystic PVL vs. control, p < 0.05) (Fig. 2A). Serum BAP levels showed no differences among groups (early cystic PVL, 2201 ± 99 lmol/ l; late cystic PVL, 2282 ± 56 lmol/l; controls, 2272 ± 76 lmol/l) (Fig. 2B). OSI showed no significant differences between late cystic PVL and controls, but was significantly higher in early cystic PVL than in late cystic PVL or controls (early cystic PVL, 0.13 ± 0.062; late cystic PVL, 0.043 ± 0.08; controls, 0.047 ± 0.07; early cystic PVL vs. late cystic PVL, p < 0.05; early cystic PVL vs. controls, p < 0.05; late cystic PVL vs. controls, p = 0.25 (Fig. 2C). Postnatal duration until identification of cysts displayed significant negative correlations with OSI and TH level (r = 0.497, n = 22, p < 0.05 and r = 0.50, n = 22, p < 0.05, respectively) (Fig. 3A,B). 4. Discussion The present study demonstrated that OSI and TH level at birth were significantly higher in early cystic PVL than in late cystic PVL or controls. In addition, postnatal duration until identification of cysts was significantly negatively correlated with OSI and TH level. Although many studies have investigated risk factors in an attempt to reduce the development of PVL, preventive techniques remain elusive. Understanding the onset timing of cystic PVL is difficult. Ultrasonography echodensity is first seen 24–48 h after ischaemic insult. In some cases, the finding is transient, while in others the change persists beyond a week, evolving into periventricular cysts after around 18 days (range 10–39 days). Cysts become absorbed and disappear within 2– 3 months [26,27]. We thus considered early cystic PVL

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Fig. 1. Ultrasonography and magnetic resonance imaging in infants with early and late cystic PVL. Ultrassonography, coronal views at 5 days old (A), and parasagittal T1 weighted images at 40 weeks corrected age, in infants born at 31 weeks with early cystic PVL. Ultrassonography, parasagittal views at 28 days old (C), and parasagittal T1 weighted images at 40 weeks corrected age, in infants born at 33 weeks with late cystic PVL. There are periventricular cysts (arrow).

as cases displaying cysts within 10 days, and that early cystic PVL was mainly associated with antenatal and intrapartum factors. Several authors have suggested that antenatal exposure to indomethacin, low Apgar score, hypotension, hypocarbia, apnoea, sepsis and CAM are associated with occurrence of cystic PVL [28–30]. In our study, frequencies of PROM and CAM were significantly higher in early cystic PVL than in late cystic PVL or controls. In terms of postnatal factors, duration of ventilation, oxygen therapy and apnea were significantly higher in late cystic PVL than in controls or early cystic PVL. This suggests that early onset of cystic PVL might be due to inflammation and/or infection caused by antenatal factors, and that late onset might be due to postnatal factors, particularly poor respiratory state. Primary antioxidants prevent oxygen radical formation either by removing free radical precursors or by inhibiting catalysis, such as glutathione peroxidase,

superoxide dismutase, and catalase. Secondary antioxidants such as vitamins C and E react with ROS that have already formed to achieve either removal or inhibition. Endogenous antioxidants exist intracellularly, on the cell membrane and extracellularly [31,32]. Although many antioxidants can be present in the human body, circulating antioxidants cannot be viewed as simple chemicals, and measurement of individual components is unlikely to yield a complete picture of the in vivo situation. Oxidative stress has been hypothesised to play a key role in the pathogenesis of cystic PVL in premature infants, although direct evidence is lacking. Immature oligodendrocytes in vitro are particularly vulnerable to ROS, and free radical scavengers protect immature oligodendrocytes from injury [17]. Inder et al. reported that premature infants with evidence of white matter injury at term display significantly elevated levels of

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Table 1 Antenatal and intrapartum factors in early and late cystic PVL and control groups. Characteristic

Early cystic PVL (n = 10)

Late cystic PVL (n = 12)

Control (n = 22)

Birth weight (g) Gestational age (weeks) Apgar Score (1 min) Apgar Score (5 min) pH at birth Administration of Mean blood pressure at Base excess at birth Maximum FiO2 at birth PaO2 at birth PaCO2 at birth Hematocrit at birth Male Cesarean section Small for gestational age Multiple gestations Placental abruption Antenatal steroids therapy PROM CAM

1444 (1018–1654) 31.5 (29.0–34.1) 8 (5–9) 8 (5–9) 7.42 (7.21–7.52) 2 (20%) 39.0 (28.0–72.3) 1.3 ( 6.0–6.0) 0.4 (0.3–1.0) 100 (32–273) 39.0 (26.0–90.0) 41.1 (52.2–27.8) 4 (40.0%) 8 (80.0%) 3 (30.0%) 5 (50.0%) 1 (10.0%) 4 (40.0%) 5 (50.0%) ,– 4 (40.0%) ,–

1377 (956–2040) 31.7 (25.5–34.2) 6 (1–8) 7.5 (1–9) 7.39 (7.19–7.55) 2 (16.6%) 38.0 (29.3–43.0) 0.75 ( 4.3–4.0) 0.6 (0.3–1.0) 109 (54–338) 35.9 (23–241) 38.7(31.8–50.3) 6 (50.0%) 9 (75.0%) 13 (25.0%) 6 (50.0%) 2 (16.6%) 3 (25.0%) 1 (9.0%) 2 (16.6%)

1374 (706–2434) 31.9 (25.4–34.8) 8 (1–10) 9 (4–10) 7.39 (7.26–7.7) 3 (13.6%) 36.6 (23–41) 2.4 ( 15.4–2.4) 0.4 (0.25–1.0) 134 (34–475) 42 (11.2–116.2) 39.2 (34.3–48.5) 12 (55.5%) 10 (59.0%) 4 (18.2%) 8 (36.3%) 2 (9.0%) 8 (36.3%) 3(13.6%) 2 (9.0%)

Data are expressed as medians with ranges in parentheses. Analysis of variance was used to compare continuous data, followed by Bonferroni posthoc testing, and the v2 test or Fisher’s exact test to compare dichotomous outcomes. PROM, preterm rupture of membrane; CAM, chorioamnionitis.   p < 0.05 compared with control. – p < 0.05 compared with early cystic PVL.

Table 2 Postnatal factors in early and late cystic PVL and control groups. Characteristic

Early cystic PVL (n = 10)

Late cystic PVL (n = 12)

Control (n = 22)

Duration of ventilation (days) Duration of oxygen treatment (days) Surfactant therapy Indomethacin therapy Cathecholamine therapy Duration of cathecholamine therapy Transfusion of red blood cell Mean PaCO2 /minimum PaCO2 within 24 h Mean PaCO2/minimum PaCO2 from 24 h to 48 h Mean PaCO2/minimum PaCO2 from 48 h to 72 h Mean SpO2 within 24 h Mean SpO2 from 24 h to 48 h Mean SpO2 from 48 h to 72 h Mean FiO2 within 24 h Mean FiO2 from 24 h to 48 h Mean FiO2 from 48 h to 72 h Erythropoietin therapy Toral parental nutrition and lipids IV Iron administration Steroid therapy Chronic lung disease Apnea sepsis Retinopathy of prematurity Necrotizing enterocolitis Intraventricular hemorrhage

2 (0–8) 6 (1–13) 9 (100%) 3 (33.3%) 8 (88.8%) 3 (0–3) 3 (30.0) 38.0 (35–46)/35.0 (29–42) 34.0 (31.5–46)/31.0 (23.2–43) 38.3 (27–53)/34.0 (23–46) 98 (97–98) 98 (96–98) 98 (96–100) 0.23 (0.21–0.26) 0.23 (0.21–0.23) 0.23 (0.21–0.26) 7 (70%) 3 (30%) 6 (60%) 3 (30%) 1 (10%) 3 (30%) 0 2 (20%) 0 0

12 (2–37) ,– 11 (2–37) ,– 11 (91.7%) 4 (33.3%) 11 (90.1%) 5.0 (0–7) 4 (33.3%) 35.9 (23–48)/34.5(26–45) 34.7(46–29)/32.0 (24–46) 35.0 (32–44)/36.5 (27.8–46) 98(94–100) 98.5 (94–100) 97.5 (93–100) 0.23 (0.21–0.27) 0.24 (0.21–0.35) 0.22 (0.21–0.30) 9 (75%) 5 (41.6%) 9 (75%) 2 (16.6%) 2 (16.6%) 8 (75%)  , 1 (8.3%) 3 (25%) 0 0

2 (1–42) 5 (1–89) 19 (90.4%) 4 (19.0%) 18 (85.5%) 2.8 (0–4) 5 (22.7%) 36.7 (26.5–44.5)/34.0 (22–39) 35 (25–41.7)/30.0 (18–41) 35.3 (30.5–43)/34.0 (24.1–53) 98 (94–100) 98 (95–100) 98 (95–100) 0.25 (0.21–0.35) 0.22 (0.21–0.24) 0.21 (0.21–0.24) 18 (81.8%) 4 (18.1%) 17 (77.2%) 7 (31.8%) 1 (4.5%) 5 (22.7%) 2 (9.0%) 1 (4.5%) 1 (4.5%) 1 (4.5%)

Data are expressed as medians with ranges in parentheses. Analysis of variance was used to compare continuous data, followed by Bonferroni posthoc testing and the v2 test or Fisher’s exact test to compare dichotomous outcomes.   p < 0.05 compared with controls. – p < 0.05 compared with early cystic PVL.

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(B) µmol/l

(A) Carr Unit 600 †, †,

36

3000

500

5

400

2500

300 15 38 25 29

2000

200

1

100 1500 0

Early PVL Late PVL (C)

Early PVL Late PVL

Control

Control

0.4 †,

0.3

0.2 38 15 29 25

0.1

0

Early PVL

Late PVL

Control

Fig. 2. Serum TH and BAP levels and OSI in control, early cystic PVL, and late cystic PVL groups. (A) TH; (B) BAP; (C) OSI. Values shown are median levels (25th/75th box; 10th/90th error bars and individual outliers). Analysis of variance was used to compare continuous data, followed by Bonferroni post-hoc test.  p < 0.05, compared to control; –p < 0.05, compared to late PVL.

(A) 0.3

(B) Carr Unit 500 400

0.2 300 200 0.1 100 0

0

10

0 0 10 20 20 30 The postnatal days in which the cysts were identified

30

Fig. 3. Correlation between postnatal age at which cyst was identified, OSI, and TH level. (A) OSI (r = 0.497, p < 0.05); (B) TH level (r = 0.500, p < 0.05). Coefficients of correlation were tested using the Pearson 2-tailed correlation coefficient, and if data were non-parametric, Spearman’s 2-tailed test was used.

cerebrospinal fluid protein carbonyl and 8-isoprotane in comparison with premature infants without white matter injury [22]. That finding was based on CSF samples taken at 27 ± 8 days in PVL cases and 22 ± 4.7 days

in non-PVL cases. Ahola et al. showed that plasma ascorbyl radical levels were increased at 3 days postpartum in infants who later developed PVL [20]. These studies seem to have investigated ROS produced postna-

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tally. We obtained samples at birth (63 h after birth), much earlier than in previous studies. Our finding of higher TH levels at birth in early cystic PVL compared to late cystic PVL and controls suggests that ROS produced antenatally and intrapartum might be associated with early onset of cystic PVL, and that ROS produced postnatally or other factors might be associated with late onset of cystic PVL. In pathological conditions with oxidant/antioxidant imbalance, the oxidative stress concept suggests that high oxidant levels and low antioxidant levels are involved in poor outcomes [33–35]. This study found that mean BAP tended to be lower in early PVL than in late PVL or controls, but no significant differences were identified. To evaluate oxidative stress status, we therefore measured the ratio of TH to BAP, as an indicator of the degree of oxidative stress. Our results showed that OSI was significantly higher in early cystic PVL than in late cystic PVL or controls. Interestingly, negative correlations were found between postnatal age at which cysts were identified and both OSI and TH level. This suggests that neonates with much more oxidative stress and ROS at birth have earlier onset of cystic PVL. To the best of our knowledge, no previous reports have examined oxidative stress, ROS and antioxidants at birth in cases of cystic PVL. The present study also found that the frequencies of PROM and CAM as antenatal and intrapartum factors were significantly higher in early cystic PVL than in late cystic PVL or controls. This finding suggests that the significantly higher OSI and TH in early cystic PVL than in late cystic PVL and controls might be provoked by PROM and CAM. Oxidative stress markers in the serum, but not in the CSF, are likely to reflect systemic changes other than the disturbances in the brain. But it seems to be reasonable that the systemic oxidative stress provoked by PROM and CAM could lead to the early onset of cystic PVL. In conclusion, this study documented an association between early cystic PVL and both elevated ROS and oxidative stress, although we could not conclude whether high TH and OSI was the cause of early cystic PVL or an effect. This is the first report to find that neonates with much more oxidative stress at birth display earlier onset of cystic PVL. Although these findings require confirmation and amplification with a larger number of patients and more accurate timing of PVL, the data provide an insight into potential pathogenic mechanisms and may lead to protective therapies against PVL in premature infants. References [1] Saugstad OD. Oxidative stress in the newborn – a 30-year perspective. Biol Neonate 2005;88:228–36.

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