[Risk factors on the occurrence and prognosis of neonatal hyaline membrane disease].

OBJECTIVE: To identify risk factors with related to the occurrence and prognosis of neonatal hyaline membrane disease (HMD) and to develop effective measures to prevent and treat the disease. METHODS: A case control (1 : 4 paired) study was undertaken, with 62 neonates with HMD as a case group paired with 248 sick neonates without HMD and respiratory disorders as a control group. The controls were matched with the cases by admission time (+/- 7 d), birth weight (+/- 200 g) and gestational age (+/- 3 d). All of the patients came from the neonatal intensive care unit (NICU) in the West China Second University Hospital from June 2008 to January 2009. Conditional logistic regression analysis was performed to identify risk factors associated with the development and prognosis of HMD. RESULTS: Fetal distress, placenta previa, preeclampsia, placental abruption, maternal diabetes, and multiple births were identified as risk factors associated with the development of HMD, with an OR 10.459, 9.382, 8.884, 7.817, 7.727, and 7.217, respectively (P < 0.05). The Cochran Armitage trend test showed that the mortality of HMD decreased with the increase of gestational age and birth weight (P < 0.05). The mortality of HMD increased significantly in the patients with complication such as pulmonary hemorrhage, respiratory failure, neonatal asphyxia, and gastrointestinal hemorrhage (P < 0.05). CONCLUSION: Prevention of premature birth and treatment with high risk pregnancy and complications can reduce the mortality of HMD.

Reduced incidence of hyaline membrane disease in extremely premature infants following delay of delivery in mother with preterm labor: use of ritodrine and betamethasone.

Data from two groups of infants (24 to 28 weeks' gestational age) excluded from a controlled trial of the use of calf lung surfactant extract for the prevention of hyaline membrane disease are reported. The two groups were excluded from the trial because the mothers had received betamethasone for greater than 24 hours prior to delivery or because, on admission to the hospital, labor was too far advanced for proper informed consent to enter the trial. Attempts were made to delay delivery of threatened premature labor by the use of ritodrine in all mothers without evidence of infection, heavy vaginal bleeding, or severe preeclampsia and to induce surfactant production by maternal injection of betamethasone. A prospective scoring system and respiratory support variables were used to compare the groups. Infants born to mothers who successfully completed this regimen had a 28% incidence of hyaline membrane disease v a 68% incidence in infants in whose mothers it was unsuccessful due to inability to stop advanced labor (P = .001). Inspired oxygen, mean airway pressure, and ventilator rate were lower and the ventilator efficiency index was higher in the treated group during the first 48 hours of life. An aggressive approach to postpone premature delivery and to induce surfactant production by using tocolysis and a regimen of glucocorticoids reduces the incidence of hyaline membrane disease in very premature infants, 24 to 28 weeks' gestation.

Double-blind clinical trial of calf lung surfactant extract for the prevention of hyaline membrane disease in extremely premature infants.

A prospective, double-blind, controlled trial was conducted to determine whether instillation of an exogenous surfactant into the lungs before the first breath could prevent hyaline membrane disease. The surfactant is calf lung lipid extracted from saline lung lavage. Entry was limited to infants who were 24 to 28 weeks' gestation, who were born at Children's Hospital of Buffalo, and whose mothers had not received betamethasone for more than 24 hours before birth. Treated infants received 3 mL (90 mg) of calf lung surfactant extract instilled into their trachea before the first breath; control infants received 3 mL of normal saline. A prospective scoring system and respiratory support variables were used to compare the groups. At 48 hours of age, only two of 14 calf lung surfactant extract-treated infants (14%) had hyaline membrane disease compared with seven of 13 control infants (54%) (P = .033). Inspired oxygen, mean airway pressure, ventilator rate and ventilator efficiency index were also lower in the treated group during the first 48 hours of life (P less than .01 to P less than .001). Calf lung surfactant extract instillation at birth appears to be an effective material and method of preventing hyaline membrane disease in extremely premature infants.

Initial clinical trial of EXOSURF, a protein-free synthetic surfactant, for the prophylaxis and early treatment of hyaline membrane disease.

EXOSURF is a protein-free surfactant composed of 85% dipalmitoylphosphatidylcholine, 9% hexadecanol, and 6% tyloxapol by weight. A single dose of 5 mL of EXOSURF per kilogram body weight, which gave 67 mg of dipalmitoylphosphatidylcholine per kilogram body weight, or 5 mL/kg air was given intratracheally in each of two controlled trials: at birth to neonates 700 through 1350 g (the prophylactic trial, n = 74) or at 4 to 24 hours after birth to neonates greater than 650 g who had hyaline membrane disease severe enough to require mechanical ventilation (the rescue trial, n = 104). In both studies, time-averaged inspired oxygen concentrations and mean airway pressures during the 72 hours after entry decreased significantly (P less than .05) in the treated neonates when compared with control neonates. Thirty-six percent of the treated neonates in the rescue study had an incomplete response to treatment or relapsed within 24 hours, suggesting the need for retreatment in some neonates. In the rescue trial, risk-adjusted survival increased significantly in the treated group. There were no significant differences in intracranial hemorrhages, chronic lung disease, or symptomatic patent ductus arteriosus between control and treated infants in either trial.

Prevention of hyaline membrane disease in premature lambs by apneic oxygenation and extracorporeal carbon dioxide removal.

Hyaline membrane disease is found only in lungs where pulmonary ventilation has been established, i.e. after birth. We delivered eleven fetal lambs of a gestational age of 128-130 days but instead kept their lungs in total apnea and inflated to constant pressure, while removing all metabolically produced carbon dioxide with an extracorporeal membrane lung. Oxygen was provided by the membrane lung, and by apneic oxygenation through the natural lungs. Hence, arterial blood gases remained always normal, without any pulmonary ventilation. After 6-66 h the lungs had sufficiently cleared to allow normal mechanical pulmonary ventilation in 10 our of 11 lambs so treated. In a control group treated with mechanical ventilation alone, five of seven lambs died within the first 24 h of severe hyaline membrane disease.

Effect of corticosteroids and fetomaternal disorders on the L:S ratio.

Hydrocortisone or placebo was administered to 126 women at risk for premature delivery who had immature lecithin:sphingomyelin (L:S) ratios in order to induce early surfactant synthesis. In 70 subjects (37 steroid-treated patients, 33 controls), L:S ratio was determined a second time between 9 hours and 7 days after therapy had been initiated. The treatment group showed a significant increase in the L:S ratio when compared to those who received the placebo. Moreover, patients who had fetomaternal disorders that accelerated or delayed lecithin production were also found to have increased L:S ratios after treatment. Fewer newborns developed respiratory distress syndrome (RDS) in the treatment group than in the control group and those in the former category who were affected by RDS had a milder clinical course.

Acceleration of fetal pulmonary maturity.

Neonatal pulmonary complications attributable to pulmonary immaturity are among the more serious problems attending premature birth. Various observations indicate that glucocorticoids play an important role in the maturation of the fetal lung. Moreover, prenatal maternal administration of corticosteroids has been attended by significantly improved neonatal outcome, including a reduction in the incidences of respiratory distress syndrome (RDS), hyaline membrane disease, and mortality due to intraventricular hemorrhage. Success of treatment is related directly to gestational age, with best results occurring between 30 and 32 weeks' gestation. Significant effects have been reported as early as 28 weeks' and as late as 34 weeks' gestation. The potential maternal and neonatal risks of this therapy have not yet been established. Animal studies using relatively high doses of corticosteroids have resulted in an inhibition of deoxyribonucleic acid (DNA) synthesis and mitosis, leading to profound complications and a rise in fetal mortality. Although follow-up of human subjects has been limited and of short duration, no consistent postnatal effects have been noted. The apparent lifesaving benefits of the treatment, combined with only rare and usually correctable fetal, neonatal, and maternal complications, indicate that the use of corticosteroids for prevention of neonatal respiratory problems may be an important advance in reproductive medicine. It remains to be established, however, what the optimal agent and dose are, and what, if any, are the long-term effects of this therapy.

Drug therapy of the fetus.

The fetus has become an intended object of drug therapy administered through the mother with the successful prevention of hyaline membrane disease with glucocorticoids. Maternal drug treatment has now been undertaken for a variety of fetal problems, including arrhythmias, congestive heart failure, infections, and inborn errors of adrenal metabolism. Interestingly, this planned maternal drug exposure during pregnancy coincided with increasing concerns during the last two decades about inadvertent transplacental exposure of the fetus to licit and illicit drugs. Efforts to direct drug therapy to the fetus have pointed out important gaps in knowledge of the pharmacology of the maternal-placental-fetal-unit (MPFU), whereas other observations illustrated recognized principles of the pharmacology of the MPFU. Many of these principles fit the basic framework of pharmacokinetics: absorption, distribution, metabolism and excretion. Rapid changes in maternal-placental physiology and fetal development during gestation, however, lead to dramatic variations in these processes throughout pregnancy.

Exogenous surfactant therapy in hyaline membrane disease.

Exogenous surfactant therapy appears to offer promise in the treatment and possible prevention of HMD. Laboratory investigations have begun to reveal the molecular basis for surfactant metabolism and the relationship of this complex process to alveolar stability and pulmonary function. There is every reason to encourage clinical investigation with surfactant therapy in parallel with further basic research. Nevertheless, pediatricians must proceed in small steps with carefully designed studies to address specific questions regarding both efficacy and toxicity. Results from various studies must be shared and discussed and every attempt must be made to eventually provide standardized, readily available preparations of known efficacy and toxicity. Efforts by many investigators make it seem probable that this goal will be achieved in the near future.

Increased survival in low birth weight neonates given prophylactic surfactant.

OBJECTIVE: To compare the effectiveness of a prophylactic surfactant treatment strategy (PRO) to the effectiveness of a rescue (RESC) surfactant treatment strategy in patients at high risk for developing hyaline membrane disease (HMD). STUDY DESIGN: We analyzed data from a retrospective cohort consisting of all patients admitted to the neonatal intensive care units at the centers participating in the recently completed Infasurf-Survanta Comparative Trial. To be in the cohort, a patient had to be admitted during the trial, be <48 hours of age on admission, have a gestational age of <30 weeks, have a birth weight of 501 to 1250 gm, and be free of congenital anomalies. Twelve centers participated in this study. They contributed 1097 patients of whom 381 were treated with a PRO strategy. RESULTS: Survival was significantly higher in the PRO-strategy patients (84% vs 72%, p < 0.05) as was survival without oxygen requirement at a postconceptional age of 36 weeks (60% vs 46%, p < 0.05). In addition, the patients with PRO had a lower prevalence of grade III and IV intraventricular hemorrhage (IVH, 9% vs 14%, p < 0.05). All analyses were controlled for birth weight and type of study center. CONCLUSION: These data support the conclusion that using a PRO treatment strategy results in improved survival in patients at risk for developing HMD. A PRO treatment strategy may also decrease the likelihood of developing a severe IVH.

Meta-analyses of surfactant replacement therapy of infants with birth weights less than 2000 grams.

OBJECTIVES: We conducted a meta-analysis of surfactant replacement therapy to determine (1) the efficacy of surfactant therapy in the reduction of short-term morbidity and long-term outcome in terms of bronchopulmonary dysplasia (BPD) and mortality; (2) whether there are differences in efficacy between modified natural surfactant and synthetic surfactant; (3) the effectiveness of prophylactic surfactant therapy; and (4) whether there are differences in efficacy between the prophylactic approach and the rescue strategy. STUDY DESIGN: We included studies in which infants with birth weights between 500 and 1500 gm were eligible. Studies were grouped into the following categories: (1) rescue therapy with modified natural surfactant; (2) rescue therapy with synthetic surfactant; (3) prophylaxis with modified natural surfactant; (4) prophylaxis with synthetic surfactant; (5) prophylaxis versus rescue studies; (6) modified natural surfactant versus Exosurf (Burroughs-Wellcome Co., Research Triangle Park, NC) studies. The relative risk ratios, corrected for study size, were calculated for the outcome variables (pneumothorax, incidence of BPD, survival, survival without BPD, prevention of hyaline membrane disease [HMD], and intraventricular hemorrhage [IVH]). RESULTS AND CONCLUSION: Surfactant therapy is efficacious in reducing the risk for pneumothorax and increasing the chance for survival without BPD. Synthetic surfactant is not efficacious in the prevention of HMD. Modified natural surfactant is more effective in reducing the risk of pneumothorax and increasing the chance for survival without BPD than is synthetic surfactant. These data do not support the use of either synthetic or modified natural surfactant for routine prophylaxis.

Use of surfactant in the delivery room.

Surfactant supplementation in prevention and treatment of surfactant deficient hyaline membrane disease has been widely studied. This article focuses on the prevention of HMD by preventilatory, tracheal instillation of surfactant in the delivery room.

Pulmonary surfactant replacement in respiratory distress syndrome.

Exogenous surfactant therapy in infants with HMD leads to dramatic improvement in oxygenation and disease course. Both prophylactic and rescue treatments have shown a significant reduction in morbidity and mortality from the disease. There are several questions yet to be answered regarding the most effective surfactant, the appropriate time of treatment, and the appropriate dose, as well as the number of treatments required. Based on the available data, surfactant TA has shown promising and consistent results. Another important question to be answered is the role of surfactant in milder cases of HMD and its impact on the cost of hospitalization. Hopefully, future studies will be able to provide answers to these questions.

A case report of maternal death associated with betamimetics and betamethasone administration in premature labor.

A fatal case of pulmonary edema is reported after prolonged treatment with beta-mimetics during pregnancy for threatened premature labor. The mother had received betamethasone in order to enhance fetal lung maturity. Myocardial failure occurred 5 days after discontinuation of betamimetics. The potential toxic effects of beta-adrenergic agents and their association with corticosteroids are discussed. Caution is recommended when high doses of betamimetics are to be delivered to prevent premature labor. No patient should be treated unless her cardiac condition is normal. Cardiovascular evaluation should be regularly performed during the course of treatment. No patient should be discharged after treatment without a normal cardiovascular check-up.

Chevalier Jackson Lecture: In quest of the prevention of hyaline membrane disease.

Hyaline membrane disease or respiratory distress syndrome of prematurely born infants is more common in males, in Caucasians, has a familial predisposition, and is associated with maternal diabetes and delivery by cesarean section before the onset of labor. Now known to be the sequel of surfactant deficiency, it can be predicted prenatally by assay of amniotic liquid for surface active materials produced by the fetal lung. Deficiency of adequate surfactant synthesis or secretion can result in low levels of lecithins and other phospholipids in amniotic liquid. Lung maturation can result in low levels of lecithins and other phospholipids in amniotic liquid. Lung maturation can be accelerated if labor or elective delivery can be deferred at least 24 hours. Glucocorticoids given to the mother cross the placenta and enter fetal lung tissues; specific receptors exist in the lung which permit glucocorticoids to promote cell differentiation and surfactant synthesis precociously. Clinical trials support the efficacy and lack of short-term toxicity of glucocorticoids in human pregnancy after 28 weeks gestation in the event of premature onset of labor. Maternal toxemia, infection or illness which may be aggravated by glucocorticoids may contraindicate prenatal treatment. Postnatally endogenous glucocorticoids accelerate lung maturation, and further administration confers no additional benefit.

[Induction of fetal lung maturation in the prevention of hyaline membrane disease: the connection with neonatal sepsis]. / Induzione della maturazione polmonare fetale nella profilassi della malattia da membrane ialine e sepsi neonatale.

BACKGROUND: The aim of this study was to evaluate the effect of antenatal maternal corticosteroid treatment on the frequency of neonatal outcomes and perinatal infectious morbidity among singleton pregnancies complicated by preterm delivery. METHODS: A nonrandomized analysis was performed on 189 neonates of 24-34 weeks' gestation who were born at the Department of Obstetrics and Gynecology, University of Udine, between January 2000 to December 2001. The neonates were subdivided into 3 groups: 1) 143 neonates received 2 doses of corticosteroids in a 24-hour interval and repeated after 10 days; 2) 26 neonates received 2 doses; 3) 20 neonates did not receive any treatment. Data were analysed with the Fisher exact test. p<0.05 was considered significant. RESULTS: The incidence of respiratory distress syndrome (RDS), neonatal mortality and intraventricular hemorrhage was respectively 43.4%, 3.2 % and 6.3 %. The rate of early-onset neonatal sepsis was 4.9% in the 1st group, 3.9% in the 2nd group and 5% in the 3rd group. There were no significant differences in the early-onset neonatal sepsis and the antenatal corticosteroids treatment. CONCLUSIONS: The single or the multiple courses of antenatal steroids did not apparently increase neonatal sepsis in patients with preterm delivery.

Recent advances in hyaline membrane disease.

Survival of infants with HMD has improved remarkably in the last decade. This has resulted from improved methods of diagnosis, which enables clinicians to recognize infection, the patent ductus, and the presence of pulmonary hypertension complicating HMD; from improved methods of ventilation, which result in a lower incidence of acute and chronic complications; and from a reduced incidence of pulmonary and extrapulmonary complications, such as bronchopulmonary dysplasia and retrolental fibroplasia. These advances arise from a deep understanding of pulmonary and metabolic physiology of the newborn infant with respiratory distress. Only an approach firmly rooted in an understanding of physiology, pharmacology, and biochemistry can be completely successful in the therapy of these infants.

The prevention of hyaline membrane disease: new concepts and approaches to therapy.

New approaches to hyaline membrane disease have emerged in recent years. These developments are principally attributable to advances in our understanding of the following: (1) the pathophysiology and pathogenesis of HMD in relationship to pulmonary surfactant, (2) fundamental aspects of fetal lung development, including the movement of surfactant phospholipids from fetal pulmonary fluid to the amniotic space, (3) mechanisms for accelerating lung maturation, particularly with maternally administered prenatal glucocorticoids, and (4) ventilatory techniques effective in protecting and conserving alveolar surfactant by the continuous application of end expiratory pressure. Prenatal assessment of the risk for developing hyaline membrane disease is now routinely possible by amniocentesis and analysis of the ratio of lecithin to sphingomyelin in amniotic fluid. Such predictability, coupled with the ability to postpone delviery, allows the perinatologist in some instances to provide the fetus with ample opportunity for lung development in utero. Recent clinical trials around the world with pregnant women in premature labor document a significantly lower incidence of hyaline membrane disease after antenatal glucocorticoid treatment. In neonates with the disease weighing more than 1500 gm, it is now established that reduced mortality rates accrue from the use of end expiratory positive pressure. These clinical advances offer great promise in changing the nature of HMD management from procedures that are largely supportive to approaches that are truly preventative.

[Prenatal corticotherapy and acceleration of fetal maturation. II. Results of clinical applications]. / Corticothérapie anténatale et accélération de la maturation foetale. II. Résultats des applications cliniques.

Numerous subsequent controlled trials and recent meta-analysis have confirmed the efficiency of antenatal glucocorticoid therapy in reducing both the incidence of respiratory distress syndrome (RDS) and perinatal mortality. Moreover, antenatal glucocorticoid administration reduces the odds of several severe complications relating to immaturity: intraventricular hemorrhage (IVH), ductus arteriosus patency, necrotising enterocolitis, and hemodynamic failure. Exogenous surfactant therapy has not ruled out the benefits of corticosteroids: on the contrary, a synergic effect is obtained when both antenatal and postnatal therapeutic approaches are combined. Very premature infants may also take advantage of the hormonal treatment: in this population, RDS occurrence, IVH incidence and perinatal mortality are also reduced. Unfortunately, despite convincing evidence, the incidence of antenatal steroids therapy has not yet achieved the optimal and desirable level. Obstetricians and pediatricians must be encouraged to ensure high maternal exposure to steroids when preterm delivery is likely to occur.

[The lecithin-sphynogomyelin ratio in the amniotic fluid in insulin dependent diabetic pregnancies]. / Le rapport lécithine-sphingomyéline du liquide amniotique dans les grossesses diabétiques insulino-dépendantes

A delay in the pulmonary maturation of the foetus of diabetic mothers assessed by the lecithin-sphingomyelin (L/S) ratio has been reported (2, 3, 5). A suggestion has been raised that the results of the L/S ratio should be viewed with caution in predicting lung maturity in pregnancies complicated by maternal diabetes (8). We report our findings on 52 insulin-dependent diabetic pregnancies which involved 90 estimations of the L/S ratio on the amniotic fluid. In all cases, the L/S ratio accurately reflected lung maturity, as no hyaline membrane disease (HMD) was observed with a L/S ratio greater than 2. There was no significant difference in the proportion of mature fetal lung between insulin-dependent diabetics and controls for each week of pregnancy between 32 and 38 weeks. There is no statistical difference in the mature L/S ratio between classes B + C and D + F diabetics.