Retrospectıve analysıs for newborn ınfants wıth hypoxıc-ıschemıc encephalopathy

Transcription

1 Basic Research Journal of Medicine and Clinical Sciences ISSN Vol. 1(2) pp September 2012 Available online http// Copyright 2012 Basic Research Journal Full Length Research Paper Retrospectıve analysıs for newborn ınfants wıth hypoxıc-ıschemıc encephalopathy Osman Oztekin, Salih Kalay, Gonul Tezel, Mustafa Akcakus, Nihal Oygur Akdeniz University, School of Medicine, Department of Pediatrics, Division of Neonatology, Antalya, Turkey *Corresponding author Tel; Accepted 14, September, 2012 Aim: This study aimed to assess the etiology, clinical and laboratory features and mortality rates of term neonates with hypoxic ischemic encephalopathy in Neonatal Intensive Care Unit of the Akdeniz University, Antalya, Turkey. Methods: Retrospective chart review of newborns with hypoxic ischemic encephalopathy admitted in a tertiary Neonatal Intensive Care Unit, from January 1st, 2006 to December 31st, Data regarding the gender, gestational age, type of delivery, birth weight, signs of fetal distress as tachycardia or bradycardia, APGAR score at the first and fifth minutes, clinical findings, prognosis data and magnetic resonance imaging scans were collected and analyzed. Results: Incidence of hypoxic ischemic encephalopathy was 22.8 per 1000 patients in neonatal intensive care unit. The sex distribution was 39 (51.3%) female and 37 (48.7%) male. The mean gestational age was 38.3±1.2 weeks and mean birth weight was 3140±412 gr. 72.4% of the patients were delivered with a cesarean section and 26.7% with spontaneous vaginal delivery. According to modified Sarnat and Sarnat staging, 32 (42.1%) of the patients were in Stage I, 38 (50%) in Stage II and 6 (7.9%) in Stage III. Five (83.3%) of the patients died in stage III and no patient died in stage I and II. The etiological factors for hypoxic ischemic encephalopathy were found as follows; 68.4% fetal distress, 63.2% traumatic birth and 30.2% placental pathology. Etiological factors related of hypoxic ischemic encephalopathy were found in 52 (68.4%) patients out of 76. Seizures were observed in 6.2% of the patients in stage I, 81.6% in stage II and 100% in stage III. Diffusion-weighted MRI imaging (DWI) showed ischemia in 34.4% of patients with stage I, 44.7% in stage II and 66.7% in stage III. Conventional MR imaging showed injuries in 51.9% of patients with stage I, 71.1% in stage II and 83.3% in stage III. Conclusion: Our study showed that hypoxic-ischemic encephalopathy is mostly related with perinatal risk factors. The incidence of hypoxic ischemic encephalopathy can be reduced by neonatal resuscitation programs and national programs related with follow-up of pregnancies. Keywords: Hypoxic ischemic encephalopaty, newborn, perinatal risk factors INTRODUCTİON Despite major advances in diagnostic and therapeutic improvements, hypoxic-ischemic encephalopathy (HIE), remains a serious condition that causes significant neonatal mortality and morbidity, including long-term neurodevelopmental sequelae of childhood (Lawn et al., 2005). Three clinical stages of HIE are described by the clinical findings (Sarnat and Sarnat, 1976). According to this definition, we know that patients with stage I HIE have an excellent prognosis, but patients with stage III HIE have significantly high mortality and morbidity. Prognosis of the patients with stage II HIE, however, remains hard to define (Nagy et al., 2005). Incidence of HIE is gradually decreasing, owing to the Neonatal Resuscitation Program (NRP) and improved e ducation of the healthcare personnel for postpartum approaches in recent years ( Turkish Neonatal Society 2008). Nevertheless, patients with HIE still impose a considerable burden on neonatal intensive care units. Purpose of this retrospective study is to evaluate the patients diagnosed with HIE in the Neonatal Intensive Care Unit (NICU) of a district hospital, namely, Faculty of Medicine, University of Akdeniz, Antalya, Turkey.

2 Osma et al. 20 MATERİALS AND METHODS Charts of newborns with HIE admitted in NICU of the Akdeniz University, Antalya, Turkey, from January 1 st, 2006 to December 31 st, 2011 were reviewed retrospectively. The diagnosis of HIE was made by the following criteria (Klinger et al., 2005; Shah et al., 2004): 1. At least one of the followings: (a) Apgar scores <5 at 10 minutes, (b) Metabolic acidosis ( Base deficit >-16 meq/l in the cord blood or in the first hour in arterial blood gases), (c) 5 minutes assisted ventilation, or (d) Cesarean section due to fetal distress. 2. Need for assisted ventilation at birth, 3. Lethargy/stupor, hypotonia, weak/absent sucking reflex, abnormal reflexes, 4. At least one more organ involvement in addition to the encephalopathy. Staging of HIE was made by the Sarnat and Sarnat criteria ( Sarnat and Sarnat, 1976). Cases with <37 weeks of gestation, congenital cardiac and structural abnormalities, established metabolic diseases, congenital infections or early sepsis were excluded. HIE stage according to Sarnat and Sarnat, sex, gestational age, birth weight, place of birth, type of delivery, APGAR scores, duration of mechanical ventilation, duration until complete enteral feeding and duration of hospitalization were determined from the charts. Perinatal risk factors of the included patients were determined both by communicating the delivering physician and by revieving the mother s chart. Patients who had clinical convulsions or pathological EEG findings were defined as convulsion (+) and the others were defined as convulsions (-). Results were defined either exitus or discharged ; and discharged patients were defined as with sequel or no sequel, according to their neurological evaluation. Gestational weeks were determined according to the New Ballard Score. The results of conventional brain magnetic resonance imaging (cb MRI) scans and diffusion-weighted brain magnetic resonance imaging (DWI) scans performed within postpartum three days were recorded as involvement (+) or involvement (-) from the patient charts. Patients with axial T1 A, T2 A and FLAIR sequences suggestive of hypoxia in conventional MRI scans were defined as cbmri involvement, and the ones without the sequences suggestive of hypoxia were defined as no cbmri involvement. Patients with limited diffusion suggestive of hypoxia in echoplanar imaging (EPI) and apparent diffusion coefficient (ADC) sequences were defined as DWI involvement, and the ones without the sequences with limited diffusion suggestive of hypoxia were defined as no DWI involvement. RESULTS 3323 patient charts were reviewed for this study. 76 eligible patients with HIE (2.28%) were included. According to Sarnat and Sarnat staging, 32 (42.1%) of the patients were in Stage I, 38 (50%) in Stage II and 6 (7.9%) in Stage III. 40 of them (52.6%) were born in the Hospital of Akdeniz University and 36 (47.4%) were referred from other centers. 39 (51.3%) of the patients were girls and 37 (48.7%) of them were boys. 21 (27.6%) of the babies were born through spontaneous vaginal delivery (SVD) and 55 (72.4%) were through cesarean section. Mean duration of gestation was 39±2 weeks, mean birth weight was 3140±412g, and mean APGAR scores at 1/5. min were 4±1/6±2 (Table 1). The most frequent perinatal risk factors were fetal distress 52 (68.4%), difficult labor 48 (63.2%) and placental pathologies 23 (30%) in the patients with HIE. 17 of the patients (22.3%) had more than one risk factors (Table 2). Convulsions were present in 2 patients (6.2%) with stage I, in 31 patients (81.6%) with stage II, and in 6 patients (100%) with stage III. Durations until complete enteral feeding, of mechanical ventilation, and of hospitalization were 6.5±2.8, 3.1±2.9, and 5.2±6.1 days in stage I; 8.3±4.5, 5.8±5.8, 7.5±10.8 days in stage II; 14±7.5, 41.8±41 ve 14.9±17.1 days in stage III, respectively. Five (83.3%) of the patients died in stage III and no patient died in stage I and II. Total mortality was 5/76 (6. 5%) in all patients with HIE in this study. Percentage of patients with sequel at discharge was 2 (6.2%) in stage I, 24 (63.2%) in stage II, and 1 (16.7%) in stage III, according to their neurological evaluation (Table 3). Diffusion-weighted MRI imaging (D WI) within the postpartum first three days showed ischemia in 11 (34.4%) patients with stage I, 17 (44.7%) in stage II, and 4 (66.7%) in stage III. Conventional MR imaging showed injuries in 14 (51.9%) patients with stage I, 27 (71.1%) in stage II and 5 (83.3%) in stage III (Table 4). DİSCUSSİON Hypoxic-ischemic encephalopathy is an important cause of long-term neurodevelopmental sequelae of childhood. HIE is reported to be responsible of 17% of total mortality and of 15-20% of cerebral palsy in newborns ( Volpe 2008; Evans et al., 2001). The reported incidence of HIE from different studies ranges from about 2.0 to 6.0 per 1000 live births. The incidence of HIE ranges from about 1.0 to 8.0, excluding the estimate from Nigeria (Airede 1991) based on a single hospital series which was 26.2 per 1000 live births. In our study incidence of HIE was 2.28 per 1000 neonatal intensive care unit patients. The difference between hospital and population-based estimates in general,

3 21. Basic res. J. Med. Clin. Sci. Table 1. General characteristics of the patients with HIE Sex, Female Male Birth place, Akdeniz University Others Type of delivery, Normal vaginal birth Cesarean section Duration of gestation (weeks) >40 39 (51.3%) 37 (48.7%) 40 (52.6%) 36 (47.4%) 21 (27.6%) 55 (72.4%) 58 (76.3%) 18 (23.7%) Birth weight (g)* 3140±412 APGAR1*(1. min) 4±1 APGAR5* (5. min) 6±2 HİE Stage (Sarnat&Sarnat), Stage I Stage II Stage III * Mean ± S.D. 32 (42.2%) 38 (50%) 6 (7.8%) Table 2. Established risk factor for the patients with HIE Risk factor n (%) Fetal distress 52 (68.4%) Difficult delivery 48 (63.2%) Placental pathologies 23 (30.2%) Premature rupture of the membranes 12 (15.8%) Interventions for labor 12 (15.8%) Intrauterine growth retardation 11 (14.5%) Table 3. Clinical characteristics of the patients with HIE by the stage Stage I Stage II Stage III Duration until complete enteral feding (days)* 6.5± ±4.5 14±7.5 Duration of mechanical ventilation (days)* 3.1± ± ±41 Duration of hospitalization (days)* 5.2± ± ±17.1 Convulsions, n (%) (+) (-) Result, n (%) Normal Sequel Exitus * Mean ± S.D. 2(6.2%) 30(93.8%) 30 (93.8%) 2 (6.2%) 0 (0%) 31(81.6%) 7(18.4%) 14 (36.8%) 24 (63.2%) 0 (0%) 6(100%) 0(0%) 0 (0%) 1 (16.7%) 5 (83.3%)

4 Osma et al. 22 Table 4. Involvement in cranial imaging of the patients with HIE by the stage Sarnat& DWI cbmri Sarnat Involvement No involvement Involvement No involvement Stage I 11 (34.4%) 21 (65.6%) 14 (51.9%) 13 (48.1%) Stage II 17 (44.7%) 21 (55.3%) 27 (71.1%) 11 (28.9%) Stage III 4 (66.7%) 2 (33.3%) 5 (83.3%) 1 (16.7%) DWI: diffusion-weighted brain magnetic resonance imaging; cbmri: conventional brain magnetic resonance imaging hospital-based incidence tend to be higher than population-based results. This difference is probably mainly due to referral bias since hospital based studies tend to be conducted in referral centres. Whilst some authors specifically excluded out-born cases in the calculation of incidence, referral bias is, however, still likely to be present to some extent because of antenatal referral of complicated pregnancies which are at greater risk of the outcome. American College of Obstetricians and Gynecologists and the Academy of Pediatrics concluded that the best estimate of the incidence of HIE comes from population data and was 1.9 to 3.8 per 1000 in 2003 (Kurinczuk et al., 2010). Neonatal encephalopathy is a clinical syndrome of disturbed neurologic function of the term and near term infant in the early neonatal period, manifested by respiratory difficulties, depression of tone and reflexes, obtundation, and frequently by seizures. It is classified as mild, moderate or severe (or stage I, II and III ) according to the criteria by Sarnat and Sarnat ( Kumar and Brown 2010)). Clinical status determined by Sarnat scale is the most reliable indicator of asphyxia, and Sarnat and Sarnat classification is one of the most frequently used prognostic factors. According to this classification, it is expected that neurological status would be normal in % and 67-80% of the patients with stage I and II, respectively; whereas mortality is expected in 50-89% of patients with stage III and neurological sequelae are expected 100% of the survivors in this stage ( Clotherty and Synder 2008). However, it is demonstrated that various degrees of blindness, deafness, cognitive and behavioral disturbances develop in 40% of all these patients regardless of the stage ( Dixon et al., 2002). Neurological examination was normal in 93.8%, 36.8%, and 0% of the evaluable patients in Sarnat stage I, II and III, respectively, at discharge. Proportions of the patients with sequelae were 6.2%, 63.2%, and 16.7% in Sarnat stage I, II and III, respectively, at discharge. We had a few patients with stage III, and this made difficult to compare our results with the published literature; however, percentages of the cases with nearly normal neurological development, especially in the patients with stage II, were lower than previously reported. We concluded this proportion is lower because many of our patients (47.4%) were referred from other centers and exposured unfavorable factors during the transport process. Hypoxic-ischemic encephalopathy is the most common cause of neonatal seizures. Within 6-12 hours after birth, hypotonia, jitteriness or convulsive activity are observed in 50% of severely affected babies due to cerebral or cortical involvement (Madan et al., 2005). In case of serious asphyxia, seizures might be observed within 2-3 hours after the onset of the incident. Convulsions suggest that HIE is in a moderate or severe stage. Seizures were observed in 6.2% of the patients in stage I, 81.6% in stage II and 100% in stage III. Seizures must be controlled by all means, since they decrease cerebral glucose and high-energy phosphate compounds or cause accumulation of exitotoxic amino acids, therefore increase brain damage. Our patients were given phenobarbital as the first line treatment for the seizures, and if seizures could not have been controlled by phenobarbital, then phenytoin and midazolam were added. Pulmonary involvement might be observed in babies with asphyxia, such as increased pulmonary vascular resistance, pulmonary bleeding, pulmonary edema, hyalen membrane disease due to inadequate surfactant production, or meconium aspiration syndrome. Furthermore, these babies might not have adequate respiration because of respiratory center involvement of the brain. In addition, necrotizing enterocolitis (NEC) is common in babies with asphyxia, and feeding must not be commenced for asphyxic newborns until hearing the intestinal sounds or ensuring that there is no blood in the faeces ( Clotherty and Synder 2008). As expected, durations until complete enteral feeding, of mechanical ventilation, and of hospitalization were gradually delayed with advanced stages. Early diagnosis of acute ischemia is extremely important for minimizing permanent brain damage, and sometimes, for complete prevention from HIE (Twomey et al., 2010). Multiple imaging techniques were tested for timely and accurate diagnosis. Conventional MRI ensures earlier and more accurate information compared to computerized tomography (CT) or ultrasonography (USG). In the study of Hypoxic Ischemic Encephalopaty Task Force of the Turkish Neonatal Society, findings suggestive of hypoxiaischemia were reported in 64.7% of the patients with

5 23. Basic res. J. Med. Clin. Sci. HIE, regardless of the stage ( Turkish Neonatal Society 2008). This percentage is %39.4 in our study, but we consider that evaluating the imaging results by stage would be more appropriate. However, conventional BMRI cannot demonstrate the damaged areas until 8-12 hours. As for diffusion-weighted MRI imaging (DWI), hypoxic-ischemic changes can be determined within the first couple minutes ( Vermeulen et al., 2008). cbmri and DWI performed at early phase correlated with the Sarnat stages in our patients, more the stage, more the involvement. Although, proportion for demonstrating involvement were higher with cbmri (83.3%) than DWI (66.7%) in patients with stage III. In the patients with stage I, cbmri scans were normal in 48.1% and DWI scans were normal in 65.6%. Hypoxic ischemic encephalopathy is a multifactorial disease and the distribution of different causes and causal agents is likely to vary from place to place and over time. Catastrophic intrapartum events including haemorrhage, maternal convulsions, uterine rupture and cord accidents was described in both studies with a similar frequency of 7 8% in the cases. In addition clinically obstructed labour was present in 15% of the cases in Nepal ( Ellis et al., 2000). Evidence of fetal distress in the form of meconium stained amniotic fluid was a risk factor in both data sets. The data from both studies were used to attempt an estimation of the contribution of intrapartum hypoxia to the cases overall. Less than a third (29%) of the cases had evidence of intrapartum hypoxia based on relatively non-specific criteria which have a high false positive predictive value (Badawi et al., 1998) and including Western Australia cases in which a significant intrapartum event is likely to have been associated with recent acute hypoxia; furthermore, of these cases only 4% had no antenatal risk factors identified whereas 25% did. An estimated 30% of cases of HIE in developed countries and 60% of cases in developing countries are associated with evidence of intrapartum hypoxic-ischaemia ( Kurinczuk et al., 2010). An Australian study showed that HIE risk is 5.45-fold higher if the mother was not followed during antenatal period ( Badawi et al., 1998). If a patient s gestational and delivery history is suggestive of asphixia exposure during perinatal period, can give important clues for HIE etiology ( Madan et al., 2005). 68.4% of our patients had fetal distress, 63.2% of them had traumatic birth, 30% of them had placental pathology, 15.8% of them had premature rupture of the membranes, and 14.5% of them had intrauterine growth retardation. Etiological factors related of hypoxic ischemic encephalopathy were found in 52 (68.4%) patients out of 76. This percentage was found as 29% in the study of Hypoxic Ischemic Encephalopaty Task Force of the Turkish Neonatal Society ( Turkish Neonatal Society 2008). Placental pathologies were reported as 6.4% in the same study, but in our study this ratio is much higher (30%). Since fetal distress and difficult labor terms are very familiar with the obstetrician, we might encounter with these frequently in our study. However, high frequency of placental pathologies associated with HIE in our study shows the importance of antenatal follow-up in order to prevent results of perinatal asphixia. High frequency of prenatal and perinatal risk factors in HIE etiology suggests that educational programs such as NRP would not be sufficient alone for preventing HIE. National notification programs about significance of gestational follow-up and encouraging gestational follow-up are very important for preventing HIE. There are numerous risk factors for HIE, and some of which are common in both developing and developed countries. Especially, perinatal risk factors are potentially modifiable risk factors. The management of labour includes particularly the management of labour induction and provision of better antenatal care in the developing country setting (Kurinczuk et al., 2010). HIE etiology is multifactorial, we are trying to control postnatal problems by the NRP. But our study suggests that perinatal risk factors are associated many of the patients with HIE. Inadequate gestational follow-up is a major problem for preventing HIE and its results in developing countries. This area needs further international agendas for early diagnosis and follow-up of perinatal risk factors, in addition to the NRP. REFERENCES Airede AI (1991). Birth asphyxia and hypoxic ischaemic encephalopathy incidence and severity. Ann Trop Paediatr. 11: Badawi N, Kurinczuk JJ, Keogh JM, Alessandri LM, O'Sullivan F, Burton PR (1998). Intrapartum risk factors for newborn encephalopathy: the Western Australia case control study. Br Med J. 317: Clotherty JP, Synder EY (2008). Perinatal Asphyxia. In Manual of Neonatal Care. Eds: Clotherty JP and Stark AR. 6 th ed. Lippincott Williams-Wilkins, p Dixon G, Badawi N, Kurinczuk JJ (2002). Early developmental outcomes after newborn encephalopathy. Pediatrics.109: Ellis M, Manandhar N, Manandhar DS, Costello AM (2000). Risk factors for neonatal encephalopathy in Kathmandu, Nepal, a developing country: unmatched case control study. Br Med J. 320: Evans K, Rigby AS, Hamilton P, Titchiner N, Hall DM (2001). The relationships between neonatal encephalopathy and cerebral palsy: a cohort study. J Obstet Gynaecol. 21: Klinger G, Beyene J, Shah P, Perlman M (2005). Do hyperoxemia and hypocapnia add to the risk of brain injury after intrapartum asphyxia? Arch Dis Child Fetal Neonatal Ed. 90: Kumar S, Brown SP (2010). Obstetric aspects of hypoxic ischemic encephalopathy. Early Human Development. 86; Kurinczuk JJ,White-Koning M, Badawi N (2010). Epidemiology of neonatal encephalopathy and hypoxic ischaemic encephalopathy. Early Human Development. 86; Lawn JE, Cousens S, Zupan J (2005). 4 million neonatal deaths: when? where? why? Lancet. 365: Madan A, Hamrick SEG, Ferriero DM (2005). Central Nervous System Injury and Neuroprotection. In Avery s Disease of the Newborn. Eds: Taeusch HW, Ballard RA, Gleason CA. 8 th ed. Philadelphia, Pennsylvania, USA: Saunders, p Nagy Z, Lindström K, Westerberg H (2005). Diffusion tensor imaging on teenagers, born at term with moderate hypoxic-ischemic encephalopathy. Pediatr Res. 58: Sarnat HB, Sarnat MS (1976). Neonatal encephalopathy following fetal distress: a clinical and electroencephalographic study. Arch

6 Osma et al. 24 Neurol. 33: Shah P, Riphagen S, Beyene J, Perlman M (2004). Multiorgan dysfunction in infants with post-asphyxial hypoxicischemic encephalopathy. Arch Dis Child Fetal Neonatal Ed. 89:152-5 Turkish Neonatal Society Hypoxic Ischemic Encephalopathy Study Group, Turkey (2008). Hypoxic ischemic encephalopathy in neonatal intensive care units of Turkey: risk factors, incidence and short-term prognosis. Çocuk Sağlığı ve Hastalıkları Dergisi. 51: Twomey E, Twomey A, Ryan S, Murphy J, Donoghue VB (2010). MR imaging of term infants with hypoxic-ischaemic encephalopathy as a predictor of neurodevelopmental outcome and late MRI appearances. Pediatr Radiol. 40: Vermeulen RJ, van Schie PE, Hendrik L (2008): Diffusion -weighted and conventional MR imaging in neonatal hypoxic ischemia: twoyear follow-up study. Radiology. 249: Volpe JJ (2008). Neurology of the newborn. 5 th ed. chapter 6. Philadelphia, Pennsylvania, USA: Saunders, p