TIMOLOL

Fetal Risk Summary

Timolol is a nonselective b-adrenergic blocking agent used for the treatment of hypertension, after myocardial infarction, for the prophylaxis of migraine headache, and topically for the treatment of glaucoma.

Reproductive studies in mice, rats, and rabbits at doses up to about 40 times the maximum recommended daily human dose based on patient weight of 50 kg (MRHD) found no evidence of teratogenicity (1). However, fetotoxicity (resorptions) was observed in rabbits at this dose and in mice exposed to 830 times the MRHD (a maternal toxic dose).

A study using an in vitro perfusion system of human placental tissue demonstrated that timolol crossed to the fetal side of the preparation (2). The placental transfer is consistent with the molecular weight of the compound (about 433 for timolol maleate).

A woman with glaucoma was treated throughout gestation with topical timolol, 0.5% two drops in each eye, pilocarpine, and oral acetazolamide (3). Within 48 hours of delivery at 36 weeks' gestation, the infant developed hyperbilirubinemia, hypocalcemia, hypomagnesemia, and metabolic acidosis. The toxic effects, attributed to the carbonic anhydrase inhibitor, acetazolamide (see Acetazolamide), quickly resolved on treatment. Mild hypertonicity was observed at examinations at 1, 3, and 8 months of age.

In a 1998 case report, a 37-year-old woman at 21 weeks' gestation was referred because of fetal bradycardia (74 beats/minute [bpm]) with irregularity (4). There were no cardiac structural anomalies and no fetal hydrops. The mother had been taking timolol eye drops 0.5%, one drop in each eye once daily, for glaucoma for 3 years. Because no other cause of the bradycardia could be found, the dose was reduced to 0.25% in each eye once daily at about 25 weeks' gestation. Three days later, the fetal heart rate increased to 96 bpm, and then to 120 bpm 1 week later. After consulting with an ophthalmologist, timolol was stopped completely at about 30 weeks, and 3 days later the fetal heart rate was around 130 bpm. At term, a 3025-g female infant was delivered with Apgar scores of 8 and 10 at 1 and 5 minutes, respectively. After birth, a cardiac arrhythmia developed that was diagnosed as right ventricle tachycardia (200 bpm) with atrial extra systole. The condition required digitalization. The baby was doing well at 2 months of age (4).

A case report published in 1986 described the pregnancy of a 24-year-old woman at 30 weeks' gestation who was managed for recurrent pheochromocytoma with a combination of timolol, prazosin (an a1-adrenergic blocker), and metyrosine (a tyrosine hydroxylase inhibitor) (5). Hypertension had been noted at her first prenatal visit at 12 weeks' gestation. Because of declines in fetal breathing, body movements, and amniotic fluid volume that began 2 weeks after the start of therapy, a cesarean section was conducted at 33 weeks. The 1450-g female infant had Apgar scores of 3 and 5 at 1 and 5 minutes, respectively. Mild metabolic acidosis was found on analysis of umbilical cord blood gases. Multiple infarcts were noted in the placenta but no evidence of metastatic tumor. The growth-retarded infant did well and was discharged home on day 53 of life (5).

Some b-blockers may cause intrauterine growth retardation and reduced placental weight (see Atenolol and Propranolol). Systemic treatment beginning early in the 2nd trimester results in the greatest weight reductions. This toxicity has not been consistently demonstrated in other agents within this class, but the relatively few pharmacologic differences among the drugs suggests that the reduction in fetal and placental weights probably occurs with all at some point. The lack of toxicity documentation may reflect the number and type of patients studied, the duration of therapy, or the dosage used, rather then a true difference among b-blockers. Although growth retardation is a serious concern, the benefits of maternal therapy with b-blockers may, in some cases, outweigh the risks to the fetus and must be judged on a case-by-case basis.

The systemic use near delivery of some agents in this class has resulted in persistent b-blockade in the newborn (see Acebutolol, Atenolol, and Nadolol). Thus, newborns exposed in utero to timolol should be closely observed during the first 24–48 hours after birth for bradycardia and other symptoms. The long-term effects of in utero exposure to b-blockers have not been studied but warrant evaluation.

[*Risk Factor D if used systemically in 2nd or 3rd trimesters.]

Breast Feeding Summary

Timolol is excreted into breast milk (6,7). In nine lactating women given 5 mg orally 3 times daily, the mean milk concentration of timolol 105–135 minutes after a dose was 15.9 ng/mL (6). When a dose of 10 mg 3 times daily was given to four patients, mean milk levels of 41 ng/mL were measured. The milk:plasma ratios for the two regimens were 0.80 and 0.83, respectively.

A woman with elevated intraocular pressure applied ophthalmic 0.5% timolol drops to the right eye twice daily, resulting in excretion of the drug in her breast milk (7). Maternal timolol levels in milk and plasma were 5.6 and 0.93 ng/mL, respectively, about 1.5 hours after a dose. A milk sample taken 12 hours after the last dose contained 0.5 ng/mL of timolol. Assuming that the infant nursed every 4 hours and received 75 mL at each feeding, the daily dose would be below that expected to produce cardiac effects in the infant (7).

No adverse reactions were noted in the nursing infants described in the above reports. However, infants exposed to timolol via breast milk should be closely observed for bradycardia and other signs or symptoms of b-blockade. Long-term effects of exposure to b-blockers from milk have not been studied but warrant evaluation. The American Academy of Pediatrics considers timolol to be compatible with breast feeding (8).

References

1. Product information. Blocadren. Merck, 2000.
2. Schneider H, Proegler M. Placental transfer of b-adrenergic antagonists studied in an in vitro perfusion system of human placental tissue. Am J Obstet Gynecol 1988;159:42–7.
3. Merlob P, Litwin A, Mor N. Possible association between acetazolamide administration during pregnancy and metabolic disorders in the newborn. Eur J Obstet Gynecol Reprod Biol 1990;35:85–8.
4. Wagenvoort AM, Van Vugt JMG, Sobotka M, Van Geijn HP. Topical timolol therapy in pregnancy: is it safe for the fetus? Teratology 1998;58:258–62.
5. Devoe LD, O'Dell BE, Castillo RA, Hadi HA, Searle N. Metastatic pheochromocytoma in pregnancy and fetal biophysical assessment after maternal administration of alpha-adrenergic, beta-adrenergic, and dopamine antagonists. Obstet Gynecol 1986;68:15S–8S.
6. Fidler J, Smith V, DeSwiet M. Excretion of oxprenolol and timolol in breast milk. Br J Obstet Gynaecol 1983;90:961–5.
7. Lustgarten JS, Podos SM. Topical timolol and the nursing mother. Arch Ophthalmol 1983;101:1381–2.
8. Committee on Drugs, American Academy of Pediatrics. The transfer of drugs and other chemicals into human milk. Pediatrics 1994;93:137–50.