Periventricular Leukomalacia Cases Research Articles

Diagnostic significance of serum erythropoietin as a marker of perinatal brain damage in premature newborns with very low birth weight

The search for promising markers of brain damage in premature newborns is important for the development and optimization of individual diagnostic and therapeutic approaches to neuroprotection in neonatology. Objective: to evaluate the diagnostic significance of serum erythropoietin (sEPO) on the 1st day of life as a marker of perinatal brain damage in premature infants with very low birth weight (VLBW). The study protocol was approved by the Biomedical Research Ethics Committee (Minutes No.12 of 17 November 2016) and the Scientific Council (Minutes No.19 of 29 November 2016) of the National Medical Research Center for Obstetrics, Gynecology and Perinatology named after the Academician V.I. Kulakov of Ministry of Healthcare of the Russian Federation. Written informed consent to the patients' participation in the study was obtained from their parents. The study included 47 premature infants with VLBW born in 2018 at the National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov of the Ministry of Healthcare of the Russian Federation. In these patients, sEPO was determined on the 1st day of life. Depending on the level of sEPO, infants were divided into 3 groups: group 1 – premature infants with VLBW with a low sEPO level on the 1st day of life (< 20 IU/L, n = 24); group 2 – premature infants with VLBW with an average sEPO level of 20–39 IU/L (reference values) (n = 14) – control group; group 3 – premature infants with VLBW with an elevated sEPO level (≥ 40 IU/L, n = 9). We determined the frequency of brain damage, including intraventricular hemorrhages (IVH) and periventricular leukomalacia. sEPO was not correlated with gestational age. In group 1, IVH ≤ Grade II was observed in 4/24 (16.7%) infants; in group 2, IVH ≤ Grade II was observed in 3/14 (21.4%) infants, and 1/14 (7.1%) infant had IVH Grade III; in group 3, IVH ≤ Grade II was noted in 1/9 (11.1%) infant, and IVH Grade III – in 1/9 (11.1%) infant, p > 0.05. There were no cases of periventricular leukomalacia. A high sEPO level on the 1st day of life in premature infants with VLBW was not associated with an increased risk of perinatal brain damage. The clinical value and practical significance of the determination of sEPO on the 1st day of life as a marker of perinatal brain damage in premature infants with VLBW did not demonstrate any benefits. Further studies are required to assess the role of sEPO in predicting neonatal outcomes.

Bovine colostrum to supplement the first feeding of very preterm infants: The PreColos randomized controlled trial

Gut immaturity leads to feeding difficulties in very preterm infants (<32 weeks gestation at birth). Maternal milk (MM) is the optimal diet but often absent or insufficient. We hypothesized that bovine colostrum (BC), rich in protein and bioactive components, improves enteral feeding progression, relative to preterm formula (PF), when supplemented to MM. Aim of the study is to determine whether BC supplementation to MM during the first 14 days of life shortens the time to full enteral feeding (120mL/kg/d, TFF120). This was a multicenter, randomized, controlled trial at seven hospitals in South China without access to human donor milk and with slow feeding progression. Infants were randomly assigned to receive BC or PF when MM was insufficient. Volume of BC was restricted by recommended protein intake (4-4.5g/kg/d). Primary outcome was TFF120. Feeding intolerance, growth, morbidities and blood parameters were recorded to assess safety. A total of 350 infants were recruited. BC supplementation had no effect on TFF120 in intention-to-treat analysis [n (BC)=171, n (PF)=179; adjusted hazard ratio, aHR: 0.82 (95% CI: 0.64, 1.06); P=0.13]. Body growth and morbidities did not differ, but more cases of periventricular leukomalacia were detected in the infants fed BC (5/155 vs. 0/181, P=0.06). Blood chemistry and hematology data were similar between the intervention groups. BC supplementation during the first two weeks of life did not reduce TFF120 and had only marginal effects on clinical variables. Clinical effects of BC supplementation on very preterm infants in the first weeks of life may depend on feeding regimen and remaining milk diet. http://www. gov: NCT03085277.

Case Report: Peripartum periventricular leukomalacia resulting in cerebral palsy associated with placenta previa in Japan

Intrapartum fetal heart rate monitoring abnormalities had been reported to correlate with decreased umbilical artery base excess associated with neonatal seizures. However, we present an infant born at 35 weeks of gestation diagnosed with cerebral palsy associated with periventricular leukomalacia (PVL) without fetal heart rate (FHR) monitoring abnormalities, According to the summary reports of PVL cases published on the home page of the Japan Obstetric Compensation System for Cerebral Palsy (JOCSC)), the percentage of placenta previa without FHR monitoring abnormalities in the cases of PVL was 5.7% (12/209), which seemed to be higher than the total percentage of placenta previa reported in Japan (0.3-0.5%).

Case Report: Peripartum periventricular leukomalacia resulting in cerebral palsy associated with placenta previa in Japan

Intrapartum fetal heart rate monitoring abnormalities had been reported to correlate with decreased umbilical artery base excess associated with neonatal seizures. However, we present an infant born at 35 weeks of gestation diagnosed with cerebral palsy associated with periventricular leukomalacia (PVL) without fetal heart rate (FHR) monitoring abnormalities, According to the summary reports of PVL cases published on the home page of the Japan Obstetric Compensation System for Cerebral Palsy (JOCSC)), the percentage of placenta previa without FHR monitoring abnormalities in the cases of PVL was 5.7% (12/209), which seemed to be higher than the total percentage of placenta previa reported in Japan (0.3-0.5%).

Case Report: Peripartum periventricular leukomalacia resulting in cerebral palsy associated with placenta previa in Japan

Intrapartum fetal heart rate monitoring abnormalities had been reported to correlate with decreased umbilical artery base excess associated with neonatal seizures. However, we present an infant born at 35 weeks of gestation diagnosed with cerebral palsy associated with periventricular leukomalacia (PVL) without fetal heart rate (FHR) monitoring abnormalities, According to the summary reports of PVL cases published on the home page of the Japan Obstetric Compensation System for Cerebral Palsy (JOCSC)), the percentage of placenta previa without FHR monitoring abnormalities in the cases of PVL was 5.7% (12/209), which seemed to be higher than the total percentage of placenta previa reported in Japan (0.3-0.5%).

Placenta previa as a risk factor for antenatal- and peripartum periventricular leukomalacia resulting in cerebral palsy in Japan: a retrospective study

Intrapartum fetal heart rate monitoring abnormalities had been reported to correlate with decreased umbilical artery base excess associated with neonatal seizures. After encountering a child born at 35 weeks of gestation diagnosed with cerebral palsy associated with periventricular leukomalacia (PVL) without fetal heart rate monitoring abnormalities, a review and analysis of summary reports of PVL cases published on the home page of the Japan Obstetric Compensation System for Cerebral Palsy (JOCSC). Based on the case and the review of the reports of PVL cases from JOCSC, placenta previa may be a risk factor for antenatal- and peripartum PVL resulted in cerebral palsy in Japan.

Neonatal outcome in women with preterm premature rupture of membranes (PPROM) between 18 and 26 weeks

Objective: The aim of this study was to identify adverse neonatal outcomes and identifies the predictors of adverse neonatal outcomes in premature rupture of membranes before 26 weeks.Methods: Data were collected between January 2005 and December 2011 from all pregnant women who presented preterm premature rupture of membranes (PPROM) between 18 and 26 complete weeks of gestation and were admitted to one of three Brazilian institutes. The adverse outcomes included mortality or the development of a severe morbidity during the length of stay in the neonatal intensive care unit (NICU). The descriptive statistics of the population were reported. A multiple logistic regression was performed for each predictor of neonatal adverse outcomes. The area under the receiver operating characteristics curves for the birth weight was calculated.Results: Composite adverse outcomes during the NICU stay occurred in 82.1% (n = 23) of the cases and included 33 (54%) neonatal deaths, 19 (67.8%) cases of retinopathy of prematurity (ROP), 13 (46.4%) cases of pulmonary hypoplasia (BPD), 8 (28.5%) cases of periventricular-intraventricular hemorrhage (PIH) and 3 (10.7%) cases of periventricular leukomalacia (PVL). Only 17.8% (n = 5) of the neonates survived without morbidity. The area under the curve for the birth weight was 0.90 (95% IC: 0.81–0.98) for the prediction of mortality.Conclusions: PPROM before 26 weeks has a high morbidity and mortality, and the significant predictors of neonatal mortality and adverse outcomes were antibiotic prophylaxis, latency period, GA at birth and birth weight. Nevertheless, the only independent significant predictor of survival rate was birth weight.

P16.21: Fetal weight and neonatal outcomes in pre‐viable rupture of membranes

The aim of this study was to identify the adverse neonatal outcomes, with an emphasis on mortality, morbidity (considered here as pulmonary hypoplasia, ROP, PVL and PIH) and morbimortality, and to analyze fetal weight as a predictors of adverse neonatal outcomes in pre-viable premature rupture of membranes. Data were collected between January, 2005 and December, 2011 from all of the pregnant women who presented premature rupture of membranes (PROM) between 18 and 26 complete weeks and who were admitted to one of three Brazilian institutes. The adverse outcomes included mortality or the development of a severe morbidity during the lengh of stay in the neonatal intensive care unit (NICU). The descriptive statistics of the population were reported. A multiple logistic regression was performed for fetal weight of neonatal adverse outcomes. The area under the receiver operating characteristics curves for the fetal weight was calculated. Adverse outcomes during the NICU stay occurred in 82.1% (n = 23) of the cases and included 33 (54%) deaths, 19 (67.8%) cases of retinopathy of prematurity (ROP), 13 (46.4%) cases of pulmonary hypoplasia (BPD), 8 (28.5%) cases of periventricular-intraventricular hemorrhage (PIH) and 3 (10.7%) cases of periventricular leukomalacia (PVL). Only 17.8% (n = 5) of the neonates survived without morbidity. The area under the curve for the fetal weight was 0,90 (95% IC: 0.81-0.98) for the prediction of mortality. Fetal weight was identified as an important predictor of neonatal outcome, leading us to conclude that when we choose conservative management for a pre-viable PROM pregnancy, all of the efforts should be focused on prolonging the latency period (for example, through the use of antibiotic prophylaxis) and increasing the birthweight. However, it should be noted that the fetal weight only influences the neonatal mortality and not the morbidity, which remains a concern for these neonates.

12/15-Lipoxygenase Expression Is Increased in Oligodendrocytes and Microglia of Periventricular Leukomalacia

Oxidative stress involving premyelinating oligodendrocytes (OLs) is a major factor in the pathogenesis of preterm white matter injury. In animal and cell culture studies, activation of the lipid-oxidizing enzyme 12/15-lipoxygenase (12/15-LOX) plays a central role as an inflammatory mediator in the pathology of oxidative stress and OL cell death, as well as ischemia and neuronal death. The role of 12/15-LOX, however, is unclear in the developing human brain. The mechanism of 12/15-LOX involves the production of reactive oxygen species through the metabolism of arachidonic acid, as well as direct detrimental effects on organelle membranes. Here we tested the hypothesis that the density of 12/15-LOX-expressing cells is increased in periventricular leukomalacia (PVL). Using immunocytochemistry (ICC) in human paraffin-embedded tissue, 12/15-LOX expression was seen in macrophages of the focally necrotic lesions in the periventricular white matter, as well as in glial cells throughout the surrounding white matter with reactive gliosis. Interestingly, no significant 12/15-LOX expression was detected in neurons in the cerebral cortex overlying the damaged white matter. Using a scoring system from 0 to 3, we assessed the density of 12/15-LOX-expressing cells in diffusely gliotic white matter from 20 to 43 postconceptional (PC) weeks in 19 PVL cases (median = 36 PC weeks) and 10 control (non-PVL) cases (median = 34 PC weeks). The density of 12/15-LOX-positive cells was significantly increased in the diffuse component of PVL (score = 1.17 ± 0.15) compared to controls (score = 0.48 ± 0.21; p = 0.014). Using double-label ICC, 12/15-LOX was observed in PVL in OLs of the O4 and O1 premyelinating stages, as well as in mature OLs as determined with the mature OL marker adenomatous polyposis coli (APC). In addition, 12/15-LOX expression was present in a population of CD68-positive activated microglia. There was no 12/15-LOX expression in reactive astrocytes. Finally we observed terminal deoxynucleotide transferase dUTP nick end-labeling-positive cells within the white matter of PVL that expressed 12/15-LOX and/or within close proximity of 12/15-LOX-positive cells. Our data support a role for 12/15-LOX activation as an inflammatory mediator of injury in PVL, with a contribution of 12/15-LOX to PVL-induced damage to or cell death of OLs, including those at the O1 and O4 stages.

Toll-like receptors in the immature human brain

Toll-like receptors (TLR), found on glial and neuronal cells, are major components of the innate immune system. They act as sensors that recognise pathogen-associated or damage-associate molecular patterns. There is...

Neuron deficit in the white matter and subplate in periventricular leukomalacia

The cellular basis of cognitive abnormalities in preterm infants with periventricular leukomalacia (PVL) is uncertain. One important possibility is that damage to white matter and subplate neurons that are critical to the formation of the cerebral cortex occurs in conjunction with oligodendrocyte and axonal injury in PVL. We tested the hypothesis that the overall density of neurons in the white matter and subplate region is significantly lower in PVL cases compared to non-PVL controls. We used a computer-based method for the determination of the density of microtubule-associated protein 2-immunolabeled neurons in the ventricular/subventricular region, periventricular white matter, central white matter, and subplate region in PVL cases and controls. There were 5 subtypes of subcortical neurons: granular, unipolar, bipolar, inverted pyramidal, and multipolar. The neuronal density of the granular neurons in each of the 4 regions was 54 to 80% lower (p≤0.01) in the PVL cases (n=15) compared to controls adjusted for age and postmortem interval (n=10). The overall densities of unipolar, bipolar, multipolar, and inverted pyramidal neurons did not differ significantly between the PVL cases and controls. No granular neurons expressed markers of neuronal and glial immaturity (Tuj1, doublecortin, or NG2). These data suggest that quantitative deficits in susceptible granular neurons occur in the white matter distant from periventricular foci, including the subplate region, in PVL, and may contribute to abnormal cortical formation and cognitive dysfunction in preterm survivors.

Prenatal diagnosis of cystic periventricular leukomalacia in a full term fetus

Periventricular leukomalacia is a disorder of white matter injury that is frequently found in premature infants and is the major cause of cerebral palsy. However, only a few cases of periventricular leukomalacia have been reported prenatally. Ultrasound investigation of the periventricular region could provide clues for the prenatal diagnosis and prediction of cerebral palsy. Herein, we report a case of cystic periventricular leukomalacia that was diagnosed prenatally and confi rmed postnatally by brain magnetic resonance imaging.

Episodes of hypocarbia and early-onset sepsis are risk factors for cystic periventricular leukomalacia in the preterm infant

BackgroundSeptic 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. AimsTo evaluate risk factors for cystic PVL focussing on the influence of hypocarbia. Study designRetrospective single centre case-control study. SubjectsPreterm infants 24 to 35weeks of gestational age and matched (1:2 for gender, birth year, gestational age and birth weight) controls. Outcome measuresMultivariate analysis of perinatal factors being associated with cystic PVL diagnosed by serial ultrasound examinations. ResultsUnivariate analysis of risk factors revealed lower 5 and 10min 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. 15h, p=.033). Neurodevelopmental follow-up at a median time of 46months was poor showing 88% of the cases having an adverse neurological outcome. ConclusionWe found early-onset sepsis and episodes of hypocarbia within the first days of life being independently associated with PVL.

Assessment of Cortical Visual Impairment in Infants with Periventricular Leukomalacia: a Pilot Event-Related fMRI Study

ObjectiveWe wanted to investigate the usefulness of event-related (ER) functional MRI (fMRI) for the assessment of cortical visual impairment in infants with periventricular leukomalacia (PVL).Materials and MethodsFMRI data were collected from 24 infants who suffered from PVL and from 12 age-matched normal controls. Slow ER fMRI was performed using a 3.0T MR scanner while visual stimuli were being presented. Data analysis was performed using Statistical Parametric Mapping software (SPM2), the SPM toolbox MarsBar was used to analyze the region of interest data, and the time to peak (TTP) of hemodynamic response functions (HRFs) was estimated for the surviving voxels. The number of activated voxels and the TTP values of HRFs were compared. Pearson correlation analysis was performed to compare visual impairment evaluated by using Teller Acuity Cards (TAC) with the number of activated voxels in the occipital lobes in all patients.ResultsIn all 12 control infants, the blood oxygenation level-dependent (BOLD) signal was negative and the maximum response was located in the anterior and superior part of the calcarine fissure, and this might correspond to the anterior region of the primary visual cortex (PVC). In contrast, for the 24 cases of PVL, there were no activated pixels in the PVC in four subjects, small and weak activations in six subjects, deviated activations in seven subjects and both small and deviated activations in three subjects. The number of active voxels in the occipital lobe was significantly correlated with the TAC-evaluated visual impairment (p < 0.001). The mean TTP of the HRFs was significantly delayed in the cases of PVL as compared with that of the normal controls.ConclusionDetermining the characteristics of both the BOLD response and the ER fMRI activation may play an important role in the cortical visual assessment of infants with PVL.

Potential Neuronal Repair in Cerebral White Matter Injury in the Human Neonate

Periventricular leukomalacia (PVL) in the premature infant represents the major substrate underlying cognitive deficits and cerebral palsy and is characterized as focal periventricular necrosis and diffuse gliosis in the immature cerebral white matter. We have recently shown a significant decrease in the density of neurons in PVL relative to controls throughout the white matter, including the subventricular, periventricular, and subcortical regions. These neurons are likely to be remnants of the subplate and/or GABAergic neurons in late migration to the cerebral cortex, both of which are important for proper cortical circuitry in development and throughout adulthood. Here, we tested the hypothesis that intrinsic repair occurs in PVL to attempt to compensate for the deficits in white matter neurons. By using doublecortin (DCX) immunopositivity as a marker of postmitotic migrating neurons, we found significantly increased densities (p < 0.05) of DCX-immunopositive cells in PVL cases (n = 9) compared with controls (n = 7) in the subventricular zone (their presumed site of origin), necrotic foci, and subcortical white matter in the perinatal time-window, i.e. 35-42 postconceptional weeks. These data provide the first evidence suggestive of an attempt at neuronal repair or regeneration in human neonatal white matter injury.

The Cerebral Cortex Overlying Periventricular Leukomalacia: Analysis of Pyramidal Neurons

The role of the cerebral cortex in the cognitive deficits in preterm survivors is poorly understood. Periventricular leukomalacia (PVL), the key feature of encephalopathy of prematurity, is characterized by periventricular necrotic foci and diffuse gliosis in the surrounding cerebral white matter. Here, we tested the hypothesis that reductions in the density of layer I neurons and/or pyramidal neurons in layers III and/or V are associated with PVL, indicating cortical pathology potentially associated with cognitive deficits in long-term survivors. In controls (23 gestational weeks to 18 postnatal months) (n = 15), a lack of significant differences in pyramidal density among incipient Brodmann areas suggested that cytoarchitectonic differences across functional areas are not fully mature in the fetal and infant periods. There was a marked reduction (38%) in the density of layer V neurons in all areas sampled in the PVL cases (n = 17) compared to controls (n = 12) adjusted for postconceptional age at or greater than 30 weeks, when the six-layer cortex is visually distinct (P < 0.024). This may reflect a dying-back loss of somata complicating transection of layer V axons projecting through the necrosis in the underlying white matter. This study underscores the potential role of secondary cortical injury in the encephalopathy of prematurity.

Nitrosative stress and inducible nitric oxide synthase expression in periventricular leukomalacia

Periventricular leukomalacia (PVL) is a lesion of the immature cerebral white matter in the perinatal period and associated predominantly with prematurity and cerebral ischemia/reperfusion as well as inflammation due to maternofetal infection. It consists of focal necrosis in the periventricular region and diffuse gliosis with microglial activation and premyelinating oligodendrocyte (pre-OL) injury in the surrounding white matter. We previously showed nitrotyrosine in pre-OLs in PVL, suggesting involvement of nitrosative stress in this disorder. Here we hypothesize that inducible nitric oxide synthase (iNOS) expression is increased in PVL relative to controls. Using immunocytochemistry in human archival tissue, the density of iNOS-expressing cells was determined in the cerebral white matter of 15 PVL cases [29-51 postconceptional (PC) weeks] and 16 control cases (20-144 PC weeks). Using a standardization score of 0-3, the density of iNOS-positive cells was significantly increased in the diffuse component of PVL (score of 1.8 +/- 0.3) cases compared to controls (score of 0.7 +/- 0.3) (P = 0.01). Intense iNOS expression occurred in reactive astrocytes in acute through chronic stages and in activated microglia primarily in the acute stage, suggesting an early role for microglial iNOS in PVL's pathogenesis. This study supports an important role for iNOS-induced nitrosative stress in the reactive/inflammatory component of PVL.

Thalamic Damage in Periventricular Leukomalacia: Novel Pathologic Observations Relevant to Cognitive Deficits in Survivors of Prematurity

Despite major advances in the long-term survival of premature infants, cognitive deficits occur in 30-50% of very preterm (<32 gestational weeks) survivors. Impaired working memory and attention despite average global intelligence are central to the academic difficulties of the survivors. Periventricular leukomalacia (PVL), characterized by periventricular necrosis and diffuse gliosis in the cerebral white matter, is the major brain pathology in preterm infants. We tested the novel hypothesis that pathology in thalamic nuclei critical for working memory and attention, i.e. mediodorsal nucleus and reticular nucleus, respectively, occurs in PVL. In 22 PVL cases (gestational age 32.5 +/- 4.8 wk) and 16 non-PVL controls (36.7 +/- 5.2 wk) who died within infancy, the incidence of thalamic pathology was significantly higher in PVL cases (59%; 13/22) compared with controls (19%; 3/16) (p = 0.01), with substantial involvement of the mediodorsal, and reticular nuclei in PVL. The prevention of thalamic damage may be required for the eradication of defects in survivors with PVL.

Studies on the Value of Diffusion‐Weighted MR Imaging in the Early Prediction of Periventricular Leukomalacia

Periventricular leukomalacia (PVL) is the most common cerebral injury in premature infants. While cranial ultrasonography and conventional magnetic resonance imaging (MRI) offer little for its early diagnosis, still they are much favored at present. Based on the pathologic mechanism of ischemic cerebral injury in PVL, we attempt to elucidate the effects of diffusion-weighted MR imaging (DWI) for the early diagnosis of PVL. Twelve cases of PVL in premature infants confirmed by MRI examinations were included in the current study. All cases underwent DWI in addition to conventional MR imaging (T1-weighted [T1W] and T2-weighted [T2W]) 7 days, 2 weeks, and 4 approximately 8 weeks after birth, respectively. Initial DWI examination (carried out at an average of 4.5 days after birth) revealed symmetrical and diffuse high signal in bilateral periventricular areas in all cases, while conventional MRI demonstrated normal signal. DWI examination of 2 weeks later showed irregular inhomogeneous signals in cerebral white matter, while conventional MRI revealed hyperintensity on T1WI and slight hypointensity on T2WI in corresponding areas. Four weeks later, DWI revealed various intensities of cystic low signals beside lateral ventricles, while conventional MRI showed hypointensity on T1WI and hyperintensity on T2WI in corresponding lesion, ie, change in cystic PVL. Four months later, conventional MRI evidenced gradual shrink and disappearance of cystic cavity, reduction in cerebral white matter, and ventricle enlargement. Symmetrical, diffuse hyperintensity in both lateral periventricular white matter on DWI was the earliest sign of PVL in premature infants. Imaging abnormalities provided by DWI had a close correlation with the results obtained by conventional MRI performed at the advanced stage of PVL, which suggests that DWI may be an important sequence for the early evaluation of cerebral white matter injury as well as for the prediction of PVL occurrence in premature infants.

Cystic periventricular leukomalacia in preterm infants: An analysis of obstetric risk factors

Objective To identify obstetric risk factors and to elucidate the effect of prolonged rupture of the membranes on the development of cystic periventricular leukomalacia (PVL) in preterm infants. Methods A retrospective case–control study of 95 preterm infants with the diagnosis of PVL and 245 healthy controls matched for gestational age. A total of 52 antenatal, intrapartum and neonatal characteristics were studied by univariate methods and logistic regression. Results Preterm premature rupture of membranes (PPROM) (odds ratio 2.1 [95% CI 1.3–3.4], P = .003), gestational age at PPROM ( P = .025), prolonged rupture of membranes ( P < .0001), administration of tocolytic agents (1.8 [1.1–3.0], P = .019) and antibiotics (1.9 [1.2–3.1], P = .008) were associated with PVL. The use of tocolytic agents > 24 h ( P = .008), prolonged latency between the increase in maternal leukocyte count and birth ( P = .034), spontaneous onset of labor (1.8 [1.0–2.9], P = .026), vaginal delivery (1.7 [1.1–2.8], P = .029) and male gender (1.5 [1.0–2.0], P = .04) were found more frequently in PVL cases. Preeclampsia (0.4 [0.1–0.9], P = .034), hypertension at booking ( P = .009), sonographic IUGR ( P = .020), abnormal blood flow of the umbilical artery ( P = .032) and cesarean section without labor (0.5 [0.3–0.8], P = .006) were found less frequently. In logistic regression analysis, prolonged rupture of the membranes ( P = .748), preeclampsia ( P = .973), the use of antibiotics ( P = .617) and beta-sympathomimetic tocolytic agents ( P = .563) lost statistical significance, whereas birth weight ( P = .036) became significant. Conclusion PPROM and prolonged rupture of the membranes may provoke adverse effects on the neurodevelopmental outcome of the preterm fetus. These findings may have implications on the obstetric management of PPROM beyond 30 weeks of gestation. Cesarean section without labor was less likely associated with the diagnosis of PVL.