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Effect of antenatal dexamethasone administration on the prevention of respiratory distress syndrome*
Effect of antenatal dexamethasone administration on the prevention of respiratory distress syndrome* COLLABORATIVE GROUP ON ANTENATAL STEROID THERAPY Bethesda, Maryland A double-blind, collaborative, randomized trial was init~• in 1976 to evaluate ~metha&one administered to mothers as a method of preventing neonatal r8$piratory distress syndrome (ADS). Five centers enrolled 696 women at risk for prematut:e deiivery. Up to 2Q tog of dexi:tmethaSolle pho$phate (5 mg eyery 12 hours) or _a placebo was adfnini81ered intramuseutarly. The o.Verall incidence of RDS was different between control subjects (18.0%) and sterok:Hreated mothers {12.6"/o) (P 0.05). The effect was, however, mainly attribUtable to discernible differences among singleton female infants (P. < 0.001 ), whefeas no treatmem effect was ob!ierved in male. infants (P 0.96). Non-Ca~ans were improved whema& C~ians showed little benefit .f.etal and neonatal mortality and maternal postpartUm intedlon rates were not different Neurologic examination at 40 weeks' gestation demonstrated no $ignlficant difference in the rate of abnormal outcomes in the neonatal steroid group (P 0.2). (AM. J. CasTer. GvNECOL.14t:276, 1981.)
NEONATAL respiratory distress syndrome (RDS) continues to rank as a major public health problem. Precise data on the incidence of RDS are difficult to determine because of complex contributing factors and an apparently changing rate. It has been estimated that RDS occurs in 14% to 60% of premature deliveriesat gestational ages between 28 and 35 weeks, 1 and RDS and concomitant complications of prematurity may account for up to 75% of neonatal deaths. As recently as 5 years ago, the death rate attributed primarily lO RDS was estimated to be 23 per 1,000 live births, 2 and although
Research performed pursuant to contracts NOJ-HR-6-2948, 2949,2950,2951,2952, and 2953 with the National Heart, Lung, and Blood Institul.i!, Natioool Institutes of Health. United StafRs Departmmt of Health and Human Sen•ice,,, Recei·(led for publication january 29, 1981. Revised May I 1, 1981. Accepted May 13, 1981. Reprint requests: Pmgram Office, Clinical Trwl on Antenatal StRroid Therapy, Division of Lung Diseases, National Heart, Lung, and Blood lnstitutR, National institutes of Health, Room 6AOJ, Westwood Building. Bethesda, Maryland 20205.
*See Editorial Comment following this article. **Based on the Collaborative Study on Anteootal Steroid Therapy sponscrred by the Division of Lung Diseases, Natioool Heart, Lunty and Blood Institute, National Institutes of Health, Bethesda, Maryk!nd. Detailed reports '!f a number of aspects mentioned in this paper .are now in preparation and the long-term effects of dexamethasone administration on the i:nfants are currrntly under investigation.
276
chances of neonatal sunival have improved,J{DS remains a major cause of death.'1 As more infants ~vit11 RDS survive, permanent serious sequelae of the di~or· der itself or its associated complications continue to irlcrease.4 Therefore, it is important teo explore m-easure~ that may prevent this syndrome. Animal studies in the late 1960sand early 1970s had shown that the administration ol corticq~teroids ic mothers at an appropriate time priot ro delivery an:el· crated lung maturation and resulted in viable prema· ture offspring?- 9 The first applkatiOJ) of this knowledge to the dinical setting was reported by Liggins and Howiew in New Zealand. In 1974, the Division of Lun~ Diseases, National Heart, Lung, and Blow Institute and the National Institute of Child Health and Hurnar Development jointly sponsored a workshop on Possibl< Pharmacologic Mechanisms for Enham:ement or Lun~ Maturation. The participants recommended that a clinical trial be conducted to determine r.he efficacy of ante· natal steroid administration in preventing RDS and ft assess whether there might be signiticant short- or long· term toxic effects associated with such inten·ention. Such a trial was initiatt'd in 1976. The protocol \,·a: designed to answer three questions: {I) Does dexa· methasone phosphate administered iritramu<>tularly tl the mother reduce the incidence of JtDS in the off: spring? (2) Does this inten-ention have adverse short term effects on the mother, fetus. and neonate? (:3 Does it have adverse long-term effects on the infan during the first i8 months of life? A Policy-Data Monitoring Panel com~1sed of e?<
Volume 141 Number 3
perts in biostatistics, biochemistry, pediatrics, neonatology, obstetrics, pediatric psychology, and jurisprudence (from nonparticipating institutions) was established to monitor adverse effects, progress, and quality control and to make recommendations to the National Heart, Lung, and Blood Institute for changes in the study plan. Subsequent to initiation of the study, several small, retrospective and prospective studies have reported a reduced incidence of RDS in premature infants born of corticosteroid-treated mothers. 11 - 13 To date, however, no reports have fully addressed the possible adverse short- or long-term effects on the mother, fetus, and neonate, especially with regard to the motor, neurologic, and intellectual development of the infant; and with the exception of the study by Liggins and Howie, 10 reports have not included large samples. The long-term effects of maternally administered dexamethasone upon neurologic, motor, and intellectual development of the off~pring are currently being investigated in a double-blind fashion and will be reported separately when the follow-up phase of the study is concluded. Material and methods During the first phase of the clinical trial a common study protocol was designed by the investigators from the five clinical centers and the coordinating center, with the advice of consultants. The protocol was standardized according to a manual of operations while at the same time maintaining the usual standard of patient care. After approval of the protocol and manual of operations by the Panel, the study entered into the 3 year recruitment-intervention phase in March, 1977. At present, the study is in the final follow-up phase, which will be completed in March, 1983. At that time, the last infant to enter the study will have had an opportunity to have its 36 month evaluation. Patient selection. From March I, 1977, to March I, 1980, a total of 7,893 patients from the five participating clinical centers were screened for eligibility in the study. Patients between 26 and 37 weeks' gestation who entered the hospital at high risk for premature delivery and consented to participate were considered for the study. Similar consent forms were used by all centers. Patients were t~xcluded if one or more of the following criteria were present: the cervix was dilated more than 5 em; delivery was anticipated in less than 24 hours or more than 7 days later; signs of intrauterine infection were present; corticosteroids had been administered for any reason during the current pregnancy; there was a history of peptic ulcer disease; active tuberculosis or viral keratitis existed; st~vere fetal Rh s~nsltization had developed; or the infant was likely to be unavail-
Effect of antenatal dexamethasone on prevention of ROS 277
able for follow-up. The criteria for exclusion were determined as follows: Gestational age was assessed based upon the last menstrual period, if the dates were reliable, and/or on ultrasonography to measure the fetal biparietal diameter and chest and/or abdominal circumference. In cases of uncertainty, the lecithin/sphingo~ myelin (LIS) ratio was the final criterion for exclusion. Fetal lung maturity was evaluated by measuring the LIS ratio in amniotic fluid and was standardized between centers and maintained by quality control. A value of 2.0 or its standardized equivalent indicated maturity. If gestational age was less than 34 weeks, the patient could be entered into the study without the determination of the LIS ratio, but such a determination was encouraged. Patients with hyperthyroidism, elevated blood pressure (greater than 140/90 mm Hg), "placental insufficiency," drug addiction, antinarcotic treatment (methadone), or a gestational age greater than 34 weeks could be considered for inclusion only if an LIS ratio was obtained and it did not indicate fetal pulmonary maturity. Patients were carefully assessed for the probability that they would be delivered of their infants at least 24 hours after entry into the study but not more than 7 days after the first dose of drug administration. Intervention and follow-up assessment. Eligible patients were randomized to receive either dexamethasone phosphate or placebo. Identical vials containing the material to be injected (one vial per patient) were coded uniquely across all centers by a sequential numbering system. A sealed envelope containing. the identity of the contents was attached to each vial. This envelope was to be opened only in the case of emergency and was returned to the coordinating center along with the maternal entry form. The randomization was carried out in a double-blind fashion within each center, and a scheme was designed in blocks of ten so that the maximum discrepancy at any time during the trial between the number of placebo and steroid patients within a center would be five. Both placebo and steroid were dispensed as 10 ml clear, colorless solutions which diffeied only in that one contained the steroid (dexamethasone phosphate, 4 mg/ml). A total of 1.25 ml of the selected solution was administered intramuscularly to the patient every 12 hours for a total of up to four doses (20 mg of dexamethasone phosphate). Detailed information was obtained regarding assessment of prenatal course, labor, and delivery. In some cases labor was arrested for at least 48 hours by the administration of tocol ytic agents such as ethanol or isoxsuprine. Tocolytic therapy was stopped if labor continued to progress to a cervical dilatation of 5 em or if obstetric complications arose. Detailed information
278 Collaborative Group on Antenatal Steroid Therapy
Onobn i. l:IKI \rr:_ J ( )hst(·i ( w'PH:~cnl
Table I. Comparison of treatment groups on baseline data
r·--------·c··-·--
Treatment
Data itemlvarwble
~--------------,---------------~1
No. of mothers Race distribution (%)* White Black Others Sex of infant(% male) Gestational age distribution at entry (%)t <30 wk 30 and 31 wk 32 and 33 wk ~34 wk Gestational age (wk):j: Age at entry (yr):j: Chronic hypertension(%) Preeclampsia(%) PROM(%) Use of labor-delaying drugs (%) § Et..l)anO!
Isoxsuprine None More than one drug Routine use of certain drugs (%)11 Smoking during pregnancy (%) *Chi-square analysis tChi-square analysis :!:Mean± SEM. §Chi-square analysis IIMarihu~na, heroin,
P ltu:ebu
S te·roui
P vafut
347 47.0 44.4 ll.6 :J:l.fi
46.1
44.4 9.3 SUI
OR~
O.U4
27.4 25.9
12.4 31.1 ± 0.12 24.6 ± 0.13 6.6 10.7 44.3 6.6 44.1 46.1 3.2 8.1
42.0
:22.1 2R.4 30.4 19.2 31.4 ± 0.12 24.6 :t 0 . 13 5 ') I LX 49.6
0.07 0.99
0;43 (Lf>.'l 0.16 0.37
4.0 43.6 49.3 3.1 8.:1
0.90
o.:N
:nH
for race distribution = 0.15 (2 df). for distribution of gestational age between treatment groups = 8.29 (3 df). for prevalence of use of labor-delaying- drugs between the treatment groups cocaine, methadone, methaqualone, phenobarbital, and others.
recorded for each patient included: smoking habits, :irug usage, g~neral medical and surgical history, medtcal and obstetric conditions affecting the current pregnancy, familial problems that might affect the in::idence of RDS, and data on the antepartum course of each gestation. Some of these observations included ::hronic hypertension (i.e., persistent hypertension present before 20 weeks' gestation and/or after a previous pregnancy), preeclampsia (defined by Hughes 14), and premature rupture of membranes (PROM) (evidenced by Nitrazine or fern-positive Auid in the vagina on sterile speculum examination defined as occurring at least 1 hour prior to onset of labor). The diagnosis of RDS was based on standard clinical, radiolagic, and blood gas findings. These include chest retraction, grunting, cyanosis, increased ambient oxygen requirement, hypercarbia, and a ground-glass appearance on chest x-ray with air bronchograms and elevated diaphragms. This diagnosis was confirmed in each infant at each center by the neonatal coinvestigator. Severity was defined as: ( 1) mild if supplemental oxygen alone was required, (2) moderate if some form of continuous distending airway pressure was required in addition to oxygen, and (3) severe if mechanical ventilation was required. Neonatal infection was diagnosed by positive
= 3.12 (3df').
cultures. Cultures were obtained ·when indicated--by clinical signs and syrnptoms. i\t the correcte(-l_g-e~~tationa! age of 40 weeks (determined by Dubowitz examination ar birth) aU infants in the study v:ere scheduled for a Prechtl exali1ination 1" employing visual componentsofthe Brazelton test. 16 At9and 18months following the 40 week examination. a Bayleyexamination, neurologic assessment, and general pediatric evaluation have been (or will be) administerei:t At 36 months, a McCarthy test will be conducted with a dec tailed neurologic examination and a general pediatrit· evaluation. These latter examinations are an effort to detect any long-term effects ofdexamethasone administration to the mother. Maternal samples of venous bJood, for measurements of dexamethasone. hydrocortisone. estradi(JL estrone, and estriol, were obtained at the time of entry into the study and at specified intervah aftercdexamethasone or placebo administration to the mother. Blood from umbilical cord artery and vein and -neonatal blood (the latter obtained by heel stick) were also sampled arid analyzed .for hydrocortisone· and dexamethasone. Laborat:ery~aJIUdyses. Determina:tion of the LIS ratio of the amniotic fh.iid was performed in each centerl;.ya modification of ihe method described by Gluck and
Effect of antenatal dexamethasone on prevention of RDS 279
Volume 141 Number 3
Table II. Status of randomized mothers and infants
Total randomized Mothers who lost infants before delivery Mothers delivered of infants Mothers with fetal deaths Mothers with early neonatal death before RDS assessment Mothers with infants lost to study befor<: RDS assessment
696
2
Mothers with infants available for RDS assessment Deaths after RDS assessment but befon~ Prechtl examination Lost to follow-up before Prechtl examination Prechtl examination not performed
661
347 7
349 7
Infants 743 14 Fetuses Infants 7
372
371
8 3
6 4
Infants
2
2
0
Infants
720
359
361
59
29
30
21
IO
11
40
20
20
600
300
300
14
682 12 7
Total No. of infants with Prechtl examination
associates. 17 Vials containing known concentrations of purified lecithin and sphingomyelin added to amniotic fluid were prepared at regular intervals at the Royal Victoria Hospital, Montreal, and sent to the centers where they were analyzed with the experimental samples of amniotic fluid for quality control. The determinations of estrone, estradiol, estriol, and hydrocortisone were performed in the Central Laboratory by radioimmunoassay .18 Dexamethasone was analyzed by a specific radioimmunoassay procedure with prior chromatography (devised by J. Kream, S. Mulay, D. Fukushima, and S. Solomon). Sample size and statistics. Because changes in motor, neurologic, or intellectual development of the infant after corticosteroid treatment during the last trimester of pregnancy are not known, the sample size was determined solely on the basis of the anticipated reduction in incidence of RDS and the fact that previous data 1 suggested that the frequency of RDS varied substantially with gestational age. The frequency of RDS was thus assumed to be 0.80 for infants of 26 to 28 weeks' gestational age, 0.65 at 29 to 30 weeks, and 0.25 at 31 to 34 weeks. For the population of mothers, the proportion in each gestational age stratum was assumed to be 0.10, 0.20, and 0.70, respectively. This leads to an assumed control group RDS rate of 0.385. On the basis of available data it appeared that the steroid therapy might reduce the RDS rates to 0.55, 0.45 and 0.15, respectively. Presuming data analyses would take account of the gestational age strata, a sample size of 600 was estimated to have a 90% chance of detecting the assumed effect at the I% significance level (one-
tailed test). Early in the study, it became apparent that the incidence of RDS at each center was less than anticipated. Therefore, the recruitment phase was extended for 1 year to augment the sample size so that the probability with which a 25% to 30% change could be detected would remain dose to 0.9. The data were analyzed by means of analysis of variance for measured variables and contingency table methods for categoric data. Chi-square tests for association were used to test for differences in the distribution of categoric variables between treatment groups. When treatment group comparisons were adjusted for other factors, likelihood ratio tests of partial association were used. 19• 20 These are closely related to the Mantel-Haenszel method 21 in which treatment groups are compared after stratification on the level of other factors. Finally, likelihood ratio tests of three-way partial association were used to determine whether the size of the treatment effect depended on other characteristics of the mother or child. Significance was determined by means of the asymptotic chi-square distribution of the likelihood ratio statistic.
Results Patient characteristics, mortality rate, and loss to follow-up. Of 7,893 women screened for the study, i, 197 were excluded. Approximately 83% were ineligible, 5.5% refused to participate (patient or physician), and 11.5% were excluded for a variety of reasons (requested the drug, planned adoption, or were unavailable for fol:low-up). The study criterion predominantly violated was the anticipated time to delivery (85% of
280
Collaborative Group on Antenatal Steroid Therapy
Table III. Incidence of RDS "mothers" (mothers with at least one infant with RDS) by treatment and plurality of deliveries
Table V. Outcome of Prechtl examination bv treatment for singie infants Outcum~
of Prrchtl examination
Treatment Plurality if deliveries
Placebo
Single Twins Triplets
48/299 (16.1) 10/26 (38.5) 1/3 (33.3)
31/307 (10.1) 10/24 (41.7) l/2 (50.0)
79/606 (13.0) 20/50 (40.0) (40.0) 2/5
All
59/328 (18.0)
42/333 (12.6)
1011661 (15.3)
I
Steroid
Total
Table IV. Distribution of infants by treatment and presence of RDS
:-lormal Dubious Abnormal Total
Placebo
Trdal
20(i
22:\
28
~?5
'i6
12
i
I9
246
258
429 :104
Table VL Morbidity outcomes (other than RDS) and other characteristics of single deliveries Outrome
Placebo
Steroid
l P value
Infection rate Mothers (all) Infants (infections
29/340 (8.5) I 0/299 (3.3)
27/342 (7.9) f/:"107 (1.3)
0.76 O.OY
:!39 ± 29
252± 29
0.75
:HJ.O ± 1.9
22.8 ±: 1.9
0.008
Treatment RDS
Placebo
Steroid
Total
Present Absent Total
65(18.1) 294 (81.9) 359
46 (12.7) 315 (87.3) 361
111 (15.4) 609 (84.6) 720
the 83%). Six hundred and ninety-six women were randomized into placebo and steroid treatment groups. Unadjusted baseline comparison of the two groups of mothers (Table I) suggests little difference in most aspeers of demographic and health risk factors, but the difference in mean gestational age at entry is close to nomina! significance (P == 0.07). When gestational age is distributed into the four categories listed (Table !). there is a significant difference (P = 0.04) in the age distribution between the two groups. This differem:c will be adjusted for analyses pertaining to treatment difference. An average of 3.4 doses were administered per patient, with equal distribution between the two treatment assignments. Nearly 70% of all patients received four doses, 79% received three or more, and almost 90% received at least two doses. There was no difference between centers with regard to number of doses administered. Mothers and infants lost to RDS evaluation or follow-up are listed in Table II. The 661 mothers available for RDS assessment produced 720 liveborn infants; of these mothers 328 were in the placebo group and ~)33 in the treatment group. Fetal and neonatal death rates were not significantly affected by treatment (Table II). Fetal death rate was 2.29f (Hi 371) in the placebo and 1.6% (6/372) in the steroid group. Neonatal death rate was 8/8% (32/363) in the placebo and 9.3% ( 134/ 366) in the steroid group. The combined fetal and neonatal death rate was 10.8% in both placebo and steroid groups. Major outcomes. The incidence of RDS amqng mothers, i.e., the proportion of mothers with at least one RDS infant, was decreased in the dexamethasone
within 72 hr)
Time to delivery (hr)* Duration of hospital stay (days)* Birth weight (gm)* Placental weight (gm)* Distribution of mode of delivery (%)t Vaginal Cesarean section
1,940 ± 43 473 ± 24
2,042 ± 43 510 ± 23
67.3 32.7
67.0 33.0
0.09 0.29
0.98
*Mean± S!':M. tChi-square test for distribution of mode of deJivery between treatment groups =
QTouo comoared to the olacebo uQTouo ( 12.6% versus l8.0o/r, P = 0.05) (Table III), this difference l)eiiig in the same direction among centers (data nQt shown). However, ther.e was no apparent effect of dexamethasone treatment on the incidence (}[" RDS among moth~ ers having plural deliveries (Table Ill). Infants.of the treated mothers showed an overall reducedjnddence of RDS (P = 0.04) (Table IV). Approximately two thirds of the RDS cases were severe in each group and there was no indication that dexamethasone in.fluenced the degree of severity (data not shownJ. The Preditl examination performed at 40 weeks' corrected. gestational age showed no difference in rate of abnormal outcomes between the two groups either in single births [4.9% ( 12/246) versus ·2.7o/c (7/258), P = '0.2] (Table V) or w:hen all infants indudingmult~ple births were consider:ed (data not shown), 4lthol.lgh in both cases the trend suggested more beneficial outcomes in the steroid group. There was no apparent association between treatment and postpartum .infections (Table VI). There was also no effect of treatment on other postpartum complications including hyperten~i~n or (_J
l
J.
1
1
Effect of antenatal dexamethasone on prevention of RDS
Volume 141 Number 3
MEAN VALUES OF FETAL PLASMA DATA
MEAN VALUES OF MATERNAL PLASMA DATA A
-Placebo
7
D
6
-Placebo o---""1)
5
e
---
4
"' w
E
\
3
I :::E
Steroid
\
\
z
281
\\\
I
____1 }-----
~
"'c
z
=~
(/)
30
;;
!w
E
40
36
0
~
26 20 15
80 a:
10 5
c
> %
0
L_--~----~-----L--~
~
F
50
: ~\
e "' E
.... 0 0
~
\f
en w
0 TIME!hounol
\l--l----~ 12
24
36
46
TIME (hourol
Fig. 1. Determination of steroids in maternal, cord, and neonatal plasma following administration of dexamethasone. Values are expressed as mean± 2 SEM.A-C, Concentrations of steroids in maternal plasma during and after administration of four doses, shown for women delivered of their infants more than 50 hours after the first dose (50 to 195 subjects per point for each of the two groups). The concentrations of dexamethasone, hydrocortisone, and estradiol differed significantly (P < 0.0001) between the placebo group and the steroid group at each point after administration at zero up to 50 hours. D-F, Dexamethasone determinations in cord vein blood (zero time) for deliveries within 12 hours of the last dose to the mother and in the neonate thereafter demonstrated the presence and disappearance of the steroid in the steroid-treated group ( 10 to 72 subjects per point) compared to the placebo group (32 to 114 subjects per point) (P < 0.0001 at time zero; P < 0.01 at 12 and 24 hours; P > 0.15 at 48 hours). Cord venous (E) and arterial (F) plasma hydrocortisone concentrations and the neonatal plasma levels thereafter within 12 hours o(the last dose of dexamethasone were suppressed in the dexamethasone group ( 16 to 87 subjects per point) compared to control subjects (30 to 112 subjecrs per point). (P < 0.05 at time zero forE but not statistically significant for F; at 12. 24. and 48 hours. P = 0.08, 0.0001, and 0.13, respectively, for both E and F.)
hypersensitivity reactions (data not shown). The incidence of infections in infants of singleton births, as diagnosed by positive bacteriologic cultures within 72 hours, was less in the infants of dexamethasone-treated mothers (1.3% versus 3.3%). A similar difference was observed when aii infants were considered ( 1.4% ver-
sus 3.1%) and the difference between dexamethasone and placebo persisted beyond 72 hours (data not shown). Duration of hospital stay was shorter for the infants of dexamethasone-treated mothers (P == 0.008). Mean birth weights and time to delivery did not differ significantly (Table VI).
UnoblT 1. 1~~~ 1
282 Collaborative Group on Antenatal Steroid Therapy
< ibs1e1 (~\nt·coi.
-\m
Table VII. Percentage of single infants with RDS by treatment and various subgroups .::__--.,.---·-·-·----Trealmrnt
Sub-groups
Availability of LIS ratio at entry LIS immature LIS not assessed Mode of delivery*t Vaginal Cesarean In labor Not in labor State of labor unknown Preeclampsia* (P = 0.02):1: i~u
Yes PROM* (P == 0.03)t No Yes Sex (P = O.OOI):j: Male Female Sex unknown Race (P = 0.02):1= White, not Hispanic Black, not Hispanic Others§ Duration in studyt <24 hr 24 hr to 7 days
....._,
">7
PL"'lcebo
Steroid
16.0 (481299)
10.1 (31 /307)
17.3 (24/139) 15.0 (24/]60)
8.7 (14/l60) 11.6(17/117)
II. 9 23.7 11.3 40.5 3
6.8 14.7 12.8 15.9 4
(24/202) (22/93) (6/53) (!5/37)
~
P
~~aluf
1 otal.·,
n.o (791606! 0.03 () :\9
(14/205) (14/95) (6/47) (7/44)
9.3 19.1 12.0 27.2 7 /1.1\01
1
1\
(38/407) (36/188) (12/100) (2218!) /1':'0/I"I._'U"\-\.
14. i (37 /262) 27.3 (9/33)
7.9 (21/267) 21.2 (7/33)
V.U~l
11.\J \:JOI J.::;")
0:57
24.2 (16/66)
18.1 (29/160) 12.6 (17/135)
8.8 (13/147) 9.8 (15/153)
0.016 0.45
13.7 (42i307) II. I (32/288)
14.1 (24/170) 18.8 (241128)
14.9 (24/161) 4.8 (7/146)
0.96 <0.001
11.5 (481331) ll.3 (3ll274)
j
l
19.7 (28/l42) 9.8 ( 13/ 132) 28.0 (7/25)
16.7 (23/138) 4.3 (6/l38) 6.4 (2/31)
16.0 (8/50) 20.1 (29/ 144) !0.5 (ll/105)
19.6 (ll/56) 9.3 (14/l51) 6.0 (6/lOO)
0.42 0.076 0.028
18.2 (51/280) 7.0 ( i 9f270) 16.1
(9/56)
17.9(l9/l06) 14.6 (43/295) R.::l (17 /20.<;)
*Mode of delivery, preeclampsia, and PROM recorded-for only 595 of the 606 women with single births. t P vaiues are not reported for comparison of RDS rares in these subgroups because the risk factors rriay be aHected by tn:atrnent assignment after randomization. :j:P values for the comparison of RDS between treatment gr-oups controlling for that variable. §Includes North American Indians and Hispanics.
The dexamethasone concentrations in maternal blood, taken as a function of time during the adminisc tration of the four doses, is shown in Fig. 1, A, for women delivered of their infants more than 50 hours following the first dose. In the steroid-treated group there was a rise and fall in plasma dexamethasone; but no •mch in the olacebo llrouo. Hv------- ch::~mre ------o- occurred ------• v drocortisone and estradiol concentrations in maternal plasma (Fig. 1, B and C) showed a pronounced decrease after dexamethasone administration. Analyses of extended blood sampling on a limited number of mothers indicated a return to control values by 72 hours (data not shown). Fig. l,D, shows the presence in the umbilical vein (zero time) of dexamethasone and its subs.equent disappearance in the newborn infant compared to placebo groups. The highest concentration of dexamethasone were found in umbilical and neonatal plasma from infants who were delivered within 12 hours after the- administration of the last dose of de1
·
J
xamethasone. Irrespective of whethe-r th-is represented the first or the fourth dose, the vatuesat zero time were similar and therefore the data were: pooled. These concentrations did not exceed 7 ng/rnland returned to control values within 48 hours. The concentration of hydrocortisone in umbilical vein and artery was also suppressed (Fig. l, E and F). Treatment.et'fect On ltD8 in . _~u_ps. Because most of the observed. ti·eatment effects appeared to be in the singleton group, this group has been exami-ned in further detail. Forsingleton irifants (Table VII), the l 0. 1% incidence of RDS in the steroid group differed significantly from the i6.0% incidence in theplacebo group (P = 0.93).* The reduction in incidence of RDS was consistent regardless of whether or. not LIS ratioassessment was available. to aid in the decisiQn on-entry *P values in Table VH represent comparison between
placebo and steroid within each su~roup; by simpie chi· square analyses with I degree of freedom (df).
Volume 141 Number 3
Effect of antenatal dexamethasone on prevention of ADS 283
Table VIII. Percentage of single infants with RDS by treatment in race/sex subgroups Treatment
I
Race/sex subgroups
Placebo
Female White, not Hispanic Black, not Hispanic Others*
24.2 (16/66} 9.6 (5/52) 30.0 (3/10) 16.0 (12175) 10.0 (8/80) 26.7 (4/15)
Steroid
P value
Total
9.4 (6/64) 1.5 (1167) 0 (0115)
0.02 0.04 0.05
16.9 (22/l30) 5.9 (6/119) 12.0 (3/25)
23.0 (17174) 7.0 (5171) 12.5 (2/l6)
0.39 0.52 0.32
19.5 (291149) 8.6 (131151) 19.4 (6/31)
Male
White, not Hispanic Black, not Hispanic Others*
*Includes North American Indians and Hispanics.
Table IX. Percentage of single infants with RDS by treatment and subgroups of gestational age at delivery and duration in study Gestational age at delivery (Dubowitz)
<30 wk
Duration in study
<24 hr 24-7 days >7 days 30-34 wk <24 hr 24-7 days >7 days 34+ wk <24 hr 24-7 days >7 days Dubowitz determination not performed
Placebo
33.3 41.6 100.0 31.8 25.4 26.9 0 6.2 5.2
( I/3) (5112) (Ill)
(7/22) (16/63) (7/26) (0/25) (4/64) (4177)
into the study, although a significant reduction was observed only in the group with known immature LIS ratios. The results in Table VII indicate that RDS incidence is associated with preeclampsia, PROM, gender, and race. It is also associated with gestational age at entry and with center (data not shown). The difference in RDS incidence in the two treatment groups was sig· nificant when adjusted for these six factors simultaneously (P 0.025) or when adjusted for each factor individually. Since dexamethasone appears to affect incidence of RDS differently in the various subgroups, further statistical analyses explored this phenomenon. In these analyses, the impact of each factor on treatment effect is analyzed by means of chi-square test adjusted for the presence of the other five factors. Time to delivery and mode of delivery were not included in the adjustments since they are outcomes determined after randomization and therefore could have been influenced by treatment. There was an apparent increased incidence of RDS associated with cesarean delivery occurring without previous labor and also with the presence of preeclampsia. In contrast, a decrease in the incidence of RDS was associated with PROM but only in the placebo group. There is some evidence that
Steroid
P value
Total
66.6 (2/3) 60.0 (3/5) 50.0 (112) 30.8 (8/26) 10.6 (7/66) 26.3 (5/19) 3.8 (1/26) 5.0 (4/80) 0 (0/77)
0.41 0.54 0.39 0.75 0.03 1.0 0.32 0.74 0.05
50.0 (3/6) 47.0 (8/17) 66.6 (2/3) 31.2 ( 15/48) 17.8 (23/129) 26.7 (12/45) 1.9 (1/51)
5.5 {81144) 2.6 (41154) 9
treatment effect was modified by PROM (X~ == 3.84, P 0.05) and possibly by preeclampsia
284
Collaborative Group on Antenatal Steroid Therapy
( kr ohc r ,"\ n1
and "other" male infants, respectively, Reduction in RDS incident:e ot:<.:urred primarily in the 30 to 34 weeks' gestational age group among those who delivered belwecn ~~ hours and 7 davs (Table!:\).
Comment Although this cooperative study of 661 mothers and 720 premature infants of different racial and ethnit: backgrounds in five geographicallv separated clinical centers has demonstrated that rnaternal dexamethasone treatment prior to premature delivery reduces the o\Trall incidence of diagnosed RDS in the nc\vborn infant in accordance with previous studies, JO-ra it has also uncovered previously unkno\vn limitations of the port'ntial usefulness of such therapy. Moreover, in thi,., study the synthetic corticosteroid or ·estrogens in mother and fetus (Fig. l) and the neurologic developmt'nt of the infant (Table V) ha\'e been measured. Prechtl examinations of the infants at 40 weeks' corrected gestational age showed a trend toward fewer abnormal fetuses in the steroid-treated group although the difference was not significant. It must be emphasized, however, that long-term neurologic and devdoprnt;>ntaJ follow-up must he completed hefon: ;1 statement can be made about the risks of dexamethasone to tht;> fetus that mav be susoected based on nrevi' ' ' ous studies. 22 - 26 The demographit: factors in the two groups were comparable except for gestational age (Table !). This is apparently due to chance, and the treatment benefit remains significant after adjustment for this difference. The distribution of risk factors in each group, including the use of varying tot:olvtic drugs, was the same. Dexamethasone did not appear to reduce the incidence of RDS in newborn twins or triplets (Table ll I). The numbers were small in this subgroup, and caution must be exercised in making generalizations, but the total lack of steroid effect in multiple births is an incentin: for further investigation into this problem. It is possible that steroid dynamics are different in multiple births and also that different concentrations of dexamethasone may reach the fetuses. Although previous im·t;>stigations had not shown a relationship between gender and treatment efficacy, a highly significant association was found in this study (Table VII). In fau, signihcant reduction in RDS incidence in the steroid group occurred only among female infants (Table VIII). A relationship, although not at the same level of significance, was also found between race and treatment efficacy (Table VII). Further analyses (Table VIII) suggested that white, male infants received no benefit from treatment, and although the incidence of
\
r . l91i 1 Jb.'llt't. C~vrwcol.
RDS was less among black and "other" mak infants after dexamethasone treatment; the diHtTcnn·s were not statistically signihcant. I 'he !lUillbt'lc'> in tiv:'c Hlh· groups are small. howe\'et. and results should be imnpreted with caution. The sex a~ well a-; the race int.crat'· tion with treatment effect w·as unanticipated and w111 be explored further in future reports. The neonatal mortalit\' rate 1' as lower in hr1th the steroid and placebo groups n1.>1S{ and H.HC(, JT:,j)('ttively) than 'Wotild have been expected on the ba~is of previous studic:,, This might have occurred as a result uf our patient selection t:riteria -and ntight ha\T accounted for our inabilitv 10 demonstrate ,m ellen of steroid on neonatal 1nnrtafity rates, wluch h~aJ been suggested in other trials.'"· ;:: On the other hand, early and intensive ruaternal. le.tai, and neonatal sur\·eiltance and intervention nla) ha\'c reduc:ed the impact ol treatment nn the neonatal mortality ratC'. There was no difference in incidence of infections in the mother:,; receiving steroid or placebo in thi., stuch, but the infant:,; born of mothers receiving steroids showed a decreased_ incidence of infection (within 72 hours) (fable \' l), However, it must be kept in mind that cultures were obtained on the basis ol symptoms rather th:w from a random selenion or I rom all infams. Thi'> decrease mav be related. in pan. to the dt'creased incidnu:e of RDS in this group. There was also no effect of steroid treatment on other postpartum complicatiom whic-h suggests wnsidt~rable specificity of corticostermd effect on developing processt;>s. A> previouslv reported/' cesarean section was found to be associated with an increased risk of RDS as compared with vagina~ delivery (Table VII). The risk of RDS is most significant in the mother who undergoes cesarean section when not in labor. The effect ol' the ~t.eroid treatment ('uul.d not completely overcome the apparent diiferenu: benveen cesarean and vaginal ddivery (see Results). PROM was associated with a decreased inciden<.:c o! RDS in the placebo group, as previouslv reporte(F~";;; (! abk' \'II). In contrast to cesarea11 section. the effect of PROM on RDS is climini~hed follow.ing dexamethasone treatment, suggesting that this et'l<:·ct may be nwdiated through a mechanism similar to exogcnow• steroid administration and that thl' n,·o cflech at-e nr)t additive. Preeclampsia was associated with an increased_ incidence of RDS in the placebo group wltich, inpa.rt. may be attributed to the fact that this complication fn:yuently necessitates early delivery, resulting in an int:rt;>ased incidence of prematuritv. Althougn_othet· -Studies have shown a higher incidence ol mature US ratios in hypertensive women with premature deliveries,:" -:1 3 complications sut:h as chn;nic and acn-!e fetal asphvxia
Volume HI Number 3
may occur as a result of the preeclampsia and may cause severe metabolic changes in the fetus. These changes may account for the increased incidence of RDS in such infants with presumed mature LIS ratios. The relationship of treatment, RDS, gestational age at delivery, and duration in study (Table IX) suggests that reduction in RDS occurred primarily in the group at 30 to 34 weeks' gestational age, among those infants who were delivered between 24 hours and 7 days after initiation of treatment. This observation should, however, be interpreted with caution because duration in study is an outcome determined after randomization. The appearance of de~amethasone in the fetus following treatment demonstrates the availability of the synthetic corticosteroid in the circulation for a period of exceeding 12 hours after the last dose (Fig. 1). The impact of this dose of steroid on maternal and fetal adrenal response and on estrogen metabolism in the fetoplacental unit demonstrates the drug's effectiveness on well-established fetal physiologic functions. In summary, the results of this trial confirm the findings of Liggins and HowielO and others 11 - 13 that
Effect of antenatal dexamethasone on prevention of ADS 265
prenatal steroid administration is effective in reducing the overall incidence of RDS. However, since the effect of treatment is dependent upon multiple deliveries, sex, race, and other characteristics of the infant and mother, its potential usefulness will be dictated by those limitations. These and the still unknown long-term effects of this therapy, in our opinion, indicate that antenatal steroid therapy should be used selectively and with caution. On request of the Division of Lung Diseases of the National Heart, Lung, and Blood Institute, Merck, Sharpe, & Dohme provided the drug and placebo preparations used in this study. (This acknowledgement of appreciation is in no way an endorsement of a particular product.) Special acknowledgement is given to the following consultants who assisted in the preparation of the study p~:otocol: Glen Aylward, Ph.D., Alfred Brann, M.D., Josephine Brown, Ph.D., Philip Farrell, M.D., Ph.D., Alan Hodson, M.D., Frank Pedersen, M.D., James Schwartz, M.D., William Taeusch, M.D., and Edward Tronick, Ph.D.
REFERENCES 1. Farrell, P.M., and Avery, M. E.: Hyaline membrane disease, Am. Rev. Respir. Dis. 111:657, 1975. 2. Farrell, P. M., and Wood, R. M.: Epidemiology of hyaline membrane disease in the United States. Analysis of national mortality statistics, Pediatrics 58:167, 1976. 3. Inselman, L. S.: Respiratory distress syndrome, Pediatr. Ann. 7:34, 1978. 4. Kamper,].: Long term prognosis of infants with severe idiopathic respiratory distress syndrome. I. Neurological and mental outcome, Acta Paediatr. Scand. 67:61, 1978. 5. DeLemos, R. A., Shermeta, D. W., Knelson,J. H., Kotas, R., and Avery, M. E.: Acceleration of appearance of pulmonary surfactant in the fetal lamb by administration of corticosteroids, Am. Rev. Respir. Dis. 102:459, 1970. 6. Kikkawa, Y., Motoyama, E. K., and Gluck, L.: Study of the lungs of fetal and newborn rabbits, Am.]. Pathol. 52: 177, 1968. 7. Wang, N. S., Kotas, R. V., Avery, M. E., and Thurlbeck, W. M.: Accelerated appearance of osmiophilic bodies in fetal lungs following steroid injection, J. Appl. Physiol. 30:362, 1971. 8. Taeusch, H. W., Heitner, M., and Avery, M. E.: Accelerated lung maturation and increased survival in premature rabbits treated with hydrocortisone, Am. Rev. Respir. Dis. 105:971, 1972. · 9. Platzker, A. C. G., Kitterman, J. A., Mescher, E. J., Clements, J. A., and Tooley, W. H.: Surfactant in the lung and tra~;heal fluid of the fetal lamb and acceleration of its appearance by dexamethasone, Pediatrics 56:554, 1975. 10. Liggins, G. C., and Howie, R. N.: A controlled trial of antepartum glucocorticoid treatment for prevention of the respiratory distress syndrome in premature infants, Pediatrics 50:515, 1972.
ll. Caspi, E., Schreyer, P. Weinraub, Z., Reif, R., Levi, I., and Mundel, G.: Prevention of the respiratory distress syndrome in premature infants by antepartum glucocorticoid therapy, Br.J. Obstet. Gynaecol. jil3:187, 1976. 12. Papageorgiou, A. N., Desgranges, M. F., Masson, M., Colle, E., Shatz, R., and Gelfand, M. M.: The antenatal use of betamethasone in the prevention of respiratory distress syndrome. A controlled double-blind study, Pediatrics 63:73, 1979. 13. Doran, T. A., Swyer, P., MacMurray, A., Mahon, W., Enhoming, G., Bernstein, A., Falk, M., and Wood, M. M.: Results of a double-blind controlled study on the use of betamethasone in the prevention of respiratory distress syndrome, AM. j. 0BSTET. GVNECOL. 136:313, 1980. 14. Hughes, E. C.: The committee on terminology of the American College of Obstetric and Gynecology, Obstetric Gynecological Terminology, Philadelphia, 1972, F. A. Davis Company. 15. Prechtl, H., and Beintema, D.: In Lavenham, L., editor: The Neurological Examination of the Full-term Newborn Infant, London, 1964, Little Club Clinics in Developmental Medicine, No. 12, Heinemann. 16. Brazelton, T. B.: Neonatal Behavioral Assessment Scale, London, 1973, Clinics in Developmental Medicine, No. 50, Heinemann. 17. Gluck, L., Motoyama, E. K., Smits, H. L., and Kulovich, M. V.: The biochemical development of surface ac.tivity in mammalian lung, Part I, Pediatr. Res. 1:237, 1967. 18. Orczyk, G. P., Caldwell, B. V., and Behrman, H. R.: In Jaffe, B. M., and Behrman, H. R., editors: Methods of Hormone Radio-immunoassays, New York, 1974, Academic Press, Inc., pp. 333-345. 19. Bishop, Y. M. M., Fienberg, S. E., and Holland, P. W.:
286
Collaborative Group on Antenatal Steroid Therapy
lhtul>c; l \tn.!
Discrete multi\·ariate analysis: Theory and practice, Cam 1-~-~...l--~
UllUOC,
\.A......
1\'ld:"'~.,
JfV"'H::
1~/J,
--rL ..
'l.f
r 'r
1 Ut" LV1.1.1.
n ___ .
("It":')~.
0. Brown, M. B.: Screening of effects in multidimensioual
contingency tables. Appl. Stat. 25:37, 1976. I. Mantel, N., and Haenszel, W.: Statistical aspects of the
analyses of data from retrospective studies of disease, J. :-.Jatl. Cancer Inst. 22:719, 1959. '2. Howard, E., and Granoff, D. !VL: Increased voluntary running and decreased motor n)ordination in mice afte;. neonatal corticosteront' implantation, Exp. Neurol. 22: 661, 1968. :3. Winick, M., and Coscia, A .. Cortisone-induced growth failure in neonatal rats, Pediatr. Res. 2:451, 1968. :4. Schapiro, S.: Some physiological, biochemical and behavioral consequences of neonatal hormone administration: Cortisol and thyroxine. Gen. Comp. Endocrinol. 10:214,
2H.
2!!.
30.
:n.
196R.
'5 Fitzhardingt\ P. M., Eisen, A , Lejtenyi, L, Metrak ...s, K. and Ramsay, M.: Sequellae of early steroid administration in the newborn infant, Pediatrics 53:877, 1974. ~6. Anderson, G. E., and Friis-1--Iansen, B.: Hypercholester~ ulemia in the newborn. Occurrence after antenatal treatment with betamethasone-phenobarbi~al-ritodrin for the prevention of the respiratory distress syndrome, Pediatrits 62:R, 197R.
:n.
I'IKI
t_,ynetl_\1.
l 'he1, R. H .. :\llen, .\. C. .. md Md.e;m, f. H resp1rawr\ di;,tres& 1eiated ro gntati1. f: 0~'.! FT. ( _;, ~H nt.. lll:H2ti, 1971. Bauer. C. R.. Stern, L.. and Colle, E.: Prolvng.ed tUJltllre of membrane' as,ociated with a decreased incidence of respiraton distress SHHlromc. Pediatric~ 53!7. 197-1 Richardson. C. J, Pomerance. J J.. Cunningham. M. D .. and Gluck, L · A.cceiPtrne, Arch. Dl~. Child. 5i:67·i, i976. \-lorrison. J C .. Whybrew. vV. D., Bu( "'az, E. I . Wise1, \\'. L, and Fi>h, S. A.: fhe lecithin/srihlngomydin ratio in case-, associated wilh felomatnnal disease. AM. J 0BSHT. CYr..ECOL. 127::~6:1. l!J77. ··~··-/·
32.
(}h'l-k!
~~~···-··
~~
~'"'
Editorial comment From the pioneering work of Francis Moog, it was known that glLu-on1rticoids v.ere capable of accelerating developmental processes in mammalian systems. and then Liggins made the astute observation that when glucocorticoids triggered th<: onset of labor in pregnant sheep, the lambs born prematurely had well-aerated lungs, whjle a large number of control animals died of the respiratory distress syndrome (RDS). Thi~ set the stage for a large double-blind prospective stud\. which was published by Liggins and Hov. 'ie _(reference 1o_ in- paper), -on the ust of bet;~n~ethasonc- in -the prevention of RDS in a very homogeneous population (Jf women at risk recmited ill Auckland, New Zealand. While the resuJts of many small sttldies have been published in the 9 years since the results of the New Zealand study were presented, that studyremained as the only one of irs kind. Long-term f.()llow-u.p of the children was not available and the nagging questions of efficacy in the use of glucocortin1ids in humans had to be answered. The aims of the present studv were to ;-mswer some of these questions in a North American setting. The present report is a complex, multicentered, double-blind ;tudv which ''as designed to answer the following questions: (I) Does the administration of dexamethasone, in the dose described. to the mother with threatened premature delivery reduce the incidence of RDS in the premature infant( (2) Does the dexamethasone cross the placenta in sufficient amounts t(J affect fetal mctabolisln: (3} Does such corticosteroid administration have any short-term or long-term effect(-s) on the fetus? All but the last part of the third question have been answered. Dexamethasone administration does reduce RDS; it does nn~s the placenta in all subjects, and it has no demonstrable shnrt·term effects. There are manv subcategories which have been addressed, but rcsul!, ~hould he interpreted cautiously because, in sptie of significance, the !lumbers HI some groups_ are small. For example, the data on the efficacy of the drug· in black male children wil1 require further direct inYestigation to_ resolve cori?pletely. ()_t~er such data -should be interpreted similarly as areas for future investigation. The efficacy is proved under certain conditions; however, corticosteroids should be used with camion. Rnan Litt{f, M.D.
Volume 141 Number 3
Policy-Data Monitoring Panel Brian Little, M.D. (Chairman) Case Western Reserve University Cleveland, Ohio Mary Ellen Avery, M.D. Children's Hospital Boston, Massachusetts David de Mets, Ph.D. NHLBI Bethesda, Maryland Max Halperin, Ph.D. University of North Carolina Chapel Hill, North Carolina Patricia King, J.D. Georgetown Law Center Washington, D.C. Arthur Parmelee, M.D. UCLA-School of Medicine Los Angeles, California Samuel Solomon, Ph.D., F.R.S.C. Royal Victoria Hospital Montreal, Quebec, Canada David Sy!wester, Ph.D. University of Vermont Burlington, Vermont
James Ware, Ph.D. Harvard School of Public Health Boston, Massachusetts NHLBI Program Office Bitten Stripp, Ph.D., Project Officer Bethesda, Maryland Claude Lenfant, M.D., Director, Division of Lung Diseases Bethesda, ~.1aryland The study was carried out at the following centers by the following principal and coprincipal investigators who also served as members of the Steering Committee: Clinical Centers Richard Depp, ?vf.D. John Boehm, M.D. (Northwestern University) Chicago, Illinois
Effect of antenatal dexamethasone on prevention of ADS
Richard Zachman, M.D., Ph.D. Luis Curet, M.D. (University of Wisconsin) ~vfadison, Vt'isconsin Charles R. Bauer, M.D. Louis Fernandez-Rocha, !'vf.D. Gene Burkett, M.D. (University of Miami) Miami, Florida Sheldon Korones, M.D. John Morrison, M.D. Jack Schneider, M.D. Garland Anderson, M.D. (University of Tennessee) Memphis, Tennessee Henrique Rigatto, M.D. Leo Peddle, M.D. Frank Manning, M.D. (University of Manitoba) Winnipeg, Manitoba, Canada Coordinating Center Kenneth Poole, Ph.D. Vijaya Rao, Ph.D. Betty Hastings (Research Triangle Institute) Research Triangle Park, North Carolina Central Laboratory David Fukushima, Ph.D. John O'Connor, Ph.D. Jack Kream, Ph.D. (Montefiore Hospital) New York, New York
287
NEONATAL respiratory distress syndrome (RDS) continues to rank as a major public health problem. Precise data on the incidence of RDS are difficult to determine because of complex contributing factors and an apparently changing rate. It has been estimated that RDS occurs in 14% to 60% of premature deliveriesat gestational ages between 28 and 35 weeks, 1 and RDS and concomitant complications of prematurity may account for up to 75% of neonatal deaths. As recently as 5 years ago, the death rate attributed primarily lO RDS was estimated to be 23 per 1,000 live births, 2 and although
Research performed pursuant to contracts NOJ-HR-6-2948, 2949,2950,2951,2952, and 2953 with the National Heart, Lung, and Blood Institul.i!, Natioool Institutes of Health. United StafRs Departmmt of Health and Human Sen•ice,,, Recei·(led for publication january 29, 1981. Revised May I 1, 1981. Accepted May 13, 1981. Reprint requests: Pmgram Office, Clinical Trwl on Antenatal StRroid Therapy, Division of Lung Diseases, National Heart, Lung, and Blood lnstitutR, National institutes of Health, Room 6AOJ, Westwood Building. Bethesda, Maryland 20205.
*See Editorial Comment following this article. **Based on the Collaborative Study on Anteootal Steroid Therapy sponscrred by the Division of Lung Diseases, Natioool Heart, Lunty and Blood Institute, National Institutes of Health, Bethesda, Maryk!nd. Detailed reports '!f a number of aspects mentioned in this paper .are now in preparation and the long-term effects of dexamethasone administration on the i:nfants are currrntly under investigation.
276
chances of neonatal sunival have improved,J{DS remains a major cause of death.'1 As more infants ~vit11 RDS survive, permanent serious sequelae of the di~or· der itself or its associated complications continue to irlcrease.4 Therefore, it is important teo explore m-easure~ that may prevent this syndrome. Animal studies in the late 1960sand early 1970s had shown that the administration ol corticq~teroids ic mothers at an appropriate time priot ro delivery an:el· crated lung maturation and resulted in viable prema· ture offspring?- 9 The first applkatiOJ) of this knowledge to the dinical setting was reported by Liggins and Howiew in New Zealand. In 1974, the Division of Lun~ Diseases, National Heart, Lung, and Blow Institute and the National Institute of Child Health and Hurnar Development jointly sponsored a workshop on Possibl< Pharmacologic Mechanisms for Enham:ement or Lun~ Maturation. The participants recommended that a clinical trial be conducted to determine r.he efficacy of ante· natal steroid administration in preventing RDS and ft assess whether there might be signiticant short- or long· term toxic effects associated with such inten·ention. Such a trial was initiatt'd in 1976. The protocol \,·a: designed to answer three questions: {I) Does dexa· methasone phosphate administered iritramu<>tularly tl the mother reduce the incidence of JtDS in the off: spring? (2) Does this inten-ention have adverse short term effects on the mother, fetus. and neonate? (:3 Does it have adverse long-term effects on the infan during the first i8 months of life? A Policy-Data Monitoring Panel com~1sed of e?<
Volume 141 Number 3
perts in biostatistics, biochemistry, pediatrics, neonatology, obstetrics, pediatric psychology, and jurisprudence (from nonparticipating institutions) was established to monitor adverse effects, progress, and quality control and to make recommendations to the National Heart, Lung, and Blood Institute for changes in the study plan. Subsequent to initiation of the study, several small, retrospective and prospective studies have reported a reduced incidence of RDS in premature infants born of corticosteroid-treated mothers. 11 - 13 To date, however, no reports have fully addressed the possible adverse short- or long-term effects on the mother, fetus, and neonate, especially with regard to the motor, neurologic, and intellectual development of the infant; and with the exception of the study by Liggins and Howie, 10 reports have not included large samples. The long-term effects of maternally administered dexamethasone upon neurologic, motor, and intellectual development of the off~pring are currently being investigated in a double-blind fashion and will be reported separately when the follow-up phase of the study is concluded. Material and methods During the first phase of the clinical trial a common study protocol was designed by the investigators from the five clinical centers and the coordinating center, with the advice of consultants. The protocol was standardized according to a manual of operations while at the same time maintaining the usual standard of patient care. After approval of the protocol and manual of operations by the Panel, the study entered into the 3 year recruitment-intervention phase in March, 1977. At present, the study is in the final follow-up phase, which will be completed in March, 1983. At that time, the last infant to enter the study will have had an opportunity to have its 36 month evaluation. Patient selection. From March I, 1977, to March I, 1980, a total of 7,893 patients from the five participating clinical centers were screened for eligibility in the study. Patients between 26 and 37 weeks' gestation who entered the hospital at high risk for premature delivery and consented to participate were considered for the study. Similar consent forms were used by all centers. Patients were t~xcluded if one or more of the following criteria were present: the cervix was dilated more than 5 em; delivery was anticipated in less than 24 hours or more than 7 days later; signs of intrauterine infection were present; corticosteroids had been administered for any reason during the current pregnancy; there was a history of peptic ulcer disease; active tuberculosis or viral keratitis existed; st~vere fetal Rh s~nsltization had developed; or the infant was likely to be unavail-
Effect of antenatal dexamethasone on prevention of ROS 277
able for follow-up. The criteria for exclusion were determined as follows: Gestational age was assessed based upon the last menstrual period, if the dates were reliable, and/or on ultrasonography to measure the fetal biparietal diameter and chest and/or abdominal circumference. In cases of uncertainty, the lecithin/sphingo~ myelin (LIS) ratio was the final criterion for exclusion. Fetal lung maturity was evaluated by measuring the LIS ratio in amniotic fluid and was standardized between centers and maintained by quality control. A value of 2.0 or its standardized equivalent indicated maturity. If gestational age was less than 34 weeks, the patient could be entered into the study without the determination of the LIS ratio, but such a determination was encouraged. Patients with hyperthyroidism, elevated blood pressure (greater than 140/90 mm Hg), "placental insufficiency," drug addiction, antinarcotic treatment (methadone), or a gestational age greater than 34 weeks could be considered for inclusion only if an LIS ratio was obtained and it did not indicate fetal pulmonary maturity. Patients were carefully assessed for the probability that they would be delivered of their infants at least 24 hours after entry into the study but not more than 7 days after the first dose of drug administration. Intervention and follow-up assessment. Eligible patients were randomized to receive either dexamethasone phosphate or placebo. Identical vials containing the material to be injected (one vial per patient) were coded uniquely across all centers by a sequential numbering system. A sealed envelope containing. the identity of the contents was attached to each vial. This envelope was to be opened only in the case of emergency and was returned to the coordinating center along with the maternal entry form. The randomization was carried out in a double-blind fashion within each center, and a scheme was designed in blocks of ten so that the maximum discrepancy at any time during the trial between the number of placebo and steroid patients within a center would be five. Both placebo and steroid were dispensed as 10 ml clear, colorless solutions which diffeied only in that one contained the steroid (dexamethasone phosphate, 4 mg/ml). A total of 1.25 ml of the selected solution was administered intramuscularly to the patient every 12 hours for a total of up to four doses (20 mg of dexamethasone phosphate). Detailed information was obtained regarding assessment of prenatal course, labor, and delivery. In some cases labor was arrested for at least 48 hours by the administration of tocol ytic agents such as ethanol or isoxsuprine. Tocolytic therapy was stopped if labor continued to progress to a cervical dilatation of 5 em or if obstetric complications arose. Detailed information
278 Collaborative Group on Antenatal Steroid Therapy
Onobn i. l:IKI \rr:_ J ( )hst(·i ( w'PH:~cnl
Table I. Comparison of treatment groups on baseline data
r·--------·c··-·--
Treatment
Data itemlvarwble
~--------------,---------------~1
No. of mothers Race distribution (%)* White Black Others Sex of infant(% male) Gestational age distribution at entry (%)t <30 wk 30 and 31 wk 32 and 33 wk ~34 wk Gestational age (wk):j: Age at entry (yr):j: Chronic hypertension(%) Preeclampsia(%) PROM(%) Use of labor-delaying drugs (%) § Et..l)anO!
Isoxsuprine None More than one drug Routine use of certain drugs (%)11 Smoking during pregnancy (%) *Chi-square analysis tChi-square analysis :!:Mean± SEM. §Chi-square analysis IIMarihu~na, heroin,
P ltu:ebu
S te·roui
P vafut
347 47.0 44.4 ll.6 :J:l.fi
46.1
44.4 9.3 SUI
OR~
O.U4
27.4 25.9
12.4 31.1 ± 0.12 24.6 ± 0.13 6.6 10.7 44.3 6.6 44.1 46.1 3.2 8.1
42.0
:22.1 2R.4 30.4 19.2 31.4 ± 0.12 24.6 :t 0 . 13 5 ') I LX 49.6
0.07 0.99
0;43 (Lf>.'l 0.16 0.37
4.0 43.6 49.3 3.1 8.:1
0.90
o.:N
:nH
for race distribution = 0.15 (2 df). for distribution of gestational age between treatment groups = 8.29 (3 df). for prevalence of use of labor-delaying- drugs between the treatment groups cocaine, methadone, methaqualone, phenobarbital, and others.
recorded for each patient included: smoking habits, :irug usage, g~neral medical and surgical history, medtcal and obstetric conditions affecting the current pregnancy, familial problems that might affect the in::idence of RDS, and data on the antepartum course of each gestation. Some of these observations included ::hronic hypertension (i.e., persistent hypertension present before 20 weeks' gestation and/or after a previous pregnancy), preeclampsia (defined by Hughes 14), and premature rupture of membranes (PROM) (evidenced by Nitrazine or fern-positive Auid in the vagina on sterile speculum examination defined as occurring at least 1 hour prior to onset of labor). The diagnosis of RDS was based on standard clinical, radiolagic, and blood gas findings. These include chest retraction, grunting, cyanosis, increased ambient oxygen requirement, hypercarbia, and a ground-glass appearance on chest x-ray with air bronchograms and elevated diaphragms. This diagnosis was confirmed in each infant at each center by the neonatal coinvestigator. Severity was defined as: ( 1) mild if supplemental oxygen alone was required, (2) moderate if some form of continuous distending airway pressure was required in addition to oxygen, and (3) severe if mechanical ventilation was required. Neonatal infection was diagnosed by positive
= 3.12 (3df').
cultures. Cultures were obtained ·when indicated--by clinical signs and syrnptoms. i\t the correcte(-l_g-e~~tationa! age of 40 weeks (determined by Dubowitz examination ar birth) aU infants in the study v:ere scheduled for a Prechtl exali1ination 1" employing visual componentsofthe Brazelton test. 16 At9and 18months following the 40 week examination. a Bayleyexamination, neurologic assessment, and general pediatric evaluation have been (or will be) administerei:t At 36 months, a McCarthy test will be conducted with a dec tailed neurologic examination and a general pediatrit· evaluation. These latter examinations are an effort to detect any long-term effects ofdexamethasone administration to the mother. Maternal samples of venous bJood, for measurements of dexamethasone. hydrocortisone. estradi(JL estrone, and estriol, were obtained at the time of entry into the study and at specified intervah aftercdexamethasone or placebo administration to the mother. Blood from umbilical cord artery and vein and -neonatal blood (the latter obtained by heel stick) were also sampled arid analyzed .for hydrocortisone· and dexamethasone. Laborat:ery~aJIUdyses. Determina:tion of the LIS ratio of the amniotic fh.iid was performed in each centerl;.ya modification of ihe method described by Gluck and
Effect of antenatal dexamethasone on prevention of RDS 279
Volume 141 Number 3
Table II. Status of randomized mothers and infants
Total randomized Mothers who lost infants before delivery Mothers delivered of infants Mothers with fetal deaths Mothers with early neonatal death before RDS assessment Mothers with infants lost to study befor<: RDS assessment
696
2
Mothers with infants available for RDS assessment Deaths after RDS assessment but befon~ Prechtl examination Lost to follow-up before Prechtl examination Prechtl examination not performed
661
347 7
349 7
Infants 743 14 Fetuses Infants 7
372
371
8 3
6 4
Infants
2
2
0
Infants
720
359
361
59
29
30
21
IO
11
40
20
20
600
300
300
14
682 12 7
Total No. of infants with Prechtl examination
associates. 17 Vials containing known concentrations of purified lecithin and sphingomyelin added to amniotic fluid were prepared at regular intervals at the Royal Victoria Hospital, Montreal, and sent to the centers where they were analyzed with the experimental samples of amniotic fluid for quality control. The determinations of estrone, estradiol, estriol, and hydrocortisone were performed in the Central Laboratory by radioimmunoassay .18 Dexamethasone was analyzed by a specific radioimmunoassay procedure with prior chromatography (devised by J. Kream, S. Mulay, D. Fukushima, and S. Solomon). Sample size and statistics. Because changes in motor, neurologic, or intellectual development of the infant after corticosteroid treatment during the last trimester of pregnancy are not known, the sample size was determined solely on the basis of the anticipated reduction in incidence of RDS and the fact that previous data 1 suggested that the frequency of RDS varied substantially with gestational age. The frequency of RDS was thus assumed to be 0.80 for infants of 26 to 28 weeks' gestational age, 0.65 at 29 to 30 weeks, and 0.25 at 31 to 34 weeks. For the population of mothers, the proportion in each gestational age stratum was assumed to be 0.10, 0.20, and 0.70, respectively. This leads to an assumed control group RDS rate of 0.385. On the basis of available data it appeared that the steroid therapy might reduce the RDS rates to 0.55, 0.45 and 0.15, respectively. Presuming data analyses would take account of the gestational age strata, a sample size of 600 was estimated to have a 90% chance of detecting the assumed effect at the I% significance level (one-
tailed test). Early in the study, it became apparent that the incidence of RDS at each center was less than anticipated. Therefore, the recruitment phase was extended for 1 year to augment the sample size so that the probability with which a 25% to 30% change could be detected would remain dose to 0.9. The data were analyzed by means of analysis of variance for measured variables and contingency table methods for categoric data. Chi-square tests for association were used to test for differences in the distribution of categoric variables between treatment groups. When treatment group comparisons were adjusted for other factors, likelihood ratio tests of partial association were used. 19• 20 These are closely related to the Mantel-Haenszel method 21 in which treatment groups are compared after stratification on the level of other factors. Finally, likelihood ratio tests of three-way partial association were used to determine whether the size of the treatment effect depended on other characteristics of the mother or child. Significance was determined by means of the asymptotic chi-square distribution of the likelihood ratio statistic.
Results Patient characteristics, mortality rate, and loss to follow-up. Of 7,893 women screened for the study, i, 197 were excluded. Approximately 83% were ineligible, 5.5% refused to participate (patient or physician), and 11.5% were excluded for a variety of reasons (requested the drug, planned adoption, or were unavailable for fol:low-up). The study criterion predominantly violated was the anticipated time to delivery (85% of
280
Collaborative Group on Antenatal Steroid Therapy
Table III. Incidence of RDS "mothers" (mothers with at least one infant with RDS) by treatment and plurality of deliveries
Table V. Outcome of Prechtl examination bv treatment for singie infants Outcum~
of Prrchtl examination
Treatment Plurality if deliveries
Placebo
Single Twins Triplets
48/299 (16.1) 10/26 (38.5) 1/3 (33.3)
31/307 (10.1) 10/24 (41.7) l/2 (50.0)
79/606 (13.0) 20/50 (40.0) (40.0) 2/5
All
59/328 (18.0)
42/333 (12.6)
1011661 (15.3)
I
Steroid
Total
Table IV. Distribution of infants by treatment and presence of RDS
:-lormal Dubious Abnormal Total
Placebo
Trdal
20(i
22:\
28
~?5
'i6
12
i
I9
246
258
429 :104
Table VL Morbidity outcomes (other than RDS) and other characteristics of single deliveries Outrome
Placebo
Steroid
l P value
Infection rate Mothers (all) Infants (infections
29/340 (8.5) I 0/299 (3.3)
27/342 (7.9) f/:"107 (1.3)
0.76 O.OY
:!39 ± 29
252± 29
0.75
:HJ.O ± 1.9
22.8 ±: 1.9
0.008
Treatment RDS
Placebo
Steroid
Total
Present Absent Total
65(18.1) 294 (81.9) 359
46 (12.7) 315 (87.3) 361
111 (15.4) 609 (84.6) 720
the 83%). Six hundred and ninety-six women were randomized into placebo and steroid treatment groups. Unadjusted baseline comparison of the two groups of mothers (Table I) suggests little difference in most aspeers of demographic and health risk factors, but the difference in mean gestational age at entry is close to nomina! significance (P == 0.07). When gestational age is distributed into the four categories listed (Table !). there is a significant difference (P = 0.04) in the age distribution between the two groups. This differem:c will be adjusted for analyses pertaining to treatment difference. An average of 3.4 doses were administered per patient, with equal distribution between the two treatment assignments. Nearly 70% of all patients received four doses, 79% received three or more, and almost 90% received at least two doses. There was no difference between centers with regard to number of doses administered. Mothers and infants lost to RDS evaluation or follow-up are listed in Table II. The 661 mothers available for RDS assessment produced 720 liveborn infants; of these mothers 328 were in the placebo group and ~)33 in the treatment group. Fetal and neonatal death rates were not significantly affected by treatment (Table II). Fetal death rate was 2.29f (Hi 371) in the placebo and 1.6% (6/372) in the steroid group. Neonatal death rate was 8/8% (32/363) in the placebo and 9.3% ( 134/ 366) in the steroid group. The combined fetal and neonatal death rate was 10.8% in both placebo and steroid groups. Major outcomes. The incidence of RDS amqng mothers, i.e., the proportion of mothers with at least one RDS infant, was decreased in the dexamethasone
within 72 hr)
Time to delivery (hr)* Duration of hospital stay (days)* Birth weight (gm)* Placental weight (gm)* Distribution of mode of delivery (%)t Vaginal Cesarean section
1,940 ± 43 473 ± 24
2,042 ± 43 510 ± 23
67.3 32.7
67.0 33.0
0.09 0.29
0.98
*Mean± S!':M. tChi-square test for distribution of mode of deJivery between treatment groups =
QTouo comoared to the olacebo uQTouo ( 12.6% versus l8.0o/r, P = 0.05) (Table III), this difference l)eiiig in the same direction among centers (data nQt shown). However, ther.e was no apparent effect of dexamethasone treatment on the incidence (}[" RDS among moth~ ers having plural deliveries (Table Ill). Infants.of the treated mothers showed an overall reducedjnddence of RDS (P = 0.04) (Table IV). Approximately two thirds of the RDS cases were severe in each group and there was no indication that dexamethasone in.fluenced the degree of severity (data not shownJ. The Preditl examination performed at 40 weeks' corrected. gestational age showed no difference in rate of abnormal outcomes between the two groups either in single births [4.9% ( 12/246) versus ·2.7o/c (7/258), P = '0.2] (Table V) or w:hen all infants indudingmult~ple births were consider:ed (data not shown), 4lthol.lgh in both cases the trend suggested more beneficial outcomes in the steroid group. There was no apparent association between treatment and postpartum .infections (Table VI). There was also no effect of treatment on other postpartum complications including hyperten~i~n or (_J
l
J.
1
1
Effect of antenatal dexamethasone on prevention of RDS
Volume 141 Number 3
MEAN VALUES OF FETAL PLASMA DATA
MEAN VALUES OF MATERNAL PLASMA DATA A
-Placebo
7
D
6
-Placebo o---""1)
5
e
---
4
"' w
E
\
3
I :::E
Steroid
\
\
z
281
\\\
I
____1 }-----
~
"'c
z
=~
(/)
30
;;
!w
E
40
36
0
~
26 20 15
80 a:
10 5
c
> %
0
L_--~----~-----L--~
~
F
50
: ~\
e "' E
.... 0 0
~
\f
en w
0 TIME!hounol
\l--l----~ 12
24
36
46
TIME (hourol
Fig. 1. Determination of steroids in maternal, cord, and neonatal plasma following administration of dexamethasone. Values are expressed as mean± 2 SEM.A-C, Concentrations of steroids in maternal plasma during and after administration of four doses, shown for women delivered of their infants more than 50 hours after the first dose (50 to 195 subjects per point for each of the two groups). The concentrations of dexamethasone, hydrocortisone, and estradiol differed significantly (P < 0.0001) between the placebo group and the steroid group at each point after administration at zero up to 50 hours. D-F, Dexamethasone determinations in cord vein blood (zero time) for deliveries within 12 hours of the last dose to the mother and in the neonate thereafter demonstrated the presence and disappearance of the steroid in the steroid-treated group ( 10 to 72 subjects per point) compared to the placebo group (32 to 114 subjects per point) (P < 0.0001 at time zero; P < 0.01 at 12 and 24 hours; P > 0.15 at 48 hours). Cord venous (E) and arterial (F) plasma hydrocortisone concentrations and the neonatal plasma levels thereafter within 12 hours o(the last dose of dexamethasone were suppressed in the dexamethasone group ( 16 to 87 subjects per point) compared to control subjects (30 to 112 subjecrs per point). (P < 0.05 at time zero forE but not statistically significant for F; at 12. 24. and 48 hours. P = 0.08, 0.0001, and 0.13, respectively, for both E and F.)
hypersensitivity reactions (data not shown). The incidence of infections in infants of singleton births, as diagnosed by positive bacteriologic cultures within 72 hours, was less in the infants of dexamethasone-treated mothers (1.3% versus 3.3%). A similar difference was observed when aii infants were considered ( 1.4% ver-
sus 3.1%) and the difference between dexamethasone and placebo persisted beyond 72 hours (data not shown). Duration of hospital stay was shorter for the infants of dexamethasone-treated mothers (P == 0.008). Mean birth weights and time to delivery did not differ significantly (Table VI).
UnoblT 1. 1~~~ 1
282 Collaborative Group on Antenatal Steroid Therapy
< ibs1e1 (~\nt·coi.
-\m
Table VII. Percentage of single infants with RDS by treatment and various subgroups .::__--.,.---·-·-·----Trealmrnt
Sub-groups
Availability of LIS ratio at entry LIS immature LIS not assessed Mode of delivery*t Vaginal Cesarean In labor Not in labor State of labor unknown Preeclampsia* (P = 0.02):1: i~u
Yes PROM* (P == 0.03)t No Yes Sex (P = O.OOI):j: Male Female Sex unknown Race (P = 0.02):1= White, not Hispanic Black, not Hispanic Others§ Duration in studyt <24 hr 24 hr to 7 days
....._,
">7
PL"'lcebo
Steroid
16.0 (481299)
10.1 (31 /307)
17.3 (24/139) 15.0 (24/]60)
8.7 (14/l60) 11.6(17/117)
II. 9 23.7 11.3 40.5 3
6.8 14.7 12.8 15.9 4
(24/202) (22/93) (6/53) (!5/37)
~
P
~~aluf
1 otal.·,
n.o (791606! 0.03 () :\9
(14/205) (14/95) (6/47) (7/44)
9.3 19.1 12.0 27.2 7 /1.1\01
1
1\
(38/407) (36/188) (12/100) (2218!) /1':'0/I"I._'U"\-\.
14. i (37 /262) 27.3 (9/33)
7.9 (21/267) 21.2 (7/33)
V.U~l
11.\J \:JOI J.::;")
0:57
24.2 (16/66)
18.1 (29/160) 12.6 (17/135)
8.8 (13/147) 9.8 (15/153)
0.016 0.45
13.7 (42i307) II. I (32/288)
14.1 (24/170) 18.8 (241128)
14.9 (24/161) 4.8 (7/146)
0.96 <0.001
11.5 (481331) ll.3 (3ll274)
j
l
19.7 (28/l42) 9.8 ( 13/ 132) 28.0 (7/25)
16.7 (23/138) 4.3 (6/l38) 6.4 (2/31)
16.0 (8/50) 20.1 (29/ 144) !0.5 (ll/105)
19.6 (ll/56) 9.3 (14/l51) 6.0 (6/lOO)
0.42 0.076 0.028
18.2 (51/280) 7.0 ( i 9f270) 16.1
(9/56)
17.9(l9/l06) 14.6 (43/295) R.::l (17 /20.<;)
*Mode of delivery, preeclampsia, and PROM recorded-for only 595 of the 606 women with single births. t P vaiues are not reported for comparison of RDS rares in these subgroups because the risk factors rriay be aHected by tn:atrnent assignment after randomization. :j:P values for the comparison of RDS between treatment gr-oups controlling for that variable. §Includes North American Indians and Hispanics.
The dexamethasone concentrations in maternal blood, taken as a function of time during the adminisc tration of the four doses, is shown in Fig. 1, A, for women delivered of their infants more than 50 hours following the first dose. In the steroid-treated group there was a rise and fall in plasma dexamethasone; but no •mch in the olacebo llrouo. Hv------- ch::~mre ------o- occurred ------• v drocortisone and estradiol concentrations in maternal plasma (Fig. 1, B and C) showed a pronounced decrease after dexamethasone administration. Analyses of extended blood sampling on a limited number of mothers indicated a return to control values by 72 hours (data not shown). Fig. l,D, shows the presence in the umbilical vein (zero time) of dexamethasone and its subs.equent disappearance in the newborn infant compared to placebo groups. The highest concentration of dexamethasone were found in umbilical and neonatal plasma from infants who were delivered within 12 hours after the- administration of the last dose of de1
·
J
xamethasone. Irrespective of whethe-r th-is represented the first or the fourth dose, the vatuesat zero time were similar and therefore the data were: pooled. These concentrations did not exceed 7 ng/rnland returned to control values within 48 hours. The concentration of hydrocortisone in umbilical vein and artery was also suppressed (Fig. l, E and F). Treatment.et'fect On ltD8 in . _~u_ps. Because most of the observed. ti·eatment effects appeared to be in the singleton group, this group has been exami-ned in further detail. Forsingleton irifants (Table VII), the l 0. 1% incidence of RDS in the steroid group differed significantly from the i6.0% incidence in theplacebo group (P = 0.93).* The reduction in incidence of RDS was consistent regardless of whether or. not LIS ratioassessment was available. to aid in the decisiQn on-entry *P values in Table VH represent comparison between
placebo and steroid within each su~roup; by simpie chi· square analyses with I degree of freedom (df).
Volume 141 Number 3
Effect of antenatal dexamethasone on prevention of ADS 283
Table VIII. Percentage of single infants with RDS by treatment in race/sex subgroups Treatment
I
Race/sex subgroups
Placebo
Female White, not Hispanic Black, not Hispanic Others*
24.2 (16/66} 9.6 (5/52) 30.0 (3/10) 16.0 (12175) 10.0 (8/80) 26.7 (4/15)
Steroid
P value
Total
9.4 (6/64) 1.5 (1167) 0 (0115)
0.02 0.04 0.05
16.9 (22/l30) 5.9 (6/119) 12.0 (3/25)
23.0 (17174) 7.0 (5171) 12.5 (2/l6)
0.39 0.52 0.32
19.5 (291149) 8.6 (131151) 19.4 (6/31)
Male
White, not Hispanic Black, not Hispanic Others*
*Includes North American Indians and Hispanics.
Table IX. Percentage of single infants with RDS by treatment and subgroups of gestational age at delivery and duration in study Gestational age at delivery (Dubowitz)
<30 wk
Duration in study
<24 hr 24-7 days >7 days 30-34 wk <24 hr 24-7 days >7 days 34+ wk <24 hr 24-7 days >7 days Dubowitz determination not performed
Placebo
33.3 41.6 100.0 31.8 25.4 26.9 0 6.2 5.2
( I/3) (5112) (Ill)
(7/22) (16/63) (7/26) (0/25) (4/64) (4177)
into the study, although a significant reduction was observed only in the group with known immature LIS ratios. The results in Table VII indicate that RDS incidence is associated with preeclampsia, PROM, gender, and race. It is also associated with gestational age at entry and with center (data not shown). The difference in RDS incidence in the two treatment groups was sig· nificant when adjusted for these six factors simultaneously (P 0.025) or when adjusted for each factor individually. Since dexamethasone appears to affect incidence of RDS differently in the various subgroups, further statistical analyses explored this phenomenon. In these analyses, the impact of each factor on treatment effect is analyzed by means of chi-square test adjusted for the presence of the other five factors. Time to delivery and mode of delivery were not included in the adjustments since they are outcomes determined after randomization and therefore could have been influenced by treatment. There was an apparent increased incidence of RDS associated with cesarean delivery occurring without previous labor and also with the presence of preeclampsia. In contrast, a decrease in the incidence of RDS was associated with PROM but only in the placebo group. There is some evidence that
Steroid
P value
Total
66.6 (2/3) 60.0 (3/5) 50.0 (112) 30.8 (8/26) 10.6 (7/66) 26.3 (5/19) 3.8 (1/26) 5.0 (4/80) 0 (0/77)
0.41 0.54 0.39 0.75 0.03 1.0 0.32 0.74 0.05
50.0 (3/6) 47.0 (8/17) 66.6 (2/3) 31.2 ( 15/48) 17.8 (23/129) 26.7 (12/45) 1.9 (1/51)
5.5 {81144) 2.6 (41154) 9
treatment effect was modified by PROM (X~ == 3.84, P 0.05) and possibly by preeclampsia
284
Collaborative Group on Antenatal Steroid Therapy
( kr ohc r ,"\ n1
and "other" male infants, respectively, Reduction in RDS incident:e ot:<.:urred primarily in the 30 to 34 weeks' gestational age group among those who delivered belwecn ~~ hours and 7 davs (Table!:\).
Comment Although this cooperative study of 661 mothers and 720 premature infants of different racial and ethnit: backgrounds in five geographicallv separated clinical centers has demonstrated that rnaternal dexamethasone treatment prior to premature delivery reduces the o\Trall incidence of diagnosed RDS in the nc\vborn infant in accordance with previous studies, JO-ra it has also uncovered previously unkno\vn limitations of the port'ntial usefulness of such therapy. Moreover, in thi,., study the synthetic corticosteroid or ·estrogens in mother and fetus (Fig. l) and the neurologic developmt'nt of the infant (Table V) ha\'e been measured. Prechtl examinations of the infants at 40 weeks' corrected gestational age showed a trend toward fewer abnormal fetuses in the steroid-treated group although the difference was not significant. It must be emphasized, however, that long-term neurologic and devdoprnt;>ntaJ follow-up must he completed hefon: ;1 statement can be made about the risks of dexamethasone to tht;> fetus that mav be susoected based on nrevi' ' ' ous studies. 22 - 26 The demographit: factors in the two groups were comparable except for gestational age (Table !). This is apparently due to chance, and the treatment benefit remains significant after adjustment for this difference. The distribution of risk factors in each group, including the use of varying tot:olvtic drugs, was the same. Dexamethasone did not appear to reduce the incidence of RDS in newborn twins or triplets (Table ll I). The numbers were small in this subgroup, and caution must be exercised in making generalizations, but the total lack of steroid effect in multiple births is an incentin: for further investigation into this problem. It is possible that steroid dynamics are different in multiple births and also that different concentrations of dexamethasone may reach the fetuses. Although previous im·t;>stigations had not shown a relationship between gender and treatment efficacy, a highly significant association was found in this study (Table VII). In fau, signihcant reduction in RDS incidence in the steroid group occurred only among female infants (Table VIII). A relationship, although not at the same level of significance, was also found between race and treatment efficacy (Table VII). Further analyses (Table VIII) suggested that white, male infants received no benefit from treatment, and although the incidence of
\
r . l91i 1 Jb.'llt't. C~vrwcol.
RDS was less among black and "other" mak infants after dexamethasone treatment; the diHtTcnn·s were not statistically signihcant. I 'he !lUillbt'lc'> in tiv:'c Hlh· groups are small. howe\'et. and results should be imnpreted with caution. The sex a~ well a-; the race int.crat'· tion with treatment effect w·as unanticipated and w111 be explored further in future reports. The neonatal mortalit\' rate 1' as lower in hr1th the steroid and placebo groups n1.>1S{ and H.HC(, JT:,j)('ttively) than 'Wotild have been expected on the ba~is of previous studic:,, This might have occurred as a result uf our patient selection t:riteria -and ntight ha\T accounted for our inabilitv 10 demonstrate ,m ellen of steroid on neonatal 1nnrtafity rates, wluch h~aJ been suggested in other trials.'"· ;:: On the other hand, early and intensive ruaternal. le.tai, and neonatal sur\·eiltance and intervention nla) ha\'c reduc:ed the impact ol treatment nn the neonatal mortality ratC'. There was no difference in incidence of infections in the mother:,; receiving steroid or placebo in thi., stuch, but the infant:,; born of mothers receiving steroids showed a decreased_ incidence of infection (within 72 hours) (fable \' l), However, it must be kept in mind that cultures were obtained on the basis ol symptoms rather th:w from a random selenion or I rom all infams. Thi'> decrease mav be related. in pan. to the dt'creased incidnu:e of RDS in this group. There was also no effect of steroid treatment on other postpartum complicatiom whic-h suggests wnsidt~rable specificity of corticostermd effect on developing processt;>s. A> previouslv reported/' cesarean section was found to be associated with an increased risk of RDS as compared with vagina~ delivery (Table VII). The risk of RDS is most significant in the mother who undergoes cesarean section when not in labor. The effect ol' the ~t.eroid treatment ('uul.d not completely overcome the apparent diiferenu: benveen cesarean and vaginal ddivery (see Results). PROM was associated with a decreased inciden<.:c o! RDS in the placebo group, as previouslv reporte(F~";;; (! abk' \'II). In contrast to cesarea11 section. the effect of PROM on RDS is climini~hed follow.ing dexamethasone treatment, suggesting that this et'l<:·ct may be nwdiated through a mechanism similar to exogcnow• steroid administration and that thl' n,·o cflech at-e nr)t additive. Preeclampsia was associated with an increased_ incidence of RDS in the placebo group wltich, inpa.rt. may be attributed to the fact that this complication fn:yuently necessitates early delivery, resulting in an int:rt;>ased incidence of prematuritv. Althougn_othet· -Studies have shown a higher incidence ol mature US ratios in hypertensive women with premature deliveries,:" -:1 3 complications sut:h as chn;nic and acn-!e fetal asphvxia
Volume HI Number 3
may occur as a result of the preeclampsia and may cause severe metabolic changes in the fetus. These changes may account for the increased incidence of RDS in such infants with presumed mature LIS ratios. The relationship of treatment, RDS, gestational age at delivery, and duration in study (Table IX) suggests that reduction in RDS occurred primarily in the group at 30 to 34 weeks' gestational age, among those infants who were delivered between 24 hours and 7 days after initiation of treatment. This observation should, however, be interpreted with caution because duration in study is an outcome determined after randomization. The appearance of de~amethasone in the fetus following treatment demonstrates the availability of the synthetic corticosteroid in the circulation for a period of exceeding 12 hours after the last dose (Fig. 1). The impact of this dose of steroid on maternal and fetal adrenal response and on estrogen metabolism in the fetoplacental unit demonstrates the drug's effectiveness on well-established fetal physiologic functions. In summary, the results of this trial confirm the findings of Liggins and HowielO and others 11 - 13 that
Effect of antenatal dexamethasone on prevention of ADS 265
prenatal steroid administration is effective in reducing the overall incidence of RDS. However, since the effect of treatment is dependent upon multiple deliveries, sex, race, and other characteristics of the infant and mother, its potential usefulness will be dictated by those limitations. These and the still unknown long-term effects of this therapy, in our opinion, indicate that antenatal steroid therapy should be used selectively and with caution. On request of the Division of Lung Diseases of the National Heart, Lung, and Blood Institute, Merck, Sharpe, & Dohme provided the drug and placebo preparations used in this study. (This acknowledgement of appreciation is in no way an endorsement of a particular product.) Special acknowledgement is given to the following consultants who assisted in the preparation of the study p~:otocol: Glen Aylward, Ph.D., Alfred Brann, M.D., Josephine Brown, Ph.D., Philip Farrell, M.D., Ph.D., Alan Hodson, M.D., Frank Pedersen, M.D., James Schwartz, M.D., William Taeusch, M.D., and Edward Tronick, Ph.D.
REFERENCES 1. Farrell, P.M., and Avery, M. E.: Hyaline membrane disease, Am. Rev. Respir. Dis. 111:657, 1975. 2. Farrell, P. M., and Wood, R. M.: Epidemiology of hyaline membrane disease in the United States. Analysis of national mortality statistics, Pediatrics 58:167, 1976. 3. Inselman, L. S.: Respiratory distress syndrome, Pediatr. Ann. 7:34, 1978. 4. Kamper,].: Long term prognosis of infants with severe idiopathic respiratory distress syndrome. I. Neurological and mental outcome, Acta Paediatr. Scand. 67:61, 1978. 5. DeLemos, R. A., Shermeta, D. W., Knelson,J. H., Kotas, R., and Avery, M. E.: Acceleration of appearance of pulmonary surfactant in the fetal lamb by administration of corticosteroids, Am. Rev. Respir. Dis. 102:459, 1970. 6. Kikkawa, Y., Motoyama, E. K., and Gluck, L.: Study of the lungs of fetal and newborn rabbits, Am.]. Pathol. 52: 177, 1968. 7. Wang, N. S., Kotas, R. V., Avery, M. E., and Thurlbeck, W. M.: Accelerated appearance of osmiophilic bodies in fetal lungs following steroid injection, J. Appl. Physiol. 30:362, 1971. 8. Taeusch, H. W., Heitner, M., and Avery, M. E.: Accelerated lung maturation and increased survival in premature rabbits treated with hydrocortisone, Am. Rev. Respir. Dis. 105:971, 1972. · 9. Platzker, A. C. G., Kitterman, J. A., Mescher, E. J., Clements, J. A., and Tooley, W. H.: Surfactant in the lung and tra~;heal fluid of the fetal lamb and acceleration of its appearance by dexamethasone, Pediatrics 56:554, 1975. 10. Liggins, G. C., and Howie, R. N.: A controlled trial of antepartum glucocorticoid treatment for prevention of the respiratory distress syndrome in premature infants, Pediatrics 50:515, 1972.
ll. Caspi, E., Schreyer, P. Weinraub, Z., Reif, R., Levi, I., and Mundel, G.: Prevention of the respiratory distress syndrome in premature infants by antepartum glucocorticoid therapy, Br.J. Obstet. Gynaecol. jil3:187, 1976. 12. Papageorgiou, A. N., Desgranges, M. F., Masson, M., Colle, E., Shatz, R., and Gelfand, M. M.: The antenatal use of betamethasone in the prevention of respiratory distress syndrome. A controlled double-blind study, Pediatrics 63:73, 1979. 13. Doran, T. A., Swyer, P., MacMurray, A., Mahon, W., Enhoming, G., Bernstein, A., Falk, M., and Wood, M. M.: Results of a double-blind controlled study on the use of betamethasone in the prevention of respiratory distress syndrome, AM. j. 0BSTET. GVNECOL. 136:313, 1980. 14. Hughes, E. C.: The committee on terminology of the American College of Obstetric and Gynecology, Obstetric Gynecological Terminology, Philadelphia, 1972, F. A. Davis Company. 15. Prechtl, H., and Beintema, D.: In Lavenham, L., editor: The Neurological Examination of the Full-term Newborn Infant, London, 1964, Little Club Clinics in Developmental Medicine, No. 12, Heinemann. 16. Brazelton, T. B.: Neonatal Behavioral Assessment Scale, London, 1973, Clinics in Developmental Medicine, No. 50, Heinemann. 17. Gluck, L., Motoyama, E. K., Smits, H. L., and Kulovich, M. V.: The biochemical development of surface ac.tivity in mammalian lung, Part I, Pediatr. Res. 1:237, 1967. 18. Orczyk, G. P., Caldwell, B. V., and Behrman, H. R.: In Jaffe, B. M., and Behrman, H. R., editors: Methods of Hormone Radio-immunoassays, New York, 1974, Academic Press, Inc., pp. 333-345. 19. Bishop, Y. M. M., Fienberg, S. E., and Holland, P. W.:
286
Collaborative Group on Antenatal Steroid Therapy
lhtul>c; l \tn.!
Discrete multi\·ariate analysis: Theory and practice, Cam 1-~-~...l--~
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contingency tables. Appl. Stat. 25:37, 1976. I. Mantel, N., and Haenszel, W.: Statistical aspects of the
analyses of data from retrospective studies of disease, J. :-.Jatl. Cancer Inst. 22:719, 1959. '2. Howard, E., and Granoff, D. !VL: Increased voluntary running and decreased motor n)ordination in mice afte;. neonatal corticosteront' implantation, Exp. Neurol. 22: 661, 1968. :3. Winick, M., and Coscia, A .. Cortisone-induced growth failure in neonatal rats, Pediatr. Res. 2:451, 1968. :4. Schapiro, S.: Some physiological, biochemical and behavioral consequences of neonatal hormone administration: Cortisol and thyroxine. Gen. Comp. Endocrinol. 10:214,
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'5 Fitzhardingt\ P. M., Eisen, A , Lejtenyi, L, Metrak ...s, K. and Ramsay, M.: Sequellae of early steroid administration in the newborn infant, Pediatrics 53:877, 1974. ~6. Anderson, G. E., and Friis-1--Iansen, B.: Hypercholester~ ulemia in the newborn. Occurrence after antenatal treatment with betamethasone-phenobarbi~al-ritodrin for the prevention of the respiratory distress syndrome, Pediatrits 62:R, 197R.
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Editorial comment From the pioneering work of Francis Moog, it was known that glLu-on1rticoids v.ere capable of accelerating developmental processes in mammalian systems. and then Liggins made the astute observation that when glucocorticoids triggered th<: onset of labor in pregnant sheep, the lambs born prematurely had well-aerated lungs, whjle a large number of control animals died of the respiratory distress syndrome (RDS). Thi~ set the stage for a large double-blind prospective stud\. which was published by Liggins and Hov. 'ie _(reference 1o_ in- paper), -on the ust of bet;~n~ethasonc- in -the prevention of RDS in a very homogeneous population (Jf women at risk recmited ill Auckland, New Zealand. While the resuJts of many small sttldies have been published in the 9 years since the results of the New Zealand study were presented, that studyremained as the only one of irs kind. Long-term f.()llow-u.p of the children was not available and the nagging questions of efficacy in the use of glucocortin1ids in humans had to be answered. The aims of the present studv were to ;-mswer some of these questions in a North American setting. The present report is a complex, multicentered, double-blind ;tudv which ''as designed to answer the following questions: (I) Does the administration of dexamethasone, in the dose described. to the mother with threatened premature delivery reduce the incidence of RDS in the premature infant( (2) Does the dexamethasone cross the placenta in sufficient amounts t(J affect fetal mctabolisln: (3} Does such corticosteroid administration have any short-term or long-term effect(-s) on the fetus? All but the last part of the third question have been answered. Dexamethasone administration does reduce RDS; it does nn~s the placenta in all subjects, and it has no demonstrable shnrt·term effects. There are manv subcategories which have been addressed, but rcsul!, ~hould he interpreted cautiously because, in sptie of significance, the !lumbers HI some groups_ are small. For example, the data on the efficacy of the drug· in black male children wil1 require further direct inYestigation to_ resolve cori?pletely. ()_t~er such data -should be interpreted similarly as areas for future investigation. The efficacy is proved under certain conditions; however, corticosteroids should be used with camion. Rnan Litt{f, M.D.
Volume 141 Number 3
Policy-Data Monitoring Panel Brian Little, M.D. (Chairman) Case Western Reserve University Cleveland, Ohio Mary Ellen Avery, M.D. Children's Hospital Boston, Massachusetts David de Mets, Ph.D. NHLBI Bethesda, Maryland Max Halperin, Ph.D. University of North Carolina Chapel Hill, North Carolina Patricia King, J.D. Georgetown Law Center Washington, D.C. Arthur Parmelee, M.D. UCLA-School of Medicine Los Angeles, California Samuel Solomon, Ph.D., F.R.S.C. Royal Victoria Hospital Montreal, Quebec, Canada David Sy!wester, Ph.D. University of Vermont Burlington, Vermont
James Ware, Ph.D. Harvard School of Public Health Boston, Massachusetts NHLBI Program Office Bitten Stripp, Ph.D., Project Officer Bethesda, Maryland Claude Lenfant, M.D., Director, Division of Lung Diseases Bethesda, ~.1aryland The study was carried out at the following centers by the following principal and coprincipal investigators who also served as members of the Steering Committee: Clinical Centers Richard Depp, ?vf.D. John Boehm, M.D. (Northwestern University) Chicago, Illinois
Effect of antenatal dexamethasone on prevention of ADS
Richard Zachman, M.D., Ph.D. Luis Curet, M.D. (University of Wisconsin) ~vfadison, Vt'isconsin Charles R. Bauer, M.D. Louis Fernandez-Rocha, !'vf.D. Gene Burkett, M.D. (University of Miami) Miami, Florida Sheldon Korones, M.D. John Morrison, M.D. Jack Schneider, M.D. Garland Anderson, M.D. (University of Tennessee) Memphis, Tennessee Henrique Rigatto, M.D. Leo Peddle, M.D. Frank Manning, M.D. (University of Manitoba) Winnipeg, Manitoba, Canada Coordinating Center Kenneth Poole, Ph.D. Vijaya Rao, Ph.D. Betty Hastings (Research Triangle Institute) Research Triangle Park, North Carolina Central Laboratory David Fukushima, Ph.D. John O'Connor, Ph.D. Jack Kream, Ph.D. (Montefiore Hospital) New York, New York
287