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Risk factors of periventricular leukomalacia in singleton infants born from 23rd to 26th weeks of gestation – Retrospective study
PEPO 513 1–5 pediatria polska xxx (2017) xxx–xxx
Available online at www.sciencedirect.com
ScienceDirect journal homepage: www.elsevier.com/locate/pepo 1
Original research article/ Artykuł oryginalny
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Risk factors of periventricular leukomalacia in singleton infants born from 23rd to 26th weeks of gestation – Retrospective study
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Dawid Szpecht 1,*, Katarzyna Wiak 2, Anna Braszak 2, Emily Surzyn 2, Marta Szymankiewicz 1, Janusz Gadzinowski 1 1 2
Chair, Department of Neonatology, Poznan University of Medical Sciences, Poland Poznan University of Medical Sciences, Poznan, Poland
article info
abstract
Article history:
Introduction: Periventricular leukomalacia (PVL) is one of the most common hypoxic-
Received: 10.01.2017
ischemic pathologies among preterm newborns. The bracket most vulnerable to PVL are
Accepted: 02.02.2017
newborns born before 34 weeks’ gestation, especially those with very low and extremely
Available online: xxx
low birth weights. In a population of very low birth weight newborns, the frequency of periventricular white matter injury (PWMI) including PVL is 5–15%. The aim of our study
Keywords: Periventricular leukomalalcia Preterm infants
was to verify the potential risk factors of the occurrence of PVL among infants born bet-
Risk factors
tal Intensive Care in the Department of Neonatology, Poznan University of Medical Scien-
ween 23 and 26 weeks’ gestation. Methods: The retrospective study included a group of 115 unrelated infants born between 23 and 26 week's gestation, hospitalized in the Neonaces in 2010–2014, born in the clinic or transported to it after birth in the hospital of lower references. The diagnosis of PVL was based on transcranial ultrasound. Results: PVL was diagnosed in 17 (14.8%), including 5 (29.4%) infants born from 23 to 24 weeks’ gestation and 12 (70.6%) born from 25 to 26 weeks gestation. Higher incidence of PVL was found among infants born outside tertiary hospital (OR 7.933 (2.206–35.19); p = 0.0005) and newborns diagnosed with III and IV intraventricular hemorrhage (IVH) (OR 3.273 (1.042–10.28); p = 0.036). Conclusions: Delivery in the third-level hospital as well as IVH prevention significantly reduces the risk of PVL. Well-developed prenatal care, fetus transport in utero and delivery in the third-level hospital seem to be crucial in the prevention of this pathology. © 2017 Polish Pediatric Society. Published by Elsevier Sp. z o.o. All rights reserved.
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Introduction
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One of the most common hypoxic-ischemic pathologies among preterm newborns is periventricular leukomalacia
(PVL). The frequency of this pathology is inversely proportional to gestational age and birth weight. The most vulnerable bracket is newborns born before 34 weeks’ gestation, especially with very low and extremely low birth weight. In a population of very low birth weight newborns
* Corresponding author at: Department of Neonatology, Poznan University of Medical Sciences, ul. Polna 33, 60-535 Poznań, Poland. Tel.: +48 502145181; fax: +48 618419411. E-mail address: [email protected] (D. Szpecht). http://dx.doi.org/10.1016/j.pepo.2017.02.002 0031-3939/© 2017 Polish Pediatric Society. Published by Elsevier Sp. z o.o. All rights reserved.
Please cite this article in press as: Szpecht D, et al. Risk factors of periventricular leukomalacia in singleton infants born from 23rd to 26th weeks of gestation – Retrospective study. Pediatr Pol. (2017), http://dx.doi.org/10.1016/j.pepo.2017.02.002
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the frequency of periventricular white matter injury (PWMI), including PVL is 5–15% [1]. PVL is a white matter injury (WMI) in the form of nerve tissue necrosis in the border zone of vascularization; this is dorsally and laterally to lateral ventricles. There are four stages of this pathology advancement, from increased periventricular echogenicity to the existence of large cavities, reaching deep into the white matter. WMI is a major cause of cerebral palsy, causing severe disability in motor and intellectual areas, as well as vision and hearing disorders [2–4]. The pathogenesis of PVL is complex. Among the risk factors are: chronic or subacute hypoxia, intrauterine infection, bradycardia, apnea, hypotension, and anemia. It often occurs in infants born to mothers with diabetes and prepregnancy obesity. PVL generally coexists with III and IV degree of intraventricular hemorrhage (IVH) and is located around post hemorrhagic changes [2, 5]. The aim of our study was to analyze of potential risk factors of PVL among newborns born between 23 and 26 weeks’ gestation.
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Material and methods
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The study population
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The study included infants born between 23 and 26 weeks’ gestation, and hospitalized in Neonatal Intensive Care in the Department of Neonatology University of Medical Sciences in 2010–2014, born in the same clinic or transported to it after birth. The study included 115 unrelated newborns. The study did not include infants born in a week of pregnancy other than 23–26 weeks, newborns from multiple pregnancies, pregnancies in which there was a death of one of the fetuses, infants with chromosomal aberrations and TORCH group intrauterine infections.
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Periventricular leukomalacia – definition
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The diagnosis of PVL was based on transcranial ultrasound, which was performed in accordance with local standards, based on the guidelines of Polish Neonatal Society – transcranial ultrasound was performed on 1st day of life, the 3rd, and the 7th day of life, and further research depending on the extent of changes found in previous studies. In newborns diagnosed with III and IV grade of IVH, ultrasound was performed at least once a week and after diagnosis of ventricle expansion; every 3 days [6]. Periventricular leukomalacia was defined according to de Vries criteria (Table I) [7].
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Risk factors
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The analysis included following potential risk factors of PVL: 1. Maternal: mother's age, maternal cigarette smoking during pregnancy, mother's hypertension, cervical incompetence, premature rupture of membranes (PROM), antenatal steroidotherapy (according to the recommendation of the Polish Society of Gynecology, used when mothers are at risk of preterm delivery between 24 and 34 weeks of pregnancy at a dose of 2 12 mg intramuscularly), the
Table I – Periventricular leukomalacia according to de Vries criteria Grade I
II
III
IV
Cranial ultrasound findings
Number of patients n = 17(%)
Increased periventricular echogenicity persisting more than 7 days Increased periventricular echogenicity developing into small periventricular cysts Increased periventricular echogenicity developing into extensive periventricular, occipital and frontoparietal cysts Increased periventricular echogenicity in deep white matter developing into extensive subcortical cysts
3 (17.6%)
6 (35.3%)
6 (35.3%)
2 (11.8%)
way of delivery (vaginal birth vs. cesarean section), delivery in (inborn) or outside (out born) third-level hospitals, placental abruption (partial or total). 2. Neonatal: gender, gestational age (GA; weeks), birth weight (BW; grams), intrauterine growth restriction (IUGR; defined as birth weight under 3rd percentile), birth asphyxia (defined as APGAR score less than 6 at 10 min and pH < 7.0 or blood base excess (BE) < 15 mmol/l in cord blood); intrauterine infection, kind of respiratory ventilation (invasive or non-invasive), hypotension therapy (defined as mean blood pressure below value corresponding to neonate's gestational age with pre-existing symptoms of hypotension such as blood circulation disorders, delayed capillary return, oliguria, metabolic acidosis) in the first 7 days of life (supply of crystalloid (bolus 10–15 ml/kg) and/or catecholamines), metabolic acidosis therapy with the use of NaHCO3 in the first 7 days of life (when the blood pH <7.2 and/or BE < 10), occurrence and the final degree of IVH by Papille scale (Grade I – bleeding only in the germinal matrix; II – bleeding inside the ventricles; III – ventricles enlarged by the accumulated blood; IV – bleeding extends into the brain tissue around the ventricles) [8] and the presence of post-hemorrhagic hydrocephalus. Baseline characteristic of enrolled infants is shown in Table II.
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Statistical analysis
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Chi-square test without or with Yates correction was applied for comparisons of dichotomous variables, where appropriate. The odds ratio (OR) and 95% confidence intervals (95% CI) were calculated for statistically significant variables. Unconditional logistic regression analysis was used to adjust for the effect of confounders such as gender, GA, BW; intrauterine growth restriction (IUGR), birth asphyxia, intrauterine infection; respiratory ventilation, hypotension, acidosis, IVH, post-hemorrhagic hydrocephalus (PHH), maternal age, cigarettes, maternal hypertension, cervical incompetence, premature rupture of membranes (PROM), prenatal
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Please cite this article in press as: Szpecht D, et al. Risk factors of periventricular leukomalacia in singleton infants born from 23rd to 26th weeks of gestation – Retrospective study. Pediatr Pol. (2017), http://dx.doi.org/10.1016/j.pepo.2017.02.002
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Table II – Baseline characteristic of enrolled infants Group with PVL (N = 17; 14.8%)
110 111 112 113 114 115 116 117
118 119 120 121 122 123 124 125 126 127 128 129 130 131 132 133 134 135 136
137 138 139 140 141 142 143 144 145 146 147 148 149 150 151 152 153 154
Maternal Maternal age <25 25–35 >35 Cigarettes Yes No Hypertension Yes No Cervical incompetence Yes No PROM Yes No Prenatal steroids Yes No Mode of delivery Vaginal Cesarean section Third level hospital Outborn Inborn Placental abruption Yes No Neonatal Gender Male Female Gestational age (week) 23–24 25–26 Birth weight (gram) <750 750–1000 >1000 IUGR Yes No Asphyxia Yes No Intrauterine infection Yes No Respiratory ventilation Non-invasive Conventional Hypotension therapy Yes No Acidosis therapy Yes No IVH No I II III
Group without PVL (N = 98; 85.2%)
Table II (Continued ) p
5 (29.4%) 10 (58.8%) 2 (11.8%)
16 (16.3%) 69 (70.4%) 13 (13.3%)
0.435
3 (17.6%) 14 (82.4%)
5 (5.1%) 93 (94.9%)
0.174
0 (0.0%) 17 (100%)
5 (5.1%) 93 (94.9%)
1.000
2 (11.8%) 15 (88.2%)
15 (15.3%) 83 (84.7%)
0.992
1 (5.9%) 16 (94.1%)
9 (9.2%) 89 (90.8%)
0.984
12 (70.6%) 5 (29.4%)
72 (73.5%) 26 (26.5%)
0.961
12 (70.6%) 5 (29.4%)
57 (58.2%) 41 (41.8%)
0.486
6 (35.3%) 11 (64.7%)
14 (14.3%) 84 (85.7%)
0.035
2 (11.8%) 15 (88.2%)
6 (6.1%) 92 (93.9%)
0.743
9 (52.9%) 8 (47.1%)
53 (54.1%) 45 (45.9%)
0.860
5 (29.4%) 12 (70.6%)
25 (25.5) 73 (74.5%)
0.969
7 (41.2%) 7 (41.2%) 3 (17.6%)
27 (27.5%) 53 (54.1%) 18 (18.4%)
0.503
1 (5.9%) 16 (94.1%)
2 (2.0%) 96 (98.0%)
0.926
12 (70.6%) 5 (29.4%)
50 (51.0%) 48 (49.0%)
0.219
10 (58.8%) 7 (41.2%)
46 (46.9%) 52 (53.1%)
0.521
0 (0.0%) 17 (100.0%)
6 (6.1%) 92 (93.9%)
0.590
13 (76.5%) 4 (23.5%)
84 (85.7%) 14 (14.3%)
0.544
15 (88.2%) 2 (11.8%)
87 (88.8%) 11 (11.2%)
0.726
0 0 3 10
0 19 49 23
0.0004
(0.0%) (0.0%) (17.7%) (58.8%)
(0.0%) (19.4%) (50.0%) (23.5%)
IV Hydrocephalus Yes No
Group with PVL (N = 17; 14.8%)
Group without PVL (N = 98; 85.2%)
4 (23.5%)
7 (7.1%)
2 (11.8%) 15 (88.2%)
6 (6.1%) 92 (93.9%)
p
0.743
steroids, mode of delivery, inborn/out-born patients, placental abruption, was used to make adjustment of parameters. A p-value below 0.05 was judged to be statistically significant. Aforementioned statistical calculations were performed using CytelStudio version 10.0, created January 16, 2013 (CytelStudio Software Corporation, Cambridge, USA), and Statistica version 10, 2011 (Stat Soft, Inc., Tulsa, USA).
Results The study included 115 newborns. The average birth weight was 1192.09 663.82 g. In the study group PVL was found in 17 newborns (14.8%). The number of deaths among the patients was 12 (10%), including 2 deaths (2%) of the infants with PVL. Statistical analysis revealed higher incidence of PVL among infants born outside third-level hospitals (OR 7.933 (2.206–35.19); p = 0.0005). In the study group, 95 (82.6%) of the neonates were inborn and 20 (17.4%) outborn. Out of all the children, PVL occurred in 6 (30%) outborn neonates and 11 (11%) inborn neonates (p = 0.035). In addition, PVL occurred significantly more often among children who were diagnosed with III and IV grade of IVH (OR 3.273 (1.042–10.28); p = 0.036) – 14 infants with PVL had III and IV grade of IVH (82.3%, p = 0.0004). Statistical analysis showed no statistically significant relationship between other analyzed risk factors and the occurrence of PVL in the study group.
Discussion The following risk factors for PVL in premature neonates were shown previously: low birth weight [1], maternal cigarette smoking [9], the time interval between PPROM and termination of pregnancy beyond 48 hours [10], intrauterine infection as chorioamonitis or fetal inflammatory response syndrome (FIRS) [10, 11], that was not confirmed in our study. In our analysis, PVL was significantly more common among infants born outside third-level hospitals. The tertiary hospitals are specialized institutions intended for pregnant women at risk of preterm birth and fetal pathology cases. In Poland, these institutions were implemented at the end of 1998. Early prenatal diagnosis allows there quired patient to be transferred quickly, before delivery to such center, where access to the best methods and equipment necessary to reduce mortality and complications among newborns will be provided.
Please cite this article in press as: Szpecht D, et al. Risk factors of periventricular leukomalacia in singleton infants born from 23rd to 26th weeks of gestation – Retrospective study. Pediatr Pol. (2017), http://dx.doi.org/10.1016/j.pepo.2017.02.002
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Among the many risk factors of PVL examined in our study, childbirth outside the third-level hospitals significantly increases risk of this pathology. Similar conclusions were reached by Boland et al. in their trial involving 541 live births between 22nd and 27th week of pregnancy. Outborn newborns had an increased risk of PVL in comparison to inborn newborns. At the same time, it is worth noting that these studies showed no influence of the place of birth on increased mortality [12]. The above relation has not been shown in studies of Palmer et al. on 898 infants, of whom 61 newborns were diagnosed with PVL. Among infants with PVL, we did not observe a higher incidence of this pathology in the outborn group [13]. Arad et al. in a study of 150 infants with extremely low birth weight inborns and outborns showed no higher incidence of PVL in any group [14]. Similar conclusions were reached by Baud et al. on 702 inborn and outborn infants [15]. It should be noted, however, that the above studies, which results are different from those obtained by us, come from previous years (2000, 2005, 2008). This may be due to the considerable progress not only in the neonatal care in tertiary hospitals, but also in the improvement of antenatal care (transport of fetus in utero in case of risk of preterm labor or antenatal steroid therapy). In a study published by Hasselager et al., the quality of neonatal care of newborns born between 22th and 28th week of pregnancy in the tertiary hospital was compared before and after a few years since the implementation of referral hospitals. There was a significant decrease in the frequency of IVH in tertiary centers in the years since the introduction of reform. However, no such relation was observed in the case of bronchopulmonary dysplasia (BPD) and PVL [16]. At this point, it is worth quoting the results of the study EPICE, including patients from 19 regions in 11 European countries. The impact of the procedures associated with the care of prematurely born newborns on mortality and neonatal morbidity was assessed. The study included 7336 patients born between 24 and 31 + 6 week of pregnancy. The procedures were: birth in hospital with neonatal care, prenatal intake of steroids, effective prevention of hypothermia and supply of surfactant during 2 hours after birth or early initiation of ventilation positive pressure in infants born before 28 week of pregnancy. In newborns who have used all four procedures (58.3% of the study population) reported a lower mortality and morbidity (including PVL) than in infants who received up to 3 of them [17]. In our study group PVL occurred significantly more often among children diagnosed with III and IV grade of IVH. Kusters et al. revealed in their study, that other factors increase the risk of co-occurrence of IVH grade III and PVL and other IVH grade IV and PVL. For the first group there are such dependencies as high frequency ventilation, ventilation with the use of continuous positive airway pressure, patent ductus arteriosus, the use of steroids in the postnatal period and bronchopulmonary dysplasia. The co-occurrence of IVH grade IV and PVL predispose ventilation using continuous positive airway pressure, oxygen therapy after 28th day of birth and late-onset sepsis [18]. Wang et al. study demonstrated that the occurrence of isolated PVL is primarily associated with neonatal sepsis, while the cooccurrence of PVL with low degrees of IVH (I and II) is
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associated with a low Apgar score at 5 minutes and prolonged mechanical ventilation. Coexistence of PVL with IVH, compared to an isolated PVL, worsens the prognosis on neurological development. Coexistence of PVL with IVH, compared to an isolated PVL, worsens the prognosis on neurological development – cerebral palsy (CP) occurred among 63.1% infants with cPVL and without IVH, 73.8% infants with low-grade IVH and 88.4% infants with highgrade IVH [19]. It is worth considering that if the PVL is more common in outborn newborns and those with IVH higher degrees, whether it may be observed the significant relationship in the incidence of IVH in preterm inborn or outborn infants. In our previous study, including group of 110 inborn and outborn infants born between 23 and 26 weeks’ gestation, which is mostly the same group, especially taking into account the gestational age, as in our present study of risk factors for PVL, no significant difference in the incidence of IVH among outborn and inborn infants was revealed [20].
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Conclusion
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1. Delivery in the third-level hospital reduces the incidence of PVL. 2. IVH prevention based on excellent neonatal care, welltrained staff and a high level of procedures used in tertiary centers, as well as adequate prenatal care appears to be crucial in the prevention of IVH and significantly reduces the risk of PVL. 3. The development of procedures and neonatal care raises our hope for the future, with the expectation to reduce the incidence of PVL in premature infants.
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Authors’ contributions/ Wkład autorów
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DS – study design, data collection and interpretation, statistical analysis, literature search. KW, AB – study design, data interpretation, literature search. ES – study design. MS, JG – acceptance of final manuscript version.
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Conflict of interest/ Konflikt interesu
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None declared.
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Financial support/ Finansowanie
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None declared.
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Ethics/ Etyka
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The work described in this article has been carried out in accordance with The Code of Ethics of the World Medical Association (Declaration of Helsinki) for experiments involving humans; EU Directive 2010/63/EU for animal
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Please cite this article in press as: Szpecht D, et al. Risk factors of periventricular leukomalacia in singleton infants born from 23rd to 26th weeks of gestation – Retrospective study. Pediatr Pol. (2017), http://dx.doi.org/10.1016/j.pepo.2017.02.002
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experiments; Uniform Requirements for manuscripts submitted to Biomedical journals.
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[11] Hofer N, Kothari R, Morris N, Müller W, Resch B. The fetal inflammatory response syndrome is a risk factor for morbidity in preterm neonates. Am J Obstet Gynecol 2013;209(6):542e1–542e11. http://dx.doi.org/10.1016/j. ajog.2013.08.030. [12] Boland RA, Davis PG, Dawson JA, Doyle LW. Outcomes of infants born at 22–27 weeks’ gestation in Victoria according to outborn/inborn birth status. Arch Dis Child – Fetal Neonatal Ed fetalneonatal 2016. http://dx.doi.org/10.1136/ archdischild-2015-310313. [13] Palmer KG, Kronsberg SS, Barton BA, et al. Effect of inborn versus outborn delivery on clinical outcomes in ventilated preterm neonates: secondary results from the NEOPAIN trial. J Perinatol 2005;25:270–275. http://dx.doi.org/10.1038/ sj.jp.7211239. [14] Arad I, Braunstein R, Bar-Oz B. Neonatal outcome of inborn and outborn extremely low birth weight infants: relevance of perinatal factors. Isr Med Assoc J 2008;10: 457–461. [15] Baud O, Zupan V, Lacaze-Masmonteil T, Audibert F, Shojaei T, Thebaud B, et al. The relationships between antenatal management, the cause of delivery and neonatal outcome in a large cohort of very preterm singleton infants. BJOG 2000;107:877–884. http://dx.doi.org/10.1002/0471743984. vse0960. [16] Hasselager AB, Børch K, Pryds OA. Improvement in perinatal care for extremely premature infants in Denmark from 1994 to 2011. Dan Med J 2016;63:1–5. [17] Zeitlin J, Manktelow BN, Piedvache A, Cuttini M, Boyle E, Heijst AV, et al. Use of evidence based practices to improve survival without severe morbidity for very preterm infants: results from the EPICE population based cohort. BMJ 2016;354:i2976. http://dx.doi.org/10.1136/bmj.i2976. [18] Kusters CDJ, Chen ML, Follett PL, Dammann O. “Intraventricular” hemorrhage and cystic periventricular leukomalacia in preterm infants: how are they related? J Child Neurol 2009;24:1158–1170. http://dx.doi.org/10.1177/ 0883073809338064. [19] Wang L-W, Lin Y-C, Tu Y-F, Wang S-T, Huang C-C, for the Taiwan Premature Infant Developmental Collaborative Study Group. Isolated Cystic Periventricular Leukomalacia Differs from Cystic Periventricular Leukomalacia with Intraventricular Hemorrhage in Prevalence, Risk Factors and Outcomes in Preterm Infants. Neonatology 2016;111:86–92. http://dx.doi.org/10.1159/000448615. [20] Szpecht D, Nowak I, Kwiatkowska P, Szymaniiewicz M, Gadzinowski J. Intraventricular hemorrhage in neonates born from 23 to 26 weeks of pregnancy—retrospective analysis of risk factors. Adv in Clin Exp Med 2017 [Epub ahead of print].
Please cite this article in press as: Szpecht D, et al. Risk factors of periventricular leukomalacia in singleton infants born from 23rd to 26th weeks of gestation – Retrospective study. Pediatr Pol. (2017), http://dx.doi.org/10.1016/j.pepo.2017.02.002
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Available online at www.sciencedirect.com
ScienceDirect journal homepage: www.elsevier.com/locate/pepo 1
Original research article/ Artykuł oryginalny
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Risk factors of periventricular leukomalacia in singleton infants born from 23rd to 26th weeks of gestation – Retrospective study
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Dawid Szpecht 1,*, Katarzyna Wiak 2, Anna Braszak 2, Emily Surzyn 2, Marta Szymankiewicz 1, Janusz Gadzinowski 1 1 2
Chair, Department of Neonatology, Poznan University of Medical Sciences, Poland Poznan University of Medical Sciences, Poznan, Poland
article info
abstract
Article history:
Introduction: Periventricular leukomalacia (PVL) is one of the most common hypoxic-
Received: 10.01.2017
ischemic pathologies among preterm newborns. The bracket most vulnerable to PVL are
Accepted: 02.02.2017
newborns born before 34 weeks’ gestation, especially those with very low and extremely
Available online: xxx
low birth weights. In a population of very low birth weight newborns, the frequency of periventricular white matter injury (PWMI) including PVL is 5–15%. The aim of our study
Keywords: Periventricular leukomalalcia Preterm infants
was to verify the potential risk factors of the occurrence of PVL among infants born bet-
Risk factors
tal Intensive Care in the Department of Neonatology, Poznan University of Medical Scien-
ween 23 and 26 weeks’ gestation. Methods: The retrospective study included a group of 115 unrelated infants born between 23 and 26 week's gestation, hospitalized in the Neonaces in 2010–2014, born in the clinic or transported to it after birth in the hospital of lower references. The diagnosis of PVL was based on transcranial ultrasound. Results: PVL was diagnosed in 17 (14.8%), including 5 (29.4%) infants born from 23 to 24 weeks’ gestation and 12 (70.6%) born from 25 to 26 weeks gestation. Higher incidence of PVL was found among infants born outside tertiary hospital (OR 7.933 (2.206–35.19); p = 0.0005) and newborns diagnosed with III and IV intraventricular hemorrhage (IVH) (OR 3.273 (1.042–10.28); p = 0.036). Conclusions: Delivery in the third-level hospital as well as IVH prevention significantly reduces the risk of PVL. Well-developed prenatal care, fetus transport in utero and delivery in the third-level hospital seem to be crucial in the prevention of this pathology. © 2017 Polish Pediatric Society. Published by Elsevier Sp. z o.o. All rights reserved.
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Introduction
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One of the most common hypoxic-ischemic pathologies among preterm newborns is periventricular leukomalacia
(PVL). The frequency of this pathology is inversely proportional to gestational age and birth weight. The most vulnerable bracket is newborns born before 34 weeks’ gestation, especially with very low and extremely low birth weight. In a population of very low birth weight newborns
* Corresponding author at: Department of Neonatology, Poznan University of Medical Sciences, ul. Polna 33, 60-535 Poznań, Poland. Tel.: +48 502145181; fax: +48 618419411. E-mail address: [email protected] (D. Szpecht). http://dx.doi.org/10.1016/j.pepo.2017.02.002 0031-3939/© 2017 Polish Pediatric Society. Published by Elsevier Sp. z o.o. All rights reserved.
Please cite this article in press as: Szpecht D, et al. Risk factors of periventricular leukomalacia in singleton infants born from 23rd to 26th weeks of gestation – Retrospective study. Pediatr Pol. (2017), http://dx.doi.org/10.1016/j.pepo.2017.02.002
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the frequency of periventricular white matter injury (PWMI), including PVL is 5–15% [1]. PVL is a white matter injury (WMI) in the form of nerve tissue necrosis in the border zone of vascularization; this is dorsally and laterally to lateral ventricles. There are four stages of this pathology advancement, from increased periventricular echogenicity to the existence of large cavities, reaching deep into the white matter. WMI is a major cause of cerebral palsy, causing severe disability in motor and intellectual areas, as well as vision and hearing disorders [2–4]. The pathogenesis of PVL is complex. Among the risk factors are: chronic or subacute hypoxia, intrauterine infection, bradycardia, apnea, hypotension, and anemia. It often occurs in infants born to mothers with diabetes and prepregnancy obesity. PVL generally coexists with III and IV degree of intraventricular hemorrhage (IVH) and is located around post hemorrhagic changes [2, 5]. The aim of our study was to analyze of potential risk factors of PVL among newborns born between 23 and 26 weeks’ gestation.
39
Material and methods
40
The study population
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The study included infants born between 23 and 26 weeks’ gestation, and hospitalized in Neonatal Intensive Care in the Department of Neonatology University of Medical Sciences in 2010–2014, born in the same clinic or transported to it after birth. The study included 115 unrelated newborns. The study did not include infants born in a week of pregnancy other than 23–26 weeks, newborns from multiple pregnancies, pregnancies in which there was a death of one of the fetuses, infants with chromosomal aberrations and TORCH group intrauterine infections.
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Periventricular leukomalacia – definition
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The diagnosis of PVL was based on transcranial ultrasound, which was performed in accordance with local standards, based on the guidelines of Polish Neonatal Society – transcranial ultrasound was performed on 1st day of life, the 3rd, and the 7th day of life, and further research depending on the extent of changes found in previous studies. In newborns diagnosed with III and IV grade of IVH, ultrasound was performed at least once a week and after diagnosis of ventricle expansion; every 3 days [6]. Periventricular leukomalacia was defined according to de Vries criteria (Table I) [7].
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Risk factors
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The analysis included following potential risk factors of PVL: 1. Maternal: mother's age, maternal cigarette smoking during pregnancy, mother's hypertension, cervical incompetence, premature rupture of membranes (PROM), antenatal steroidotherapy (according to the recommendation of the Polish Society of Gynecology, used when mothers are at risk of preterm delivery between 24 and 34 weeks of pregnancy at a dose of 2 12 mg intramuscularly), the
Table I – Periventricular leukomalacia according to de Vries criteria Grade I
II
III
IV
Cranial ultrasound findings
Number of patients n = 17(%)
Increased periventricular echogenicity persisting more than 7 days Increased periventricular echogenicity developing into small periventricular cysts Increased periventricular echogenicity developing into extensive periventricular, occipital and frontoparietal cysts Increased periventricular echogenicity in deep white matter developing into extensive subcortical cysts
3 (17.6%)
6 (35.3%)
6 (35.3%)
2 (11.8%)
way of delivery (vaginal birth vs. cesarean section), delivery in (inborn) or outside (out born) third-level hospitals, placental abruption (partial or total). 2. Neonatal: gender, gestational age (GA; weeks), birth weight (BW; grams), intrauterine growth restriction (IUGR; defined as birth weight under 3rd percentile), birth asphyxia (defined as APGAR score less than 6 at 10 min and pH < 7.0 or blood base excess (BE) < 15 mmol/l in cord blood); intrauterine infection, kind of respiratory ventilation (invasive or non-invasive), hypotension therapy (defined as mean blood pressure below value corresponding to neonate's gestational age with pre-existing symptoms of hypotension such as blood circulation disorders, delayed capillary return, oliguria, metabolic acidosis) in the first 7 days of life (supply of crystalloid (bolus 10–15 ml/kg) and/or catecholamines), metabolic acidosis therapy with the use of NaHCO3 in the first 7 days of life (when the blood pH <7.2 and/or BE < 10), occurrence and the final degree of IVH by Papille scale (Grade I – bleeding only in the germinal matrix; II – bleeding inside the ventricles; III – ventricles enlarged by the accumulated blood; IV – bleeding extends into the brain tissue around the ventricles) [8] and the presence of post-hemorrhagic hydrocephalus. Baseline characteristic of enrolled infants is shown in Table II.
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Statistical analysis
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Chi-square test without or with Yates correction was applied for comparisons of dichotomous variables, where appropriate. The odds ratio (OR) and 95% confidence intervals (95% CI) were calculated for statistically significant variables. Unconditional logistic regression analysis was used to adjust for the effect of confounders such as gender, GA, BW; intrauterine growth restriction (IUGR), birth asphyxia, intrauterine infection; respiratory ventilation, hypotension, acidosis, IVH, post-hemorrhagic hydrocephalus (PHH), maternal age, cigarettes, maternal hypertension, cervical incompetence, premature rupture of membranes (PROM), prenatal
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Please cite this article in press as: Szpecht D, et al. Risk factors of periventricular leukomalacia in singleton infants born from 23rd to 26th weeks of gestation – Retrospective study. Pediatr Pol. (2017), http://dx.doi.org/10.1016/j.pepo.2017.02.002
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Table II – Baseline characteristic of enrolled infants Group with PVL (N = 17; 14.8%)
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137 138 139 140 141 142 143 144 145 146 147 148 149 150 151 152 153 154
Maternal Maternal age <25 25–35 >35 Cigarettes Yes No Hypertension Yes No Cervical incompetence Yes No PROM Yes No Prenatal steroids Yes No Mode of delivery Vaginal Cesarean section Third level hospital Outborn Inborn Placental abruption Yes No Neonatal Gender Male Female Gestational age (week) 23–24 25–26 Birth weight (gram) <750 750–1000 >1000 IUGR Yes No Asphyxia Yes No Intrauterine infection Yes No Respiratory ventilation Non-invasive Conventional Hypotension therapy Yes No Acidosis therapy Yes No IVH No I II III
Group without PVL (N = 98; 85.2%)
Table II (Continued ) p
5 (29.4%) 10 (58.8%) 2 (11.8%)
16 (16.3%) 69 (70.4%) 13 (13.3%)
0.435
3 (17.6%) 14 (82.4%)
5 (5.1%) 93 (94.9%)
0.174
0 (0.0%) 17 (100%)
5 (5.1%) 93 (94.9%)
1.000
2 (11.8%) 15 (88.2%)
15 (15.3%) 83 (84.7%)
0.992
1 (5.9%) 16 (94.1%)
9 (9.2%) 89 (90.8%)
0.984
12 (70.6%) 5 (29.4%)
72 (73.5%) 26 (26.5%)
0.961
12 (70.6%) 5 (29.4%)
57 (58.2%) 41 (41.8%)
0.486
6 (35.3%) 11 (64.7%)
14 (14.3%) 84 (85.7%)
0.035
2 (11.8%) 15 (88.2%)
6 (6.1%) 92 (93.9%)
0.743
9 (52.9%) 8 (47.1%)
53 (54.1%) 45 (45.9%)
0.860
5 (29.4%) 12 (70.6%)
25 (25.5) 73 (74.5%)
0.969
7 (41.2%) 7 (41.2%) 3 (17.6%)
27 (27.5%) 53 (54.1%) 18 (18.4%)
0.503
1 (5.9%) 16 (94.1%)
2 (2.0%) 96 (98.0%)
0.926
12 (70.6%) 5 (29.4%)
50 (51.0%) 48 (49.0%)
0.219
10 (58.8%) 7 (41.2%)
46 (46.9%) 52 (53.1%)
0.521
0 (0.0%) 17 (100.0%)
6 (6.1%) 92 (93.9%)
0.590
13 (76.5%) 4 (23.5%)
84 (85.7%) 14 (14.3%)
0.544
15 (88.2%) 2 (11.8%)
87 (88.8%) 11 (11.2%)
0.726
0 0 3 10
0 19 49 23
0.0004
(0.0%) (0.0%) (17.7%) (58.8%)
(0.0%) (19.4%) (50.0%) (23.5%)
IV Hydrocephalus Yes No
Group with PVL (N = 17; 14.8%)
Group without PVL (N = 98; 85.2%)
4 (23.5%)
7 (7.1%)
2 (11.8%) 15 (88.2%)
6 (6.1%) 92 (93.9%)
p
0.743
steroids, mode of delivery, inborn/out-born patients, placental abruption, was used to make adjustment of parameters. A p-value below 0.05 was judged to be statistically significant. Aforementioned statistical calculations were performed using CytelStudio version 10.0, created January 16, 2013 (CytelStudio Software Corporation, Cambridge, USA), and Statistica version 10, 2011 (Stat Soft, Inc., Tulsa, USA).
Results The study included 115 newborns. The average birth weight was 1192.09 663.82 g. In the study group PVL was found in 17 newborns (14.8%). The number of deaths among the patients was 12 (10%), including 2 deaths (2%) of the infants with PVL. Statistical analysis revealed higher incidence of PVL among infants born outside third-level hospitals (OR 7.933 (2.206–35.19); p = 0.0005). In the study group, 95 (82.6%) of the neonates were inborn and 20 (17.4%) outborn. Out of all the children, PVL occurred in 6 (30%) outborn neonates and 11 (11%) inborn neonates (p = 0.035). In addition, PVL occurred significantly more often among children who were diagnosed with III and IV grade of IVH (OR 3.273 (1.042–10.28); p = 0.036) – 14 infants with PVL had III and IV grade of IVH (82.3%, p = 0.0004). Statistical analysis showed no statistically significant relationship between other analyzed risk factors and the occurrence of PVL in the study group.
Discussion The following risk factors for PVL in premature neonates were shown previously: low birth weight [1], maternal cigarette smoking [9], the time interval between PPROM and termination of pregnancy beyond 48 hours [10], intrauterine infection as chorioamonitis or fetal inflammatory response syndrome (FIRS) [10, 11], that was not confirmed in our study. In our analysis, PVL was significantly more common among infants born outside third-level hospitals. The tertiary hospitals are specialized institutions intended for pregnant women at risk of preterm birth and fetal pathology cases. In Poland, these institutions were implemented at the end of 1998. Early prenatal diagnosis allows there quired patient to be transferred quickly, before delivery to such center, where access to the best methods and equipment necessary to reduce mortality and complications among newborns will be provided.
Please cite this article in press as: Szpecht D, et al. Risk factors of periventricular leukomalacia in singleton infants born from 23rd to 26th weeks of gestation – Retrospective study. Pediatr Pol. (2017), http://dx.doi.org/10.1016/j.pepo.2017.02.002
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Among the many risk factors of PVL examined in our study, childbirth outside the third-level hospitals significantly increases risk of this pathology. Similar conclusions were reached by Boland et al. in their trial involving 541 live births between 22nd and 27th week of pregnancy. Outborn newborns had an increased risk of PVL in comparison to inborn newborns. At the same time, it is worth noting that these studies showed no influence of the place of birth on increased mortality [12]. The above relation has not been shown in studies of Palmer et al. on 898 infants, of whom 61 newborns were diagnosed with PVL. Among infants with PVL, we did not observe a higher incidence of this pathology in the outborn group [13]. Arad et al. in a study of 150 infants with extremely low birth weight inborns and outborns showed no higher incidence of PVL in any group [14]. Similar conclusions were reached by Baud et al. on 702 inborn and outborn infants [15]. It should be noted, however, that the above studies, which results are different from those obtained by us, come from previous years (2000, 2005, 2008). This may be due to the considerable progress not only in the neonatal care in tertiary hospitals, but also in the improvement of antenatal care (transport of fetus in utero in case of risk of preterm labor or antenatal steroid therapy). In a study published by Hasselager et al., the quality of neonatal care of newborns born between 22th and 28th week of pregnancy in the tertiary hospital was compared before and after a few years since the implementation of referral hospitals. There was a significant decrease in the frequency of IVH in tertiary centers in the years since the introduction of reform. However, no such relation was observed in the case of bronchopulmonary dysplasia (BPD) and PVL [16]. At this point, it is worth quoting the results of the study EPICE, including patients from 19 regions in 11 European countries. The impact of the procedures associated with the care of prematurely born newborns on mortality and neonatal morbidity was assessed. The study included 7336 patients born between 24 and 31 + 6 week of pregnancy. The procedures were: birth in hospital with neonatal care, prenatal intake of steroids, effective prevention of hypothermia and supply of surfactant during 2 hours after birth or early initiation of ventilation positive pressure in infants born before 28 week of pregnancy. In newborns who have used all four procedures (58.3% of the study population) reported a lower mortality and morbidity (including PVL) than in infants who received up to 3 of them [17]. In our study group PVL occurred significantly more often among children diagnosed with III and IV grade of IVH. Kusters et al. revealed in their study, that other factors increase the risk of co-occurrence of IVH grade III and PVL and other IVH grade IV and PVL. For the first group there are such dependencies as high frequency ventilation, ventilation with the use of continuous positive airway pressure, patent ductus arteriosus, the use of steroids in the postnatal period and bronchopulmonary dysplasia. The co-occurrence of IVH grade IV and PVL predispose ventilation using continuous positive airway pressure, oxygen therapy after 28th day of birth and late-onset sepsis [18]. Wang et al. study demonstrated that the occurrence of isolated PVL is primarily associated with neonatal sepsis, while the cooccurrence of PVL with low degrees of IVH (I and II) is
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associated with a low Apgar score at 5 minutes and prolonged mechanical ventilation. Coexistence of PVL with IVH, compared to an isolated PVL, worsens the prognosis on neurological development. Coexistence of PVL with IVH, compared to an isolated PVL, worsens the prognosis on neurological development – cerebral palsy (CP) occurred among 63.1% infants with cPVL and without IVH, 73.8% infants with low-grade IVH and 88.4% infants with highgrade IVH [19]. It is worth considering that if the PVL is more common in outborn newborns and those with IVH higher degrees, whether it may be observed the significant relationship in the incidence of IVH in preterm inborn or outborn infants. In our previous study, including group of 110 inborn and outborn infants born between 23 and 26 weeks’ gestation, which is mostly the same group, especially taking into account the gestational age, as in our present study of risk factors for PVL, no significant difference in the incidence of IVH among outborn and inborn infants was revealed [20].
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Conclusion
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1. Delivery in the third-level hospital reduces the incidence of PVL. 2. IVH prevention based on excellent neonatal care, welltrained staff and a high level of procedures used in tertiary centers, as well as adequate prenatal care appears to be crucial in the prevention of IVH and significantly reduces the risk of PVL. 3. The development of procedures and neonatal care raises our hope for the future, with the expectation to reduce the incidence of PVL in premature infants.
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Authors’ contributions/ Wkład autorów
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DS – study design, data collection and interpretation, statistical analysis, literature search. KW, AB – study design, data interpretation, literature search. ES – study design. MS, JG – acceptance of final manuscript version.
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Conflict of interest/ Konflikt interesu
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None declared.
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Financial support/ Finansowanie
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None declared.
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Ethics/ Etyka
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The work described in this article has been carried out in accordance with The Code of Ethics of the World Medical Association (Declaration of Helsinki) for experiments involving humans; EU Directive 2010/63/EU for animal
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Please cite this article in press as: Szpecht D, et al. Risk factors of periventricular leukomalacia in singleton infants born from 23rd to 26th weeks of gestation – Retrospective study. Pediatr Pol. (2017), http://dx.doi.org/10.1016/j.pepo.2017.02.002
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experiments; Uniform Requirements for manuscripts submitted to Biomedical journals.
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Please cite this article in press as: Szpecht D, et al. Risk factors of periventricular leukomalacia in singleton infants born from 23rd to 26th weeks of gestation – Retrospective study. Pediatr Pol. (2017), http://dx.doi.org/10.1016/j.pepo.2017.02.002
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