Timing of antenatal corticosteroids and neonatal pulmonary mechanics

Timing of antenatal corticosteroids and neonatal pulmonary mechanics Cindy McEvoy, MD, Susan Bowling, RRT, Kathleen Williamson, RRT, Jeff Collins, MD, Lama Tolaymat, MD, and James Maher, MD Pensacola, Florida OBJECTIVE: We sought to compare lung mechanics in infants treated with multiple courses of antenatal corticosteroids with those in matched control infants delivered >7 days from dosing and those of matched untreated infants. STUDY DESIGN: Eighteen infants who received multiple courses of corticosteroids and were delivered within 7 days of dosing were matched with 18 infants who received 1 course of corticosteroids >7 days before delivery (remote) and 18 untreated infants. Respiratory compliance and functional residual capacity were measured within 36 hours. Differences were compared by analysis of variance. RESULTS: Infant demographics were similar. Respiratory compliance was higher in the multiple-course group than in the remote or untreated group (P < .02). Functional residual capacity was higher in the multiple-course group than in the untreated group (P < .05) but similar to that found in the remote group. CONCLUSION: Babies delivered after multiple courses of corticosteroids and within 7 days of dosing demonstrated improved respiratory compliance compared with untreated and remotely treated infants. This suggests that the enzyme system responsible for surfactant production can be repetitively induced despite prior treatment with corticosteroids. The increased functional residual capacity in remotely treated infants may reflect a maturation of lung architecture independent of surfactant production. (Am J Obstet Gynecol 2000;183:895-9.)

Key words: Respiratory compliance, lung volume, timing of antenatal corticosteroids, preterm infants

The initial work of Liggins and Howie1 evaluating the effects of glucocorticoids in neonatal outcome clearly demonstrated that a single course of antenatal corticosteroids given to women at risk for preterm delivery reduced the incidence of respiratory distress syndrome and neonatal death. This study, as well as a meta-analysis by Crowley,2 indicated that the beneficial effects from a single course of antenatal corticosteroids began within 24 hours of dosing and lasted for approximately 7 days. Our ability to identify and treat women who will subsequently be delivered of their infants within this treatment window is limited. Therefore it is not uncommon for a woman who was treated with antenatal corticosteroids not to have been delivered of her infant 7 days after treatment. Because of the lack of clinical data, many clinicians address this dilemma by repetitively administering corFrom the Department of Pediatrics and Obstetrics, Sacred Heart Hospital, University of Florida. Presented in part at the Twentieth Annual Meeting of the Society for Maternal-Fetal Medicine, Miami Beach, Florida, January 31–February 5, 2000. Reprint requests: Cindy McEvoy, MD, Department of Pediatrics, UHN 51, Oregon Health Science University, 3181 SW Sam Jackson Park Rd, Portland, OR 97201. Copyright © 2000 by Mosby, Inc 0002-9378/2000 $12.00 + 0 6/6/108876 doi:10.1067/mob.2000.108876

ticosteroids to gravid women who have not been delivered 7 days past treatment when they believe that the patient is still at high risk for preterm delivery.3 Animal studies have demonstrated structural maturational changes in lung histologic characteristics and pulmonary function after a single course of antenatal corticosteroids,4 but some studies have suggested that repetitive dosing of antenatal corticosteroids provides no additional benefit to lung function.5 In addition, retrospective studies have documented decreased fetal growth after multiple courses of antenatal corticosteroids.6 Our objective was to examine the lung volume (specifically functional residual capacity) and respiratory compliance assessed by pulmonary function studies in babies who were exposed to >1 course of antenatal corticosteroids but who were delivered within 7 days of dosing. These values were then compared with those measurements in infants who were treated with 1 course but were delivered >7 days from dosing and those of untreated infants. Methods Inclusion criteria. Eighteen infants who had received multiple courses of antenatal corticosteroid therapy were prospectively studied over a 2-year period. The study was approved by the institutional review board of the hospital, and consent was obtained from the parents. Infants 895

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were eligible for the study if they fulfilled the following criteria: (1) birth weight ≤2500 g, (2) gestational age ≤35 weeks, (3) appropriate for gestational age, (4) administration of ≥2 courses of antenatal corticosteroids (two 12-mg doses of betamethasone, for a total dose of 24 mg, given intramuscularly every 12 hours, with delivery within 7 days of therapy), and (5) performance of a test of pulmonary function within 36 hours of birth and before surfactant therapy, if required. These infants were then matched for gestational age, birth weight, race, and sex with 18 preterm infants who had received a remote course of antenatal corticosteroids (two 12-mg doses of betamethasone given intramuscularly >7 days before delivery) and with 18 untreated preterm infants who also had pulmonary function tests done within 36 hours of birth. Infants who received incomplete courses of betamethasone, infants with multiple congenital anomalies, or those delivered after maternal clinical chorioamnionitis were excluded. Infants who required surfactant had to be studied before its administration, which was given as a rescue therapy if the infant required >30% oxygen during mechanical ventilation. Study design. Infants were prospectively studied within the first 36 hours of life and before surfactant therapy if required. All infants were studied in the supine position while quietly asleep. If the infants were intubated, endotracheal suctioning was performed before each study. The study end points were the differences in functional residual capacity and passive respiratory compliance in the multiple-course group versus the remotely treated group versus the untreated group of infants. Neither muscle relaxants nor sedatives were used during the study period. Measurements. Functional residual capacity and passive respiratory mechanics were measured with a computerized infant system (SensorMedics 2600; SensorMedics Corp, Yorba Linda, Calif). Functional residual capacity was measured with the nitrogen-washout method,7 and respiratory mechanics were measured with the singlebreath occlusion technique.8 For the nitrogen-washout technique, calibration was done with 2 known volumes, one greater than and one less than the infant’s estimated functional residual capacity. When these volumes were washed out, the computer constructed a calibration line for the system at the specific flow rate. For the measurement of functional residual capacity, the infant was switched in at end expiration from his or her baseline fraction of inspired oxygen to 100% oxygen at the flow rate used for calibration. The test was complete when the nitrogen concentration reached 0. Data from the nitrogen analyzer were presented in real time on the screen, both numerically and as a graph. The nitrogen washed out was proportional to the area under the integration curve, showing a fast rise, peak, and then a gradual decline to baseline. After approximately 1 minute, the washout should have been complete. The

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computer calculated the functional residual capacity from the alveolar nitrogen and the integral of the nitrogen from the calibration line. It also corrected for dead space present and corrected for body temperature and pressuresaturated conditions. Total functional residual capacity was related to body weight. A nitrogen-washout test result was accepted if the following criteria were met: (1) The baby was supine and quietly asleep; (2) the test was initiated at end expiration; (3) there was no evidence of leak on tracing of washout; (4) there were consistent tracings; (5) there was a coefficient of variation of <10%.9, 10 Passive respiratory mechanics were measured with the single-breath occlusion technique.8 The airway was occluded at end inspiration until the airway pressure plateau was observed and the Hering-Breuer reflex was invoked. The occlusion was then released, and the flow and volume of the passive exhalation were recorded and displayed as a flow-volume curve. The linear portion of the flow-volume curve was identified, and a regression line was drawn to obtain the best fit. From the intercepts on the flow and volume axis, respiratory system compliance and resistance were calculated. Acceptance criteria for the single-breath occlusion included the following: (1) stable end-expiratory baseline, (2) plateau pressure lasting >100 ms, (3) plateau pressure varying by <±0.125 cm H2O, (4) acceptable flow-volume curve by visual inspection, with linear data segment identified, and (5) a coefficient of variation <20%.9, 10 Statistical analysis. Analysis of variance was used to assess the statistical differences in functional residual capacity and respiratory compliance among the 3 groups of patients (SPSS for Windows, Release 7.5; Statistical Package for the Social Sciences, Chicago, Ill). The Tukey post hoc multiple comparison test was used to assess specific differences between groups. The level of significance was set at P < .05 for all tests. Values are expressed as mean ± SEM. Results Eighteen infants treated with multiple courses (range, 2-6 courses; median, 2 courses) of antenatal corticosteroids, 18 matched infants treated with a single course of remote antenatal corticosteroids (range, 8.5-43.5 days between dosing and delivery), and 18 matched untreated infants were studied (Table I). The infants were all approximately 1850 g at a gestational age of 32 weeks. Fifty percent were girls, and 80% were white. There was no significant difference between the multiple-course group and the remotely treated group in terms of oxygen or need for intermittent mandatory ventilation at the time of study, but the multiple-course group did require less oxygen and intermittent mandatory ventilation at the time of the pulmonary function testing and required less surfactant therapy than the untreated infants (Table I). There was no significant difference between the multiplecourse and the remotely treated groups’ functional residual

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Fig 1. Mean values for functional residual capacity for infants receiving multiple courses of corticosteroids, infants receiving a remote course of corticosteroids, and untreated infants. Values are displayed as mean ± SEM. Asterisk, P < .05, versus untreated infants.

Table I. Clinical characteristics of study population

Birth weight (g, mean ± SEM) Gestational age (wk, mean ± SEM) Female sex (%) White (%) Fraction of inspired oxygen at study (%) Surfactant need (%) On ventilation at study (%)

Multiple courses of corticosteroids (n = 18)

Remote course of corticosteroids (n = 18)

Untreated (n = 18)

1791 ± 107 31.5 ± 0.6 56 78 21 000* 011†

1855 ± 119 32.3 ± 0.6 56 89 27 11 22*

1857 ± 154 32.2 ± 0.5 39 78 28 33 56

*P < .05, versus untreated infants. †P < .01, versus untreated infants.

capacities (28.3 ± 1.6 mL/kg vs 26.8 ± 2.0 mL/kg; P = .56), but the multiple-course group’s functional residual capacity was significantly higher than that of the untreated infants (22.4 ± 1.9 mL/kg; Fig 1). The infants who received multiple courses had a significantly higher respiratory compliance (1.47 ± 0.15 mL/cm H2O/kg) than either the remotely treated infants (1.01 ± 0.10 mL/cm H2O/kg; P = .01) or the untreated infants (1.00 ± 0.10 mL/cm H2O/kg; P = .02; Fig 2). Comment Antenatal corticosteroid therapy represented a major advance in the treatment of preterm delivery, and since its introduction, various reports have elucidated a maturational effect involving the pulmonary and neurologic systems. Antenatal corticosteroids exert their effect by binding to nuclear receptors and facilitating transcription of new proteins. In effect, glucocorticoids redirect the focus of the developing fetus from growth toward differentiation in anticipation of preterm delivery.11 If the administration of corticosteroids is appropriately timed to presage premature delivery, the beneficial effects re-

duce neonatal mortality, respiratory distress syndrome, and intraventricular hemorrhage. What if corticosteroid therapy is not followed by preterm delivery? The induction in the surfactant pool is a temporary phenomenon,11 and if preterm delivery does not occur, this surfactant pool may be recycled. Animal research has delineated an adverse effect on fetal development, including impaired antenatal growth after repetitive administration of antenatal corticosteroids.12 Human studies have also suggested a potential for adverse maternal and neonatal side effects to repetitive dosing, but prospective trials are lacking.6 Also complicating any assessment of the neonatal effect of antenatal corticosteroids are the advancements in neonatal care and improved survival of viable infants. Our study demonstrated that babies delivered after ≥2 courses of antenatal corticosteroids but within 7 days of the last treatment demonstrated a significantly improved respiratory compliance compared with untreated, as well as remotely treated, infants. This improved respiratory compliance is most likely related to induction of the surfactant pool. Previous studies have demonstrated that

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Fig 2. Mean values for respiratory compliance for infants receiving multiple courses of corticosteroids, infants receiving a remote course of corticosteroids, and untreated infants. Values are displayed as mean ± SEM. Asterisk, P < .02, multiple courses versus remote course and multiple courses versus untreated infants.

administration of antenatal corticosteroids may induce an increase in surfactant pool size,11 and studies examining the effect of neonatal surfactant administration on pulmonary mechanics have demonstrated a significant improvement in lung compliance after surfactant administration.13 The fact that the lung compliance improved after a second course of corticosteroids is presumptive evidence of an ability to repetitively induce a surfactant pool in a preterm infant. The fact that the lung compliance of a baby who received a single course of corticosteroids but was delivered outside of the 7-day treatment window was no different than that of an untreated baby suggests that this improved compliance is a time-limited phenomenon and that if preterm delivery does not ensue, this surfactant pool dissipates. The functional residual capacity of babies delivered after repetitive dosing but within the optimal treatment window was found to be significantly higher than that of the untreated infants. There are 2 ways to improve the lung volume of a preterm infant—either increase the number of alveoli that are recruited or increase the distention of the alveoli. Animal studies have demonstrated histologic evidence of structural change with an increase in air space volume after antenatal administration of corticosteroids.14 The increase in functional residual capacity of the remotely treated infants may be further evidence of the maturational change in lung architecture that appears to be independent of surfactant production. Although further research is needed to more fully delineate the beneficial and adverse effects of repetitive dosing of corticosteroids, our preliminary report suggests that when corticosteroids are repetitively administered, it is possible to repetitively induce improvement in respiratory compliance, probably through recruitment of a sur-

factant pool. Furthermore, if the delivery occurs outside the treatment window, some improvement in lung volume is seen, suggesting that maturational changes have occurred. However, additional studies are needed to confirm these findings. It is appropriate to administer antenatal corticosteroids to a gravid woman who is believed to be at risk for premature delivery. Until well-controlled studies are reported that can more completely explore the risks and benefits of multiple courses of antenatal corticosteroids, routine administration of weekly corticosteroids should probably not be given. In most cases the option of a rescue course of corticosteroids can be attempted if delivery appears imminent in a pregnant woman who has been remotely treated.15 REFERENCES

1. Liggins GC, Howie RN. A controlled trial of antepartum glucocorticoid treatment for prevention of the respiratory distress syndrome in premature infants. Pediatrics 1972;50:515-25. 2. Crowley P. Antenatal corticosteroid therapy: a meta-analysis of the randomized trials, 1972 to 1994. Am J Obstet Gynecol 1995;173:322-35. 3. National Institutes of Health Consensus Development Conference. Effects of corticosteroids for fetal maturation on perinatal outcomes. Am J Obstet Gynecol 1995;173:246-52. 4. Jobe A, Polk D, Ikegami M, Newnham J, Sly P, Kohen R, et al. Lung responses to ultrasound-guided fetal treatments with corticosteroids in preterm lambs. J Appl Physiol 1993;75:2099-105. 5. Polk D, Ikegami M, Jobe AH, Sly P, Kohan R, Newnham J. Preterm lung function after retreatment with antenatal betamethasone in preterm lambs. Am J Obstet Gynecol 1997;176:308-15. 6. Banks BA, Cnaan A, Morgan MA, Parer JT, Merrill JD, Ballard PL, et al. Multiple courses of antenatal corticosteroids and outcome of premature neonates. Am J Obstet Gynecol 1999;181: 709-17. 7. Gerhardt T, Hehre D, Bancalari E, Watson H. A simple method for measuring functional residual capacity by N2 washout in small animals and newborn infants. Pediatr Res 1992;29:1165-9. 8. Lesouef PN, England SJ, Bryan AC. Passive respiratory mechan-

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ics in newborns and children. Am Rev Respir Dis 1984;129: 522-56. American Thoracic Society/European Respiratory Society. Respiratory mechanics in infants: physiologic evaluation in health and disease. Am Rev Respir Dis 1993;147:474-96. McEvoy C, Bowling S, Williamson K, Durand M. Increases in functional residual capacity (FRC) at two different doses of dexamethasone in very low birth weight (VLBW) infants: a doubleblind, randomized trial [abstract]. Pediatr Res 1996;39:229A. Ballard PL, Ballard RA. Scientific basis and therapeutic regimens for use of antenatal glucocorticoids. Am J Obstet Gynecol 1995;173:254-62. Jobe AH, Newnham J, Willet K, Sly P, Ikegami M. Fetal versus ma-

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ternal and gestational age effects of repetitive antenatal glucocorticoids. Pediatrics 1998;102:1116-25. 13. Kelly E, Bryan H, Possmayer F, Frndova H, Bryan C. Compliance of the respiratory system in newborn infants pre- and postsurfactant replacement therapy. Pediatr Pulmonol 1993;15: 225-30. 14. Bunton TE, Plopper CG. Triamcinolone-induced structural alteration in the development of the lung of the fetal rhesus macaque. Am J Obstet Gynecol 1984;148:203-15. 15. American College of Obstetricians and Gynecologists Committee on Obstetric Practice. Antenatal corticosteroid therapy for fetal maturation. Washington: The College; 1998. p. 14-5. ACOG Committee Opinion No.: 210 .

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