Ambroxol for women at risk of preterm birth for preventing neonatal respiratory distress syndrome

There is a lack of scientific research evidence for the routine use of ambroxol for women at risk of preterm birth for preventing neonatal respiratory distress syndrome (RDS).

RDS is a disease caused by a deficiency of surfactants (substances that lower surface tension) in the lungs of newborn babies. These substances keep the alveoli at the ends of the airways open and enable the entry of air into the lungs so that the newborn is able to breathe and oxygenate its body. RDS occurs mainly in preterm newborns. A number of interventions such as giving the baby surfactant and prenatal corticosteroids are used to prevent the syndrome. Ambroxol facilitates the removal of bronchial secretions and can stimulate production of surfactant. Giving ambroxol to pregnant women during preterm labour may be protective for the newborn babies, with fewer maternal adverse effects with prenatal steroids. The main side-effects of ambroxol are diarrhoea, gastric irritation, nausea, vomiting and headache.

We did not identify any trials comparing ambroxol with dexamethasone (corticosteroid) in this review. Nor did we identify any trials comparing ambroxol combined with corticosteroid versus corticosteroid alone, or placebo/no treatment. The review identified 14 small studies involving a total of 1047 women (and their 1077 newborns), that compared ambroxol with corticosteroid (betamethasone), or to placebo/no treatment. Three of the studies did not report on the outcomes of interest for this review. The results of the review are based on very low to moderate quality evidence.

There were no clear evidence of differences in the incidence of RDS or perinatal mortality in newborns of women who were given ambroxol when compared with newborns of women who received either a corticosteroid (betamethasone) or placebo/no treatment. Similarly, there was no clear difference between groups in terms of nausea and vomiting (the only maternal adverse effects that were reported).

For the review's secondary outcomes, none of the included studies reported on the incidence of bronchopulmonary dysplasia, periventricular haemorrhage, necrotising enterocolitis or rate of maternal mortality. One small study (comparing ambroxol with placebo/no treatment) found no difference between groups for the neonatal outcomes of 'need for mechanical ventilation' or 'administration of pulmonary surfactant'.

There is insufficient evidence to support or refute the practice of giving ambroxol to pregnant women at risk of preterm birth for preventing neonatal RDS. More research in this area is necessary in order to evaluate the effectiveness and safety of this intervention.

Authors' conclusions: 

This review is based on very low to moderate quality evidence from 14 small trials (many are published in the form of conference abstracts with minimal methodological details provided). There is insufficient evidence to support or refute the practice of giving ambroxol to women at risk of preterm birth for preventing neonatal RDS, perinatal mortality and adverse effects. More research is needed in order to fully evaluate the benefits and risks of this intervention.

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Background: 

Respiratory distress syndrome (RDS) is caused by a deficiency of pulmonary surfactant (an active agent that keeps pulmonary alveoli open and facilitates the entry of air to the lungs, thus improving the oxygenation of the newborn).

A number of interventions such as pulmonary surfactant and prenatal corticosteroids are used to prevent RDS. Ambroxol has been studied as a potential agent to prevent RDS, but effectiveness and safety has yet to be evaluated.

Objectives: 

To evaluate the efficacy and safety of giving ambroxol to pregnant women who are at risk of preterm birth, for preventing neonatal RDS.

Search strategy: 

We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (29 November 2013), CENTRAL (The Cochrane Library 2013, Issue 11), Embase (1988 to November 2013), MEDLINE (PubMed 1970 to November 2013), LILACS (1982 to November 2013), the WHO International Clinical Trials Registry Platform (ICTRP) (November 2013) and reference lists of retrieved studies.

Selection criteria: 

Randomised controlled trials (RCTs) comparing the administration of ambroxol given to pregnant women at risk of preterm birth versus placebo, antenatal corticosteroids (betamethasone or dexamethasone), or no treatment.

We did not identify any trials comparing ambroxol with dexamethasone (corticosteroid) in this review. Nor did we identify any trials comparing ambroxol combined with corticosteroid versus corticosteroid alone, or placebo/no treatment.

Data collection and analysis: 

Two review authors independently assessed trials for inclusion and trial quality. Two review authors independently extracted data. Data were checked for accuracy.

Main results: 

We included 14 studies (in 18 trial reports), involving 1047 pregnant women at risk of preterm birth with 1077 newborns. However, three of the included studies did not report on this review's outcomes of interest. We carried out two main comparisons: ambroxol versus antenatal corticosteroids (betamethasone); and ambroxol versus placebo or no treatment. Seven RCTs provided data for our comparison of ambroxol versus corticosteroid (betamethasone) and two trials contributed data to our comparison of ambroxol compared to placebo or no treatment.

The included studies were generally judged as having either 'low' risk of bias or 'unclear' risk of bias (because the trial reports provided insufficient details about methods of sequence generation, allocation concealment and blinding).

Primary outcomes

There was no clear evidence of a difference in the incidence of RDS among newborns born to women who received ambroxol when compared to newborns of women who were given the corticosteroid, betamethasone (risk ratio (RR) 0.79, 95% confidence interval (CI) 0.59 to 1.07, seven RCTs, 728 women/758 newborns, moderate quality evidence) or placebo/no treatment (average RR 0.74; 95% CI 0.46 to 1.20, two studies, 204 women/204 newborns,T2= 0.07; I2= 53%, low-quality evidence). Results were imprecise and consistent with appreciable benefit as well as negligible effect.

Similarly, there was no clear evidence of a difference in the rates of perinatal mortality between the group of women who received ambroxol and women in the corticosteroid (betamethasone) group (RR 0.51, 95% CI 0.23 to 1.12, six studies, 648 women/657 newborns, moderate quality evidence) or the placebo/no treatment group (RR 0.61; 95% CI 0.19 to 1.98, one study, 116 women/116 newborns, low-quality evidence).

In terms of maternal adverse effects, there was no clear differences (in nausea or vomiting) between those women who received ambroxol compared to either those women who received corticosteroids (betamethasone) (average RR 3.45; 95% CI 0.34 to 35.51, three studies, 305 women, T2= 2.82; I2= 67%, very low-quality evidence), or women who received placebo or no treatment (RR 1.79; 95% CI 0.45 to 7.13, one study, 116 women, low-quality evidence). No other adverse effects (e.g. diarrhoea, gastric irritation and headache) were reported in the included studies.

Secondary outcomes

For the review's secondary outcomes, none of the included studies reported on the incidence of bronchopulmonary dysplasia, periventricular haemorrhage, necrotising enterocolitis or rate of maternal mortality.

One small trial (involving 88 women) comparing ambroxol with placebo or no treatment, reported no difference between groups in terms of the need for mechanical ventilation in the neonate (RR 0.94; 95% CI 0.73 to 1.21, 88 women/88 babies, low-quality evidence) or the administration of pulmonary surfactant (RR 1.19; 95% CI 0.61 to 2.30, one RCT, 88 women/88 babies, low-quality evidence).

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