Original Article ⅢⅢⅢⅢⅢⅢⅢⅢⅢⅢⅢⅢⅢⅢ Antecedents of Clinically Significant Pulmonary Hemorrhage Among Newborn Infants

Thomas M. Berger, MD mature infants and infants with severe intrauterine growth restriction, Elizabeth N. Allred, MS the incidence is as high as 50 per 1000 live births.2 With recent im- Linda J. Van Marter, MD, MPH provements in the survival of increasingly immature infants and the observation that exogenous surfactant treatment might be associated 3 OBJECTIVE: with increased risk of PHs, there has been renewed interest in this To evaluate risk factor profiles associated with clinically significant pul- potentially life-threatening respiratory complication. In very low birth monary hemorrhage (PH) in preterm (PT) and term infants. weight infants, severe PH markedly increases the risk of death or chronic lung disease,4 but does not significantly affect long-term 4,5 STUDY DESIGN: neurodevelopmental outcome in survivors. The pathogenesis of PH Case-control study of all infants with PH cared for in three Harvard- is unknown. affiliated neonatal intensive care units between 1987 and 1994. We initiated this study in an effort to identify risk factors associated with PH, with the ultimate aims of contributing to the under- RESULTS: standing of the pathogenesis of PH and identifying preventive strate- A total of 50 cases of PH occurred in PT infants (gestational age (GA) of gies. Յ34 weeks), and 26 cases occurred in near-term/full-term (NT/FT) infants (GA of Ͼ34 weeks). The median age at the time of PH was 46 METHODS hours among PT infants compared with 6 hours among NT/FT infants. For PT infants, four factors best predicted PH: a GA of between 24 and 26 We conducted a case-control study of clinically significant PHs among weeks and antenatal glucocorticoid treatment reduced the risk (odds infants admitted to the neonatal intensive care units (NICUs) of the ratios (ORs) of 0.7 and 0.3, respectively), whereas requirement for resus- Joint Program in Neonatology in Boston, MA. The study was approved citation with positive pressure ventilation and thrombocytopenia were by the Institutional Review Boards of each participating hospital. associated with increased risk (ORs of 4.3 and 4.0, respectively). Among Eligible infants were born over an 8-year period (1987 to 1994) and the NT/FT infants, the model included three variables: meconium aspi- were admitted to NICUs at one of three hospitals: Children’s Hospital, ration (OR 4.9), requirement for resuscitation with positive pressure Brigham and Women’s Hospital, and Beth Israel Hospital (all in ventilation (OR 2.9), and hypotension (OR 3.5). Boston, MA). The study period spans three different eras of surfactant use at these institutions: the presurfactant era (1987 to 1989), a CONCLUSION: 4-year period of surfactant replacement therapy with a synthetic sur- Antecedent factors and timing of PH differ between PT and NT/FT in- factant (Exosurf Neonatal (dipalmitoylphosphatidyllcholine, hexade- fants, suggesting that the mechanisms contributing to PH are influenced canol, tyloxapol)) (1990 to 1993), and a period during which a natu- by developmental maturity as well as perinatal and neonatal medical ral surfactant (Survanta (beractant)) was used to treat respiratory conditions and interventions. distress syndrome (after 1994). Surfactant was administered to infants Journal of Perinatology 2000; 5:295–300. hospitalized in the study NICUs using a rescue strategy. We defined PH as the presence of hemorrhagic fluid in the tra- chea accompanied by respiratory decompensation requiring increased Ͼ Clinically apparent pulmonary hemorrhage (PH) occurs at a rate respiratory support (i.e., an FIO2 increase of 10%, any increase in of 1 to 12 per 1000 live births.1 In high-risk groups, such as pre- peak inspiratory pressure, and any increase in positive end expiratory

Division of Newborn Medicine (T. M. B., E. N. A., L. J. V.), Department of Pediatrics, Harvard pressure) or intubation within 60 minutes of the appearance of the Medical School, Boston, MA; and Harvard School of Public Health (E. N. A.), Harvard Medical hemorrhagic fluid. All subjects were identified using the list of NICU School, Boston, MA. diagnoses maintained in the Joint Program in Neonatology database. These results were presented in part at the 18th International Symposium on Neonatal In- Medical records of potential cases were reviewed by the principal intensive Care, Milan, Italy, November 6–8, 1998. vestigator (T. M. B.) to confirm that the episodes of PH fulfilled the Address correspondence and reprint requests to Thomas M. Berger, MD, Neonatal and Pedi- atric Intensive Care Unit, Kinderspital Luzern, CH-6000 Luzern 16, Switzerland. E-mail above criteria. A total of 76 cases of PH were identified from the popu- address: [email protected] lation of admissions over the 8-year period. A total of 152 control

infants from the study NICUs were matched with the index cases by Table 1 Characteristics of the Study Population birth year and within a 200-gm birth weight range. Because our study aim was to identify antecedents of PH, data PT infants NT/FT infants (Յ34 weeks) (Ͼ34 weeks) collection focused on the clinical course before the occurrence of the hemorrhage. Data for matched controls were collected for identical Cases Controls Cases Controls ϭ ϭ ϭ ϭ time periods or until NICU discharge, whichever came first. (n 50) (n 98) (n 26) (n 54) Clinical data collected incorporated information regarding ma- GA (weeks) 27 27 38.5 39 ternal and infant demographics, complications of pregnancy, labor, Birth weight (gm) 943 935 3103 3065 and delivery. Initial disease severity was assessed using physiological Weight for GA category data of the first 24 postnatal hours to calculate the score for acute SGA 8 6 0 6 neonatal physiology (SNAP-1).6 Disease severity was again computed AGA 82 93 85 90 for the 24-hour time period immediately preceding the first PH epi- LGA 0 1 15 4 sode (SNAP-2). If PH occurred before 24 hours of age, only one SNAP Male sex 57 53 65 52 Race value was recorded. For infants who received surfactant replacement White 70 65 85 78 therapy, the brand of surfactant and the number of doses given were Black 16 22 4 7 noted. Diagnoses, complications, and therapies relevant to the respira- Latino 8 9 4 11 tory, cardiovascular, and central nervous systems were evaluated. Asian 4 3 4 2 Respiratory and hemodynamic parameters were abstracted from nurs- Other 2 1 3 2 ing and respiratory flow sheets. For infants who died during their GA and birth weight data are median values. All other values are column percentages. SGA, NICU stay, we attempted to determine whether PH was the precipitat- small for GA; AGA, appropriate for GA; LGA, large for GA. ing cause of death. Univariate analyses were performed using the Fisher’s exact test for categorical data and the Wilcoxon rank sum test to compare me- PH occurred later among PT infants on average than among Ͻ dian values. Variables related to PH with a p value of 0.30 and NT/FT infants. The median age at the time of the first PH was 46 variables of prior interest, regardless of statistical significance were hours in PT infants compared with only 6 hours in NT/FT infants selected as potential candidates for multivariate analyses. Multivariate (Figure). Nine PT infants had more than one episode of PH, com- logistic regression analyses were conducted using Stata statistical pared with only one infant in the NT/FT group who had recurrent software, Release 5 (Stata Corporation, College Station, TX), in a hemorrhage. Before the PH, 42% of PT infants received Exosurf and step-down modeling procedure using the likelihood ratio test to 20% received Survanta. Neither the type of surfactant nor the number achieve the model with the smallest number of statistically significant of doses contributed significantly to PH risk after adjusting for other variables. To assess the extent to which illness severity influenced the factors in the multivariate analyses. However, study power to evaluate variables in the models, SNAP scores were introduced into the models, the hypothesis that surfactant treatment was associated with PH risk after determining the best models. was low (0.52). The NT/FT cases had higher SNAP-1 scores than their controls. In RESULTS contrast, SNAP-1 scores did not differ between cases and controls in the PT group. However, PT case infants showed no improvement in Over an 8-year-period (1987 to 1994), 76 cases of PH were identified. SNAP scores over time. This was demonstrated by higher SNAP-2 Gestational age (GA)-specific prevalence showed a bimodal distribu- scores among PT cases than among their matched control subjects tion. Therefore, we chose to conduct separate analyses for each GA (Table 2). Յ group: infants born at 34 weeks’ gestation were analyzed as preterm We conducted logistic regression multivariate modeling sepa- Ͼ (PT) infants, and infants born at 34 weeks’ gestation were consid- rately for each GA group both with and without SNAP as an indicator ered near-term/full-term (NT/FT) infants. A total of 50 cases of PH of severity of illness. A number of antenatal, perinatal, and neonatal occurred among PT infants for whom the median GA was 27 weeks factors were considered as potential confounding factors. In each of and the median birth weight was 943 gm. There were 26 cases among the four models, we tested the candidate confounding factors in a the NT/FT infants whose median GA was 38.5 weeks and median birth step-down approach to achieve the most parsimonious model for each weight was 3103 gm (Table 1). GA group (Table 3). Mortality rates were 38% and 23% for the PT cases the NT/FT cases, respectively. PH was considered to be the principal cause of PT Infants death in 27% of the fatal PT cases and 17% of the fatal NT/FT cases. Among the group of subjects born at Յ34 weeks’ gestation, a variable PH was also judged to be an important contributing factor to mortal- for the youngest gestations (24 to 26 weeks’ gestation) was entered in ity in an additional 53% of fatal PT cases and 17% of fatal NT/FT the logistic regression model to provide an additional adjustment for cases. biologic immaturity. The most parsimonious model included three

296 Journal of Perinatology 2000; 5:295–300 Risk Factors of PH in Newborn Infants Berger et al.

Figure 1. Timing of PH by postnatal age among the two groups of study subjects: those born at Յ34 weeks’ gestation (PT infants) and those born at Ͼ34 weeks’ gestation (NT/FT infants). additional factors: antenatal glucocorticoid treatment, delivery room risk of PH: meconium aspiration increased the risk fivefold, and in- resuscitation with positive pressure ventilation, and a platelet count of fants with hypotension or resuscitation with positive pressure ventila- Ͻ100,000 ϫ 106/liter before the PH. Maternal receipt of a complete tion had three times the risk for PH compared with those without each course of antenatal glucocorticoids was associated with a reduced risk risk factor. Adjustment for SNAP category had a modest effect on the of PH compared with those whose mothers received none or a partial ORs for meconium aspiration and resuscitation with positive pressure course. After adjusting for all other variables in the model, a fourfold ventilation. However, adjusting for SNAP category was associated with increased risk was associated with both thrombocytopenia and the a reduction in the OR for hypotension from 3.5 to 2.0. A prehemor- need for positive pressure ventilation during delivery room resuscita- rhage SNAP score of Ն24 was associated with a fivefold increase in tion. In models including SNAP, scores of Ն24 were associated with the risk of PH, and SNAP scores of 17 to 23 were associated with a five times the risk of PH; scores of 17 to 23 conferred twice the risk, doubling of PH risk, compared with infants whose SNAP scores were compared with scores of Ͻ17. The addition of SNAP to the model did Ͻ17. not change the odds ratio (OR) for antenatal glucocorticoid therapy and only slightly reduced the ORs for thrombocytopenia and positive pressure ventilation. DISCUSSION Case series and autopsy reports, as summarized by Fekete and Nem- NT/FT Infants eth,7 have correlated neonatal PH with a number of conditions, in- The most parsimonious logistic regression model for the subjects born cluding perinatal asphyxia, surfactant deficiency, pneumonia, hypo- at Ͼ34 weeks’ gestation included three variables: meconium aspira- thermia, septicemia, coagulation disorders, congenital heart disease, tion, hypotension, and delivery room resuscitation with positive pres- central nervous system lesions, and oxygen toxicity. Other authors sure ventilation. Each of these factors was associated with increased have extended the list of possible causes to include aspiration of maternal blood,8 intrathoracic gastrogenic cysts,9 intravenous administration of hyperosmolar solutions,10 diffuse pulmonary embolism with Table 2 SNAP-1 and SNAP-2 Scores drug microaggregates,11 and urea cycle defects accompanied by hy- PT infants (Յ34 weeks) NT/FT infants (Ͼ34 weeks) perammonemia.12,13 14 15 Cases Controls p value Cases Controls p value In separate reports Adamson et al. and Cole et al. showed that the lung effluents of infants with PH had low hematocrits and con- SNAP-1 20 19 0.14 25 13 Ͻ0.0001 tained only small molecular weight plasma proteins. They concluded SNAP-2 21 15 Ͻ0.0001 N/A N/A N/A that the lung effluent in most cases of neonatal PH is hemorrhagic 15 SNAP-1 is the SNAP score in the first 24 postnatal hours. SNAP-2 is the SNAP score in the 24 edema rather than whole blood. Because most of their patients suf- hours before the PH (or equivalent time periods for matched controls). SNAP-2 scores were fered some degree of perinatal asphyxia, Cole et al.15 speculated that recorded for only four NT/FT cases because most NT/FT infants experienced their PH within left ventricular failure with a subsequent increase in pulmonary capil- the first postnatal day. Therefore, SNAP-2 and SNAP-1 were identical for most NT/FT infants. lary pressure was the most important precipitating factor.

Journal of Perinatology 2000; 5:295–300 297 Berger et al. Risk Factors of PH in Newborn Infants

Table 3 Final Logistic Regression Models for each GA Group Final multivariate model SNAP-adjusted final model

OR (95% CI) p value OR (95% CI) p value

PI infants GA of 24–26 weeks 0.7 (0.3, 1.5) 0.34 0.5 (0.2, 1.1) 0.10 Antenatal glucocorticoids 0.3 (0.1, 0.7) 0.007 0.3 (0.1, 0.8) 0.02 Resuscitation with positive pressure ventilation 4.3 (1.4, 13.3) 0.01 2.9 (0.9, 9.1) 0.07 Platelet count of Ͻ100,000 ϫ 106/liter 4.0 (1.1, 14.5) 0.09 3.4 (0.9, 13.2) 0.07 SNAP score of 17–23 — — 2.2 (0.7, 6.6) 0.16 SNAP score of Ն24 — — 5.3 (1.7, 15.5) 0.003 NT/FT Infants Meconium aspiration 4.9 (1.5, 15.7) 0.007 4.0 (1.2, 13.6) 0.03 Resuscitation with positive pressure ventilation 2.9 (0.9, 8.8) 0.07 2.6 (0.8, 8.3) 0.10 Hypotension 3.5 (1.2, 10.3) 0.03 2.0 (0.6, 6.8) 0.28 SNAP score of 17–23 — — 2.4 (0.5, 10.8) 0.25 SNAP score of Ն24 — — 5.4 (1.2, 24.4) 0.03

Values are ORs and 95% CIs after adjusting for all other variables in the model.

Almost 20 years later, West et al.16 observed that alveolar overdis- transvascular protein leak appeared to be independent of pulmonary tension combined with high pulmonary capillary pressure caused artery pressure.22 It is conceivable that glucocorticoids induce vascu- breaks in the epithelial/endothelial barrier, resulting in leakage of lar structural or biochemical changes that make pulmonary capillar- hemorrhagic edema fluid into the air spaces. They identified the ies less susceptible to stress failure. The apparent protective influence major forces involved in what they termed stress failure of pulmonary on PH of a very young GA is more challenging to explain. Selective capillaries to be: (1) circumferential tension in the capillary wall pre-PH mortality of the infants who were most immature and criti- resulting from the capillary transmural pressure, (2) surface tension cally ill might explain this observation. Another possibility is that the of the alveolar lining layer, which acts to support the bulging capil- immature infant’s incomplete pulmonary alveolarization, accompa- lary wall, and (3) longitudinal tension of tissue elements in the alveo- nied by wide interstitial spaces, reduces the transfer of hemorrhagic lar wall associated with inflation of the lung.16 They showed that pulmonary edema to air spaces, thus reducing the likelihood of clini- stress failure of pulmonary capillaries is the likely mechanism caus- cal detection. ing high-permeability pulmonary edema, which is typical of neuro- In our study, surfactant replacement therapy, either with Exosurf genic pulmonary edema,17 high-altitude pulmonary edema,18 and or Survanta, did not increase the risk of clinically significant PH. In a even exercise-induced PH observed in race horses.19 We speculate that 1993 meta-analysis of 11 surfactant trials that collected data on the stress failure of pulmonary capillaries might play a role in the patho- occurrence of PH prospectively, Raju and Langenberg3 reported a genesis of PH in the newborn infant. pooled estimate of relative risk for PH with any surfactant therapy of In the majority of our PT cases, PH occurred at the end of the 1.47 (95% confidence interval (CI) of 1.05 to 2.07; p Ͻ 0.05). This second postnatal day (median age 46 hours), closely matching the finding resulted from a significant increase in PHs in trials in which observation made by Tomaszewska et al.5 in a study of 58 very low synthetic surfactants were used in a prevention strategy.3 Data from birth weight infants with PH (median age 40 hours). The need for more recent prospective randomized placebo-controlled surfactant delivery room resuscitation with positive pressure ventilation in this trials confirmed these observations.23–25 Because our study NICUs used group of patients is likely a marker of perinatal depression, lung dis- only a rescue strategy for surfactant treatment, our observation that ease, or extreme immaturity. Mechanical ventilation with its inherent surfactant replacement therapy did not increase the risk of clinically risk of alveolar overdistension might contribute to stress failure of significant PH is consistent with prior studies. pulmonary capillaries by adding pulmonary capillary wall stress Among NT/FT infants, PH occurs shortly after birth: the majority through tension on tissue elements in the alveolar wall.16 of our patients in this category developed PH only 6 hours after birth. Among our PT study subjects, antenatal glucocorticoid therapy Therefore, it is likely that PH among these infants is influenced by and a very immature GA were associated with reduced risk of PH. factors operating in the antenatal and immediate perinatal periods. Glucocorticoid-induced surfactant production20 and reduced capillary The risk factors identified by the multivariate analyses are more com- permeability21 might explain this observation. In a rat model of high- mon after intrauterine hypoxia. An association between meconium altitude pulmonary edema, a dexamethasone-induced reduction in aspiration and PH has been described previously.26,27 Meconium aspi-

298 Journal of Perinatology 2000; 5:295–300 Risk Factors of PH in Newborn Infants Berger et al.

ration frequently is associated with pulmonary hypertension, and neonatal acute physiology. a physiologic severity index for neonatal intensive severe perinatal depression can lead to myocardial dysfunction that care. Pediatrics 1993;91:617–23. raises left atrial and pulmonary venous pressures. Both of these patho- 7. Fekete M, Nemeth A. Neonatal pulmonary haemorrhage, birthweight, gesta- physiological mechanisms increase pulmonary capillary transmural tional age, and intrauterine growth. Acta Paediatr Hung 1985;26:65–73. pressures28 which, according to West’s stress failure hypothesis, might 8. Ceballos R. Aspiration of maternal blood in the etiology of massive pulmonary exceed the strength of the pulmonary capillary wall. hemorrhage in the newborn infant. J Pediatr 1968;72:390–3. SNAP scores were used to ensure that the variables predicting PH did 9. Macpherson RI, Reed MH, Ferguson CC. Intrathoracic gastrogenic cysts: a cause not simply reflect sicker infants. Although some variables did not attain of lethal pulmonary hemorrhage in infants. J Can Assoc Radiol 1973;24:362–9. nominal statistical significance when SNAP was added to the model, the 10. Simmons MA, Palmer W, Fink AG, Blumhagen JA. Neonatal pulmonary hemor- ORs remained elevated, suggesting the variables predict more than severity rhage associated with administration of hyperosmolal solution. Am J Dis Child of illness. Of note, for NT/FT infants, PH was more likely to occur in the 1978;132:208. first 24 hours. Therefore, only SNAP-1 was evaluated. 11. Fenton AC, Tanner MS, Wandless JG. Pulmonary haemorrhage as a complication In summary, PH occurs in both PT and NT/FT newborn infants. of neonatal anaesthesia. Anaesthesia 1988;43:156–7. PH in PT infants occurs later and is associated with a higher mortality 12. Farriaux JP, Ponte C, Pollitt RJ, Lequien P, Formstecher P, Dhondt JL. Carbamyl- rate than PH in NT/FT infants. Results of the multivariate logistic phosphate-synthetase deficiency with neonatal onset of symptoms. Acta Paediatr regression analyses identified distinct risk factor profiles for the two Scand 1977;66:529–34. GA categories. Among PT infants, antenatal glucocorticoids were 13. Plochl E, Bachmann C. Pulmonary hemorrhages in newborn infants with in- found to be protective, whereas the need for delivery room resuscita- born errors of the 1st 2 phases of the urea cycle [in German]. Monatsschr Kinder- tion with positive pressure ventilation and thrombocytopenia were heilkd 1983;131:714–5. associated with increased risk of PH. Stress failure of pulmonary capil- 14. Adamson TM, Boyd RD, Normand IC, Reynolds EO, Shaw JL. Haemorrhagic laries resulting from increased wall stress associated with alveolar pulmonary oedema (“massive pulmonary haemorrhage”) in the newborn. Lan- overinflation, in some instances exaggerated by a bleeding diathesis cet 1969;1:494–5. due to thrombocytopenia, might explain this observation. Among 15. Cole VA, Normand IC, Reynolds EO, Rivers RP. Pathogenesis of hemorrhagic NT/FT infants, meconium aspiration, need for delivery room resusci- pulmonary edema and massive pulmonary hemorrhage in the newborn. Pediat- tation with positive pressure ventilation, and systemic hypotension rics 1973;51:175–87. were significant risk factors. We speculate that, among the NT/FT 16. West JB, Tsukimoto K, Mathieu-Costello O, Prediletto R. Stress failure in pulmo- infants, pulmonary hypertension and myocardial dysfunction after nary capillaries. J Appl Physiol 1991;70:1731–42. intrauterine hypoxia elevate pulmonary capillary pressure, causing 17. West JB, Mathieu-Costello O. High altitude pulmonary edema is caused by stress stress failure and intra-alveolar hemorrhage. Recognition of the dis- failure of pulmonary capillaries. Int J Sports Med 1992;13(Suppl 1):S54–8. tinct risk profiles may help to develop better preventative and thera- 18. West JB, Colice GL, Lee YJ, et al. Pathogenesis of high-altitude pulmonary oe- peutic strategies among PT and NT/FT infants at risk of developing dema: direct evidence of stress failure of pulmonary capillaries. Eur Respir J PH. The finding of a protective effect of antenatal glucocorticoid ther- 1995;8:523–9. apy offers yet another argument for uniform administration of ante- 19. West JB, Mathieu-Costello O. Stress failure of pulmonary capillaries as a mecha- natal glucocorticoids in threatened premature deliveries. nism for exercise-induced pulmonary haemorrhage in the horse. Equine Vet J 1994;26:441–7. References 20. Crowley PA. Antenatal corticosteroid therapy: a meta-analysis of the randomized 1. van Houten J, Long W, Mullett M, et al. Pulmonary hemorrhage in premature trials, 1972 to 1994. Am J Obstet Gynecol 1995;173:322–35. infants after treatment with synthetic surfactant: an autopsy evaluation. The 21. Ikegami M, Jobe AH, Seidner S, Yamada T. Gestational effects of corticosteroids American Exosurf Neonatal Study Group I and the Canadian Exosurf Neonatal and surfactant in ventilated rabbits. Pediatr Res 1989;25:32–7. Study Group [published erratum appears in J Pediatr 1992;120:762]. J Pediatr 22. Stelzner TJ, O’Brien RF, Sato K, Weil JV. Hypoxia-induced increases in pulmonary 1992;120:S40–4. transvascular protein escape in rats: modulation by glucocorticoids. J Clin Invest 2. Sly PD, Drew JH. Massive pulmonary haemorrhage: a cause of sudden unex- 1988;82:1840–7. pected deaths in severely growth retarded infants. Aust Paediatr J 1981;17:32–4. 23. Lotze A, Mitchell BR, Bulas DI, Zola EM, Shalwitz RA, Gunkel JH. Multicenter 3. Raju TN, Langenberg P. Pulmonary hemorrhage and exogenous surfactant study of surfactant (beractant) use in the treatment of term infants with severe therapy: a metaanalysis. J Pediatr 1993;123:603–10. respiratory failure. Survanta in Term Infants Study Group. J Pediatr 1998;132: 4. Pandit PB, O’Brien K, Asztalos E, Colucci E, Dunn MS. Outcome following pul- 40–7. monary haemorrhage in very low birthweight neonates treated with surfactant. 24. McMillan D, Chernick V, Finer N, et al. Effects of two rescue doses of synthetic Arch Dis Child Fetal Neonatal Ed 1999;81:F40–4. surfactant in 344 infants with respiratory distress syndrome weighing 750 to 1249 5. Tomaszewska M, Stork E, Minich NM, Friedman H, Berlin S, Hack M. Pulmo- grams: a double-blind, placebo-controlled multicenter Canadian trial. Canadian nary hemorrhage: clinical course and outcomes among very low-birth-weight Exosurf Neonatal Study Group. J Pediatr 1995;126:S90–8. infants. Arch Pediatr Adolesc Med 1999;153:715–21. 25. Smyth J, Allen A, MacMurray B, et al. Double-blind, randomized, placebo- 6. Richardson DK, Gray JE, McCormick MC, Workman K, Goldmann DA. Score for controlled Canadian multicenter trial of two doses of synthetic surfactant or

Journal of Perinatology 2000; 5:295–300 299 Berger et al. Risk Factors of PH in Newborn Infants

air placebo in 224 infants weighing 500 to 749 grams with respiratory dis- 27. Thibeault DW, Hall FK, Sheehan MB, Hall RT. Postasphyxial lung disease in tress syndrome. Canadian Exosurf Neonatal Study Group. J Pediatr 1995; newborn infants with severe perinatal acidosis. Am J Obstet Gynecol 1984;150: 126:S81–9. 393–9. 26. Pandit PB, Dunn MS, Colucci EA. Surfactant therapy in neonates with respiratory 28. Manohar M. Pulmonary artery wedge pressure increases with high-intensity deterioration due to pulmonary hemorrhage. Pediatrics 1995;95:32–6. exercise in horses. Am J Vet Res 1993;54:142–6.

300 Journal of Perinatology 2000; 5:295–300