Albuterol

 Risk Factor: CM
 Class: AUTONOMICS / Sympathomimetics (Adrenergics)

Contents of this page:

Fetal Risk Summary
Breast Feeding Summary
References
Questions and Answers

Fetal Risk Summary

Albuterol is a b-sympathomimetic used to prevent premature labor (see also Terbutaline and Ritodrine) (1,2,3,4,5,6,7,8,9,10,11 and 12). In twins, however, a double-blind, controlled study involving 144 women (74 treated with albuterol and 70 treated with placebo) observed no difference between the groups in the length of gestation, birth weight, or fetal outcome, except fewer infants in the albuterol group had respiratory distress syndrome (13).

In an in vitro experiment using perfused human placentas, 2.8% of infused drug crossed to the fetal side, but the method only used about 5% of the exchange area of the total placenta (14). Maternal serum concentrations during IV and oral albuterol therapy have been reported (15).

Reproduction studies in mice observed an increase in the incidence of cleft palate at a SC dose of 0.25 mg/kg (0.4 times the maximum recommended human oral dose [MRHD]) and higher (16). Cranioschisis was observed in 37% of the fetuses from pregnant rabbits treated with a 50 mg/kg dose of albuterol (78 times the MRHD) (16).

No published reports linking the use of albuterol to human congenital anomalies have been located, but the majority of reports do not involve 1st trimester exposures. However, in a surveillance study of Michigan Medicaid recipients conducted between 1985 and 1992 involving 229,101 completed pregnancies, 1,090 newborns had been exposed to albuterol during the 1st trimester (F. Rosa, personal communication, FDA, 1993). A total of 48 (4.4%) major birth defects were observed (43 expected). Specific data were available for six defect categories, including (observed/expected) 9/11 cardiovascular defects, 2/2 oral clefts, 2/0.6 spina bifida, 1/2 limb reduction defects, 0/3 hypospadias, and 6/3 polydactyly. Only with the latter defect is there a suggestion of a possible association, but other factors, including the mother's disease, concurrent drug use, and chance, may be involved.

A brief 1980 report described a patient who was treated with a continuous IV infusion of albuterol for 17 weeks via a catheter placed in the right subclavian vein (10,17,18). A normal male infant was delivered within a few hours of stopping the drug. A 1982 report described the use of albuterol in two women with incompetent cervix from the 14th week of gestation to near term (19). Both patients were delivered of normal infants.

Adverse reactions observed in the fetus and mother after albuterol treatment are secondary to the cardiovascular and metabolic effects of the drug. Albuterol may cause maternal and fetal tachycardia with fetal rates exceeding 160 beats/minute (1,2 and 3,12,20). Major decreases in maternal blood pressure have been reported with both systolic and diastolic pressures dropping more than 30 mm Hg (2,4,6). Fetal distress after maternal hypotension was not mentioned. One study observed a maximum decrease in diastolic pressure of 24 mm Hg (34% decrease) but a rise in systolic pressure (20). Other maternal adverse effects associated with albuterol have been acute congestive heart failure, pulmonary edema, and death (21,22,23,24,25,26,27,28 and 29).

Like all b-mimetics, albuterol may cause transient fetal and maternal hyperglycemia followed by an increase in serum insulin (4,30,31,32 and 33). Cord blood levels of insulin are about twice those of untreated control infants and are not dependent on the duration of exposure, gestational age, or birth weight (32,33). These effects are more pronounced in diabetic patients, especially in juvenile diabetics, with the occurrence of significant increases in glycogenolysis and lipolysis (20,34,35). Maternal blood glucose should be closely monitored and neonatal hypoglycemia prevented with adequate doses of glucose.

A group of 20 women in premature labor, treated with oral albuterol (4 mg every 4 hours for several weeks), was matched with a control group of women who were not in premature labor (36). The mean gestational ages at delivery for the treated and nontreated patients were 36.4 and 37.0 weeks, respectively. No significant differences were found between the groups for cord blood concentrations of insulin, triiodothyronine (T3), thyroxine (T4), and thyroid-stimulating hormone (TSH). However, growth hormone levels were significantly higher in the treated group than in control patients (36.5 vs. 17.4 ng/mL, respectively, p<0.001). The investigators did not determine the reason for the elevated growth hormone level but speculated that it could be caused by either the use of betamethasone for fetal lung maturation in some women of the albuterol group (and resulting fluctuations in fetal blood glucose and insulin levels), or direct adrenergic stimulation of the fetal pituitary (36). Of interest, of the 12 women who received betamethasone, cord blood growth hormone levels in 11 were compared with those of 8 untreated control women. Although the levels in the treated patients were higher (39.5 vs. 31.4 ng/mL), the difference was not significant.

Albuterol decreases the incidence of neonatal respiratory distress syndrome similar to the way that other b-mimetics do (13,37,38). Long-term evaluation of infants exposed to in utero b-mimetics has been reported, but not specifically for albuterol (39,40). No harmful effects were observed in these infants. However, a brief 1994 Reference described the use of b-sympathomimetics (albuterol, N=1; ritodrine N=7) in eight infants from a group of 16 with retinopathy of prematurity (41). In a matched control group with retinopathy, only 1 of 16 infants was exposed to ritodrine (p<0.008). The authors speculated that the b-sympathomimetics had compromised retinal perfusion in utero leading to ischemia and eventually to the ophthalmic complication (41).

The effects of inhaled albuterol on maternal and fetal hemodynamics were first published as an abstract (42) and then as a full report (43). Twelve pregnant asthmatic women between 33 and 39 weeks' gestation received two deep inhalations of a 0.05% solution as recommended by the manufacturer. No effects on the mean maternal, uterine, or fetal hemodynamics were observed.

In contrast to the above, a 1997 case report described fetal tachycardia from the inadvertent administration of a double dose of inhaled albuterol over 24 hours (44). The 34-year-old woman at 33 weeks' gestation received a metered-dose inhaler (two 90-g actuations every 46 hours; 5 doses over 24 hours) and albuterol nebulizer treatment (2.5 mg) every 4 hours (5 doses over 24 hours). Three hours after the last dose, fetal tachycardia (>200 beats/minute) was detected (maternal heart rate was 90100 beats/minute). Atrial flutter of 420 beats/minute was detected by fetal echocardiography with a predominate 2:1 conduction. Eight hours later, spontaneous conversion to a normal rate occurred. A normal infant was delivered at term and did well during the 4 days of hospitalization.

Breast Feeding Summary

No reports describing the use of albuterol during human lactation or measuring the amount, if any, of the drug excreted in milk have been located. Other drugs in the class (e.g., terbutaline) are considered compatible with breast feeding and albuterol, most likely, is also compatible.

References

1. Liggins GC, Vaughan GS. Intravenous infusion of salbutamol in the management of premature labor. J Obstet Gynaecol Br Commonw 1973;80:2933.
2. Korda AR, Lynerum RC, Jones WR. The treatment of premature labor with intravenous administered salbutamol. Med J Aust 1974;1:7446.
3. Hastwell G. Salbutamol aerosol in premature labour. Lancet 1975;2:12123.
4. Hastwell GB, Halloway CP, Taylor TLO. A study of 208 patients in premature labor treated with orally administered salbutamol. Med J Aust 1978;1:4659.
5. Hastwell G, Lambert BE. A comparison of salbutamol and ritodrine when used to inhibit premature labour complicated by ante-partum haemorrhage. Curr Med Res Opin 1979;5:7859.
6. Ng KH, Sen DK. Hypotension with intravenous salbutamol in premature labour. Br Med J 1974;3:257.
7. Pincus R. Salbutamol infusion for premature labour - the Australian trials experience. Aust NZ Obstet Gynaecol 1981;21:14.
8. Gummerus M. The management of premature labor with salbutamol. Acta Obstet Gynecol Scand 1981;60:3757.
9. Crowhurst JA. Salbutamol, obstetrics and anaesthesia: a review and case discussion. Anaesth Intensive Care 1980;8:3943.
10. Lind T, Godfrey KA, Gerrard J, Bryson MR. Continuous salbutamol infusion over 17 weeks to pre-empt premature labour. Lancet 1980;2:11656.
11. Kuhn RJP, Speirs AL, Pepperell RJ, Eggers TR, Doyle LW, Hutchison A. Betamethasone, albuterol, and threatened premature delivery: benefits and risks. Study of 469 pregnancies. Obstet Gynecol 1982;60:4038.
12. Eggers TR, Doyle LW, Pepperell RJ. Premature labour. Med J Aust 1979;1:2136.
13. Felicity Ashworth M, Spooner SF, Verkuyl DAA, Waterman R, Ashurst HM. Failure to prevent preterm labour and delivery in twin pregnancy using prophylactic oral salbutamol. Br J Obstet Gynaecol 1990;97:87882.
14. Sodha RJ, Schneider H. Transplacental transfer of b-adrenergic drugs studied by an in vitro perfusion method of an isolated human placental lobule. Am J Obstet Gynecol 1983;147:30310.
15. Haukkamaa M, Gummerus M, Kleimola T. Serum salbutamol concentrations during oral and intravenous treatment in pregnant women. Br J Obstet Gynaecol 1985;92:12303.
16. Product information. Proventil. Schering Corporation, 2000.
17. Boylan P, ODiscoll K. Long-term salbutamol or successful Shirodkar suture? Lancet 1980;2:1374.
18. Addis GJ. Long-term salbutamol infusion to prevent premature labor. Lancet 1981;1:423.
19. Edmonds DK, Letchworth AT. Prophylactic oral salbutamol to prevent premature labour. Lancet 1982;1:13101.
20. Wager J, Fredholm B, Lunell NO, Persson B. Metabolic and circulatory effects of intravenous and oral salbutamol in late pregnancy in diabetic and non-diabetic women. Acta Obstet Gynecol Scand 1982;Suppl 108:416.
21. Whitehead MI, Mander AM, Hertogs K, Williams RM, Pettingale KW. Acute congestive cardiac failure in a hypertensive woman receiving salbutamol for premature labour. Br Med J 1980;280:12212.
22. Poole-Wilson PA. Cardiac failure in a hypertensive woman receiving salbutamol for premature labour. Br Med J 1980;281:226.
23. Fogarty AJ. Cardiac failure in a hypertensive woman receiving salbutamol for premature labour. Br Med J 1980;281:226.
24. Davies PDO. Cardiac failure in a hypertensive woman receiving salbutamol for premature labour. Br Med J 1980;281:2267.
25. Robertson M, Davies AE. Cardiac failure in a hypertensive woman receiving salbutamol for premature labour. Br Med J 1980;281:227.
26. Crowley P. Cardiac failure in a hypertensive woman receiving salbutamol for premature labour. Br Med J 1980;281:227.
27. Whitehead MI, Mander AM, Pettingale KW. Cardiac failure in a hypertensive woman receiving salbutamol for premature labour (reply). Br Med J 1980;281:227.
28. Davies AE, Robertson MJS. Pulmonary oedema after the administration of intravenous salbutamol and ergometrine-case report. Br J Obstet Gynaecol 1980;87:53941.
29. Milliez, Blot Ph, Sureau C. A case report of maternal death associated with betamimetics and betamethasone administration in premature labor. Eur J Obstet Gynaecol Reprod Biol 1980;11: 95100.
30. Thomas DJB, Dove AF, Alberti KGMM. Metabolic effects of salbutamol infusion during premature labour. Br J Obstet Gynaecol 1977;84:4979.
31. Wager J, Lunell NO, Nadal M, Ostman J. Glucose tolerance following oral salbutamol treatment in late pregnancy. Acta Obstet Gynecol Scand 1981;60:2914.
32. Lunell NO, Joelsson I, Larsson A, Persson B. The immediate effect of a B-adrenergic agonist (salbutamol) on carbohydrate and lipid metabolism during the third trimester of pregnancy. Acta Obstet Gynecol Scand 1977;56:4758.
33. Procianoy RS, Pinheiro CEA. Neonatal hyperinsulinism after short-term maternal beta sympathomimetic therapy. J Pediatr 1982;101:6124.
34. Barnett AH, Stubbs SM, Mander AM. Management of premature labour in diabetic pregnancy. Diabetologia 1980;188:3658.
35. Wager J, Fredholm BB, Lunell NO, Persson B. Metabolic and circulatory effects of oral salbutamol in the third trimester of pregnancy in diabetic and non-diabetic women. Br J Obstet Gynaecol 1981;88:35261.
36. Desgranges M-F, Moutquin J-M, Peloquin A. Effects of maternal oral salbutamol therapy on neonatal endocrine status at birth. Obstet Gynecol 1987;69:5824.
37. Hastwell GB. Apgar scores, respiratory distress syndrome and salbutamol. Med J Aust 1980;1:1745.
38. Hastwell G. Salbutamol and respiratory distress syndrome. Lancet 1977;2:354.
39. Wallace RL, Caldwell DL, Ansbacher R, Otterson WN. Inhibition of premature labor by terbutaline. Obstet Gynecol 1978;51:38792.
40. Freysz H, Willard D, Lehr A, Messer J, Boog G. A long term evaluation of infants who received a beta-mimetic drug while in utero. J Perinat Med 1977;5:949.
41. Michie CA, Braithwaite S, Schulenberg E, Harvey D. Do maternal b-sympathomimetics influence the development of retinopathy in the premature infant? Arch Dis Child 1994;71:F149.
42. Rayburn WF, Atkinson BD, Gilbert KA, Turnbull GL. Acute effects of inhaled albuterol (Proventil) on fetal hemodynamics (abstract). Teratology 1994;49:370.
43. Rayburn WF, Atkinson BD, Gilbert K, Turnbull GL. Short-term effects of inhaled albuterol on maternal and fetal circulations. Am J Obstet Gynecol 1994;171:7703.
44. Baker ER, Flanagan MF. Fetal atrial flutter associated with maternal beta-sympathomimetic drug exposure. Obstet Gynecol 1997;89:861.