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. 2014 Oct 31;2014(10):CD009708. doi: 10.1002/14651858.CD009708.pub2

Heytmanek 1990.

Methods Design: randomised controlled trial (2 arms).
 Multicentre study: yes (10 centres).
 International: Italy.
 Follow‐up period: until delivery.
 Per‐protocol analysis: no.
 Intention‐to‐treat analysis: no.
Participants N = enrolled and randomised pregnant women 141.
Experimental group: n = 75 (ambroxol (EG)).
Control group: n = 66 (betamethasoneCG)).
114 participants completed study and analysed (59 women EG group/55 women CG group).
1.‐ Sex:
EG group: 30 boys/29 girls (50.84% boys/49.15% girls).
CG group: 21 boys/34 girls (38.18% boys/61.81% girls).
Total group: 51 boys/63 girls (44.74% boys/55.26% girls).
2.‐ Gestational age (weeks):
≤ 37 weeks: 114 newborns.
3.‐ Birthweight (g):
EG group: 2119 (+/‐ 665).
CG group: 2156 (+/‐ 576).
4.‐ Apgar score: (points)
1° min.
EG group: 7 (+/‐ 2).
CG group: 7 (+/‐ 2).
5.‐ Inclusion criteria:

  • Pregnancy termination due to pathological pregnancy with or without premature labour activity between the 28' and 36 weeks' gestation.

  • Delivery later than 72 hours after the start of lung maturity stimulation.

  • Secured gestational age by date last menstrual period and corresponding ultrasound.

  • If possible reference to immature lungs before the start of therapy by amniocentesis.


6.‐ Exclusion criteria:

  • Severe hypertension (blood pressure greater than 160/100 mmHg).

  • Class B‐R diabetes.

  • Urine with albumin.

  • Oedema.

  • Pregnant women with more than 2 weeks disagreement in assessing gestational age between anamnestic data, ultrasonographic data.
Interventions 1. Experimental group: (ambroxol) was given 1000 mg in 500 mL of 5% glucose solution intravenously for 5 days + placebo 2 mL intravenously.
2. Control group: (betamethasone) received 50 mL of placebo in 500 mL of 5% glucose solution intravenously for 5 days + 2 mL (8 mg) of betamethasone intravenously for 2 days.
Co‐intervention: none.
Treatment duration: 3‐5 days.
Outcomes Primary:

  • RDS frequency.

  • Severity of RDS.

  • Mortality.
Notes 1.‐ A priori sample size estimation:  no.
 2.‐ Sponsor: not reported.
 3.‐ Rol of sponsor: not reported.
 4.‐ Conflict of interest: no reported.
 5.‐ Number of clinical trial: no reported.
Risk of bias
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Unclear risk Quote: "Eligible participants were randomised to receive either betamethasoneor Ambroxol" (page 444).
Comment: insufficient information to permit judgment of 'Low risk' or 'High risk'.
Allocation concealment (selection bias) Unclear risk Comment: insufficient information to permit judgment of 'Low risk' or 'High risk'.
Blinding of participants and personnel (performance bias) Unclear risk Quote: "It was a double blind study" (page 444).
Comment: due to the way in which the treatments were managed, we thought it likely that the intervention was masked.
Blinding of outcome assessment (detection bias) Unclear risk Quote: "It was a double blind study" (page 444).
Comment: due to the way in which the treatments were managed, we thought it likely that the intervention was masked.
Incomplete outcome data (attrition bias) 
 All outcomes Low risk Comment: data for primary outcome available for 80.9% (excluding fetal deaths and early neonatal death before RDS assessment) of the randomised sample, with balanced reasons for withdrawals or losses to follow‐up.
Selective reporting (reporting bias) Low risk Comment: all the outcomes listed in the method section described in results.
Other bias Low risk Comment: no other potential source of bias.