Review: British Medical Journal

SALBUTAMOL
Objectives:
The objectives of this evidence summary are to advice a decision on the retention of salbutamol as
a tocolytic in the Essential Drugs List, and to illustrate why its indication as a treatment for preterm
birth needs to be removed. Salbutamol is considered as representative of other betamimetic drugs
in this context.
Background:
Preterm birth affects 5-22% of pregnancies (1) and is one of the main global causes of newborn
deaths. It burdens healthcare systems, communities, and is distressing to families. Preterm babies
are at higher risk of dying or suffering complications and sequels. Care of preterm babies
frequently demands hospitalisation in units staffed by highly skilled personnel and requiring
technologically advanced equipment.
Tocolytics are used to treat women with threatened preterm birth under the premise that stopping
uterine activity will reduce preterm birth and its associated complications, and will give more time
for treatments aimed at maturing the baby’s lungs. WHO Model Formulary 2004 lists salbutamol
as the betamimetic for use in preterm birth (p 379).
Evidence summary:
IN PRETERM BIRTH
Drugs used as tocolytics include betamimetics (β2 Agonists), calcium channel blockers,
magnesium sulphate, oxytocin receptor antagonists, prostaglandin inhibitors and ethanol. An
overview (search date September 2003) assessed the clinical effects of tocolytics in women with
threatened preterm labor (1) and identified one systematic review of 8 randomised controlled trials
(RCTs) (2) . A subsequently published Cochrane Review (Search date May 2003) assessed the effects
of betamimetics in preterm labor with a meta-analysis of 11 RCTs including 4 unpublished
RCTs (3) . In comparing betamimetics with placebo, the overview and recent Cochrane review shared
seven studies. Salbutamol was not evaluated in any of the RCTs comparing betamimetics with
placebo. The overview and the Cochrane review concluded that compared with placebo,
betamimetics do not significantly reduce preterm deliveries, perinatal mortality or neonatal
morbidity despite prolonging pregnancy (1-3) . Betamimetics significantly increased maternal adverse
effects in a high proportion of women (1-3) . Major outcomes are summarised in Table 1. Prevention
of respiratory distress syndrome: Betamimetics should in theory reduce respiratory distress
syndrome by prolonging exposure to lung maturing agents, but this has not been found in RCTs
yet (1; 3; 5) .
OTHER INDICATIONS
External cephalic version: A systeamtci review found that betamimetics are effective in
facilitating external cephalic version, and reducing related cesarean sections (4) . Only one small
RCT out of the six RCTs in the review evaluated salbutamol, and it found no significant reduction
in failed cephalic version (15/30 with salbutamol v 16/30 with placebo; RR 0.94, 95%CI 0.57 -
1.53) (4) . The systematic review didn’t evaluate adverse effects.
Impaired fetal growth: Betamimetics have been used to reduce impaired fetal growth although
the evidence collated in a systematic review was insufficient to demonstrate that they are safe and
effective (6) .
Placenta previa: use of betamimetics in placenta previa is controversial and lacks supporting
evidence (7) .
Fetal distress: There is no evidence to support the use of betamimetics for fetal distress in second
stage of labor, and the only RCT identified in a systematic review found an unwanted increase of
forceps deliveries (8) . A Cochrane review found three RCTs that evaluated betamimetics in
intrapartum fetal distress. Two of these trials compared a betamimetic to placebo and one

compared to magnesium sulfate. There was no evidence for or against the use of betamimetics in
terms of substantive outcomes. However, surrogate outcomes such as stopping the uterine
contractions and reduced fetal heart rate abnormalities suggest that betamimetics may be useful for
“buying time” to transfer patients to appropriate facilities and prepare them for cesarean section or
operative delivery (9) .
Facilitating cesarean section: A systematic review of the evidence on the effects of tocolysis for
assisting delivery at cesarean section is under way (10) .
It must be noted that the regimen used for indications other than the treatment of preterm labor are
typically single, slow injection with close monitoring of the heart rate as compared to more
prolonged use in the treatment of preterm labor.
Recommendation:
• Retain betamimetics in the essential drug list because
o There is evidence that they are useful in facilitating external cephalic version and
reduce the need for related cesarean sections.
o They may be useful for "buying time" for intrapartum fetal distress
• Remove its indication as a tocolytic in preterm birth.
• Recommendations and any other indications in pregnancy need to be revisited as new
evidence on the safety and effectiveness of salbutamol and other betamimetics in
pregnancy becomes available.
Table 1. Effects of tocolysis with betamimetics for preterm labor, compared with placebo (1; 3)
Outcomes Overview RCTs AR [%] AR [%] OR 95% CI Original Sources
Outcomes Cochrane ¤ Betamimetic Placebo
‡
Perinatal death
Perinatal death (7 days)
Respiratory distress
syndrome
Need to stop treatment
8 ( 2 )
11 ( 3 )
6 ( 2 )
8 ( 3 )
3 ( 2 )
5 ( 3 )
62/682 [9%]
16/712 [2%]
117/639 [18%]
123/644 [19%]
25/88 [28%]
77/590 [13%]
48/604 [8%]
20/620 [3%]
140/565 [25%]
136/575 [24%]
0/86 [0%]
5/491 [1%]
1.08
0.84
0.76
0.87
11.50
11.38
0.72 to 1.62
0.46 to 1.55
0.57 to 1.01
0.71 to 1.08
4.80 to 27.50
5.21 to 24.86
(11; 12; 13; 14; 15; 16;
17; 18; 19; 20; 21; 22)
(11; 12; 13; 14; 15; 16;
19; 20; 22)
(11; 12; 15; 16; 18)
Palpitations
3 ( 2 ) 200/420 [48%] 19/243 [4%] 10.15 7.42 to 13.87 (11; 14; 15; 16)
4 ( 3 ) 213/570 [37%] 19/472 [4%] 10.11 6.56 to 15.58
Dyspnea † 2 ( 2 ) 55/406 [14%] 4/408 [1%] 6.57 3.87 to 11.18 (11; 15)
2 ( 3 ) 55/406 [14%] 14/408 [3%] 3.86 2.21 to 6.77
Chest pains 2 ( 2 ) 39/406 [10%] 3/408 [1%] 6.17 3.31 to 11.51 (11; 15)
2 ( 3 ) 39/406 [10%] 3/408 [1%] 11.29 3.81 to 33.46
Headache
2 ( 2 ) 84/236 [23%] 22/371 [6%] 3.97 2.63 to 5.99 (11; 14; 16)
3 ( 3 ) 98/516 [19%] 22/420 [5%] 4.07 2.60 to 6.35
Nausea 1 ( 2 ) 72/352 [20%] 42/356 [12%] 1.90 1.27 to 2.83 (11)
Vomiting 2 ( 2 ) 48/366 [13%] 29/371 [8%] 1.79 1.11 to 2.87 (11; 14)
Nausea or vomiting 3 ( 3 ) 107/516 [21%] 50/416 [12%] 1.76 1.29 to 2.42 (11; 14; 16)
AR = Absolute Risk; OR = Odds ratio; CI = Confidence interval. Percentages in brackets were not published in the original report.
¤RCT numbers in bold in the second column highlight perfect study matches; differences can be attributed to variation in statistics used.
‡Citation in bold in the last column represent studies included in both systematic reviews.
†Data suggests that one of the reviews had an error in data input and analysis that may explain the difference in magnitudes.

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