Theophylline

Name: THEOPHYLLINE
Class: Respiratory Drug (Bronchodilator)
Risk Factor: CM

Fetal Risk Summary

Theophylline is the bronchodilator of choice for asthma and chronic obstructive pulmonary disease in the pregnant patient (1,2,3,4,5 and 6). No published reports linking the use of theophylline with congenital defects have been located.
Reproduction studies in mice and rats at oral doses up to approximately 2.0 and 3.0 times, respectively, the recommended human dose on a body surface area basis (RHD) revealed no evidence of teratogenicity (7). At a slightly lower dose (about 2.5 times the RHD) in rats, embryo toxicity, but not maternal toxicity, was observed.
In a surveillance study of Michigan Medicaid recipients involving 229,101 completed pregnancies conducted between 1985 and 1992, 1,240 newborns had been exposed to theophylline and 36 to aminophylline during the 1st trimester (F. Rosa, personal communication, FDA, 1993). A total of 68 (5.5%) major birth defects were observed (53 expected) with theophylline and 1 (2.8%) major defect (2 expected) with aminophylline. For theophylline, specific data were available for six defect categories, including (observed/expected) 20/12 cardiovascular defects, 5/1 oral clefts, 2/0.5 spina bifida, 5/4 polydactyly, 0/2 limb-reduction defects, and 2/3 hypospadias. Three of the defect categories, cardiovascular, oral clefts, and spina bifida, suggest an association with the drug, but other factors, such as the mother's disease, concurrent drug use, and chance, may be involved. For aminophylline, the single defect was a polydactyly.
The Collaborative Perinatal Project monitored 193 mother-child pairs with 1st-trimester exposure to theophylline or aminophylline (8). No evidence was found for an association with malformations.
Theophylline crosses the placenta, and newborn infants may have therapeutic serum levels (9,10,11,12 and 13). Transient tachycardia, irritability, and vomiting have been reported in newborns delivered from mothers consuming theophylline (9,10). These effects are more likely to occur when maternal serum levels at term are in the high therapeutic range or above (therapeutic range 8–20 µg/mL) (11). Cord blood levels are approximately 100% of the maternal serum concentration (12,13).
In patients at risk for premature delivery, aminophylline (theophylline ethylenediamine) was found to exert a beneficial effect by reducing the perinatal death rate and the frequency of respiratory distress syndrome (14,15). In a nonrandomized study, aminophylline 250 mg IM every 12 hours up to a maximum of 3 days was compared with betamethasone, 4 mg IM every 8 hours for 2 days (15). Patients in the aminophylline group were excluded from receiving corticosteroids because of diabetes (4 patients), hypertension (10 patients), and ruptured membranes for more than 24 hours (4 patients). The aminophylline and steroid groups were comparable in length of gestation (32.5 weeks vs. 32.1 weeks), male:female infant sex ratio (10:8 vs. 8:8), Apgar scores (7.6 vs. 7.7), birth weight (1720 g vs. 1690 g), and hours between treatment and delivery (73 vs. 68). Respiratory distress syndrome occurred in 11% (2 of 18) of the aminophylline group compared with 0% (0 of 16) of the corticosteroid group (n.s.). A significant difference (p=0.01) was found in the incidence of neonatal infection with 8 of 16 (50%) of the betamethasone group having signs of infection and none in the aminophylline group. The mechanism proposed for aminophylline-induced fetal lung maturation is similar to that observed with betamethasone: enhancement of tissue cyclic AMP by inhibition of cyclic AMP phosphodiesterase and a corresponding increased production and/or release of phosphatidylcholine (15).
An IV infusion of aminophylline has been tested for its tocolytic effects on oxytocin-induced uterine contractions (16). A slight decrease in uterine activity occurred in the first 15 minutes, but this was related to the effect on contraction intensity, not frequency. The author concluded that aminophylline was a poor tocolytic agent. However, a more recent in vitro study examined the effect of increasing concentrations of aminophylline on pregnant human myometrium (17). Aminophylline produced a dose-related decrease in contraction strength and a non-dose-dependent lengthening of the period of contraction. In this study, the authors concluded that aminophylline may be a clinically useful tocolytic agent (17).
A reduction in the occurrence of preeclampsia among pregnant asthmatic women treated with theophylline has been reported (18). Preeclampsia occurred in 1.2% (1 of 85) of patients treated with theophylline compared with 8.8% (6/68) (p<0.05) of asthmatic patients not treated with the drug. Although the results were significant, the small numbers indicate that the results must be interpreted cautiously (18). The authors proposed a possible mechanism for the protective effect, if indeed it does occur, involving the inhibition of platelet aggregation and the altering of vascular tone, two known effects of theophylline (18).
Concern over the depressant effects of methylxanthines on lipid synthesis in developing neural systems has been reported (19). Recent observations that infants treated for apnea with theophylline exhibit no overt neurologic deficits at 9–27 months of age are encouraging (20,21). However, the long-term effects of these drugs on human brain development are not known (19).
Frequent, high-dose asthmatic medication containing theophylline, ephedrine, phenobarbital, and diphenhydramine was used throughout pregnancy by one woman who delivered a stillborn girl with complete triploidy (22). Although drug-induced chromosomal damage could not be proven, theophylline has been shown in in vitro tests to cause breakage of chromosomes in human lymphocytes (23). However, the clinical significance of this breakage is doubtful.
Theophylline withdrawal in a newborn exposed throughout gestation has been reported (12). Apneic spells developed at 28 hours after delivery and became progressively worse over the next 4 days. Therapy with theophylline resolved the spells.
The pharmacokinetics of theophylline during pregnancy have been studied (24,25). One report suggested that plasma concentrations of theophylline fall during the 3rd trimester because of an increased maternal volume of distribution (24). However, a more recent study found a significantly lower clearance of theophylline during the 3rd trimester, ranging in some cases between 20% and 53% less (25). Two women had symptoms of toxicity requiring a dosage reduction.

Breast Feeding Summary

Theophylline is excreted into breast milk (26,27). A milk:plasma ratio of 0.7 has been measured (27). Estimates indicate that less than 1% of the maternal dose is excreted into breast milk (26,27). However, one infant became irritable secondary to a rapidly absorbed oral solution of aminophylline taken by the mother (26). Because very young infants may be more sensitive to levels that would be nontoxic in older infants, less rapidly absorbed theophylline preparations may be advisable for nursing mothers (10,28). Except for the precaution that theophylline may cause irritability in the nursing infant, the American Academy of Pediatrics considers the drug to be compatible with breast feeding (29).

References

1. Greenberger P, Patterson R. Safety of therapy for allergic symptoms during pregnancy. Ann Intern Med 1978;89:234–7.
2. Weinstein AM, Dubin BD, Podleski WK, Spector SL, Farr RS. Asthma and pregnancy. JAMA 1979;241:1161–5.
3. Hernandez E, Angell CS, Johnson JWC. Asthma in pregnancy: current concepts. Obstet Gynecol 1980;55:739–43.
4. Turner ES, Greenberger PA, Patterson R. Management of the pregnant asthmatic patient. Ann Intern Med 1980;93:905–18.
5. Pratt WR. Allergic diseases in pregnancy and breast feeding. Ann Allergy 1981;47:355–60.
6. Lalli CM, Raju L. Pregnancy and chronic obstructive pulmonary disease. Chest 1981;80:759–61.
7. Product information. Theo-Dur. Key Pharmaceuticals, 2000.
8. Heinonen OP, Slone D, Shapiro S. Birth Defects and Drugs in Pregnancy. Littleton, MA: Publishing Sciences Group, 1977:367,370.
9. Arwood LL, Dasta JF, Friedman C. Placental transfer of theophylline: two case reports. Pediatrics 1979;63:844–6.
10. Yeh TF, Pildes RS. Transplacental aminophylline toxicity in a neonate. Lancet 1977;1:910.
11. Labovitz E, Spector S. Placental theophylline transfer in pregnant asthmatics. JAMA 1982;247:786–8.
12. Horowitz DA, Jablonski W, Mehta KA. Apnea associated with theophylline withdrawal in a term neonate. Am J Dis Child 1982;136:73–4.
13. Ron M, Hochner-Celnikier D, Menczel J, Palti Z, Kidroni G. Maternal-fetal transfer of aminophylline. Acta Obstet Gynecol Scand 1984;63:217–8.
14. Hadjigeorgiou E, Kitsiou S, Psaroudakis A, Segos C, Nicolopoulos D, Kaskarelis D. Antepartum aminophylline treatment for prevention of the respiratory distress syndrome in premature infants. Am J Obstet Gynecol 1979;135:257–60.
15. Granati B, Grella PV, Pettenazzo A, Di Lenardo L, Rubaltelli FF. The prevention of respiratory distress syndrome in premature infants: efficacy of antenatal aminophylline treatment versus prenatal glucocorticoid administration. Pediatr Pharmacol (New York) 1984;4:21–4.
16. Lipshitz J. Uterine and cardiovascular effects of aminophylline. Am J Obstet Gynecol 1978;131:716–8.
17. Bird LM, Anderson NC Jr, Chandler ML, Young RC. The effects of aminophylline and nifedipine on contractility of isolated pregnant human myometrium. Am J Obstet Gynecol 1987;157:171–7.
18. Dombrowski MP, Bottoms SF, Boike GM, Wald J. Incidence of preeclampsia among asthmatic patients lower with theophylline. Am J Obstet Gynecol 1986;155:265–7.
19. Volpe JJ. Effects of methylxanthines on lipid synthesis in developing neural systems. Semin Perinatol 1981;5:395–405.
20. Aranda JV, Dupont C. Metabolic effects of methylxanthines in premature infants. J Pediatr 1976;89:833–4.
21. Nelson RM, Resnick MB, Holstrum WJ, Eitzman DV. Development outcome of premature infants treated with theophylline. Dev Pharmacol Ther 1980;1:274–80.
22. Halbrecht I, Komlos L, Shabtay F, Solomon M, Book JA. Triploidy 69, XXX in a stillborn girl. Clin Genet 1973;4:210–2.
23. Weinstein D, Mauer I, Katz ML, Kazmer S. The effect of methylxanthines on chromosomes of human lymphocytes in culture. Mutat Res 1975;31:57–61.
24. Sutton PL, Koup JR, Rose JQ, Middleton E. The pharmacokinetics of theophylline in pregnancy. J Allergy Clin Immunol 1978;61:174.
25. Carter BL, Driscoll CE, Smith GD. Theophylline clearance during pregnancy. Obstet Gynecol 1986;68:555–9.
26. Yurchak AM, Jusko WJ. Theophylline secretion into breast milk. Pediatrics 1976;57:518–25.
27. Stec GP, Greenberger P, Ruo TI, Henthorn T, Morita Y, Atkinson AJ Jr, Patterson R. Kinetics of theophylline transfer to breast milk. Clin Pharmacol Ther 1980;28:404–8.
28. Berlin CM. Excretion of methylxanthines in human milk. Semin Perinatol 1981;5:389–94.
29. Committee on Drugs, American Academy of Pediatrics. The transfer of drugs and other chemicals into human milk. Pediatrics 1994;93:137–50.

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