Prenatal Corticosteroids and Respiratory Distress Syndrome Prevention in Infants less than 35 Weeks of Gestational Age

2014/2015 Patrícia Isabel Azevedo Campos Prenatal Corticosteroids and Respiratory Distress Syndrome Prevention in Infants less than 35 Weeks of Gestational Age março, 2015 Mestrado Integrado em Medicina Área: Neonatologia Tipologia: Dissertação Trabalho efetuado sob a Orientação de: Professora Doutora Maria Hercília Ferreira Guimarães Pereira Areias E sob a Coorientação de: Dr. Gustavo Marcondes Duarte Rocha Trabalho organizado de acordo com as normas da revista: Journal of Pediatric and Neonatal Individualized Medicine Patrícia Isabel Azevedo Campos Prenatal Corticosteroids and Respiratory Distress Syndrome Prevention in Infants less than 35 Weeks of Gestational Age março, 2015 1 Prenatal Corticosteroids and Respiratory Distress Syndrome Prevention in Infants less than 35 Weeks of Gestational Age Patrícia Campos, medical student1; Gustavo Rocha, MD2; Filipa Flor-de-Lima, MD1,2; Hercília Guimarães, MD, PhD1,2 1 Faculty of Medicine of Porto University. Alameda Professor Hernâni Monteiro, 4200-319 Porto, Portugal 2 Neonatal Intensive Care Unit, Department of Pediatrics, Centro Hospitalar São João. Alameda Professor Hernâni Monteiro, 4200-319 Porto, Portugal Corresponding author: Patrícia Campos (mim[email protected]) 2 Abstract Introduction: Preterm delivery is associated with an increased risk of newborn morbidity and mortality. Respiratory distress syndrome (RDS) is the most common comorbidity. It has been proven that this syndrome can be prevented with the administration of prenatal corticosteroids to women at threat of preterm delivery before 35 weeks of gestational age. Aim: To evaluate the risk factors, severity, co-morbidities and mortality of this condition in newborns less than 35 weeks of gestational age and to assess the association between the elapsed time since the administration of the last dose of a full cycle of corticosteroids and the frequency and severity of RDS. Methods: In this descriptive retrospective study were included all newborns below 35 weeks of gestational age born at our center between January 1, 2012 and December 31, 2014 and admitted in Neonatal Intensive Care Unit (NICU). We excluded newborns with major malformations, chromosomopathies, hydrops or congenital TORCH infection. Results: A total of 234 newborns were studied. Eighty-three (35.5%) newborns had RDS and 151 (64.5%) remained without RDS. Prenatal corticosteroids were used in 90.1% of all newborns. When adjusted to the severity of RDS, a higher birth weight and a higher gestational age were associated with a significant reduction in mortality. The use of vasopressor support was significantly associated with an increase of mortality. Conclusion: Clinical chorioamnionitis, placental abruption, abnormal umbilical flow, and caesarean section were more frequent in infants with RDS. The use of peripartum antibiotics was significantly less frequent in infants with RDS. The last dose of a full cycle of prenatal corticosteroids must be given at least 10.5 hours before the delivery to prevent RDS. 3 Keywords: Respiratory distress syndrome, prenatal corticosteroids, preterm birth, newborn, neonatal intensive care unit, risk factors 4 Introduction Preterm delivery is associated with an increased risk of newborn morbidity and death. Respiratory distress syndrome (RDS) is its most common consequence and cause of morbidity in these newborns. [1-3] The administration of prenatal corticosteroids to women at threat of preterm delivery before 35 weeks of gestational age has been proved to prevent RDS by increasing maturation of fetal lung and other tissues. [4, 5]. Prenatal corticosteroids have also been associated to a diminished risk of intraventricular hemorrhage (IVH), necrotizing enterocolitis (NEC), early sepsis and neonatal death. [2, 4] The major benefit of prenatal corticosteroids is observable when delivery occurs between 24 hours and seven days after the beginning of therapy, but the effect seems to be diminished 14 days after the administration. [2-4, 6] The most recent evidences showed that multiple courses were not recommended due to associations with reduced fetal growth, increased risk of adrenal suppression and due to failure to reduce the risk of death. [2, 7, 8] However, according to the 2013 Update of the European Consensus Guidelines on the Management of Neonatal RDS in Preterm Infants, a rescue course can be administered if more than two to three weeks have passed since the first course, in women at threat of preterm delivery and gestational age below 33 weeks. [6] The natural progression of RDS consists of a state of pulmonary insufficiency, caused by a deficiency of surfactant production in fetal lungs with structural immaturity, starting at delivery and followed by an increase in severity throughout the first two days of life. [2, 6]. If not treated, the disease can progress to respiratory failure and sometimes to death of the newborn. [6] Risk factors for this pathology are multiple gestation, maternal diabetes, chorioamnionitis, caesarean section, male sex, fifth minute Apgar score lower than seven, low birth weight and low gestational age. [9, 10] Prenatal corticosteroid therapy and preterm rupture of membranes reduce the risk of RDS. [10] This study aims to evaluate the risk factors, severity, co-morbidities and mortality of RDS in newborns less than 35 weeks of gestational age and to assess if the elapsed time from administration of the last dose of a full cycle of corticosteroids influences the frequency and severity of RDS. 5 Methods The authors performed a descriptive retrospective study of all newborn infants less than 35 weeks of gestational age born between January 1, 2012 and December 31, 2014 at Hospital São João, admitted to the Neonatal Intensive Care Unit (NICU). Those with major malformations, chromosomopathies, hydrops or congenital TORCH (Toxoplasmosis; Others such as syphilis, varicella-zoster or parvovirus B19; Rubella; Cytomegalovirus; and Herpes) infection were excluded. The demographic, prenatal, delivery, and placental data, as well as information regarding evolution in NICU, treatment at discharge and necropsy results of deceased newborns were collected from clinical charts and retrospectively analyzed. RDS was diagnosed by a combination of clinical and radiographic features according to the criteria of the 2013 Update on the European Consensus Guidelines on the Management of Neonatal Respiratory Distress Syndrome in Preterm Infants. [6] These criteria are: (1) PaO2 < 50 mmHg or central cyanosis in room air or a need for supplemental oxygen to maintain PaO2 > 50 mmHg or to maintain oxygen saturation > 85% within the first 24 hours of life and; (2) a chest radiography consistent with RDS (reticulogranular appearance to lung fields with or without low lung volumes and air bronchograms) within the first 24 hours of life. [6] For practical purposes, we classified RDS in grades I to III according to the radiographic results (I - light, slight reticulogranular appearance; II - moderate, reticulogranular appearance with air bronchograms; III – severe, unclear cardiac borders or white lung). [11] Gestational age (completed weeks) was determined by menstrual age in women with regular menstrual cycles, by ultrasonography when a discrepancy of two or more weeks between menstrual age and ultrasonographic age occurred or in the absence of a menstrual date, or by the New Ballard Score in the absence of obstetrical indexes. [12] Intrauterine growth restriction was defined as a birth weight below the 3rd centile of Fenton`s growth charts. [13] Histological chorioamnionitis classification was made according to the method proposed by Blanc WA (stage I: intervilositis, stage II: chorionitis, stage III: chorioamnionitis). [14] Funisitis was defined as polymorphonuclear leukocytes in the wall of umbilical vessels or in Wharton’s jelly. [15] Villitis was diagnosed by the presence of a mononuclear infiltrate in the villous tree. [16] Vasculitis was defined as a polymorphonuclear leukocytes infiltrate in the chorionic or umbilical vessel walls. [17] Bronchopulmonary dysplasia (BPD) was diagnosed when a requirement for supplementary oxygen persisted for at least 28 days after delivery associated to characteristic radiographic features. Classification was according to the National Institutes of Health consensus criteria. [18] Patent ductus arteriosus (PDA) was confirmed by echocardiography with Doppler. [19, 20] NEC was defined by clinical findings, such as feeding intolerance longer than 24 hours and abdominal distention, the presence of radiological features such as intramural air, perforation or meconium plug syndrome or by definitive surgical findings. NEC was classified according to modified Bell staging criteria. [21] IVH was diagnosed when transfontanellar ultrasound showed intraventricular bleeding confined to the periventricular area (grade 1), without ventricular dilatation (grade 2), with ventricular dilatation (grade 3) or with parenchymal involvement (grade 4). [22] Periventricular leukomalacia (PVL) was diagnosed when a hypoechoic cyst in the periventricular white matter was observable in the ultrasound. [22] Retinopathy of prematurity (ROP) was diagnosed and graded by ophthalmologists according to the International Classification of Retinopathy of Prematurity revised. [23] Sepsis was suspected in the presence of positive laboratory findings in patients with suggestive clinical features and diagnosed when a blood culture turned out to be positive. [22] Pneumonia was diagnosed by a combination of clinical and laboratory findings, and a chest radiographic showing patchy infiltrate, granularity, air bronchogram or consolidation. [24] Pneumothorax was suspected by clinical findings and confirmed by a chest radiographic showing air in the pleural space. [25] 12 Conclusion Clinical chorioamnionitis, placental abruption and abnormal umbilical flow are risk factors for RDS. Peripartum antibiotherapy is indirectly related to prevention of RDS. Newborns with RDS have more frequently neonatal co-morbidities, namely BPD, PDA, IVH (≥ grade 3), ROP (≥ grade 2), sepsis, pneumonia, pneumothorax, acute renal failure, thrombocytopenia with platelet transfusion, anemia with red blood cells transfusion and gastroesophageal reflux. A full cycle of prenatal corticosteroids was fundamental to prevent higher grades of severity of RDS. Higher gestational age and birth weight were associated with a significant reduction in mortality. Vasopressor support, on the other hand, was associated with an increased mortality. Delivery in less than 10.5 hours since the last dose of a full cycle of prenatal corticosteroids was associated with a higher risk of onset of RDS, with a sensibility of 80%. A higher risk of onset of moderate to severe RDS occurred in newborns born in less than 6.5 hours since the last dose of a full cycle of prenatal corticosteroids, with 83.3% of sensibility. 13 References 1. Asztalos, E.V., K.E. Murphy, M.E. Hannah, A.R. Willan, S.G. Matthews, A. Ohlsson, E.N. Kelly, S. Saigal, S. Ross, M.F. Delisle, K. Amankwah, P. Guselle, A. Gafni, S.K. Lee, B.A. Armson, R. Sananes, L. Tomat, and Multiple Courses of Antenatal Corticosteroids for Preterm Birth Study Collaborative Group. Multiple courses of antenatal corticosteroids for preterm birth study: 2-year outcomes. Pediatrics, 2010. 126(5): p. e1045-55. 2. Wilms, F.F., J.Y. Vis, D.A. Pattinaja, R.A. Kuin, M.C. Stam, J.M. Reuvers, and B.W. Mol. 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Natl Vital Stat Rep, 2013. 62(8): p. 1-26. 15 Tables and Figures Table 1 – Demographic and prenatal data Total (n=234) RDS (n=83) Without RDS (n=151) p Gender, n (%) Male 134 (57.3) 44 (53.0) 90 (59.6) 0.330* Female 100 (42.7) 39 (47.0) 61 (40.4) 0.330* Birth weight (grams), mean (±SD) 1658 (±578) 1225 (±516) 1896 (±462) <0.0001§ Gestational age (weeks), median (min-max) 32 (23-34) 30 (23-34) 33 (27-34) <0.0001¥ Intrauterine growth restriction, n (%) 39 (16.7) 18 (21.7) 21 (13.9) 0.127* Multiple gestation, n (%) 81 (34.6) 24 (28.9) 57 (37.7) 0.174* Maternal diseases, n (%) Chronic hypertension 23 (9.8) 12 (14.5) 11 (7.3) 0.078* Human Immunodeficiency Virus infection 1 (0.4) 0 1 (0.7) 0.999∞ Hepatitis B infection 2 (0.9) 1 (1.2) 1 (0.7) 0.999∞ Pregnancy complications, (%) Gestational diabetes 21 (9.0) 10 (12.0) 11 (7.3) 0.223* Gestational hypertension 13 (5.6) 3 (3.6) 10 (6.6) 0.390∞ Pre-eclampsia 46 (19.7) 17 (20.5) 29 (19.2) 0.814* HELLP syndrome** 7 (3.0) 4 (4.8) 3 (2.0) 0.249∞ Clinical chorioamnionitis 13 (5.6) 10 (12.0) 3 (2.0) 0.002∞ Placental abruption 21 (9.0) 12 (14.5) 9 (6.0) 0.030* Abnormal umbilical flow 34 (14.5) 29 (22.9) 15 (9.9) 0.007* Hydramnios 7(3.0) 3 (3.6) 4 (2.6) 0.701∞ Oligoamnios 9 (3.8) 5 (6.0) 4 (2.6) 0.286∞ Prenatal Steroids, n (%) 210 (90.1) 74 (90.2) 136 (90.1) 0.965* Betametasone 160 (76.2) 52 (70.3) 108 (79.4) 0.137* Dexametasone 50 (23.8) 22 (29.7) 28 (20.6) 0.175* Full first cycle 146 (69.5) 50 (67.6) 96 (70.6) 0.650* Full rescue cycle 8 (3.8) 2 (2.7) 6 (4.4) 0.715∞ Time between the last dose of a full cycle of steroids and delivery (hours), median (min-max) 75 (1-1148) 59 (1-1148) 81.5 (1-1096) 0.271¥ Positive group β streptococcus screening, n (%) 11 (45.8) 5 (55.6) 6 (40.0) 0.675∞ Premature membrane rupture, n (%) 49 (21.1) 13 (16.0) 36 (23.8) 0.166* Peripartum antibiotics, n (%) 99 (42.3) 27 (32.5) 72 (47.7) 0.025* Placental histology, n (%) Chorioamnionitis 54 (24.3) 25 (30.5) 29 (20.7) 0.101* Funisitis 7 (3.2) 4 (4.9) 3 (2.1) 0.428∞ Vilitis 14 (6.3) 3 (3.7) 11 (7.9) 0.263∞ Vasculitis 18 (8.1) 9 (11.1) 9 (6.4) 0.220* Hemorrhage 1 (0.5) 0 1 (0.7) 0.999∞ Ischemia 97 (43.7) 34 (41.5) 63 (45.0) 0.608* *Chi-square test, ∞Fisher’s exact test, §Independent t test, ¥Mann-Whitney U test ** HELLP syndrome: Hemolysis, elevated liver enzymes and low platelet count Syndrome 16 Table 2 - Delivery and evolution in neonatal intensive care unit Total (n=234) RDS (n=83) Without RDS (n=151) p Delivery, n (%) Vaginal 95 (40.6) 26 (31.3) 69 (45.7) 0.032* C-section 139 (59.4) 57 (68.7) 82 (54.3) 0.032* Apgar score, n (%) 1st min <7 74 (31.6) 47 (56.6) 27 (17.9) <0.0001* 5th min <7 22 (9.4) 17 (20.5) 5 (3.3) <0.0001* Resuscitation, n (%) 96 (41.0) 62 (74.7) 34 (22.5) <0.0001* Early nasal CPAP, n (%) 75 (32.1) 28 (33.7) 47 (31.1) 0.682* Early invasive ventilation, (%) 42 (18.1) 40 (48.8) 0 <0.0001∞ Neonatal morbidities, n (%) Bronchopulmonary dysplasia 15 (6.4) 15 (18.1) 0 <0.0001∞ Patent ductus arteriosus 59 (25.2) 42 (50.6) 17 (11.3) <0.0001* Surgical treatment 6 (10.2) 6 (14.3) 0 0.002∞ Necrotizing enterocolitis (≥ grade 2A) 0 0 0 - Intraventricular hemorrhage (≥ grade 3) 9 (3.9) 7 (8.5) 2 (1.3) 0.010∞ Hydrocephalus 1 (0.4) 1 (1.2) 0 0.355∞ Periventricular leukomalacia 5 (2.2) 3 (3.7) 2 (1.3) 0.346∞ Retinopathy of prematurity (≥ grade 2) 12 (5.2) 11 (13.4) 1 (0.7) <0.0001∞ Sepsis 27 (11.5) 22 (26.5) 5 (3.3) <0.0001* Pneumonia 6 (2.6) 6 (7.2) 0 0.002∞ Pneumothorax 8 (3.4) 8 (9.6) 0 <0.0001∞ Atelectasis 7 (3.0) 7 (8.4) 0 0.001∞ Seizures 3 (1.3) 3 (3.6) 0 0.044∞ Acute renal failure 15 (6.4) 14 (16.9) 1 (0.7) <0.0001∞ Thrombocytopenia with platelet transfusion 16 (6.8) 16 (19.3) 0 <0.0001∞ Anemia with red blood cells transfusion 58 (24.8) 44 (53.0) 14 (9.3) <0.0001* Gastroesophageal reflux 24 (10.3) 17 (20.5) 7 (4.6) <0.0001* Vasopressor support, n (%) 15 (6.4) 14 (16.9) 1 (0.7) <0.0001∞ Vasopressor support (days), median (min-max) 2 (1-25) 2.5 (1-25) 1 (1-1) 0.308¥ Oxygen therapy, n (%) 82 (35.2) 64 (78.0) 18 (11.9) <0.0001∞ Oxygen therapy (days), median (min-max) 4 (1-191) 6 (1-191) 1.5 (1-6) <0.0001¥ Invasive ventilation, n (%) 57 (24.4) 57 (68.7) 0 <0.0001∞ Invasive ventilation (days), median (min-max) 5 (1-88) 5 (1-88) - - Parenteral nutrition, n (%) 175 (76.1) 75 (93.8) 100 (66.7) <0.0001* Parenteral nutrition (days), median (min-max) 9 (1-90) 14 (1-90) 7 (1-20) <0.0001¥ Surfactant, n (%) 67 (28.6) 67 (80.7) 0 <0.0001∞ Doses, median (min-max) 1 (1-5) 1 (1-5) 0 <0.0001¥ First dose of surfactant (hours), median (min-max) 1 (0-24) 1 (0-24) 0 0.441¥ Postnatal iv steroids, n (%) 7 (2.9) 7 (8.4) 0 0.001∞ Bronchodilators, n (%) 11 (4.7) 11 (13.3) 0 <0.0001∞ Inhaled steroids, n (%) 11 (4.7) 11 (13.3) 0 <0.0001∞ Stay in NICU (days), median (min-max) 15 (1-191) 33 (1-191) 11 (1-61) <0.0001¥ Transferred to another NICU, n (%) 59 (25.2) 10 (12.0) 49 (32.5) 0.001* Days until transference, median (min-max) 6 (1-25) 9.5 (2-25) 5 (1-22) 0.092¥ Treatment at discharge, n (%) Bronchodilator 8 (3.4) 8 (9.6) 0 <0.0001∞ Inhaled steroids 12 (5.1) 12 (14.5) 0 <0.0001∞ Oxygen 8 (3.4) 8 (9.6) 0 <0.0001∞ Deceased, n (%) 17 (7.3) 17 (20.5) 0 <0.0001∞ Causes of death, n (%) Intraventricular hemorrhage grade IV 6 (35.3) 6 (35.3) 0 0.647∞ Multiorgan dysfunction 6 (35.3) 6 (35.3) 0 0.647∞ Arrhythmia 1 (5.9) 1 (5.9) 0 0.941∞ Extreme prematurity 1 (5.9) 1 (5.9) 0 0.941∞ Pulmonary hypoplasia 2 (11.8) 2 (11.8) 0 0.882∞ Pulmonary hemorrhage 1 (5.9) 1 (5.9) 0 0.941∞ *Chi-square test, ∞Fisher’s exact test, §Independent t test, ¥Mann-Whitney U test 17 Table 3 - Demographic and clinical characteristics according to severity of RDS Mild RDS (n=35) Moderate RDS (n=32) Severe RDS (n=16) p Gestational age (weeks), median (min-max) 33 (27-34) 31 (24-34) 29 (23-34) 0.014¥ Multiple gestation, n (%) 7 (20.0) 8 (25.0) 9 (56.2) 0.025* Prenatal Steroids, n (%) 33 (94.3) 25 (80.6) 16 (100) 0.082∞ Full first cycle 26 (78.8) 18 (72.0) 6 (37.5) 0.013* Early invasive ventilation, (%) 11 (31.4) 17 (53.1) 12 (75.0) 0.010∞ Neonatal morbidities, n (%) Patent ductus arteriosus with surgical treatment 3 (8.6) 0 3 (18.8) 0.044∞ Periventricular leukomalacia 0 1 (3.2) 2 (12.5) 0.043∞ Thrombocytopenia with platelet transfusion 5 (14.3) 4 (12.5) 7 (43.8) 0.035∞ Vasopressor support, n (%) 1 (2.9) 7 (21.9) 6 (37.5) 0.003∞ Oxygen therapy, n (%) 24 (68.6) 24 (75.0) 16 (100) 0.032∞ Invasive ventilation, n (%) 18 (51.4) 25 (78.1) 14 (87.5) 0.016¥ Surfactant, n (%) 22 (62.9) 29 (90.6) 16 (100) 0.001∞ Doses, median (min-max) 1 (1-2) 1 (1-5) 2 (1-4) 0.044¥ *Chi-square test, ∞Fisher’s exact test, §One-Way ANOVA, ¥Kruskal-Wallis test Agradecimentos À Professora Hercília Guimarães, pela incansável orientação científica, disponibilidade e apoio, fundamentais para a concretização desta dissertação. Ao Dr. Gustavo Rocha e à Dra. Filipa Flor-de-Lima pela orientação científica e apoio na realização deste projeto. Aos restantes elementos da Unidade de Cuidados Intensivos Neonatais do Centro Hospitalar de S. João pelo acolhimento e simpatia demonstrados. À família e amigos por terem demonstrado apoio ao longo de todo o processo de realização deste trabalho. ANEXOS Normas da Revista Journal of Pediatric and Neonatal Individualized Medicine (JPNIM) Parecer da Comissão de Ética para a Saúde e Autorização do Conselho de Administração do Centro Hospitalar de S. João Author Guidelines The Papers must be written in English or Italian and must be original (not published elsewhere in whole or in part). Text Please submit the text in a Word file. Papers length should be generally around 20,000 characters. All acronyms in the text should be expanded at first mention, followed by the abbreviation in parentheses. Please use the following font: Times New Roman, 11 pt. 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