Kattner et al, Accelerated lung maturation following maternal steroid treatment
j. Pennat. Med. 20 (1992) 449-457
449
Accelerated lung maturation following maternal steroid treatment in infants born before 30 weeks gestation Evelyn Kattner, Boris Metze, Evelyn Waiß, and Michael Obladen
Department of Neonatology, Children's Hospital, University Clinics Rudolf Virchow, Berlin, Fed. Rep. of Germany
1
Introduction
Twenty years after LIGGINS demonstrated improved lung expansion in preterm lambs following maternal glucocorticoid treatment [22], and showed a reduction in neonatal respiratory distress syndrome (RDS) in those infants whose mothers were treated with antepartum betamethasone [23], some controversy still exists as to whether this treatment is effective in very immature fetuses. A recent survey of 375 German departments of obstetrics revealed that only half of the obstetricians use glucocorticoids before 28 weeks of gestation [16]. With the progress of modern perinatal medicine, infants with a birthweight between 1000 and 1500 g and without malformations now have a 96% chance of survival [41]. Smaller infants, however, are still at risk of severe RDS, and still have a considerable mortality and morbidity despite modern ventilatory techniques and surfactant administration: presently, survival rates of 16, 53, 63, and 72% are reported for infants born at 24, 25, 26, and 27 weeks of gestation, respectively [14]. It should be of concern if it is shown that effective prevention of RDS is withheld from the most endangered group of neonates on the basis of retrospective observations [13, 42] or of the difficulties posed by the small number of cases [3, 39]. On the other hand, it is worrying to find that most obstetricians do not hesitate to give glucocorticoid treatment beyond 34 weeks gestation [16], a gestational age when RDS is very unlikely to occur [28]. The aim of our study was: 1. To review the literature to find prospective controlled trials of infants born at less than 30
Curriculum vitae Dr. E. KATTNER, PhD, was born in Leipzig, Germany, in 1947. She studied biology, mathematics, teaching, and medicine in Hamburg. She obtained her degree in medicine in 1978 and finished her training in paediatrics in 1984. Her primary interests are those of medical genetics and neonatology. She has been working in this field since 1983. Her main topic of research is the composition of neonatal tracheal aspirates.
weeks gestation, and to perform a meta-analysis from these studies and to calculate the odds and confidence intervals of the incidence of RDS. 2. To compare the phospholipid composition in tracheal aspirates from preterm infants born before 30 weeks of gestation who were admitted to our own intensive care unit and whose mothers were or were not given betamethasone antenatally. 2 2.1
Methods and patients Meta-analysis of controlled trials
The published literature was searched for prospective controlled trials of glucocorticoid treatment in pregnancies threatened by preterm labor.
1992 by Walter de Gruyter & Co. BerlinBrought · New York to you by | New York University Bobst Library Technical Services Authenticated Download Date | 6/28/15 11:40 PM
450
Kattner et al, Accelerated lung maturation following maternal steroid treatment
Beta- and dexamethasone were selected because they are able to pass through the placenta without considerable metabolism [2, 21]. Furthermore, synthetic steroids have a higher affinity for the glucocorticoid receptor of the lung than the natural ones [17]. We focused the search on infants born before 30 completed weeks of gestation and examined the incidence of RDS and mortality. As there was no trial exclusively designed for pregnancies with such severely immature fetuses, we chose studies that specified the occurrence of RDS at various gestational ages in their study populations. For each study, results were compared, and Fisher's exact test or chi square analysis (with Yates' correction, if case number < 100) was performed. For the incidence of RDS and mortality, homogeneity was tested [45], the data were pooled and chi-square analysis was performed. The 95% confidence intervals for the relative reduction in morbidity were calculated [6].
ments. For statistical evaluation chi-square, or Fisher's exact tests were used. Medians of quantitative variables were tested by the Mann-Whitney U-Wilcoxon rank sum test.
3 Results 3.1 Literature search
2.3 Phospholipid analysis
We found nine prospective controlled trials which reported the incidence of RDS in infants born before 30 weeks gestation. Survival in relation to gestational age and treatment was reported in only four of them. Table I and figure 1 summarize the 250 preterm infants of less than 30 weeks reported in these controlled trials. Similarity of treated and control groups was shown and significant reduction in incidence of RDS could be demonstrated in those infants prenatally treated with glucocorticoids. Death occurred in 16 of 47 treated infants and 16 of 56 control infants (n. s.). This may only be a statistical problem caused by having too few cases in each group. Table II illustrates the important interrelation of case number and type II error for the published trials on prevention of RDS with antenatal glucocorticoid treatment: due to low number of subjects, there is a considerable risk of not detecting a significant benefit of glucocorticoid treatment even if it did exist. Example: in infants of less than 30 weeks gestation the number of cases in the meta-analysis leads to a statistical power of only 52%. That means that there is a risk of nearly 50% of not finding a 10%-reduction in RDS-incidence. So the number of infants of less than 28 weeks gestation is far too small (n = 98) to attain significance compared to the 698 cases required to prove statistically a hypothetical reduction in RDS-incidence from 75 to 65%.
To assess pulmonary maturity, we determined the phospholipid profile by two-dimensional thin layer chromatography as described by KULOVICH et al. [19]. We used densitometric evaluation (Desage Quick Scan Densitometer) and computer correction of zero-calibration, baseline drift, and incomplete separation of peaks (Spectra Physics 4100) as previously described [37]. This technique allows one to determine lung maturity with a lecithin/sphingomyelin cut-off ratio of 2.7. In addition, phosphatidylglycerol was measured. Knowledge of the antenatal treatment given was not available to those making these measure-
3.2 Patient results Both groups of our own infants, in whom maternal glucocorticoid treatment could be confirmed or excluded and in whom tracheal aspirates were analysed, were comparable in gestational age (mean, SD): 27.6 + 1.3 and 27.5 ± 1.3 weeks respectively, sex distribution (female 53% in the treated group vs 55% in the untreated group). Prolonged rupture of membranes (> 24 hours) was documented in 30% of the treated women and in 13% of those not given steroids.
2.2 Patients We studied the tracheal aspirates from 135 preterm infants who were born at less than 30 weeks gestation and in whom prenatal use of betamethasone could be either confirmed or excluded. We did not distinguish between incomplete, complete or repeated steroid cycles. As an endpoint, survival until discharge from hospital was recorded. Immediately after birth, tracheal aspirates were collected when therapeutic suctioning of the endotracheal tube was necessary. In infants without an endotracheal tube, pharyngeal aspirates were collected immediately after birth.
J. Perinat. Med. 20 (1992) Brought to you by | New York University Bobst Library Technical Services Authenticated Download Date | 6/28/15 11:40 PM
451
Kattner et al, Accelerated lung maturation following maternal steroid treatment
Table I. Prospective controlled trials on maternal beta-/dexamethasone treatment (< 24 h — 7 days) and incidence of RDS in immature infants of less than 30 weeks gestation Year
Author
Reference
j. Pennat. Med. 20 (1992) 449-457
449
Accelerated lung maturation following maternal steroid treatment in infants born before 30 weeks gestation Evelyn Kattner, Boris Metze, Evelyn Waiß, and Michael Obladen
Department of Neonatology, Children's Hospital, University Clinics Rudolf Virchow, Berlin, Fed. Rep. of Germany
1
Introduction
Twenty years after LIGGINS demonstrated improved lung expansion in preterm lambs following maternal glucocorticoid treatment [22], and showed a reduction in neonatal respiratory distress syndrome (RDS) in those infants whose mothers were treated with antepartum betamethasone [23], some controversy still exists as to whether this treatment is effective in very immature fetuses. A recent survey of 375 German departments of obstetrics revealed that only half of the obstetricians use glucocorticoids before 28 weeks of gestation [16]. With the progress of modern perinatal medicine, infants with a birthweight between 1000 and 1500 g and without malformations now have a 96% chance of survival [41]. Smaller infants, however, are still at risk of severe RDS, and still have a considerable mortality and morbidity despite modern ventilatory techniques and surfactant administration: presently, survival rates of 16, 53, 63, and 72% are reported for infants born at 24, 25, 26, and 27 weeks of gestation, respectively [14]. It should be of concern if it is shown that effective prevention of RDS is withheld from the most endangered group of neonates on the basis of retrospective observations [13, 42] or of the difficulties posed by the small number of cases [3, 39]. On the other hand, it is worrying to find that most obstetricians do not hesitate to give glucocorticoid treatment beyond 34 weeks gestation [16], a gestational age when RDS is very unlikely to occur [28]. The aim of our study was: 1. To review the literature to find prospective controlled trials of infants born at less than 30
Curriculum vitae Dr. E. KATTNER, PhD, was born in Leipzig, Germany, in 1947. She studied biology, mathematics, teaching, and medicine in Hamburg. She obtained her degree in medicine in 1978 and finished her training in paediatrics in 1984. Her primary interests are those of medical genetics and neonatology. She has been working in this field since 1983. Her main topic of research is the composition of neonatal tracheal aspirates.
weeks gestation, and to perform a meta-analysis from these studies and to calculate the odds and confidence intervals of the incidence of RDS. 2. To compare the phospholipid composition in tracheal aspirates from preterm infants born before 30 weeks of gestation who were admitted to our own intensive care unit and whose mothers were or were not given betamethasone antenatally. 2 2.1
Methods and patients Meta-analysis of controlled trials
The published literature was searched for prospective controlled trials of glucocorticoid treatment in pregnancies threatened by preterm labor.
1992 by Walter de Gruyter & Co. BerlinBrought · New York to you by | New York University Bobst Library Technical Services Authenticated Download Date | 6/28/15 11:40 PM
450
Kattner et al, Accelerated lung maturation following maternal steroid treatment
Beta- and dexamethasone were selected because they are able to pass through the placenta without considerable metabolism [2, 21]. Furthermore, synthetic steroids have a higher affinity for the glucocorticoid receptor of the lung than the natural ones [17]. We focused the search on infants born before 30 completed weeks of gestation and examined the incidence of RDS and mortality. As there was no trial exclusively designed for pregnancies with such severely immature fetuses, we chose studies that specified the occurrence of RDS at various gestational ages in their study populations. For each study, results were compared, and Fisher's exact test or chi square analysis (with Yates' correction, if case number < 100) was performed. For the incidence of RDS and mortality, homogeneity was tested [45], the data were pooled and chi-square analysis was performed. The 95% confidence intervals for the relative reduction in morbidity were calculated [6].
ments. For statistical evaluation chi-square, or Fisher's exact tests were used. Medians of quantitative variables were tested by the Mann-Whitney U-Wilcoxon rank sum test.
3 Results 3.1 Literature search
2.3 Phospholipid analysis
We found nine prospective controlled trials which reported the incidence of RDS in infants born before 30 weeks gestation. Survival in relation to gestational age and treatment was reported in only four of them. Table I and figure 1 summarize the 250 preterm infants of less than 30 weeks reported in these controlled trials. Similarity of treated and control groups was shown and significant reduction in incidence of RDS could be demonstrated in those infants prenatally treated with glucocorticoids. Death occurred in 16 of 47 treated infants and 16 of 56 control infants (n. s.). This may only be a statistical problem caused by having too few cases in each group. Table II illustrates the important interrelation of case number and type II error for the published trials on prevention of RDS with antenatal glucocorticoid treatment: due to low number of subjects, there is a considerable risk of not detecting a significant benefit of glucocorticoid treatment even if it did exist. Example: in infants of less than 30 weeks gestation the number of cases in the meta-analysis leads to a statistical power of only 52%. That means that there is a risk of nearly 50% of not finding a 10%-reduction in RDS-incidence. So the number of infants of less than 28 weeks gestation is far too small (n = 98) to attain significance compared to the 698 cases required to prove statistically a hypothetical reduction in RDS-incidence from 75 to 65%.
To assess pulmonary maturity, we determined the phospholipid profile by two-dimensional thin layer chromatography as described by KULOVICH et al. [19]. We used densitometric evaluation (Desage Quick Scan Densitometer) and computer correction of zero-calibration, baseline drift, and incomplete separation of peaks (Spectra Physics 4100) as previously described [37]. This technique allows one to determine lung maturity with a lecithin/sphingomyelin cut-off ratio of 2.7. In addition, phosphatidylglycerol was measured. Knowledge of the antenatal treatment given was not available to those making these measure-
3.2 Patient results Both groups of our own infants, in whom maternal glucocorticoid treatment could be confirmed or excluded and in whom tracheal aspirates were analysed, were comparable in gestational age (mean, SD): 27.6 + 1.3 and 27.5 ± 1.3 weeks respectively, sex distribution (female 53% in the treated group vs 55% in the untreated group). Prolonged rupture of membranes (> 24 hours) was documented in 30% of the treated women and in 13% of those not given steroids.
2.2 Patients We studied the tracheal aspirates from 135 preterm infants who were born at less than 30 weeks gestation and in whom prenatal use of betamethasone could be either confirmed or excluded. We did not distinguish between incomplete, complete or repeated steroid cycles. As an endpoint, survival until discharge from hospital was recorded. Immediately after birth, tracheal aspirates were collected when therapeutic suctioning of the endotracheal tube was necessary. In infants without an endotracheal tube, pharyngeal aspirates were collected immediately after birth.
J. Perinat. Med. 20 (1992) Brought to you by | New York University Bobst Library Technical Services Authenticated Download Date | 6/28/15 11:40 PM
451
Kattner et al, Accelerated lung maturation following maternal steroid treatment
Table I. Prospective controlled trials on maternal beta-/dexamethasone treatment (< 24 h — 7 days) and incidence of RDS in immature infants of less than 30 weeks gestation Year
Author
Reference
