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Luerti et al, Prevention of RDS 227

J. Perinat. Med.15 (1987) 227

An alternative to steroids for prevention of respiratory distress syn-drome (RDS): multicenter controlled study to compare ambroxol andbetamethasone

Massimo Luerti1, Adriano Lazzarin2, Enzo Corbella3, and Guido Zavattini1

1IV Department of Obstetrics and Gynecology, 2 Department of InfectiousDiseases, and 3III Department of Pediatrics, L. Sacco Hospital, University ofMilan, Italy

1 Introduction

The respiratory distress syndrome (RDS) con-tinues to rank as a major cause of mortalityamong non-malformed infants. Even when it isnot fatal, the disease may have late sequelae,involving mainly the central nervous system(CNS) and the cardiopulmonary apparatus.The incidence of RDS is inversely correlatedwith gestational age. Its cause is the insufficientproduction of substances that lower surfacetension (surfactants) in fetal lungs.The experience of LIGGINS and HOWIE [7] withantenatal maternal administration of steroidsfor prevention of RDS led to widespread adop-tion of this preventive approach. Further stud-ies substantially confirmed the effectiveness ofthe steroids but also brought to light severalconditions in which the benefit was slight or nil[1, 2, 4, 11].These conditions include: 1) treatment to deliv-ery time less than 24 hours and more than oneweek, 2) gestational age less than 30 and morethan 34 weeks, 3) rupture of membranes (ROM)more than 48 hours prior to delivery, 4) malesex, 5) white race, 6) multiple pregnancy, and7) fetal acidosis.Furthermore steroids have potential maternal,fetal and neonatal adverse effects [4,16,17,19],among which the most dangerous is probably

Curriculum vitae

Dr. MASSIMO LuEim wasborn in Milan on 1946. Hetook the degree in Medi-cine in 1970 and thespeciality in Obstetrics andGynecology in 1974. He isauthor or co-author of 93scientific publicationsabout arguments of perina-tal medicine as well as ofgynecologic oncology andcontraception. He is a fel-low of the Italian Society of Obstetrics and Gynecologyas well as of the Italian Society of Perinatal Medicine.He is co-editor of the volumes "New trends in fetal lungimmaturity" and "Diagnosis and treatment of fetal lungimmaturity".

the increased incidence of neonatal infection,to which preterm infants are already more sus-ceptible. The percentage of deaths due to infec-tion within 28 days of birth was higher andpolymorphonuclear leukocytes (PMNL)functions were reduced in infants whosemothers had received steroids for prevention ofRDS than in those whose mothers had not beentreated [5].All this has encouraged attempts to find al-ternative treatments of at least equal efficacybut without adverse reactions. Many substan-

1987 by Walter de Gruyter & Co. Berlin · New York

228 Luerti et al, Prevention of RDS

ces have been held to be capable of stimulatingsurfactant production: aminophylline, thyroidhormones, cyclic-AMP, ethanol, fibroblast-pneumocyte factor, bromhexine and others.None of them — for various reasons — hasbeen accepted as a true alternative to steroids.

A series of experimental data have demon-strated that ambroxol, a benzylamine, stimula-tes surfactant production and secretion by typeII pneumocytes, even though the mechanism ofaction is not yet fully understood.

The most important experimental findings arethat ambroxol:1) increases surfactant phospholipids concen-

trations in the amniotic and fetal trachealfluid [3, 10];

2) stimulates the development of intracellularorganelles involved in the surfactant secre-tion process [18];

3) increases pulmonary compliance in the rab-bit neonate [12]. Ambroxol readily crossessthe placental barrier and concentrates elec-tively in the fetal lungs and liver [13];

4) and it has been demonstrated that am-broxol lowers the incidence of RDS in pre-term infants born of treated mothers com-pared to mothers given placebo [8, 20].

The aim of this study was to evaluate the effec-tiveness of ambroxol versus the steroids in re-ducing the incidence of RDS in preterm new-borns with particular regard to the occurrenceof neonatal infection.

2 Materials and methods

Starting in September 1981, we organized arandomized multicenter trial in which fourcenters in the Lombardy region and two centersin other regions took part.Women at 27 to 34 weeks' gestation withthreatened premature or planned premature la-bor were admitted into the trial.

Criteria for exclusion were:1) Delivery expected within 24 hours;2) More than two weeks disagreement in as-

sessing gestational age using patient's his-tory data and ultrasound data;

3) Severe hypertension (B. P. more than 160/100 mmHg);

4) Class-B-R diabetes;5) Hyperthyroidism;6) Drug addiction with heroin up to the third

trimester of pregnancy;7) Previous treatment during pregnancy with

drugs enhancing fetal lung maturity.

Tocolysis with a beta-mimetic agent wasallowed to delay labor.

Consenting patients admitted to the trial wererandomly treated, on the basis of chance num-ber tables, with betamethasone or ambroxol.The study was stratified with separated rando-mization for each center and accurate controlwas performed on correct use of random tables.The betamethasone group received 6mg ofbetamethasone phosphate and 6 mg of betame-thasone acetate intramuscularly, and the dosewas repeated 24 hours later. The ambroxolgroup received the drug diluted in 500 ml salineas a slow intravenous infusion according to along regimen (1 g/day for 5 days) or a shortregimen (l g every 12 hours for 4 times). Thetwo ambroxol dosage regimens were chosenfreely in relation to the expected delay of labor.Because of different route and frequency ofadministration of the two drugs a blinded studywas too complicated to be performed.

The diagnosis of RDS was based on the exist-ence of one or more of both clinical and radio-logical signs given in table I and its severity wasrated according to the gas-analytical criteriashown. The diagnosis of maternal puerperalinfection was based upon either the finding ofa skin temperature more than 38 °C on twooccasions (temperatures beeing measured atleast every 6 hours), or a clinical evaluationconsistent with endometritis or wound infec-tion. The diagnosis of neonatal infection wasbased upon clinical and radiological criteriaand confirmed by a positive culture.

Evaluation of maternal and neonatal infectionrate was performed in infants born at eachgestational age only in the four Lombardy re-gional centers, owing to reasons of organiza-tion. Neonatal pathology was reviewed in all

J. Perinat. Med. 15 (1987)


Table I. Criteria for diagnosis of RDS.

RDS defined by the presence of:Beginning before 4 hours of lifeDuration more than 24 hours

Clinical signs (one or more):

Radiological signs:

Respiratory rate >60/minIntracostal retractionsFlaring of the alae nasiGrunting on expirationCyanosis in room air with falling in PO2 below 60 mmHg

Thoracic roentgenogram showing reticulogranular patternand/or air bronchograms

Severity was defined as:- Mild: if arterial or tcPo2 50-80 mmHg with room FiCh ^ 0.3- Moderate: if arterial or tcPo2 50-80 mmHg with FiO2 between 0.4. and 0.6. -» c PAP— Severe: if arterial or tcPo2 mmHg < 50 or Pco2 > 60 with FiO2 between 0.4 and 1 -> assisted ventilation.

cases by a neonatal coinvestigator who wasblinded as to the treatment. All data werechecked and analyzed with an Apple II com-puter at the IVth Department of Obstetricsand Gynecology of the University of Milan,L. Sacco Hospital. Statistical analyses were byStudent's t-test and the chi-square test.

3 ResultsAs of November 15, 1984, 288 randomizedpatients had delivered 315 neonates. Thirty-eight patients were excluded because of eitherthe presence of criteria for exclusion or proce-dural errors. There were 2 stillbirths. Ninety-nine neonates were born after the 37th week ofpregnancy. 7 died of other causes within the

first 3 hours of life before the onset of RDScould be established. The incidence of RDS wasassessed in 169 viable neonates born before the37th completed week of gestation (259 days ofamenorrhea). Of these, 86 were born from 76mothers treated with betamethasone and 83from 76 mothers treated with ambroxol (tableII).All the betamethasone patients completed onecourse of treatment, whereas 14 of the am-broxol group (18%) received less than thescheduled number of doses because of onset oflabor. Comparison of the mothers in the twogroups showed no significant differences in themain maternal factors affecting the develop-ment of RDS (table III). The two groups ofmothers were also compared as to use of beta-

Table Π. Study population.

Groups

Betamethasone

Total randomizedExcluded from the studyFetal deathsLiveborn after the 37th weekEarly neonatal death before RDS assessment

Mothers

12921

1292

Infants

14422

1332

Ambroxol

Mothers

159151

625

Infants

171161

665

Available for RDS assessment 76 86 76 83



Table III. Characteristics of treatment groups (mothers)1.

Characteristic Groups

Betamethasone

Gestational age at delivery mean< 34 weeks (%)> 34 weeks (%)

Treatment to delivery time meanROM to delivery time mean + SMultiple pregnancy (%)Cesarean section (%)Placenta previa (%)

± S. D. (days)

± S. D. (days). D. (hours)

(n =

229.0532314.127.310324

76)

± 17.270%30%

± 15.9+ 15.4

13%42%

5%

Ambroxol(n =

231.9522411.426.97

332

76)

+ 13.868%32%

+ 12.9+ 17.6

9%43%3%

1 Statistical analysis. The difference between the two groups was not significant for any of the recorded characteris-tics.

mimetic agents, and no significant differencewas found (table IV). There was no significantdifference between the two groups of neonatesas regards main neonatal factors affecting thedevelopment of RDS (table V). The overallincidence of RDS was higher in the betametha-sone group (31%) than in the ambroxol group(13%) as was the incidence of mild, moderate,severe and fatal RDS. The difference was sig-nificant (P < 0.05) (table VI).

The incidence of RDS was generally higher inthe betamethasone group vs ambroxol groupin five centers (29% vs 13%, 40% vs 10%, 35%vs 15%, 29% vs 13%, 24% vs 8%), whereas

in one group it was comparable (13% in thebetamethasone group vs 14% in the ambroxolgroup).The incidence of RDS in neonatal subgroupsdivided on the basis of twin births, gestationalage, ROM to delivery time, treatment to deliv-ery time and sex of the newborn was in everycase higher in the betamethasone group. Thedifference was significant in twin births, whendelivery was prior to the 31st week, when ROMoccurred more than 48 hours earlier, and infemale infants. As well as in these conditions,in which steroids are known not to be effective,the difference was significant when the treat-

Table IV. Use of betamimetic drugs1.

Betamimetic agents

NoneRitodrineIsoxsuprineSalbutamolMore than one drug

Mean total dosage (mg)*Mean duration of treatment (days)

Betamethasone(n = 76)Cases (%)

4481149

494.78.3

5631451

+ 639.1± 8.7

Ambroxol(n = 76)Cases (%)

55036

12

581.98.8

66648

16

± 835.9± 10.9

1 = Statistical analysis. The difference between the groups was not significant for any of the recorded characteris-tics.

* = Dosage equalized to ritodrine according to a isoxsuprine/ritodrine dosage ratio of 5:1 and a salbutamol/ritodrine dosage ratio of 1:10.



Table V. Characteristics of treatment groups (infants)1

Characteristic

Gestational age mean + S. D. (days)^ 34 weeks> 34 weeks

Birth weight mean + S. D. (gm)< 1.500> 1.500

Apgar Γ (mean + S.D.)Apgar 5" (mean + S. D.)Twins (%)

GroupsBetamethasone(n = 86)

228.8 + 17.760 70%26 30%

1927 + 540.023 27%63 73%

5.6 + 2.97.2 ± 1.9

20 23%

Ambroxol(n = 83)

232.5 + 13.656 68%27 32%

1982 + 527.014 16%70 84%

5.9 ± 2.67.3 ± 2.0

13 17%

= Statistical analysis. The difference between the groups was not significant for any of the recorded characteristics.

Table VI. Incidence of RDS1.

RDS Betamethasone Ambroxol(n = 86) (n = 83)

Cases (%) Cases (%)

RDS

No RDSMild

{ ModerateSevereFatal

599756

6910867

727202

879202

1 = Statistical analysis: X2 = 11,27 (d.f. =4)P < 0.05

ment to delivery interval was between 2 and 7days, i.e. the limit within which steroids areeffective (table VII).The incidence of RDS was 15% in neonateswhose mothers had been given the long dosageregimen and 12% in neonates whose mothershad been given the short dosage regimen. Thedifference was not significant.The infants born in the four Lombardy regionalcenters included 100 in the betamethasonegroup and 140 in the ambroxol group. Thepuerperal infection rate in the mothers of theseinfants was 33% in the betamethasone groupand 36% in the ambroxol group (the differencewas not significant). In the same 240 infants,the betamethasone group had a slightly lower

gestational age at birth (242 days), a slightlyhigher treatment to delivery interval (29.3 days)and a slightly higher percentage of cases withROM >48 hours (24%) than the ambroxolgroup (246 days, 28.5 days and 19% respec-tively). Although none of these differences weresignificant, the neonatal infection rate throughthe 28th day of life was significantly higher (P< 0.05) in the betamethasone group (18% withfour fatalities) than in the ambroxol group (9%with one fatality). The infected neonates in thebetamethasone group had a significantly lowermean gestational age, significantly shortermean treatment to delivery interval and a sig-nificantly longer ROM to delivery time thanthe non-infected neonates; whereas, there wasno difference between the infected and non-infected neonates in the ambroxol group asregards these three parameters (table VIII). Alldeaths for infection occurred after the firstweek of life. The type of infection and thecausal agents are listed in table IX.

The perinatal mortality of infants in the trialwas 9% (11/122) in the betamethasone groupand 8% (13/155) in the ambroxol group; the28 day neonatal mortality was 12% (14/121) inthe betamethasone group and 8% (13/154) inthe ambroxol group; both differences were notsignificant (table X).



Table VII. Incidence of RDS in subgroups (infants).

Subgroups

Single delivery infantsMultiple delivery infants

Gestational age< 30 weeks

31 -34 weeks> 34 weeks

ROM to delivery time^24 hours

25 -48 hours> 48 hours

Treatment to delivery time< 2 days

2- 7 day s> 7 days

SexFemaleMale

Betamethasone(n = 86)RDS Cases

20/687/18

10/1213/494/25

14/49O/ 5

13/32

5/1613/359/35

15/3512/51

(%)

2939

832616

28

41

313726

4323

Ambroxol(n = 83)RDS Cases

11/690/14

21 16/513/25

9/60O/ 52/18

3/241/197/40

5/456/38

(%)

160

291212

15

11

125

17

1116

P

<r Π 01s. \J.\J i

< 0.05

<0.01

< 0.01

< 0.01

Table VIII. Characteristics of infected infants in treatment groups.

Treatment

Betamethasone group (n = 100)Gestational age mean ± S. D. (days)Treatment to delivery time mean + S. D. (days)ROM >48 hours (%)

Ambroxol group (n = 140)Gestational age mean + S. D. (days)Treatment to delivery time mean + S. D. (days)ROM >48 hours (%)

Infected infants

226.5 ± 23.613.5 + 19.538

243.5 + 17.520.3 ± 23.814

Non-infectedinfants

246 + 23.733.6 + 26.715

249.2 ± 21.328.5 + 22.027

Ρ

< 0.005< 0.005<0.01

> 0.05>0.05>0.05

The mean gestational age at treatment and atdelivery, birth weight, Apgar score at 1 and 5min were significantly lower in RDS than non-RDS cases; however, mean ROM to deliverytime, percentage of male sex, incidence of cesar-ean section and, particularly, use of beta-mime-tics and mean treatment to delivery time, whichwere thought to be more decisive than steroid

prevention [15] in reducing the incidence ofRDS, were not significantly different in RDSand non-RDS cases (table XI).

The only short-term negative side effects seenin the mothers, the fetuses, or the neonatesafter ambroxol administration were nausea andheadache in about 10% of the mothers.



Table IX. Neonatal infections.

Ambroxol groupEtiologic agent Type of infection

and day of onset

Betamethasone groupEtiologic agent

S. aureus

S. albusS. albusS. albusS. albus

Candida sp.Candida sp.Candida sp.

E. coliE. coliE. coli

Pseudomonas sp.

K. pneumoniae

Streptococcus spp.

Subcutaneous abscess (16th)Subcutaneous abscesses (12th)*

Skin infection (26th)Skin infection (10th)Skin infection (13th)Skin infection (14th)Skin infection (15th)

Oral moniliasis (12th)Oral moniliasis (17th)Oral moniliasis (10th) °Oral moniliasis (12th)Oral moniliasis (14th)Oral moniliasis (4th)

UTI(llth)UTI (16th)UTI(25th)°UTI (4th)UTI (26th)UTI (12th)UTI (10th)UTI (27th)UTI (20th)

Pneumonia (2nd)tPneumonia (5th)tPneumonia (llth)fPneumonia (2nd)

Sepsis (12th)tSepsis (22nd)t

Conjunctivitis (2nd)*Conjunctivitis (18th)

Otitis media (16th)Omphalitis (7th)Pharyngitis (3rd)

S. aureus

S. albus

Candida sp.Candida sp.Candida sp.

EnterobacterProteus sp. + K. pneumoniaeProteus sp.E. coliE. coliK. pneumoniae

P. aeruginosa + E. coliPseudomonas sp.Pseudomonas sp.

S. marcescens + P. aeruginosa

E. coliP. aeruginosa

S. aureusProteus mirabilis + S. epidermidis

Morbidity rate = 9% (13/140)Mortality rate = 0.7% (1/140)

Morbidity rate = 18% (18/100)Mortality rate = 4% (4/100)

0 Associated moniliasis and UTI (urinary tract infection)* Associated conjunctivitis and subcutaneous abscessest Death



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Table XI. Factors influencing the development of RDS in our study population.

RDS(n = 38)

Gestational age at delivery meanBirth weight mean + S. D. (g)

± S. D. (days)

Gestational age at treatment mean + S.D. (days)Treatment to delivery time meanROM to delivery time mean ± SUse of betamimetics (%)Cesarean section (%)Male sex (%)Placenta previa (%)Apgar Γ (mean ± S.D.)Apgar 5' (mean + S. D.)Ambroxol treatment (%)

± S.D. (days). D. (hours)

2221636210

1263924549

83.55.9

29

±±++±

±±

19522

1413

118

2.01.7

no-RDS(n = 131)

2332041219.0

135788415426.47.6

55

±±±+±

±±

14504

1315

151

2.61.9

Ρ

< 0.005< 0.001< 0.005> 0.05>0.05> 0.05> 0.05> 0.05> 0.05< 0.001< 0.001< 0.005

4 Discussion

The fact that none of the substances allegedto increase surfactant production has yet beenaccepted as a true alternative to steroids forprevention of RDS is probably due to the diffi-culty of correct clinical evaluation of their effi-cacy. There are few other cases of drug efficacyassessment in which the final effect — in thepresent instance the lowering of the incidenceof RDS — can be influenced by such a largenumber of different factors, of which thosecurrently known are:1) gestational age at delivery, 2) birth weight,3) gestational age at treatment, 4) treatment todelivery time, 5) ROM to delivery time, 6) modeof delivery, 7) neonatal condition at birth, 8)sex of the newborn, 9) race of the newborn, 10)use of beta-mimetic tocolytic agents, 11) twinbirths, 12) fetal levels of PRL, T3 and T4, 13)maternal smoking habits, 14) obstetric abnor-malities including placenta previa, diabetes, Rhimmunization, hypertension.

If to these is added the difficulty of extrapolat-ing animal model data to humans, it becomesclear that any assessment of the efficacy of adrug for RDS prevention must necessarily bemade by means of multiple randomized humantrials in which the principal interfering factorsare either excluded or homogeneously distrib-uted among the groups studied. Such trialsshould also be multicenter in nature, so as to

reduce the effect of variety in the quality ofprenatal care.

Our study has certain limitations, mainly dueto the fact that it is not blinded, even if non-excluded interference factors were homogene-ously distributed between the two groups.

Moreover, the percentage of low birth weightinfants was slightly, though not significantly,higher in the betamethasone group, even if am-broxol was significantly more effective thanbetamethasone in infants born before the 31stweek.Our incidence of RDS was rather high, com-pared with that reported by others [1, 4, 7, 14]and this was probably due to the fact thatwe also considered all cases of mild RDS. Weconsider noteworthy that in the ambroxolgroup the incidence of RDS was significantlylower in the severe cases taken alone where adiagnostic error is less probable.

Thus, although clearly our results are by nomeans conclusive, they suggest that ambroxolis at least as effective as the steroids for preven-tion of RDS and is effective also in cases ste-roids are not, such as twin delivery, ROM morethan 48 hours prior to delivery, female sex.

Despite several experimental data demonstrat-ing its effectiveness in stimulating surfactantproduction, this drug had found only a some-



what limited use for RDS prevention, mainlybecause the usual dosage regimen (1 g/day for5 days) is too long for cases of threatenedpremature delivery, especially if there is con-comitant ROM, as confirmed by the high per-centage of cases that did not complete the totaldosage regimen in our trial too.With a view to concluding clinical trials withthis substance, we had already successfullychecked that it significantly modified the palmi-tic acid/stearic acid (P/S) ratio in amniotic fluid,as compared with a placebo [9], using the moretime intensive dosage regimen in which 4 g wereadministered in 36 hours. This same regimenwas available in this trial and gave better resultsthan the long dosage regimen, although thedifference was not significant.The higher incidence of bacterial and micoticinfections in the infants of the betamethasonegroup can be related to the findings of LAZZA-RIN [6], showing a significant defect of PMNLactivity and a significant decrease of OKT4 +cells (currently considered as T-helpers), in 10preterm infants of the betamethasone group ascompared either with 10 preterm infants of theambroxol group or 10 preterm infants born tonon-treated mothers or 10 healthy term infants.The damage to immunocompetent cell

functions might be the cause of the higher infec-tion rate in steroid treated infants and warrantsgreat caution in the use of immunosuppressordrugs in preterm newborns, which are alreadysusceptible to a high incidence of infectiouspathology, due to functional immaturity of cel-lular immune responsiveness. Our findings sug-gest that steroids might actually raise the riskof infection in very low birth weight infantsand when ROM occurs more than 48 hoursbefore delivery.

In contrast, current knowledge suggests thatambroxol lacks negative maternal, fetal andneonatal side effects. This is a major advantage,indicating this drug as a valid alternative tosteroids for prevention of RDS, if its efficacyis confirmed by further studies, also in thosepatients that were excluded in our trial, becauseof the presence of a relative counterindicationto the use of steroids (hypertension, diabetes).

Since gestational age, birth weight and neonatalwell-being were the only decisive factors affect-ing the development of RDS in our trial, it isapparent that, together with maternal adminis-tration of ambroxol, adequate tocolysis andgood prenatal care assure the most favorablemodes of delivery to preterm infants.

Summary

The results are reported of a multicenter randomizedstudy of the effectiveness of maternal administration ofbetamethasone versus ambroxol, a substance of thegroup of the benzylamines, for prevention of RDS inpreterm infants.Women of 27 to 34 weeks gestation with threatenedpremature delivery or planned premature delivery wereadmitted to the trial. Between September 1981 and Nov-ember 1984 a total of 288 randomized patients delivered315 neonates. The incidence of RDS was assessed in 169viable neonates born before the 37th week.Of these 86 were born of 76 mothers treated with beta-methasone and 83 of 76 mothers treated with ambroxol.The overall incidence of RDS was significantly (P

< 0.05) higher in the betamethasone group (31%) thanthe ambroxol group (13%). Ambroxol was significantlymore effective than betamethasone in twin births, ininfants born before the 31st week, when ROM to deliv-ery time was more than 48 hours, when treatment todelivery time was between 2 and 7 days and in femaleinfants.The neonatal infection rate was significantly higher (P< 0.05) in the group of betamethasone treated infants(18% with four fatalities) than in the group of ambroxoltreated infants (9% with one fatality).These results suggest that ambroxol may be a validalternative to steroids for prevention of RDS.

Keywords: Lung maturity, respiratory distress syndrome (RDS), surfactant.



Zusammenfassung

Vergleich von Ambroxol und Betamethason zur Preventiondes RDS — eine multizentrische kontrollierte StudieEs werden die Ergebnisse einer multizentrischen rando-misierten Studie vorgestellt, in der die Wirksamkeit vonBetamethason bzw. Ambroxol, eine Substanz aus derGruppe der Benzylamine, zur Prävention eines RDS beiFrühgeborenen miteinander verglichen wurde.In die Studie aufgenommen wurden Frauen von der 27.bis 34. Schwangerschaftswoche mit drohender Frühge-burt bzw. geplanter vorzeitiger Entbindung. ZwischenSeptember 1981 und November 1984 wurde ein Kollek-tiv von 288 randomisierten Patienten zusammengestellt,die von insgesamt 315 Neugeborenen entbunden wordenwaren. Bei 169 lebenden Kindern vor der 37. Wochewurde ein RDS diagnostiziert. 86 dieser Kinder warenaus der Gruppe von 76 Müttern, die mit Betamethasonbehandelt worden waren, 83 aus der Gruppe von 76

Müttern, die Ambroxol erhalten hatten. In der Betame-thason-Gruppe war die Inzidenz eines RDS signifikanthöher (p < 0.05) als in der Ambroxolgruppe (31% ver-sus 13%).Bei Zwillingsgeburten, bei Kindern vor der 31. Woche,bei länger als 48 h zurückliegendem Blasensprung, beieinem Zeitraum von 2 bis 7 Tagen von Behandlungsbe-ginn bis zur Entbindung und bei weiblichen Neugebore-nen war Ambroxol signifikant wirksamer als Betametha-son.Die neonatale Infektionsrate war in der Betamethason-Gruppe signifikant höher als in der Ambroxol-Gruppe(p < 0.05; 18% mit 4 Todesfällen versus 9% mit einemTodesfall).Unsere Ergebnisse zeigen, daß bei der Prävention desRDS Ambroxol eine echte Alternative zu den Steroidensein kann.

Schlüsselwörter: Lungenreife, respiratorisches Distress-Syndrom (RDS), Surfactant.

Resume

Une alternative aux stero'ides pour la prevention du syn-drome de detresse respiratoire (SDR): etude multicentri-que avec groupe controle comparant ambroxol versus beta-methasoneOn rapporte les resultats d'une etude multicentriquerandomisee de l'efficacite de la prise maternelle de beta-methasone versus ambroxol, substance du groupe desbenzylamines, dans la prevention du SDR chez les en-fants prematures.Sont entrees dans l'essai les femmes de 27 ä 34 semainesde gestation avec une menace d'accouchement prema-ture ou un accouchement premature programme. Entreseptembre 1981 et novembre 1984, 288 patierites rando-misees, au total, ont donne naissance ä 315 nouveaux-nes. On a estime l'incidence du SDR ä 169 nouveaux-nes viables nes avant la 37eme semaine. Parmi ceux-ci86 sont nes de 76 meres traitees par betamethasone et83 de 76 meres traitees par ambroxol. L'incidence globale

du SDR a ete de fagon significative (p < 0,05) pluselevee dans le groupe avec betamethasone (31%) quedans le groupe avec ambroxol (13%).L'ambroxol est plus efficace de fagon significative quela betamethasone chez les jumeaux, chez les enfantsnes avant la 3lerne semaine, lorsque l'intervalle enfrel'ouverture de l'oeuf et l'accouchement etait superieur ä48 heures, lorsque le delai entre le traitement et l'accou-chement etait compris entre 2 et 7 jours, et chez lesenfants de sexe feminin.Le taux d'infections neonatales a ete de fagon significa-tive (p < 0,05) plus eleve dans le groupe des enfantstraites par betamethasone (18% avec 4 deces) que dansle groupe des enfants traites par ambroxol (9% avec lseul deces).Ces resultats suggerent que Pambroxol peut representerune alternative valable aux stero'ides dans la preventiondu SDR.

Mots-cles: Maturite pulmonaire, surfactant, syndrome de detresse respiratoire (SDR).

Acknowledgements: We thank Istituto De Angeli S. p. A., Milan, Italy for providing ambroxol (Mucosolvan 1000).

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Received April 10, 1986. Revised August 15, 1986. Ac-cepted September 16, 1986.

Dr. Massimo LuertiClinica Ostetrica e Ginecologica VIIUniversitä di MilanoOspedale L. Saccovia G. B. Grassi 741-20157 Milano/Italy


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