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Episodes of hypocarbia and early-onset sepsis are risk factors for cystic periventricular leukomalacia in the preterm infant
Early Human Development 88 (2012) 27–31
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Early Human Development j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / e a r l h u m d ev
Episodes of hypocarbia and early-onset sepsis are risk factors for cystic periventricular leukomalacia in the preterm infant B. Resch a, b,⁎, K. Neubauer a, N. Hofer a, E. Resch a, U. Maurer c, J. Haas d, W. Müller b a
Research Unit for Neonatal Infectious Diseases and Epidemiology, Medical University of Graz, Austria Division of Neonatology, Department of Pediatrics, Medical University of Graz, Austria Ambulatory of Neurodevelopmental Follow-up, Department of Pediatrics, Medical University of Graz, Australia d Medical Statistics, Department of Gynecology and Obstetrics, Medical University of Graz, Austria b c
a r t i c l e
i n f o
Article history: Received 25 May 2011 Received in revised form 18 June 2011 Accepted 21 June 2011 Keywords: Early-onset sepsis Hypocarbia Neurodevelopmental outcome Periventricular leukomalacia Preterm infant
a b s t r a c t Background: Septic episodes in preterm infants recently have been reported to be associated with periventricular leukomalacia (PVL). The role of hypocarbia as an independent risk factor for PVL in clinical studies raises many questions without conclusive answers. Aims: To evaluate risk factors for cystic PVL focussing on the influence of hypocarbia. Study design: Retrospective single centre case-control study. Subjects: Preterm infants 24 to 35 weeks of gestational age and matched (1:2 for gender, birth year, gestational age and birth weight) controls. Outcome measures: Multivariate analysis of perinatal factors being associated with cystic PVL diagnosed by serial ultrasound examinations. Results: Univariate analysis of risk factors revealed lower 5 and 10 min Apgar scores, and higher rates of neonatal seizures, early-onset sepsis, neonatal steroids, respiratory distress syndrome with surfactant replacement therapy, and episodes of hypocarbia significantly being associated with PVL. Multivariate analysis using a logistic regression model revealed early-onset sepsis and hypocarbia being significantly associated with PVL (p = .022 and .024, respectively). Lowest PaCO2 values did not differ as did not the duration of hypocarbia, but the onset of hypocarbia was significantly later in PVL cases compared to controls (mean 26 vs. 15 h, p = .033). Neurodevelopmental follow-up at a median time of 46 months was poor showing 88% of the cases having an adverse neurological outcome. Conclusion: We found early-onset sepsis and episodes of hypocarbia within the first days of life being independently associated with PVL. © 2011 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Cystic periventricular leukomalacia (PVL) is one of the most severe and frequent cause of cerebral palsy in children surviving preterm birth. The pathogenesis of PVL yet is not completely understood. The majority of the theories consider the necrotic foci to be hypoxic– ischemic lesions, resulting from impaired perfusion at the vascular border zones between ventriculopedal and ventriculofugal arteries, as the latter are poorly developed in preterm infants. Besides periventricular vascular anatomic factors and pressure-passive cerebral circulation the intrinsic vulnerability of cerebral white matter (a particular vulnerability of rapidly differentiating oligodendroglial cells) of preterm infants plays an important role [1]. An alternative view focuses on the role of intrauterine infection and the fetal ⁎ Corresponding author at: Klinische Abteilung für Neonatologie, Univ. Klinik für Kinder-und Jugendheilkunde, Medizinische Universität Graz, Austria. Tel.: + 43 316 385 81134; fax: + 43 316 385 2678. E-mail address: [email protected] (B. Resch). 0378-3782/$ – see front matter © 2011 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.earlhumdev.2011.06.011
inflammatory response syndrome [2]. When microorganisms or their antigens gain access to the foetus, they can stimulate the production of cytokines and a systemic response termed foetal inflammatory response syndrome, which has been implicated as a cause of foetal or neonatal injury that leads to damage of the brain and others organs [3,4]. The risk of cerebral palsy is influenced by the extent and site of cyst formation. Extensive occipito-parietal cysts have the worst prognosis, the best being isolated frontal cysts [5]. Early detection of cysts is often associated with chorioamnionitis and premature rupture of the membranes, multiple pregnancy (death of co-twin, placental vascular anastomoses) or antenatal haemorrhage. Other factors that have been reported to be associated with cystic PVL, and some of them are discussed controversially, include asphyxia, perinatal acidosis, respiratory distress, septicaemia and bacterial infections, hyperbilirubinaemia, persistent ductus arteriosus, mode of delivery, preeclampsia, pneumothorax, necrotising enterocolitis, arterial hypotension, and hypocarbia [6,7]. The role of hypocarbia as an independent risk factor for PVL in clinical studies raises many questions without conclusive answers [8].
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B. Resch et al. / Early Human Development 88 (2012) 27–31
The aim of the study was to evaluate risk factors for PVL focussing on the influence of hypocarbia by means of a retrospective casecontrol study. 2. Patients and methods This study was a retrospective analysis of all infants with PVL documented by ultrasound scans (US) admitted to the Division of Neonatology of the Department of Pediatrics of the Medical University of Graz, Austria, compared to matched controls between 1999 and 2008. The medical charts, the US and the data from our Ambulatory of Neurodevelopmental Follow-up were reviewed. The study was approved by the local ethic committee (21-051 ex 09/10). For the analysis of risk factors prenatal characteristics including maternal age, number of pregnancy, multiple pregnancy, history of abortion, maternal haemorrhage, preeclampsia/eclampsia, preterm premature rupture of the membranes (PPROM), clinical chorioamnionitis (CCA), abnormal prepartal cardiotocography, breech presentation, caesarean section, perinatal characteristics including maternal steroids, maternal antibiotics, Apgar scores at 1, 5 and 10 min, umbilical artery pH, capillary pH within 30 min after birth, birth weight, small for gestational age (SGA), gender, and postnatal characteristics including asphyxia, early-onset sepsis (EOS), arterial hypotension, hyperbilirubinaemia, intra-/periventricular haemorrhage, persistent ductus arteriosus, respiratory distress syndrome, respiratory support (mechanical ventilation including continuous positive airway pressure ventilation-CPAP), hypocarbia, seizures, and apnoeas infants with diagnosis of PVL were compared with two controls matched for gestational age (± 1 week), birth weight (±200 g), sex, and year of birth. If there was no adequate control we recruited controls from the year before or after. 2.1. Definitions of risk factors Small for gestational age (SGA) was defined as birth weight below 10th percentile. Foetal distress was defined as abnormal cardiotocography and/or meconium stained amniotic fluid. Preeclampsia was diagnosed when a pregnant woman developed high blood pressure (two separate readings taken at least 6 h apart of 140/90 or more) and proteinuria. PPROM was defined as onset before labour. CCA was defined as maternal fever higher than 38 °C together with at least one of the following symptoms: maternal or foetal tachycardia, uterine tenderness, foul-smelling amniotic fluid or maternal leukocytosis/Creactive protein (CRP) values above 50 mg/L [9]. Maternal steroids included two doses of betamethasone given parenteral to induce lung maturation. Maternal antibiotics included maternal treatment with antibiotics during labour. Asphyxia was characterized by foetal distress, an Apgar score of 5 or less after 5 min, and an umbilical artery pH less than 7.10. Apnoeas were defined as either desaturation below 80% or bradycardia below 80 bpm or both with the need of stimulation or an increase of inspired fraction of oxygen. Arterial hypotension was defined as a mean arterial blood pressure, measured with Dinamap, below 95% limits [10] and requiring treatment. Hyperbilirubinaemia was defined as increased bilirubin values with the need for phototherapy. Neonatal seizures were defined as paroxysmal alterations in neurological function, either subtle, tonic, clonic, or myoclonic, with autonomic nervous system changes and different from the symmetrical tremor of jitteriness that was confirmed in most cases by cerebral function monitoring or EEG. Neonatal steroids were given in case of oxygen dependency N 40% or failure to extubate the baby between days 7 and 10 of life. Until 2006 dexamethasone was used and since 2007 treatment was started with hydrocortisone and switched in case of unresponsiveness to betamethasone; duration was always restricted to a seven-day treatment course. Intraventricular haemorrhage (IVH) grades I to III was diagnosed by ultrasound scans (US) and classified according to Papile
[11]. Periventricular haemorrhage (IVH grade IV) was not present in the study group. Persisting ductus arteriosus Botalli was always confirmed by echocardiography with need for treatment with ibuprofen. Routinely infants with diagnosis of respiratory distress syndrome (RDS) and treatment with surfactant receive indomethacine prophylaxis for three days. RDS was defined as dyspnoea presenting within 4 to 6 h of delivery, additional oxygen requirement to prevent cyanosis, and reticulogranular chest X-ray appearance. Hypocarbia was defined as an arterial carbon dioxide partial pressure (pCO2) less than 35 mmHg (b4.67 kPa) for at least 1 h within the first five days of life. Transcutaneous pCO2 measurement in case of prematurity is not performed at our ward, thus, values derive from repeated arterial blood gas measurements. The shortest time interval in our records between two repeated blood gas measurements was 2 h. In case of normalization of pCO2 by the second measurement the estimated duration thus was calculated as 1 h. Additionally minimal values, time of onset in hours post partum, duration in hours, repeated episodes, and the total duration of hypocarbic episodes in hours were noted. Usually preterm infants with need for mechanical ventilation have arterial canulas for regular monitoring of blood gases at our ward, and values are documented on separate sheets within the medical records including details on respiratory support (mechanical ventilation and continuous positive airway pressure—CPAP). The diagnosis EOS was divided in blood culture and clinical proven sepsis. Blood cultures were drawn from every patient with suspected infection before starting antibiotic treatment. However, cases with positive microbial growth likely to derive from contamination were not classified as true infections. For clinical EOS at least three out of five clinical signs of sepsis with positive maternal risk factors and/or positive laboratory sepsis screen had to be present within the first 72 h of life [12] with antibiotic treatment for ≥7 days. In all cases diagnosed as having early-onset sepsis CRP values were above 8 mg/L. Clinical signs of sepsis included: a) respiratory symptoms (apnoea, tachypnoea, retractions, cyanosis, respiratory distress); b) cardiocirculatory symptoms (tachy- or bradycardia, arterial hypotonia); c) neurological symptoms (lethargy, irritability, seizures); d) hypoor hyperthermia (core temperature N38.5 °C or b36.0 °C); e) poor skin colour or prolonged capillary refilling time N2 s [13,14]. Maternal risk factors included PPROM, intra-amniotic infection and fever during labour [15]. For a positive laboratory sepsis screen at least two out of four measured parameters had to be out of normal ranges: CRP N8 mg/L, white blood cell count N34,000/μL or b9000/μL, absolute neutrophil countN14,400/μL or b7000/μL (b2000/μL in the first 24 h of life), immature to total neutrophil ratio N.2 [16,17]. Cranial US scans were routinely obtained in all preterm infants on days 1, 3, 5, and thereafter once a week in case of pathological findings. Real-time US scans were performed with a commercially available unit (Advanced Technology Laboratories Inc., Bothell, WA, USA) using a 7.5 or 8.2 MHz transducer, and multiple images were obtained in the coronal and sagittal planes through the anterior fontanel. The US scans were reviewed for the day of diagnosis of periventricular echodensities (PVE) and cystic PVL, the site of the cysts and the maximum diameter of the largest cysts. PVE were defined as confluent areas of increased echogenicity comparable with the echogenicity of the choroid plexus. Confirmation of the findings in both the coronal and sagittal planes was required before a definitive diagnosis was made. The site of the cysts was described in terms of its being anterior (A)—anterior to the frontal horn of the lateral ventricle, parietal (P)—lateral to the body of the lateral ventricle, or occipital (O)—adjacent and lateral to the occipital horn of the lateral ventricle. The maximum diameters of the largest cysts were measured in both the coronal and sagittal planes and the maximum value was noted [18]. For neurodevelopmental outcome infants were examined at the corrected for prematurity age of 4, 8, 12, 18 and 24 months, thereafter once a year. Assessment of outcome was made using the developmental
B. Resch et al. / Early Human Development 88 (2012) 27–31
tests as described by Griffith [19] in the first two years, by Kaufman [20] after these years, and neurological examinations as described by AmielTison [21] and Touwen [22]. Classification of mental outcome included normal, developmental delay, and mild to severe mental retardation. Classification of neurological outcome included normal, minor neurological abnormalities (including dystonia, hypotonia and asymmetry), hemiplegia (one side of body, arm more than leg), diplegia (minimal upper extremity involvement, legs more impaired) and tetraplegia (severe involvement of all extremities, legs more than arms). Classification of visual disorders included normal, strabismus, myopia, severe visual impairment and blindness. Classification of hearing disorders included hearing deficiency and deafness. Other findings included microcephaly and dystrophy. Statistical analyses were done with t-test and Wilcoxon test for numerical data after checking the normality assumption with the Kolmogorov–Smirnov-test. Categorial data were tested with Chisquare using Yates correction and Fisher's exact test as appropriate. Multivariate analysis was performed with a logistic regression model using SAS (SAS Institute Inc. Cary, NC), SPSS (Spss Inc. Chicago, Illinois) and StatXact4 and LogXact (Cytel, Cambridge, MA).
3. Results During the study period 1999 to 2008 a total of 3103 preterm infants ≤ 35 weeks of gestational age were admitted to our neonatal ward. Fifty-eight infants (1.9%) died during the first two weeks of life and were excluded from final analysis. All infants were screened by serial cranial ultrasound examinations for PVE and subsequent development of cystic PVL. Forty-seven preterm infants finally were diagnosed as having cystic PVL. Perinatal data of the study population and 94 matched controls are provided in Table 1. Median time of first diagnosis of PVE was on day 2 and median time of first diagnosis of cysts was on day 16 with a range from 1 to 64 days. Median latency time between last ultrasound scan and first diagnosis of cysts was 7 days. Thirty-one infants (66%) were diagnosed as having bilateral PVL, and cysts were located occipital or parieto-occipital or anterior-parieto-occipital in 36 infants (77%). Median maximum single cyst diameter was 7 mm with a range from 1 to 30 mm. Median follow-up at 46 months (range 12 to 114) revealed five infants (11%) as having developed normally, four (8%) having developmental delay or minor neurological abnormalities, and 37 (78%) having cerebral palsy. One infant (2%) died on day 41 due to late-onset sepsis with multi-organ failure. Six infants (12.8%) had only follow-up visits up to one year of corrected age. Eight infants (17%)
Table 1 Perinatal data of 47 preterm infants with cystic periventricular leukomalacia (PVL) compared to 94 controls matched for year of birth, gestational age, birth weigth, and gender, between 1999 and 2008: univariate analysis. Characteristics
PVL group n = 47
Matched controls n = 94 p value
Gestational age, weeks Birth weight, grams Male gender SGA Breech presentation Foetal distress Caesarean section Umbilical artery pH Apgar 1 min Apgar 5 min Apgar 10 min Capillary pHa
30.3 ± 2.3 (25–35)
30.4 ± 2.4 (24–35)
.430
1450 ± 550 (618–2500) 22 (47) 2 (4.3) 10 (21) 20 (43) 29 (62) 7.30 ± .08 6.7 ± 1.9 8.3 ± 1.4 8.8 ± 1.0 7.17 ± .09
1446 ± 358 (685–2510 44 (47) 9 (9.6) 23 (25) 32 (34) 72 (77) 7.28 ± .09 7.1 ± 2.1 8.8 ± 1.2 9.2 ± 1.0 7.23 ± .14
.476 .500 .135 .374 .119 .047 .175 .195 .036 .042 .060
Data are presented as n (%) or mean ± SD (range). SGA = small for gestational age, PVL = periventricular leukomalacia. a Within 30 min post partum (not available in all newborns).
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were diagnosed as having mental retardation, 16 (35%) having strabismus, 6 (13%) having visual, and none having hearing impairment. Seizure disorders were diagnosed in eight infants (17%). Two infants (4%) had diagnosis of microcephaly. Univariate analysis of risk factors revealed lower 5 and 10 min Apgar scores, and higher rates of neonatal seizures, EOS, neonatal steroids, respiratory distress syndrome with surfactant replacement therapy, and episodes of hypocarbia significantly being associated with PVL (see Tables 1 and 3). In vitro fertilisation, caesarean section, and preeclampsia were negatively correlated with PVL (see Tables 1 and 2). Episodes of hypocarbia were analysed in detail from 2002 to 2008. In the years 1999 to 2001 medical charts were not available for detailed analyses. Lowest PaCO2 values did not differ between PVL cases and controls as did not the duration of hypocarbia. The onset of hypocarbia was significantly later in PVL cases compared to controls (see Table 3). EOS was proven by positive blood culture in four cases (3 E. coli, 1 Enterococci) and based on the definition of clinical sepsis in 17 cases. Two positive blood cultures (Streptococcus viridans and Bacillus species, respectively) were classified as contaminants. EOS and hypocarbia were significantly associated with PVL (p = .022 and .024, respectively) following multivariate analysis using a logistic regression model and including all parameters with a level of significance below .1. Neonatal steroids remained near the level of significance (p = .050).
4. Discussion Our single centre retrospective case-control study over a 10-year time period revealed early-onset sepsis (EOS) and hypocarbia being significantly associated with cystic PVL by multivariate logistic regression analysis. In a former analysis we found PPROM, chorioamnionitis, multiple pregnancy and hyperbilirubinaemia to be significant risk factors associated with the development of cystic PVL [18]. Bacterial infections were diagnosed more often in the PVL group (50% vs. 37%) with an odds ratio of 1.7, but findings still were not significant in this former 1:1 matched case-control study. Despite the fact that PROM and chorioamnionitis have been identified as certain risk factors associated with PVL in the premature infant via an exaggerated foetal inflammatory response syndrome [2– 4,6,18,23], conflicting results exist concerning the association of postnatally acquired bacterial infections and septic episodes on cerebral damage in preterm infants. Recently, in a prospective cohort study including preterm infants with birth weights between 500 and 1500 g, 58% of the infants developed any kind of PVL including prolonged PVE, and sepsis (clinical and culture proven) and mechanical ventilation were more common observed in the group
Table 2 Maternal risk factors of 47 preterm infants with cystic periventricular leukomalacia (PVL) compared to 94 controls matched for year of birth, gestational age, birth weight, and gender, between 1999 and 2008: univariate analysis. Risk factor
PVL n = 47
Controls n = 94
p value
Maternal age, years Number of pregnancy Multiple pregnancy History of abortion In vitro fertilisation Maternal haemorrhage Preeclampsia PPROM Chorioamnionitis Maternal steroids Maternal antibiotics
28.6 ± 6.2 (18–40) 2.2 ± 1.2 (1–6) 22 (36) 15 (32) 1 (2.1) 6 (13) 2 (4.3) 17 (36) 14 (30) 25 (53) 22 (47)
29.8 ± 6.1 (16–45) 2.2 ± 1.4 (1–6) 29 (31) 30 (32) 10 (11) 12 (13) 16 (17) 34 (36) 25 (27) 56 (60) 53 (37)
.143 .438 .264 .434 .043 .444 .019 .464 .291 .438 .097
Data are presented as n (%) or mean ± SD (range). PPROM, preterm premature rupture of the membranes.
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Table 3 Neonatal risk factors of 47 preterm infants with cystic periventricular leukomalacia (PVL) compared to 94 controls matched for year of birth, gestational age, birth weight, and gender, between 1999 and 2008: univariate analysis. Risk factor
PVL n = 47
Controls n = 94
p value
Asphyxia Apnoeas Arterial hypotension Hyperbilirubinaemiaa Neonatal seizures Early-onset sepsis Neonatal antibiotics Neonatal steroids IVH I-III PDAa RDS Respiratory supportb Days on respiratory supportb Hypocarbiac Lowest PaCO2 value
4 (8.5) 30 (64) 11 (23) 17 (36) 4 (8.5) 11 (23) 33 (70) 10 (21) 13 (28) 12 (26) 34 (72) 37 (79) 12.8 ± 15.4 (0–66) 21/31 (68) 31.3 ± 2.9 (23.2–34.8)
.434 .297 .394 .164 .011 .024 .485 .020 .096 .269 .013 .080 .090
Time of onset of hypocarbia, hours post partum Duration of hypocarbia in hoursd
25.7 ± 23.3 (2.5–96)
9 (9.6) 55 (59) 25 (27) 27 (29) 1 (1.1) 10 (11) 65 (69) 9 (9.6) 17 (18) 29 (31) 51 (54) 65 (69) 9.4 ± 13.6 (0–69) 22/62 (35) 30.9 ± 3.0 (24.6–34.9) 15.4 ± 9.3 (1–38) 15.3 ± 16.1 (2–48)
17.8 ± 23.4 (2–75)
b.002 .327 .033 .346
Data are presented as n (%) or mean ± SD (range). IVH intraventricular hemorrhage, PDA persistent ductus arteriosus, CPAP continuous positive airway pressure, RDS respiratory distress syndrome with surfactant replacement therapy. a Needing treatment. b Mechanical ventilation including CPAP due to respiratory disease. c PaCO2 b 35 mm Hg (b 4.67 kPa) within the first 5 days of life, study period limited to 2002–2008. d Including all episodes of hypocarbia.
with PVL (23.5 vs. 2.7% and 86 vs. 59%, respectively) [24]. Again recurrent postnatal infections were associated with progressive white matter injury diagnosed by MRI in a study including 133 premature infants below 34 weeks gestational age [25]. This finding is consistent with emerging evidence that white matter injury is attributable to oligodendrocyte precursor susceptibility to inflammation, hypoxia, and ischemia [26]. In another prospective cohort study of 192 unselected preterm infants (gestational age b30 weeks), who were evaluated for sepsis and necrotizing enterocolitis (NEC) and underwent imaging at term-equivalent age and neurodevelopmental outcome at 2 years corrected age, infants with sepsis/NEC had significantly more white matter abnormalities on MRI at term compared with infants in the no-sepsis/NEC group [27]. Both postnatal sepsis and NEC are associated with sharply elevated concentrations of proinflammatory cytokines systemically. Thus, such infants may be more likely to exhibit diminished cerebral blood flow at a given blood pressure due to the presence of cerebrovascular autoregulatory impairment [26]. This possibility might be of extreme importance, because abundant experimental data show that infection/inflammation can potentiate hypoxic ischemic insults to the brain and convert a subthreshold insult to a seriously damaging event [26]. A case-control study of 167 neonates born between 23 and 34 weeks gestation revealed PVL being significantly associated with positive blood and cerebrospinal fluid cultures [28] and with chronic diffuse capsular deciduitis and the presence of capsular decidual plasma cells as the placental histopathologic correlates. During the last years only a few studies were published reevaluating risk factors associated with PVL [29–34]. Perinatal inflammatory processes including chorioanionitis and PPROM still remained a consistent finding. Hypocarbia is commonly observed during the first days of life in preterm infants requiring ventilatory support independent of the
mode of ventilation [35–38]. The majority of studies reporting on an association of hypocarbia with white matter disease noted moderate to severe hypocarbia (b4 and b3.3 kPa, respectively), and some did not find single episodes but a certain time period of hypocarbia significantly associated with PVL. These findings might suggest that mild and short episodes of hypocarbia are well tolerated in preterm infants, with certain limitations to very low and extremely low birth weight infants, respectively [8]. In contrast extremely low PaCO2 values have been observed in neonates during high frequency jet ventilation without development of PVL [35,36]. Cerebral blood flow has to fall to 25% of baseline over a certain time period and blood pressure has to be extremely low to cause white matter damage in preterm infants. Possible reasons for the apparent specific vulnerability of preterm infants to hypocarbia might be the poorly developed escape mechanisms especially in case of cerebral arterial vasoconstriction resulting in hypocapnic ischemia and the sensitization of the immature brain to hypoxemia by hypocarbia itself [8]. Our results could not clarify at what PaCO2 level or over which time period hypocarbia might be dangerous for the immature brain. Interestingly, the mean onset of hypocarbia was significantly later compared to controls suggesting that hypocarbia during the first hours after birth is better tolerated than later episodes of hypocarbia. Our results are limited by the retrospective design of the study but nevertheless are based on careful evaluation of medical records. These data confirm own findings in twins where hypocarbia was the only risk factor by comparison of the PVL case with its healthy sibling [39]. In conclusion we found early-onset sepsis and hypocarbia being significantly associated with PVL by multivariate logistic regression analysis. Neurodevelopmental follow-up at a median time of 46 months was poor showing 88% of the cases having an adverse neurological outcome. References [1] Volpe JJ. Neurology of the newborn. Philadelphia: WB Saunders; 2001. 217–497. [2] Damman O, Levinton A. Maternal intrauterine infection, cytokines, and brain damage in the preterm newborn. Pediatr Res 1997;42:1–8. [3] Yoon BH, Romero R, Yang SH, et al. Interleukin-6 concentrations in umbilical cord plasma are elevated in neonates with white matter lesions associated with periventricular leukomalacia. Am J Obstet Gynecol 1996;174:1433–40. [4] Yoon BH, Romero R, Park JS, et al. Microbial invasion of the amniotic cavity with ureaplasma urealyticum is associated with a robust host response in fetal, amniotic, and maternal compartments. Am J Obstet Gynecol 1998;179:1254–60. [5] Pierrat V, Duquennoy C, van Haastert IC, Ernst M, Guilley N, De Vries LS. Ultrasound diagnosis and neurodevelopmental outcome of localised and extensive cystic periventricular leucomalacia. Arch Dis Child Fetal Neonatal Ed 2001;84: F151–6. [6] Zupan V, Gonialez P, Lacaze-Masmonteil T, Boithias C, D' Allest A-M, Deliail M, et al. Periventricular leukomalacia: risk factors revisited. Dev Med Child Neurol 1996;38:1061–7. [7] Resch B, Vollaard E. Cystic periventricular leukencephalomalacia. Wien Med Wochenschr 2002;152:27–30. [8] Resch B. The role of hypocarbia in the development of cystic periventricular leukomalacia. Curr Pediatr Rev 2008;4:227–32. [9] Baud O, Ville Y, Zupan V, Boithias C, Lacaze-Masmonteil T, Gabilan JC, et al. Are neonatal brain lesions due to intrauterine infection related to mode of delivery? Br J Obstet Gynaecol 1998;105:121–4. [10] Low JA, Froese AB, Smith JT, Galbraith RS, Sauerbrei EE, Karchmar EJ. Blood pressure and heart rate of the preterm newborn following delivery. Clin Invest Med 1991;14:183–7. [11] Papile LA, Munsick-Bruno G, Schaefer A. Relationship of cerebral intraventricular hemorrhage and early childhood neurologic handicaps. J Pediatr 1983;103:273–7. [12] Resch B, Gusenleitner W, Müller WD. Procalcitonin and interleukin-6 in the diagnosis of early-onset sepsis of the neonate. Acta Paediatr 2003;92(2):243–5. [13] Buck C, Bundschu J, Gallati H, Bartmann P, Pohlandt F. Interleukin-6: a sensitive parameter for the early diagnosis of neonatal bacterial infection. Pediatrics 1994;93:54–8. [14] Töllner U. Early diagnosis of septicemia in the newborn. Clinical studies and sepsis score. Eur J Pediatr 1982;138:331–7. [15] Gibbs RS. Obstetric factors associated with infections of the fetus and newborn infant. In: Remington JS, Klein JO, editors. Infectious diseases of the fetus and newborn infant. 4th ed. Philadelphia: Saunders; 1995. p. 1241–63. [16] Philip AGS, Hewitt JR. Early Diagnosis of Neonatal Sepsis. Pediatrics 1980;65: 1036–41. [17] Gerdes JS, Polin RA. Sepsis screen in neonates with evaluation of plasma fibronectin. Pediatr Infect Dis J 1987;6(5):443–6.
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[30] Thomas W, Speer CP. Chorioamnionitis: important risk factor or innocent bystander for neonatal outcome? Neonatology 2011;99:177–87. [31] Hamrick SEG, Miller SP, Leonard C, Gudden DV, Goldstein R, Ramaswamy V, et al. Trends in severe brain injury and neurodevelopmental outcome in premature newborn infants: the role of cystic periventricular leukomalacia. J Pediatr 2004: 593–9. [32] Liu JL, Li J, Qin G-L, Chen Y-Hm, Wang Q. Periventricular leukomalacia in premature in fants in Mainland China. Am J Perinatol 2008;25:535–40. [33] Hatzidaki E, Giahnakis E, Maraka S, Korakaki E, Manoura A, Saitakis E, et al. Risk factors for periventricular leukomalacia. Acta Obstet Gynecol 2009;88:110–5. [34] Bauer M, Fast C, Haas J, Resch B, Lang U, Pertl B. Cystic periventricular leukomalacia in preterm infants: an analysis of obstetric risk factors. Early Hum Dev 2009;85: 163–9. [35] Wiswell TE, Graziani LJ, Kornhauser MS, Cullen J, Merton DA, McKee L, et al. Highfrequency jet ventilation in the early management of respiratory distress syndrome is associated with a greater risk for adverse outcomes. Pediatrics 1996;98:1035–43. [36] Keszler M, Modanlou HD, Brudno S, Cohen RS, Ryan RM, Kaneta MK, et al. Multicenter controlled clinical trial of high-frequency jet ventilation in preterm infants with uncomplicated respiratory distress syndrome. Pediatrics 1997;100: 593–9. [37] Luyt K, Wright D, Baumer JH. Randomised study comparing extent of hypocarbia in preterm infants during conventional and patient triggered ventilation. Arch Dis Child Fetal Neonatal Ed 2001;84:F14–7. [38] Cheema IU, Sinha AK, Kempley ST, Ahluwalia JS. Impact of volume guarantee ventilation on arterial carbon dioxide tension in newborn infants: a randomised controlled trial. Early Hum Dev 2007;83:183–9. [39] Resch B, Jammernegg A, Vollaard E, Maurer U, Mueller WD, Pertl B. Preterm twin gestation and cystic periventricular leucomalacia. Arch Dis Child Fetal Neonatal Ed 2004;89:F315–20.
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Early Human Development j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / e a r l h u m d ev
Episodes of hypocarbia and early-onset sepsis are risk factors for cystic periventricular leukomalacia in the preterm infant B. Resch a, b,⁎, K. Neubauer a, N. Hofer a, E. Resch a, U. Maurer c, J. Haas d, W. Müller b a
Research Unit for Neonatal Infectious Diseases and Epidemiology, Medical University of Graz, Austria Division of Neonatology, Department of Pediatrics, Medical University of Graz, Austria Ambulatory of Neurodevelopmental Follow-up, Department of Pediatrics, Medical University of Graz, Australia d Medical Statistics, Department of Gynecology and Obstetrics, Medical University of Graz, Austria b c
a r t i c l e
i n f o
Article history: Received 25 May 2011 Received in revised form 18 June 2011 Accepted 21 June 2011 Keywords: Early-onset sepsis Hypocarbia Neurodevelopmental outcome Periventricular leukomalacia Preterm infant
a b s t r a c t Background: Septic episodes in preterm infants recently have been reported to be associated with periventricular leukomalacia (PVL). The role of hypocarbia as an independent risk factor for PVL in clinical studies raises many questions without conclusive answers. Aims: To evaluate risk factors for cystic PVL focussing on the influence of hypocarbia. Study design: Retrospective single centre case-control study. Subjects: Preterm infants 24 to 35 weeks of gestational age and matched (1:2 for gender, birth year, gestational age and birth weight) controls. Outcome measures: Multivariate analysis of perinatal factors being associated with cystic PVL diagnosed by serial ultrasound examinations. Results: Univariate analysis of risk factors revealed lower 5 and 10 min Apgar scores, and higher rates of neonatal seizures, early-onset sepsis, neonatal steroids, respiratory distress syndrome with surfactant replacement therapy, and episodes of hypocarbia significantly being associated with PVL. Multivariate analysis using a logistic regression model revealed early-onset sepsis and hypocarbia being significantly associated with PVL (p = .022 and .024, respectively). Lowest PaCO2 values did not differ as did not the duration of hypocarbia, but the onset of hypocarbia was significantly later in PVL cases compared to controls (mean 26 vs. 15 h, p = .033). Neurodevelopmental follow-up at a median time of 46 months was poor showing 88% of the cases having an adverse neurological outcome. Conclusion: We found early-onset sepsis and episodes of hypocarbia within the first days of life being independently associated with PVL. © 2011 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Cystic periventricular leukomalacia (PVL) is one of the most severe and frequent cause of cerebral palsy in children surviving preterm birth. The pathogenesis of PVL yet is not completely understood. The majority of the theories consider the necrotic foci to be hypoxic– ischemic lesions, resulting from impaired perfusion at the vascular border zones between ventriculopedal and ventriculofugal arteries, as the latter are poorly developed in preterm infants. Besides periventricular vascular anatomic factors and pressure-passive cerebral circulation the intrinsic vulnerability of cerebral white matter (a particular vulnerability of rapidly differentiating oligodendroglial cells) of preterm infants plays an important role [1]. An alternative view focuses on the role of intrauterine infection and the fetal ⁎ Corresponding author at: Klinische Abteilung für Neonatologie, Univ. Klinik für Kinder-und Jugendheilkunde, Medizinische Universität Graz, Austria. Tel.: + 43 316 385 81134; fax: + 43 316 385 2678. E-mail address: [email protected] (B. Resch). 0378-3782/$ – see front matter © 2011 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.earlhumdev.2011.06.011
inflammatory response syndrome [2]. When microorganisms or their antigens gain access to the foetus, they can stimulate the production of cytokines and a systemic response termed foetal inflammatory response syndrome, which has been implicated as a cause of foetal or neonatal injury that leads to damage of the brain and others organs [3,4]. The risk of cerebral palsy is influenced by the extent and site of cyst formation. Extensive occipito-parietal cysts have the worst prognosis, the best being isolated frontal cysts [5]. Early detection of cysts is often associated with chorioamnionitis and premature rupture of the membranes, multiple pregnancy (death of co-twin, placental vascular anastomoses) or antenatal haemorrhage. Other factors that have been reported to be associated with cystic PVL, and some of them are discussed controversially, include asphyxia, perinatal acidosis, respiratory distress, septicaemia and bacterial infections, hyperbilirubinaemia, persistent ductus arteriosus, mode of delivery, preeclampsia, pneumothorax, necrotising enterocolitis, arterial hypotension, and hypocarbia [6,7]. The role of hypocarbia as an independent risk factor for PVL in clinical studies raises many questions without conclusive answers [8].
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B. Resch et al. / Early Human Development 88 (2012) 27–31
The aim of the study was to evaluate risk factors for PVL focussing on the influence of hypocarbia by means of a retrospective casecontrol study. 2. Patients and methods This study was a retrospective analysis of all infants with PVL documented by ultrasound scans (US) admitted to the Division of Neonatology of the Department of Pediatrics of the Medical University of Graz, Austria, compared to matched controls between 1999 and 2008. The medical charts, the US and the data from our Ambulatory of Neurodevelopmental Follow-up were reviewed. The study was approved by the local ethic committee (21-051 ex 09/10). For the analysis of risk factors prenatal characteristics including maternal age, number of pregnancy, multiple pregnancy, history of abortion, maternal haemorrhage, preeclampsia/eclampsia, preterm premature rupture of the membranes (PPROM), clinical chorioamnionitis (CCA), abnormal prepartal cardiotocography, breech presentation, caesarean section, perinatal characteristics including maternal steroids, maternal antibiotics, Apgar scores at 1, 5 and 10 min, umbilical artery pH, capillary pH within 30 min after birth, birth weight, small for gestational age (SGA), gender, and postnatal characteristics including asphyxia, early-onset sepsis (EOS), arterial hypotension, hyperbilirubinaemia, intra-/periventricular haemorrhage, persistent ductus arteriosus, respiratory distress syndrome, respiratory support (mechanical ventilation including continuous positive airway pressure ventilation-CPAP), hypocarbia, seizures, and apnoeas infants with diagnosis of PVL were compared with two controls matched for gestational age (± 1 week), birth weight (±200 g), sex, and year of birth. If there was no adequate control we recruited controls from the year before or after. 2.1. Definitions of risk factors Small for gestational age (SGA) was defined as birth weight below 10th percentile. Foetal distress was defined as abnormal cardiotocography and/or meconium stained amniotic fluid. Preeclampsia was diagnosed when a pregnant woman developed high blood pressure (two separate readings taken at least 6 h apart of 140/90 or more) and proteinuria. PPROM was defined as onset before labour. CCA was defined as maternal fever higher than 38 °C together with at least one of the following symptoms: maternal or foetal tachycardia, uterine tenderness, foul-smelling amniotic fluid or maternal leukocytosis/Creactive protein (CRP) values above 50 mg/L [9]. Maternal steroids included two doses of betamethasone given parenteral to induce lung maturation. Maternal antibiotics included maternal treatment with antibiotics during labour. Asphyxia was characterized by foetal distress, an Apgar score of 5 or less after 5 min, and an umbilical artery pH less than 7.10. Apnoeas were defined as either desaturation below 80% or bradycardia below 80 bpm or both with the need of stimulation or an increase of inspired fraction of oxygen. Arterial hypotension was defined as a mean arterial blood pressure, measured with Dinamap, below 95% limits [10] and requiring treatment. Hyperbilirubinaemia was defined as increased bilirubin values with the need for phototherapy. Neonatal seizures were defined as paroxysmal alterations in neurological function, either subtle, tonic, clonic, or myoclonic, with autonomic nervous system changes and different from the symmetrical tremor of jitteriness that was confirmed in most cases by cerebral function monitoring or EEG. Neonatal steroids were given in case of oxygen dependency N 40% or failure to extubate the baby between days 7 and 10 of life. Until 2006 dexamethasone was used and since 2007 treatment was started with hydrocortisone and switched in case of unresponsiveness to betamethasone; duration was always restricted to a seven-day treatment course. Intraventricular haemorrhage (IVH) grades I to III was diagnosed by ultrasound scans (US) and classified according to Papile
[11]. Periventricular haemorrhage (IVH grade IV) was not present in the study group. Persisting ductus arteriosus Botalli was always confirmed by echocardiography with need for treatment with ibuprofen. Routinely infants with diagnosis of respiratory distress syndrome (RDS) and treatment with surfactant receive indomethacine prophylaxis for three days. RDS was defined as dyspnoea presenting within 4 to 6 h of delivery, additional oxygen requirement to prevent cyanosis, and reticulogranular chest X-ray appearance. Hypocarbia was defined as an arterial carbon dioxide partial pressure (pCO2) less than 35 mmHg (b4.67 kPa) for at least 1 h within the first five days of life. Transcutaneous pCO2 measurement in case of prematurity is not performed at our ward, thus, values derive from repeated arterial blood gas measurements. The shortest time interval in our records between two repeated blood gas measurements was 2 h. In case of normalization of pCO2 by the second measurement the estimated duration thus was calculated as 1 h. Additionally minimal values, time of onset in hours post partum, duration in hours, repeated episodes, and the total duration of hypocarbic episodes in hours were noted. Usually preterm infants with need for mechanical ventilation have arterial canulas for regular monitoring of blood gases at our ward, and values are documented on separate sheets within the medical records including details on respiratory support (mechanical ventilation and continuous positive airway pressure—CPAP). The diagnosis EOS was divided in blood culture and clinical proven sepsis. Blood cultures were drawn from every patient with suspected infection before starting antibiotic treatment. However, cases with positive microbial growth likely to derive from contamination were not classified as true infections. For clinical EOS at least three out of five clinical signs of sepsis with positive maternal risk factors and/or positive laboratory sepsis screen had to be present within the first 72 h of life [12] with antibiotic treatment for ≥7 days. In all cases diagnosed as having early-onset sepsis CRP values were above 8 mg/L. Clinical signs of sepsis included: a) respiratory symptoms (apnoea, tachypnoea, retractions, cyanosis, respiratory distress); b) cardiocirculatory symptoms (tachy- or bradycardia, arterial hypotonia); c) neurological symptoms (lethargy, irritability, seizures); d) hypoor hyperthermia (core temperature N38.5 °C or b36.0 °C); e) poor skin colour or prolonged capillary refilling time N2 s [13,14]. Maternal risk factors included PPROM, intra-amniotic infection and fever during labour [15]. For a positive laboratory sepsis screen at least two out of four measured parameters had to be out of normal ranges: CRP N8 mg/L, white blood cell count N34,000/μL or b9000/μL, absolute neutrophil countN14,400/μL or b7000/μL (b2000/μL in the first 24 h of life), immature to total neutrophil ratio N.2 [16,17]. Cranial US scans were routinely obtained in all preterm infants on days 1, 3, 5, and thereafter once a week in case of pathological findings. Real-time US scans were performed with a commercially available unit (Advanced Technology Laboratories Inc., Bothell, WA, USA) using a 7.5 or 8.2 MHz transducer, and multiple images were obtained in the coronal and sagittal planes through the anterior fontanel. The US scans were reviewed for the day of diagnosis of periventricular echodensities (PVE) and cystic PVL, the site of the cysts and the maximum diameter of the largest cysts. PVE were defined as confluent areas of increased echogenicity comparable with the echogenicity of the choroid plexus. Confirmation of the findings in both the coronal and sagittal planes was required before a definitive diagnosis was made. The site of the cysts was described in terms of its being anterior (A)—anterior to the frontal horn of the lateral ventricle, parietal (P)—lateral to the body of the lateral ventricle, or occipital (O)—adjacent and lateral to the occipital horn of the lateral ventricle. The maximum diameters of the largest cysts were measured in both the coronal and sagittal planes and the maximum value was noted [18]. For neurodevelopmental outcome infants were examined at the corrected for prematurity age of 4, 8, 12, 18 and 24 months, thereafter once a year. Assessment of outcome was made using the developmental
B. Resch et al. / Early Human Development 88 (2012) 27–31
tests as described by Griffith [19] in the first two years, by Kaufman [20] after these years, and neurological examinations as described by AmielTison [21] and Touwen [22]. Classification of mental outcome included normal, developmental delay, and mild to severe mental retardation. Classification of neurological outcome included normal, minor neurological abnormalities (including dystonia, hypotonia and asymmetry), hemiplegia (one side of body, arm more than leg), diplegia (minimal upper extremity involvement, legs more impaired) and tetraplegia (severe involvement of all extremities, legs more than arms). Classification of visual disorders included normal, strabismus, myopia, severe visual impairment and blindness. Classification of hearing disorders included hearing deficiency and deafness. Other findings included microcephaly and dystrophy. Statistical analyses were done with t-test and Wilcoxon test for numerical data after checking the normality assumption with the Kolmogorov–Smirnov-test. Categorial data were tested with Chisquare using Yates correction and Fisher's exact test as appropriate. Multivariate analysis was performed with a logistic regression model using SAS (SAS Institute Inc. Cary, NC), SPSS (Spss Inc. Chicago, Illinois) and StatXact4 and LogXact (Cytel, Cambridge, MA).
3. Results During the study period 1999 to 2008 a total of 3103 preterm infants ≤ 35 weeks of gestational age were admitted to our neonatal ward. Fifty-eight infants (1.9%) died during the first two weeks of life and were excluded from final analysis. All infants were screened by serial cranial ultrasound examinations for PVE and subsequent development of cystic PVL. Forty-seven preterm infants finally were diagnosed as having cystic PVL. Perinatal data of the study population and 94 matched controls are provided in Table 1. Median time of first diagnosis of PVE was on day 2 and median time of first diagnosis of cysts was on day 16 with a range from 1 to 64 days. Median latency time between last ultrasound scan and first diagnosis of cysts was 7 days. Thirty-one infants (66%) were diagnosed as having bilateral PVL, and cysts were located occipital or parieto-occipital or anterior-parieto-occipital in 36 infants (77%). Median maximum single cyst diameter was 7 mm with a range from 1 to 30 mm. Median follow-up at 46 months (range 12 to 114) revealed five infants (11%) as having developed normally, four (8%) having developmental delay or minor neurological abnormalities, and 37 (78%) having cerebral palsy. One infant (2%) died on day 41 due to late-onset sepsis with multi-organ failure. Six infants (12.8%) had only follow-up visits up to one year of corrected age. Eight infants (17%)
Table 1 Perinatal data of 47 preterm infants with cystic periventricular leukomalacia (PVL) compared to 94 controls matched for year of birth, gestational age, birth weigth, and gender, between 1999 and 2008: univariate analysis. Characteristics
PVL group n = 47
Matched controls n = 94 p value
Gestational age, weeks Birth weight, grams Male gender SGA Breech presentation Foetal distress Caesarean section Umbilical artery pH Apgar 1 min Apgar 5 min Apgar 10 min Capillary pHa
30.3 ± 2.3 (25–35)
30.4 ± 2.4 (24–35)
.430
1450 ± 550 (618–2500) 22 (47) 2 (4.3) 10 (21) 20 (43) 29 (62) 7.30 ± .08 6.7 ± 1.9 8.3 ± 1.4 8.8 ± 1.0 7.17 ± .09
1446 ± 358 (685–2510 44 (47) 9 (9.6) 23 (25) 32 (34) 72 (77) 7.28 ± .09 7.1 ± 2.1 8.8 ± 1.2 9.2 ± 1.0 7.23 ± .14
.476 .500 .135 .374 .119 .047 .175 .195 .036 .042 .060
Data are presented as n (%) or mean ± SD (range). SGA = small for gestational age, PVL = periventricular leukomalacia. a Within 30 min post partum (not available in all newborns).
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were diagnosed as having mental retardation, 16 (35%) having strabismus, 6 (13%) having visual, and none having hearing impairment. Seizure disorders were diagnosed in eight infants (17%). Two infants (4%) had diagnosis of microcephaly. Univariate analysis of risk factors revealed lower 5 and 10 min Apgar scores, and higher rates of neonatal seizures, EOS, neonatal steroids, respiratory distress syndrome with surfactant replacement therapy, and episodes of hypocarbia significantly being associated with PVL (see Tables 1 and 3). In vitro fertilisation, caesarean section, and preeclampsia were negatively correlated with PVL (see Tables 1 and 2). Episodes of hypocarbia were analysed in detail from 2002 to 2008. In the years 1999 to 2001 medical charts were not available for detailed analyses. Lowest PaCO2 values did not differ between PVL cases and controls as did not the duration of hypocarbia. The onset of hypocarbia was significantly later in PVL cases compared to controls (see Table 3). EOS was proven by positive blood culture in four cases (3 E. coli, 1 Enterococci) and based on the definition of clinical sepsis in 17 cases. Two positive blood cultures (Streptococcus viridans and Bacillus species, respectively) were classified as contaminants. EOS and hypocarbia were significantly associated with PVL (p = .022 and .024, respectively) following multivariate analysis using a logistic regression model and including all parameters with a level of significance below .1. Neonatal steroids remained near the level of significance (p = .050).
4. Discussion Our single centre retrospective case-control study over a 10-year time period revealed early-onset sepsis (EOS) and hypocarbia being significantly associated with cystic PVL by multivariate logistic regression analysis. In a former analysis we found PPROM, chorioamnionitis, multiple pregnancy and hyperbilirubinaemia to be significant risk factors associated with the development of cystic PVL [18]. Bacterial infections were diagnosed more often in the PVL group (50% vs. 37%) with an odds ratio of 1.7, but findings still were not significant in this former 1:1 matched case-control study. Despite the fact that PROM and chorioamnionitis have been identified as certain risk factors associated with PVL in the premature infant via an exaggerated foetal inflammatory response syndrome [2– 4,6,18,23], conflicting results exist concerning the association of postnatally acquired bacterial infections and septic episodes on cerebral damage in preterm infants. Recently, in a prospective cohort study including preterm infants with birth weights between 500 and 1500 g, 58% of the infants developed any kind of PVL including prolonged PVE, and sepsis (clinical and culture proven) and mechanical ventilation were more common observed in the group
Table 2 Maternal risk factors of 47 preterm infants with cystic periventricular leukomalacia (PVL) compared to 94 controls matched for year of birth, gestational age, birth weight, and gender, between 1999 and 2008: univariate analysis. Risk factor
PVL n = 47
Controls n = 94
p value
Maternal age, years Number of pregnancy Multiple pregnancy History of abortion In vitro fertilisation Maternal haemorrhage Preeclampsia PPROM Chorioamnionitis Maternal steroids Maternal antibiotics
28.6 ± 6.2 (18–40) 2.2 ± 1.2 (1–6) 22 (36) 15 (32) 1 (2.1) 6 (13) 2 (4.3) 17 (36) 14 (30) 25 (53) 22 (47)
29.8 ± 6.1 (16–45) 2.2 ± 1.4 (1–6) 29 (31) 30 (32) 10 (11) 12 (13) 16 (17) 34 (36) 25 (27) 56 (60) 53 (37)
.143 .438 .264 .434 .043 .444 .019 .464 .291 .438 .097
Data are presented as n (%) or mean ± SD (range). PPROM, preterm premature rupture of the membranes.
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B. Resch et al. / Early Human Development 88 (2012) 27–31
Table 3 Neonatal risk factors of 47 preterm infants with cystic periventricular leukomalacia (PVL) compared to 94 controls matched for year of birth, gestational age, birth weight, and gender, between 1999 and 2008: univariate analysis. Risk factor
PVL n = 47
Controls n = 94
p value
Asphyxia Apnoeas Arterial hypotension Hyperbilirubinaemiaa Neonatal seizures Early-onset sepsis Neonatal antibiotics Neonatal steroids IVH I-III PDAa RDS Respiratory supportb Days on respiratory supportb Hypocarbiac Lowest PaCO2 value
4 (8.5) 30 (64) 11 (23) 17 (36) 4 (8.5) 11 (23) 33 (70) 10 (21) 13 (28) 12 (26) 34 (72) 37 (79) 12.8 ± 15.4 (0–66) 21/31 (68) 31.3 ± 2.9 (23.2–34.8)
.434 .297 .394 .164 .011 .024 .485 .020 .096 .269 .013 .080 .090
Time of onset of hypocarbia, hours post partum Duration of hypocarbia in hoursd
25.7 ± 23.3 (2.5–96)
9 (9.6) 55 (59) 25 (27) 27 (29) 1 (1.1) 10 (11) 65 (69) 9 (9.6) 17 (18) 29 (31) 51 (54) 65 (69) 9.4 ± 13.6 (0–69) 22/62 (35) 30.9 ± 3.0 (24.6–34.9) 15.4 ± 9.3 (1–38) 15.3 ± 16.1 (2–48)
17.8 ± 23.4 (2–75)
b.002 .327 .033 .346
Data are presented as n (%) or mean ± SD (range). IVH intraventricular hemorrhage, PDA persistent ductus arteriosus, CPAP continuous positive airway pressure, RDS respiratory distress syndrome with surfactant replacement therapy. a Needing treatment. b Mechanical ventilation including CPAP due to respiratory disease. c PaCO2 b 35 mm Hg (b 4.67 kPa) within the first 5 days of life, study period limited to 2002–2008. d Including all episodes of hypocarbia.
with PVL (23.5 vs. 2.7% and 86 vs. 59%, respectively) [24]. Again recurrent postnatal infections were associated with progressive white matter injury diagnosed by MRI in a study including 133 premature infants below 34 weeks gestational age [25]. This finding is consistent with emerging evidence that white matter injury is attributable to oligodendrocyte precursor susceptibility to inflammation, hypoxia, and ischemia [26]. In another prospective cohort study of 192 unselected preterm infants (gestational age b30 weeks), who were evaluated for sepsis and necrotizing enterocolitis (NEC) and underwent imaging at term-equivalent age and neurodevelopmental outcome at 2 years corrected age, infants with sepsis/NEC had significantly more white matter abnormalities on MRI at term compared with infants in the no-sepsis/NEC group [27]. Both postnatal sepsis and NEC are associated with sharply elevated concentrations of proinflammatory cytokines systemically. Thus, such infants may be more likely to exhibit diminished cerebral blood flow at a given blood pressure due to the presence of cerebrovascular autoregulatory impairment [26]. This possibility might be of extreme importance, because abundant experimental data show that infection/inflammation can potentiate hypoxic ischemic insults to the brain and convert a subthreshold insult to a seriously damaging event [26]. A case-control study of 167 neonates born between 23 and 34 weeks gestation revealed PVL being significantly associated with positive blood and cerebrospinal fluid cultures [28] and with chronic diffuse capsular deciduitis and the presence of capsular decidual plasma cells as the placental histopathologic correlates. During the last years only a few studies were published reevaluating risk factors associated with PVL [29–34]. Perinatal inflammatory processes including chorioanionitis and PPROM still remained a consistent finding. Hypocarbia is commonly observed during the first days of life in preterm infants requiring ventilatory support independent of the
mode of ventilation [35–38]. The majority of studies reporting on an association of hypocarbia with white matter disease noted moderate to severe hypocarbia (b4 and b3.3 kPa, respectively), and some did not find single episodes but a certain time period of hypocarbia significantly associated with PVL. These findings might suggest that mild and short episodes of hypocarbia are well tolerated in preterm infants, with certain limitations to very low and extremely low birth weight infants, respectively [8]. In contrast extremely low PaCO2 values have been observed in neonates during high frequency jet ventilation without development of PVL [35,36]. Cerebral blood flow has to fall to 25% of baseline over a certain time period and blood pressure has to be extremely low to cause white matter damage in preterm infants. Possible reasons for the apparent specific vulnerability of preterm infants to hypocarbia might be the poorly developed escape mechanisms especially in case of cerebral arterial vasoconstriction resulting in hypocapnic ischemia and the sensitization of the immature brain to hypoxemia by hypocarbia itself [8]. Our results could not clarify at what PaCO2 level or over which time period hypocarbia might be dangerous for the immature brain. Interestingly, the mean onset of hypocarbia was significantly later compared to controls suggesting that hypocarbia during the first hours after birth is better tolerated than later episodes of hypocarbia. Our results are limited by the retrospective design of the study but nevertheless are based on careful evaluation of medical records. These data confirm own findings in twins where hypocarbia was the only risk factor by comparison of the PVL case with its healthy sibling [39]. In conclusion we found early-onset sepsis and hypocarbia being significantly associated with PVL by multivariate logistic regression analysis. Neurodevelopmental follow-up at a median time of 46 months was poor showing 88% of the cases having an adverse neurological outcome. References [1] Volpe JJ. Neurology of the newborn. Philadelphia: WB Saunders; 2001. 217–497. [2] Damman O, Levinton A. Maternal intrauterine infection, cytokines, and brain damage in the preterm newborn. Pediatr Res 1997;42:1–8. [3] Yoon BH, Romero R, Yang SH, et al. Interleukin-6 concentrations in umbilical cord plasma are elevated in neonates with white matter lesions associated with periventricular leukomalacia. Am J Obstet Gynecol 1996;174:1433–40. [4] Yoon BH, Romero R, Park JS, et al. Microbial invasion of the amniotic cavity with ureaplasma urealyticum is associated with a robust host response in fetal, amniotic, and maternal compartments. Am J Obstet Gynecol 1998;179:1254–60. [5] Pierrat V, Duquennoy C, van Haastert IC, Ernst M, Guilley N, De Vries LS. Ultrasound diagnosis and neurodevelopmental outcome of localised and extensive cystic periventricular leucomalacia. Arch Dis Child Fetal Neonatal Ed 2001;84: F151–6. [6] Zupan V, Gonialez P, Lacaze-Masmonteil T, Boithias C, D' Allest A-M, Deliail M, et al. Periventricular leukomalacia: risk factors revisited. Dev Med Child Neurol 1996;38:1061–7. [7] Resch B, Vollaard E. Cystic periventricular leukencephalomalacia. Wien Med Wochenschr 2002;152:27–30. [8] Resch B. The role of hypocarbia in the development of cystic periventricular leukomalacia. Curr Pediatr Rev 2008;4:227–32. [9] Baud O, Ville Y, Zupan V, Boithias C, Lacaze-Masmonteil T, Gabilan JC, et al. Are neonatal brain lesions due to intrauterine infection related to mode of delivery? Br J Obstet Gynaecol 1998;105:121–4. [10] Low JA, Froese AB, Smith JT, Galbraith RS, Sauerbrei EE, Karchmar EJ. Blood pressure and heart rate of the preterm newborn following delivery. Clin Invest Med 1991;14:183–7. [11] Papile LA, Munsick-Bruno G, Schaefer A. Relationship of cerebral intraventricular hemorrhage and early childhood neurologic handicaps. J Pediatr 1983;103:273–7. [12] Resch B, Gusenleitner W, Müller WD. Procalcitonin and interleukin-6 in the diagnosis of early-onset sepsis of the neonate. Acta Paediatr 2003;92(2):243–5. [13] Buck C, Bundschu J, Gallati H, Bartmann P, Pohlandt F. Interleukin-6: a sensitive parameter for the early diagnosis of neonatal bacterial infection. Pediatrics 1994;93:54–8. [14] Töllner U. Early diagnosis of septicemia in the newborn. Clinical studies and sepsis score. Eur J Pediatr 1982;138:331–7. [15] Gibbs RS. Obstetric factors associated with infections of the fetus and newborn infant. In: Remington JS, Klein JO, editors. Infectious diseases of the fetus and newborn infant. 4th ed. Philadelphia: Saunders; 1995. p. 1241–63. [16] Philip AGS, Hewitt JR. Early Diagnosis of Neonatal Sepsis. Pediatrics 1980;65: 1036–41. [17] Gerdes JS, Polin RA. Sepsis screen in neonates with evaluation of plasma fibronectin. Pediatr Infect Dis J 1987;6(5):443–6.
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