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Management of Glaucoma in Pregnancy and Lactation
SURVEY OF OPHTHALMOLOGY VOLUME 45 • NUMBER 5 • MARCH–APRIL 2001
CLINICAL CHALLENGES PETER J. SAVINO, EDITOR
Management of Glaucoma in Pregnancy and Lactation Sandra M. Johnson, MD,1 Mary Martinez, MD, PhD,1 and Sharon Freedman, MD2 1
Department of Ophthalmology, University of North Carolina Hospitals, Chapel Hill, North Carolina, and 2Department of Ophthalmology, Duke University, Durham, North Carolina, USA
Comments by Jonathan Myers, MD, and Ronald Gross, MD (In keeping with the format of a clinical pathologic conference, the abstract and key words appear at the end of the article)
Case Report. A 30-year-old white woman, pregnant and at 7 months’ gestation, presented with a severe frontal headache and decreased vision in her right eye. Her past ocular history was significant for trauma to the right eye as a child with globe repair, loss of her lens, and a subsequent penetrating keratoplasty. She developed glaucoma at age 19. In addition to timolol maleate gel-forming solution 0.5%, she had previously been treated with latanoprost 0.005% and brimonidine 0.2%, which were discontinued by her prior ophthalmologist at 10.5 weeks gestation. She had had an Argon laser trabeculoplasty (ALT) when she was 6.5 weeks pregnant with an intraocular pressure (IOP) 4 weeks later of 16 mm Hg while on her three medications. The treatment plan for this patient had been to decrease medications and allow higher IOP to exist to reduce the risk of medications to the developing fetus. After stopping the latanoprost and brimonidine as directed, the patient did not keep her follow-up appointment. When she was seen again 4 months later, she reported that she had remained compliant with the timolol gel-forming solution until she ran out of it 1 week prior to presentation. On examination, uncorrected visual acuity in the right eye was 20/300, which did not improve with pinhole, and 20/15 in the left. In-
traocular pressure by applanation tonometry was 45 mm Hg in the right eye (OD) and 14 mm Hg in the left (OS). The right pupil was chronically dilated and the left was normal. There was a right relative afferent pupillary defect. Automated perimetry is shown in Fig. 1. Slit-lamp examination revealed a corneal graft in the right eye and aphakia. Dilated fundus examination showed a cup to disk ratio of 0.7 OD with significant superior and superior nasal sloping (Fig. 2). The cup to disk ratio OS was 0.4 with an intact neural rim. The fundi were otherwise normal. Gonioscopy showed the anterior chamber angle to be completely open in both eyes. The patient was diagnosed with secondary chronic open angle glaucoma. Intraocular pressure had been previously controlled on three medications, but since discontinuation of medications, there was poor control despite ALT. How should her glaucoma be managed at this point of her pregnancy?
Comments Comments by Jonathan Myers, MD,1 and Ronald Gross, MD,2 1Glaucoma Service, Wills Eye Hospi449
© 2001 by Elsevier Science Inc. All rights reserved.
0039-6257/01/$–see front matter PII S0039-6257(00)00209-5
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Fig. 1. Automated perimetry OD (right) shows superior and inferior nasal defects. OS (left) is normal.
tal, Philadelphia, Pennsylvania, and 2Cullen Eye Institute, Baylor College of Medicine, Houston, Texas, USA The patient should be offered the alternatives of medical therapy or surgery in a very direct and detailed discussion. The risks presented to the fetus with medication and to her with noncompliance must be addressed and compared to those of surgery. If the patient chooses medical therapy, we would institute timolol gel-forming solution 0.5% and brimonidine with punctal occlusion and a documented discussion of the need for close follow-up and compliance.
Case Report (Continued) The decision was made to begin a 3-medication regimen, consisting of timolol gel-forming solution 0.5%, dorzolamide 2%, and brimonidine 0.2% in the affected eye. Instillation of each drop was to be followed by punctal occlusion to minimize systemic
absorption.44,63 The gel-forming form of timolol was used, since this dose form has been associated with less bradycardia, suggesting a lower systemic absorption.50 The topical carbonic anhydrase inhibitor was used to minimize systemic levels of carbonic anhydrase inhibition in mother and fetus.27,36–38,42,61 Brimonidine was chosen, since it has been categorized as class B—i.e., controlled studies in animals show no risk to the fetus, but there are no controlled studies in humans, or adverse effects in animals have not been confirmed in controlled studies in humans. Within one week, the IOP was reduced to 20 mm Hg and vision corrected to 20/50. Six weeks later, the patient again returned with the complaint of decreased vision and headache. Vision was reduced to pinhole 20/300 and the IOP was 50 mm Hg. How would you manage the patient at this juncture?
Comments (Continued) This patient has failed medical therapy. We would treat her surgically. Tube shunt surgery would be the preferred procedure in this young patient with a complicated glaucoma and prior ocular surgery.
Case Report (Continued)
Fig. 2. Right optic disk with glaucomatous cupping.
One drop of latanoprost 0.005% was given in the clinic and echothiophate 1/16 was added to the patient’s regimen. Since prostaglandins are involved in the physiology of labor and delivery, latanoprost was not continued. Because echothiophate is a quaternary ammonium, it may traverse membranes, such as the placenta, with difficulty; thus, it was chosen over pilocarpine, a tertiary cholinergic amine, which is a weak base and may traverse membranes well.5,24
GLAUCOMA MANAGEMENT IN PREGNANCY
The patient took one dose of the medication 2 days later. Her IOP was checked the following morning and found to be 21 mm Hg. By now, her pregnancy was full term and the decision was made by the patient and her nurse practitioner to induce labor, which did not result in labor and delivery. She continued on topical timolol, dorzolamide, and brimonidine without the miotic, which irritated her eye. Four days later, her IOP was 21 mm Hg and best-corrected vision was 20/100. Unfortunately, IOP rose again to 42 mm Hg in another 4 days. Induction of labor was again tried with the hopes of achieving better glaucoma control post-partum. Pilocarpine 4% was added during labor. Sustainedrelease Ocusert form of pilocarpine would probably have been a safer choice.30 Following successful delivery of a healthy infant, the IOPs remained elevated between 45 and 54 mm Hg. The patient began nursing the neonate. She was given the option of discontinuing lactation, given the need for continued glaucoma medications, but she refused. Despite treatment with various combinations of topical medications, including timolol gel-forming solution 0.5%, dipiverin 0.2%, dorzolamide 0.5% and brimonidine 0.2%, as well as several doses of systemic acetazolamide, the IOP ranged from 36 to 45 mm Hg. All drugs were administered with punctal occlusion. The infant was closely monitored in the nursery, with vital signs checked frequently, and demonstrated no apnea or bradycardia.43 The patient was given her medications immediately after nursing in an attempt to reduce the concentration in her breast milk, since drug levels in milk are often highest 30 to 120 minutes after a drug dose.30 Given the poor response to medications and the unknown concentrations in breast milk and the possible effects on the baby from ongoing exposure to glaucoma medications via nursing, the decision was made to proceed with Ahmed valve placement. Intraocular pressure post-operatively decreased to the teens on no medications. Best-corrected visual acuity remained stable at 20/60. In the following months, the pressures gradually increased to the low 20s with tenon’s cyst formation, and the patient was restarted on timolol gel-forming solution 0.5% and dorzolamide 2%. She continued to breastfeed and punctal occlusion was encouraged. The child has experienced no known health problems.
Comments (Continued) This case demonstrates the difficulties of managing glaucoma in the pregnant or nursing patient. Medications were thoughtfully selected and dosed to minimize risks to the fetus. ALT was only temporarily helpful, and despite optimization of the medi-
451
cal regimen, the IOP returned to dangerously high levels. This patient could have been offered trabeculectomy or tube implant surgery earlier in her course of therapy, even during pregnancy. There are additional risks of glaucoma surgery for pregnant patients, including those of the local anesthetic, the supine positioning, and the post-operative medications. However, there is also a risk of not controlling the glaucoma, i.e., progressive optic nerve damage and pain. In some situations, the overall risks associated with surgery are less than those of medical glaucoma therapy. If the patient has progression of visual field loss or inadequate pressure control on maximally tolerated safe medical therapy, surgery may be the next best option, either before or after ALT, depending on the patient and type of glaucoma. To facilitate the patient’s understanding and acceptance, the possible need for surgery should be mentioned early in the course of treatment, rather than only when the need for surgery is urgent. If an infant or fetus is at significant risk because of the glaucoma treatment regimen, e.g., an infant shows bradycardia from beta blockade with topical timolol, the clinician should discontinue that drug. Although the patient has the right to refuse surgery or other care regimens, she should not unnecessarily endanger a child. Few cases addressing anesthetic use in ophthalmologic surgery during pregnancy have been reported. Retrobulbar administration of bupivicaine without any complications was reported in a 35-year-old woman at 11 weeks gestation,55 and general anesthesia was used for sclerotomy surgery in a 32-week pregnant woman with no reported complications due to anesthesia.5 Reports of local anesthetic usage in the pregnant or nursing population are found more commonly in the dermatologic and dental literature. It has been estimated that 11–23% of pregnancies involve prenatal, non-labor, local anesthetic exposure,14,16 and in a large multicenter retrospective study of exposure to local anesthetics during early pregnancy, no significant increase in malformations was found.14 In another review,39 it is stressed that while bupivicaine has been reported to cause fetal bradycardia, lidocaine has not been associated with any adverse fetal effects. Both agents are commonly used for local anesthesia in ophthalmologic surgery via retrobulbar injection. A report by Shammas et al54 demonstrated the anesthesia achieved with topical and subconjunctival lidocaine was equal to that achieved with retrobulbar lidocaine for phacoemulsification and had fewer operative complications. We suggest that the local administration of lidocaine for incisional glaucoma surgery would present minimal risk to the fetus during surgery in this pregnant patient
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and could be minimized further by topical anesthesia with subconjunctival administration, if necessary. A newer option involving lidocaine jelly may be even better in limiting systemic absorption. It is desirable to defer surgery until after the first trimester of pregnancy to reduce the risk of exposure of the fetus to potentially teratogenic agents. If this surgery were offered to a nursing mother, the surgery and, thus, administration of lidocaine would be best timed immediately after nursing to avoid significant accumulation of the drug in breast milk. Obviously, the use of antimetabolites, such as 5-FU or mitomycin C, should be avoided in this population. The only other foreseeable surgical risk involves the positioning of the pregnant patient during surgery. The supine position involves the risk of aortic and vena caval compression by the gravid uterus during the late second and third trimesters, as well as gastroesophageal reflux due to decreased sphincter tone.49 The patient should be positioned with the uterus displaced laterally and emergency intubation with full stomach precautions should be available. Additionally, some authors suggest intraoperative or pre- and post-operative noninvasive fetal monitoring for major surgical procedures. We do not believe this monitoring is necessary for ophthalmologic procedures in an uncomplicated pregnancy. Post-operative medications commonly include a topical antibiotic and corticosteroid, as well as oral pain medication.57 Erythromycin base or estolate has not been associated with any adverse fetal effects, and oral and intravenous corticosteroids are commonly used in late pregnancy to stimulate fetal lung development. The use of either punctal occlusion or an ointment vehicle would decrease the systemic absorption of these medications. For post-operative pain, acetaminophen is likely the safest and usually provides adequate pain relief. While some glaucoma medications anecdotally are said to be safe in the pregnant patient, no largescale controlled trial has been published; thus we must rely on the information gathered from case studies. (For this reason, for the sake of completeness, literature is included in the reference list that is not specifically discussed in the text.2,6–9,11,12,15,19–21, 23,25,26,28,40,41,45,46,51–53,58,59,62 ) Some medications have shown adverse fetal effects in animals (Class C), such as beta-blockers, epinephrine, apraclonidine, carbonic anhydrase inhibitors, parasympathomimetics and prostaglandin analogs.25,26,31–35,48,57,58 We believe that incisional glaucoma surgery offers a relatively low fetal and neonatal risk and should be offered to the pregnant or nursing patient when the course of therapy begins to involve some higher risk class C medications. In the case of this young patient, with a complicated history and multiple prior surgeries, we
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would consider a tube shunt implant. Steps should be taken during surgery to minimize fetal and neonatal risks and post-operative medications should be carefully selected and kept to a minimum.
Authors’ Discussion Just as systemically absorbed medications may cross the placental barrier and enter the circulation of an unborn fetus, they also may be secreted into breast milk and subsequently dose the infant. Kooner has previously indicated that un-ionized, lipid-soluble drugs with small molecular weight enter milk easily, and basic compounds may become concentrated in milk.24 There is very little data on the safety of glaucoma medications for lactating women. Timolol has been shown to be concentrated in breast milk10,29 with resultant beta blockade in the infant. Its levels are higher in breast milk than in plasma. No studies have been reported on the gel-forming formulation. One of our patients is a 33-year-old woman with juvenile open angle glaucoma, who took latanoprost during an entire pregnancy along with timolol gel forming solution. She was under the care of another ophthalmologist and did not use punctal occlusion. Her pregnancy was significant for placental insufficiency, but her baby is normal. She recently used the drug for the first 14 weeks of a second pregnancy, at which time she was advised to stop it. Discontinuation did not have an adverse effect on her IOP. The baby has not been born as of this writing. Acetazolamide appears in breast milk at one-third of the maternal plasma level and has potential to cause respiratory problems or impair renal or hepatic function.56 However, infants’ plasma levels of acetazolamide after nursing from mothers on this drug have been shown to be very low, and therefore, it is considered to be compatible with breast-feeding. Timolol and acetazolamide are approved by the American Academy of Pediatrics for use during lactation.1 High doses of dorzolamide and brinzolamide caused decreased weight gain in offspring of lactating rats given high doses.31,35 Brimonidine is related to bradycardia, hypertension, hypothermia, and hypotonia or apnea in human infants under 2 months of age who receive topical doses. This suggests potential toxicity if it is excreted into human breast milk.31 The notification letter from Allergan warning of risks of Alphagan in pediatrics was received the same month that we treated our patient. Consequently, our patient did not benefit from the warning and received the drug during the end of her pregnancy and during lactation, fortunately with no adverse sequelae. Perinatal and postnatal studies in rats on mid- and high-dose apraclonidine during gestation and lactation revealed poorer weight gain and viability in offspring not statistically different from controls.34,48
GLAUCOMA MANAGEMENT IN PREGNANCY
The effects noted during lactation did not correlate with dose and were inconsistent. We are aware of one case of pilocarpine Ocusert use during lactation with no known adverse effect.30 Another of our patients is a 34-year-old patient with plateau iris syndrome, who continued pilocarpine 1% and 2% with punctal occlusions throughout pregnancy and delivered a healthy infant. Aside from the information noted above, we are aware of no other data on the appearance of topically applied medications in breast milk and effects on lactating women and their infants. Our patient’s infant appears to have had no adverse sequelae from first trimester latanoprost, timolol, and brimonidine and third trimester doses of timolol, dorzolamide, brimonidine, and single doses of latanoprost and echothiophate; or pilocarpine given during labor and delivery. Likewise, the infant was potentially exposed to short courses of dipiverin and brimonidine via breast milk. The baby was exposed to regular dosages of timolol and dorzolamide, acceptable by the American Academy of Pediatrics, without any known adverse sequelae. Punctal occlusion was used throughout the patient’s course to minimize drug concentrations in her body and subsequently to the baby. The successful use of these drugs in our patient may not translate into their safe use in all patients. Decisions on treatment in these circumstances are based on limited data, and one must carefully consider potential risks versus the benefits. The following are good principles to remember in consideration of treating pregnant women with glaucoma. Pregnancy is usually a period of lower intraocular pressure.3,4,13,17,18,22,45,47,60 ALT may serve as an alternative to medical treatment. A higher intraocular pressure may be tolerated for the gestation and lactation periods, rather than risk medication’s adverse effect. The minimum amount of medical treatment possible for glaucoma should be prescribed. Use drug doses with the lowest systemic levels in the mother, employ punctal occlusion, and refer to the FDA categories in choosing medical therapy during gestation and lactation. Incisional surgery should be considered for patients who cannot achieve an adequate intraocular pressure with no or judicious use of topical medication. Early surgery may be indicated in women of childbearing age with glaucoma to circumvent the potential adverse effects of topical medications during gestation and lactation.
References 1. __: American Academy of Pediatrics Committee on Drugs: Transfer of drugs and other chemicals into human milk [published erratum appears in Pediatrics 1990 May;85(5): 847] [see comments]. Pediatrics 84:924–36, 1989
453 2. Altman B: Ocular effects in the newborn from maternal drugs, in Leopold IH, Burns RP (eds): Symposium on Ocular Therapy. New York, John Wiley & Sons, 1979, pp 97–8 3. Avasthi P, Sethi P, Mithal S: Effect of pregnancy and labor on intraocular pressure. Int Surg 61:82–4, 1976 4. Becker B, Friedenwald JS: Clinical aqueous outflow. Arch Ophthalmol 50:557–71, 1953 5. Birks DA, Prior VJ, Silk E, Whittaker M: Echothiophate iodide treatment of glaucoma in pregnancy. Arch Ophthalmol 79:283–5, 1968 6. Blaul G: [Local beta-blockers during pregnancy]. Klin Monatsbl Augenheilkd 179:128–9, 1981 7. Bygdeman M, Kwon SU, Mukherjee T, Wiqvist N: Effect of intravenous infusion of prostaglandin E1 and E2 on motility of the pregnant human uterus. Prostaglandins and related factors 65. Am J Obstet Gynecol 102:317–26, 1968 8. Challis JR, Patrick JE, Borzelleca JF: The production of prostaglandins and thromboxanes in the feto-placental unit and their effects on the developing fetus. Semin Perinatol 4:23– 33, 1980 9. Crane CH: Effect on fetus of mothers taking a diuretic. JAMA 165:1517, 1957 10. Fidler J, Smith V, De Swiet M: Excretion of oxprenolol and timolol in breast milk. Br J Obstet Gynaecol 90:961–5, 1983 11. Genbacev O, Ratkovic M, Kraincanic M, Sulovic V: Effect of prostaglandin PGE2alpha on the synthesis of placental proteins and human placental lactogen (HPL). Prostaglandins 13:723–33, 1977 12. Gladstone GR, Hordof A, Gersony WM: Propranolol administration during pregnancy: effects on the fetus. J Pediatr 86: 962–4, 1975 13. Green K, Phillips CI, Cheeks L, Slagle T: Aqueous humor flow rate and intraocular pressure during and after pregnancy. Ophthalmic Res 20:353–7, 1988 14. Heinonen OP, Sloane D, Shapiro S: Birth defects and drugs in pregnancy. Littleton, MA, Publishing Science Group, 1977, pp 357–65 15. Hoffman LH: Antifertility effects of indomethacin during early pregnancy in the rabbit. Biol Reprod 18:148–53, 1978 16. Hollenbeck AR, Smith RF, Edens ES, Scanlon JW: Early trimester anesthetic exposure: incidence rates in an urban hospital population. Child Psychiatry Hum Dev 16:126–34, 1985 17. Horven I, Gjonnaess H: Corneal indentation pulse and intraocular pressure in pregnancy. Arch Ophthalmol 91:92–8, 1974 18. Imre J: Pregnancy and the eye, their endocrinological relationship. XV Concilium Ophthalmol Egypt III, 1937, pp 213–26 19. Karim SM, Filshie GM: Therapeutic abortion using prostaglandin F2alpha. Lancet 1:157–9, 1970 20. Karim SM, Trussell RR, Patel RC, Hillier K: Response of pregnant human uterus to prostaglandin-F2-alpha-induction of labour. Br Med J 4:621–3, 1968 21. Karim SMM, Filshie GM: The use of prostaglandin E2 for therapeutic abortion. J Obstet Gynaecol Br Commonw 79:1– 13, 1972 22. Kass MA, Sears ML: Hormonal regulation of intraocular pressure. Surv Ophthalmol 22:153–76, 1977 23. Kooner KS, Zimmerman TJ: Antiglaucoma therapy during pregnancy—Part II. Ann Ophthalmol 20:208–11, 1988 24. Kooner KS, Zimmerman TJ: Antiglaucoma therapy during pregnancy—Part I. Ann Ophthalmol 20:166–9, 1988 25. Kropp BN, Forward RB: The effect of pilocarpine on teeth and salivary glands in the rat embryo. Anat Rec 145:250–7, 1963 26. Laundauer W: The teratogenic activity of pilocarpine, pilcarpidine and their isomers, with special reference to the importance of steric configuration. J Exp Zool 132:39-50, 1956 27. Layton WM, Hallesy DW: Deformity of forelimb in rats: association with high doses of acetazolamide. Science 149:306–8, 1965 28. Lenz W: A short history of thalidomide embryopathy. Teratology 38:203–15, 1988 29. Lien EJ, Kuwahara J, Koda RT: Diffusion of drugs into prostatic fluid and milk. Drug Intell Clin Pharm 8:470, 1987
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30. Lustgarten JS, Podos SM: Topical timolol and the nursing mother. Arch Ophthalmol 101:1381–2, 1983 31. Manufacturer’s Information: Alphagan product monograph, October 1998. Allergan, Inc., Irvine, California 32. Manufacturer’s Information: Trusopt product monograph, February 1999. Merck & Co., Inc., West Point, Pennsylvania 33. Manufacturer’s Information: Xalatan monograph, 1998. Pharmacia & Upjohn, Kalamazoo, Michigan 34. Manufacturer’s Information: Iopidine monograph, 1995. Alcon Ophthalmics, Fort Worth, Texas 35. Manufacturer’s Information: Azopt product monograph, April, 1998. Alcon Ophthalmics, Fort Worth, Texas 36. Maren TH: Teratology and carbonic anhydrase inhibition. Arch Ophthalmol 85:1–2, 1971 37. 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 35:85–8, 1990 38. Miller TA, Scott WJ Jr: Abnormalities in ureter and kidney development in mice given acetazolamide-amiloride or dimethadione (DMO) during embryogenesis. Teratology 46:541–50, 1992 39. Moore PA: Selecting drugs for the pregnant dental patient. J Am Dent Assoc 129:1281–6, 1998 40. Morgan CD, Sandler M, Panigel M: Placental transfer of catecholamines in vitro and in vivo. Am J Obstet Gynecol 112: 1068–75, 1972 41. Mukherjee TK, Scerdote A: Studies on hormones controlling HCG production during pregnancy. Effects of LRH and PGF2a: preliminary observations. Clin Res 29:297A, 1986 42. Nakatsuka T, Komatsu T, Fujii T: Axial skeletal malformations induced by acetazolamide in rabbits. Teratology 45: 629–36, 1992 43. Olson RJ, Bromberg BB, Zimmerman TJ: Apneic spells associated with timolol therapy in a neonate. Am J Ophthalmol 88:120–2, 1979 44. Passo MS, Palmer EA, Van Buskirk EM: Plasma timolol in glaucoma patients. Ophthalmology 91:1361–3, 1984 45. Paterson GL, Miller SJG: Hormonal influences in simple glaucoma. Br J Ophthalmol 47:129–37, 1963 46. Patton TF, Francoeur M: Ocular bioavailability and systemic loss of topically applied ophthalmic drugs. Am J Ophthalmol 85:225–9, 1978 47. Phillips CI, Gore SM: Ocular hypotensive effect of late pregnancy with and without high blood pressure. Br J Ophthalmol 69:117–9, 1985 48. Rodwell D, Heaton J, Hackett R: Segment III peri/postnasal study of ALO 2145 in rats. Alcon Technical Report 059: 38520:0891, 1991d
JOHNSON ET AL 49. Rosen MA: Management of anesthesia for the pregnant surgical patient [see comments]. Anesthesiology 91:1159–63, 1999 50. Rosenlund EF: The intraocular pressure lowering effect of timolol in gel-forming solution [published erratum appears in Acta Ophthalmol Scand 1996 Aug;74(4):416]. Acta Ophthalmol Scand 74:160–2, 1996 51. Salminen L: Review: systemic absorption of topically applied ocular drugs in humans. J Ocul Pharmacol 6:243–9, 1990 52. Samples JR, Meyer SM: Use of ophthalmic medications in pregnant and nursing women. Am J Ophthalmol 88:120–2, 1979 53. Schneider H, Proegler M: Placental transfer of beta-adrenergic antagonists studied in an in vitro perfusion system of human placental tissue. Am J Obstet Gynecol 159:42–7, 1988 54. Shammas HJ, Milkie M, Yeo R: Topical and subconjunctival anesthesia for phacoemulsification: prospective study. J Cataract Refract Surg 23:1577–80, 1997 55. Smith RB, Linn JG Jr: Retrobulbar injection of bupivacaine (marcaine) for anesthesia and akinesia. Invest Ophthalmol 13:157–8, 1974 56. Soderman P, Hartvig P, Fagerlund C: Acetazolamide excretion into human breast milk. J Clin Pharmacol 17:599, 1965 57. Stamper RL, Lieberman MF, Drake MV (eds): Becker-Shaffer’s Diagnosis and Therapy of the Glaucomas, Chapter 36, Surgery to relieve outflow block: filtering procedures. St Louis, MO, CV Mosby, 1999, ed 7, p 591 58. Tamagawa M, Numoto T, Tanaka N, Nishino H: Reproduction study of carteolol hydrochloride in mice. Part 2. Periand postnatal toxicity. J Toxicol Sci 4:59–77, 1979 59. Tanaka N, Shingai F, Tamagawa M, Nakatsu I: Reproduction study of carteolol hydrochloride in mice. Part I. Fertility and reproductive performance. J Toxicol Sci 4:47–58, 1979 60. Wilke L: Episcleral venous pressure and pregnancy [proceedings]. Acta Ophthalmol 125 (Suppl):40–1, 1975 61. Worsham F Jr, Beckman EN, Mitchell EH: Sacrococcygeal teratoma in a neonate. Association with maternal use of acetazolamide. JAMA 240:251–2, 1978 62. Ziai N, Ory SJ, Khan AR, Brubaker RF: Beta-human chorionic gonadotropin, progesterone, and aqueous dynamics during pregnancy. Arch Ophthalmol 112:801–6, 1994 63. Zimmerman TJ, Kooner KS, Kandarakis AS, Ziegler LP: Improving the therapeutic index of topically applied ocular drugs. Arch Ophthalmol 102:551–3, 1984
The authors have no proprietary or commercial interest in any product or concept discussed in this article. Reprints are not available.
Abstract. A 30-year-old pregnant woman with glaucoma is presented. The management of her case is used as a basis for a discussion of the use of glaucoma medications, including newer formulations, during pregnancy and lactation. (Surv Ophthalmol 45:449–454, 2001. © 2001 Elsevier Science Inc. All rights reserved.) Key words. beta blockers • glaucoma • intraocular pressure • lactation • pilocarpine • pregnancy • trabeculoplasty
CLINICAL CHALLENGES PETER J. SAVINO, EDITOR
Management of Glaucoma in Pregnancy and Lactation Sandra M. Johnson, MD,1 Mary Martinez, MD, PhD,1 and Sharon Freedman, MD2 1
Department of Ophthalmology, University of North Carolina Hospitals, Chapel Hill, North Carolina, and 2Department of Ophthalmology, Duke University, Durham, North Carolina, USA
Comments by Jonathan Myers, MD, and Ronald Gross, MD (In keeping with the format of a clinical pathologic conference, the abstract and key words appear at the end of the article)
Case Report. A 30-year-old white woman, pregnant and at 7 months’ gestation, presented with a severe frontal headache and decreased vision in her right eye. Her past ocular history was significant for trauma to the right eye as a child with globe repair, loss of her lens, and a subsequent penetrating keratoplasty. She developed glaucoma at age 19. In addition to timolol maleate gel-forming solution 0.5%, she had previously been treated with latanoprost 0.005% and brimonidine 0.2%, which were discontinued by her prior ophthalmologist at 10.5 weeks gestation. She had had an Argon laser trabeculoplasty (ALT) when she was 6.5 weeks pregnant with an intraocular pressure (IOP) 4 weeks later of 16 mm Hg while on her three medications. The treatment plan for this patient had been to decrease medications and allow higher IOP to exist to reduce the risk of medications to the developing fetus. After stopping the latanoprost and brimonidine as directed, the patient did not keep her follow-up appointment. When she was seen again 4 months later, she reported that she had remained compliant with the timolol gel-forming solution until she ran out of it 1 week prior to presentation. On examination, uncorrected visual acuity in the right eye was 20/300, which did not improve with pinhole, and 20/15 in the left. In-
traocular pressure by applanation tonometry was 45 mm Hg in the right eye (OD) and 14 mm Hg in the left (OS). The right pupil was chronically dilated and the left was normal. There was a right relative afferent pupillary defect. Automated perimetry is shown in Fig. 1. Slit-lamp examination revealed a corneal graft in the right eye and aphakia. Dilated fundus examination showed a cup to disk ratio of 0.7 OD with significant superior and superior nasal sloping (Fig. 2). The cup to disk ratio OS was 0.4 with an intact neural rim. The fundi were otherwise normal. Gonioscopy showed the anterior chamber angle to be completely open in both eyes. The patient was diagnosed with secondary chronic open angle glaucoma. Intraocular pressure had been previously controlled on three medications, but since discontinuation of medications, there was poor control despite ALT. How should her glaucoma be managed at this point of her pregnancy?
Comments Comments by Jonathan Myers, MD,1 and Ronald Gross, MD,2 1Glaucoma Service, Wills Eye Hospi449
© 2001 by Elsevier Science Inc. All rights reserved.
0039-6257/01/$–see front matter PII S0039-6257(00)00209-5
450
Surv Ophthalmol 45 (5) March–April 2001
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Fig. 1. Automated perimetry OD (right) shows superior and inferior nasal defects. OS (left) is normal.
tal, Philadelphia, Pennsylvania, and 2Cullen Eye Institute, Baylor College of Medicine, Houston, Texas, USA The patient should be offered the alternatives of medical therapy or surgery in a very direct and detailed discussion. The risks presented to the fetus with medication and to her with noncompliance must be addressed and compared to those of surgery. If the patient chooses medical therapy, we would institute timolol gel-forming solution 0.5% and brimonidine with punctal occlusion and a documented discussion of the need for close follow-up and compliance.
Case Report (Continued) The decision was made to begin a 3-medication regimen, consisting of timolol gel-forming solution 0.5%, dorzolamide 2%, and brimonidine 0.2% in the affected eye. Instillation of each drop was to be followed by punctal occlusion to minimize systemic
absorption.44,63 The gel-forming form of timolol was used, since this dose form has been associated with less bradycardia, suggesting a lower systemic absorption.50 The topical carbonic anhydrase inhibitor was used to minimize systemic levels of carbonic anhydrase inhibition in mother and fetus.27,36–38,42,61 Brimonidine was chosen, since it has been categorized as class B—i.e., controlled studies in animals show no risk to the fetus, but there are no controlled studies in humans, or adverse effects in animals have not been confirmed in controlled studies in humans. Within one week, the IOP was reduced to 20 mm Hg and vision corrected to 20/50. Six weeks later, the patient again returned with the complaint of decreased vision and headache. Vision was reduced to pinhole 20/300 and the IOP was 50 mm Hg. How would you manage the patient at this juncture?
Comments (Continued) This patient has failed medical therapy. We would treat her surgically. Tube shunt surgery would be the preferred procedure in this young patient with a complicated glaucoma and prior ocular surgery.
Case Report (Continued)
Fig. 2. Right optic disk with glaucomatous cupping.
One drop of latanoprost 0.005% was given in the clinic and echothiophate 1/16 was added to the patient’s regimen. Since prostaglandins are involved in the physiology of labor and delivery, latanoprost was not continued. Because echothiophate is a quaternary ammonium, it may traverse membranes, such as the placenta, with difficulty; thus, it was chosen over pilocarpine, a tertiary cholinergic amine, which is a weak base and may traverse membranes well.5,24
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The patient took one dose of the medication 2 days later. Her IOP was checked the following morning and found to be 21 mm Hg. By now, her pregnancy was full term and the decision was made by the patient and her nurse practitioner to induce labor, which did not result in labor and delivery. She continued on topical timolol, dorzolamide, and brimonidine without the miotic, which irritated her eye. Four days later, her IOP was 21 mm Hg and best-corrected vision was 20/100. Unfortunately, IOP rose again to 42 mm Hg in another 4 days. Induction of labor was again tried with the hopes of achieving better glaucoma control post-partum. Pilocarpine 4% was added during labor. Sustainedrelease Ocusert form of pilocarpine would probably have been a safer choice.30 Following successful delivery of a healthy infant, the IOPs remained elevated between 45 and 54 mm Hg. The patient began nursing the neonate. She was given the option of discontinuing lactation, given the need for continued glaucoma medications, but she refused. Despite treatment with various combinations of topical medications, including timolol gel-forming solution 0.5%, dipiverin 0.2%, dorzolamide 0.5% and brimonidine 0.2%, as well as several doses of systemic acetazolamide, the IOP ranged from 36 to 45 mm Hg. All drugs were administered with punctal occlusion. The infant was closely monitored in the nursery, with vital signs checked frequently, and demonstrated no apnea or bradycardia.43 The patient was given her medications immediately after nursing in an attempt to reduce the concentration in her breast milk, since drug levels in milk are often highest 30 to 120 minutes after a drug dose.30 Given the poor response to medications and the unknown concentrations in breast milk and the possible effects on the baby from ongoing exposure to glaucoma medications via nursing, the decision was made to proceed with Ahmed valve placement. Intraocular pressure post-operatively decreased to the teens on no medications. Best-corrected visual acuity remained stable at 20/60. In the following months, the pressures gradually increased to the low 20s with tenon’s cyst formation, and the patient was restarted on timolol gel-forming solution 0.5% and dorzolamide 2%. She continued to breastfeed and punctal occlusion was encouraged. The child has experienced no known health problems.
Comments (Continued) This case demonstrates the difficulties of managing glaucoma in the pregnant or nursing patient. Medications were thoughtfully selected and dosed to minimize risks to the fetus. ALT was only temporarily helpful, and despite optimization of the medi-
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cal regimen, the IOP returned to dangerously high levels. This patient could have been offered trabeculectomy or tube implant surgery earlier in her course of therapy, even during pregnancy. There are additional risks of glaucoma surgery for pregnant patients, including those of the local anesthetic, the supine positioning, and the post-operative medications. However, there is also a risk of not controlling the glaucoma, i.e., progressive optic nerve damage and pain. In some situations, the overall risks associated with surgery are less than those of medical glaucoma therapy. If the patient has progression of visual field loss or inadequate pressure control on maximally tolerated safe medical therapy, surgery may be the next best option, either before or after ALT, depending on the patient and type of glaucoma. To facilitate the patient’s understanding and acceptance, the possible need for surgery should be mentioned early in the course of treatment, rather than only when the need for surgery is urgent. If an infant or fetus is at significant risk because of the glaucoma treatment regimen, e.g., an infant shows bradycardia from beta blockade with topical timolol, the clinician should discontinue that drug. Although the patient has the right to refuse surgery or other care regimens, she should not unnecessarily endanger a child. Few cases addressing anesthetic use in ophthalmologic surgery during pregnancy have been reported. Retrobulbar administration of bupivicaine without any complications was reported in a 35-year-old woman at 11 weeks gestation,55 and general anesthesia was used for sclerotomy surgery in a 32-week pregnant woman with no reported complications due to anesthesia.5 Reports of local anesthetic usage in the pregnant or nursing population are found more commonly in the dermatologic and dental literature. It has been estimated that 11–23% of pregnancies involve prenatal, non-labor, local anesthetic exposure,14,16 and in a large multicenter retrospective study of exposure to local anesthetics during early pregnancy, no significant increase in malformations was found.14 In another review,39 it is stressed that while bupivicaine has been reported to cause fetal bradycardia, lidocaine has not been associated with any adverse fetal effects. Both agents are commonly used for local anesthesia in ophthalmologic surgery via retrobulbar injection. A report by Shammas et al54 demonstrated the anesthesia achieved with topical and subconjunctival lidocaine was equal to that achieved with retrobulbar lidocaine for phacoemulsification and had fewer operative complications. We suggest that the local administration of lidocaine for incisional glaucoma surgery would present minimal risk to the fetus during surgery in this pregnant patient
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and could be minimized further by topical anesthesia with subconjunctival administration, if necessary. A newer option involving lidocaine jelly may be even better in limiting systemic absorption. It is desirable to defer surgery until after the first trimester of pregnancy to reduce the risk of exposure of the fetus to potentially teratogenic agents. If this surgery were offered to a nursing mother, the surgery and, thus, administration of lidocaine would be best timed immediately after nursing to avoid significant accumulation of the drug in breast milk. Obviously, the use of antimetabolites, such as 5-FU or mitomycin C, should be avoided in this population. The only other foreseeable surgical risk involves the positioning of the pregnant patient during surgery. The supine position involves the risk of aortic and vena caval compression by the gravid uterus during the late second and third trimesters, as well as gastroesophageal reflux due to decreased sphincter tone.49 The patient should be positioned with the uterus displaced laterally and emergency intubation with full stomach precautions should be available. Additionally, some authors suggest intraoperative or pre- and post-operative noninvasive fetal monitoring for major surgical procedures. We do not believe this monitoring is necessary for ophthalmologic procedures in an uncomplicated pregnancy. Post-operative medications commonly include a topical antibiotic and corticosteroid, as well as oral pain medication.57 Erythromycin base or estolate has not been associated with any adverse fetal effects, and oral and intravenous corticosteroids are commonly used in late pregnancy to stimulate fetal lung development. The use of either punctal occlusion or an ointment vehicle would decrease the systemic absorption of these medications. For post-operative pain, acetaminophen is likely the safest and usually provides adequate pain relief. While some glaucoma medications anecdotally are said to be safe in the pregnant patient, no largescale controlled trial has been published; thus we must rely on the information gathered from case studies. (For this reason, for the sake of completeness, literature is included in the reference list that is not specifically discussed in the text.2,6–9,11,12,15,19–21, 23,25,26,28,40,41,45,46,51–53,58,59,62 ) Some medications have shown adverse fetal effects in animals (Class C), such as beta-blockers, epinephrine, apraclonidine, carbonic anhydrase inhibitors, parasympathomimetics and prostaglandin analogs.25,26,31–35,48,57,58 We believe that incisional glaucoma surgery offers a relatively low fetal and neonatal risk and should be offered to the pregnant or nursing patient when the course of therapy begins to involve some higher risk class C medications. In the case of this young patient, with a complicated history and multiple prior surgeries, we
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would consider a tube shunt implant. Steps should be taken during surgery to minimize fetal and neonatal risks and post-operative medications should be carefully selected and kept to a minimum.
Authors’ Discussion Just as systemically absorbed medications may cross the placental barrier and enter the circulation of an unborn fetus, they also may be secreted into breast milk and subsequently dose the infant. Kooner has previously indicated that un-ionized, lipid-soluble drugs with small molecular weight enter milk easily, and basic compounds may become concentrated in milk.24 There is very little data on the safety of glaucoma medications for lactating women. Timolol has been shown to be concentrated in breast milk10,29 with resultant beta blockade in the infant. Its levels are higher in breast milk than in plasma. No studies have been reported on the gel-forming formulation. One of our patients is a 33-year-old woman with juvenile open angle glaucoma, who took latanoprost during an entire pregnancy along with timolol gel forming solution. She was under the care of another ophthalmologist and did not use punctal occlusion. Her pregnancy was significant for placental insufficiency, but her baby is normal. She recently used the drug for the first 14 weeks of a second pregnancy, at which time she was advised to stop it. Discontinuation did not have an adverse effect on her IOP. The baby has not been born as of this writing. Acetazolamide appears in breast milk at one-third of the maternal plasma level and has potential to cause respiratory problems or impair renal or hepatic function.56 However, infants’ plasma levels of acetazolamide after nursing from mothers on this drug have been shown to be very low, and therefore, it is considered to be compatible with breast-feeding. Timolol and acetazolamide are approved by the American Academy of Pediatrics for use during lactation.1 High doses of dorzolamide and brinzolamide caused decreased weight gain in offspring of lactating rats given high doses.31,35 Brimonidine is related to bradycardia, hypertension, hypothermia, and hypotonia or apnea in human infants under 2 months of age who receive topical doses. This suggests potential toxicity if it is excreted into human breast milk.31 The notification letter from Allergan warning of risks of Alphagan in pediatrics was received the same month that we treated our patient. Consequently, our patient did not benefit from the warning and received the drug during the end of her pregnancy and during lactation, fortunately with no adverse sequelae. Perinatal and postnatal studies in rats on mid- and high-dose apraclonidine during gestation and lactation revealed poorer weight gain and viability in offspring not statistically different from controls.34,48
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The effects noted during lactation did not correlate with dose and were inconsistent. We are aware of one case of pilocarpine Ocusert use during lactation with no known adverse effect.30 Another of our patients is a 34-year-old patient with plateau iris syndrome, who continued pilocarpine 1% and 2% with punctal occlusions throughout pregnancy and delivered a healthy infant. Aside from the information noted above, we are aware of no other data on the appearance of topically applied medications in breast milk and effects on lactating women and their infants. Our patient’s infant appears to have had no adverse sequelae from first trimester latanoprost, timolol, and brimonidine and third trimester doses of timolol, dorzolamide, brimonidine, and single doses of latanoprost and echothiophate; or pilocarpine given during labor and delivery. Likewise, the infant was potentially exposed to short courses of dipiverin and brimonidine via breast milk. The baby was exposed to regular dosages of timolol and dorzolamide, acceptable by the American Academy of Pediatrics, without any known adverse sequelae. Punctal occlusion was used throughout the patient’s course to minimize drug concentrations in her body and subsequently to the baby. The successful use of these drugs in our patient may not translate into their safe use in all patients. Decisions on treatment in these circumstances are based on limited data, and one must carefully consider potential risks versus the benefits. The following are good principles to remember in consideration of treating pregnant women with glaucoma. Pregnancy is usually a period of lower intraocular pressure.3,4,13,17,18,22,45,47,60 ALT may serve as an alternative to medical treatment. A higher intraocular pressure may be tolerated for the gestation and lactation periods, rather than risk medication’s adverse effect. The minimum amount of medical treatment possible for glaucoma should be prescribed. Use drug doses with the lowest systemic levels in the mother, employ punctal occlusion, and refer to the FDA categories in choosing medical therapy during gestation and lactation. Incisional surgery should be considered for patients who cannot achieve an adequate intraocular pressure with no or judicious use of topical medication. Early surgery may be indicated in women of childbearing age with glaucoma to circumvent the potential adverse effects of topical medications during gestation and lactation.
References 1. __: American Academy of Pediatrics Committee on Drugs: Transfer of drugs and other chemicals into human milk [published erratum appears in Pediatrics 1990 May;85(5): 847] [see comments]. Pediatrics 84:924–36, 1989
453 2. Altman B: Ocular effects in the newborn from maternal drugs, in Leopold IH, Burns RP (eds): Symposium on Ocular Therapy. New York, John Wiley & Sons, 1979, pp 97–8 3. Avasthi P, Sethi P, Mithal S: Effect of pregnancy and labor on intraocular pressure. Int Surg 61:82–4, 1976 4. Becker B, Friedenwald JS: Clinical aqueous outflow. Arch Ophthalmol 50:557–71, 1953 5. Birks DA, Prior VJ, Silk E, Whittaker M: Echothiophate iodide treatment of glaucoma in pregnancy. Arch Ophthalmol 79:283–5, 1968 6. Blaul G: [Local beta-blockers during pregnancy]. Klin Monatsbl Augenheilkd 179:128–9, 1981 7. Bygdeman M, Kwon SU, Mukherjee T, Wiqvist N: Effect of intravenous infusion of prostaglandin E1 and E2 on motility of the pregnant human uterus. Prostaglandins and related factors 65. Am J Obstet Gynecol 102:317–26, 1968 8. Challis JR, Patrick JE, Borzelleca JF: The production of prostaglandins and thromboxanes in the feto-placental unit and their effects on the developing fetus. Semin Perinatol 4:23– 33, 1980 9. Crane CH: Effect on fetus of mothers taking a diuretic. JAMA 165:1517, 1957 10. Fidler J, Smith V, De Swiet M: Excretion of oxprenolol and timolol in breast milk. Br J Obstet Gynaecol 90:961–5, 1983 11. Genbacev O, Ratkovic M, Kraincanic M, Sulovic V: Effect of prostaglandin PGE2alpha on the synthesis of placental proteins and human placental lactogen (HPL). Prostaglandins 13:723–33, 1977 12. Gladstone GR, Hordof A, Gersony WM: Propranolol administration during pregnancy: effects on the fetus. J Pediatr 86: 962–4, 1975 13. Green K, Phillips CI, Cheeks L, Slagle T: Aqueous humor flow rate and intraocular pressure during and after pregnancy. Ophthalmic Res 20:353–7, 1988 14. Heinonen OP, Sloane D, Shapiro S: Birth defects and drugs in pregnancy. Littleton, MA, Publishing Science Group, 1977, pp 357–65 15. Hoffman LH: Antifertility effects of indomethacin during early pregnancy in the rabbit. Biol Reprod 18:148–53, 1978 16. Hollenbeck AR, Smith RF, Edens ES, Scanlon JW: Early trimester anesthetic exposure: incidence rates in an urban hospital population. Child Psychiatry Hum Dev 16:126–34, 1985 17. Horven I, Gjonnaess H: Corneal indentation pulse and intraocular pressure in pregnancy. Arch Ophthalmol 91:92–8, 1974 18. Imre J: Pregnancy and the eye, their endocrinological relationship. XV Concilium Ophthalmol Egypt III, 1937, pp 213–26 19. Karim SM, Filshie GM: Therapeutic abortion using prostaglandin F2alpha. Lancet 1:157–9, 1970 20. Karim SM, Trussell RR, Patel RC, Hillier K: Response of pregnant human uterus to prostaglandin-F2-alpha-induction of labour. Br Med J 4:621–3, 1968 21. Karim SMM, Filshie GM: The use of prostaglandin E2 for therapeutic abortion. J Obstet Gynaecol Br Commonw 79:1– 13, 1972 22. Kass MA, Sears ML: Hormonal regulation of intraocular pressure. Surv Ophthalmol 22:153–76, 1977 23. Kooner KS, Zimmerman TJ: Antiglaucoma therapy during pregnancy—Part II. Ann Ophthalmol 20:208–11, 1988 24. Kooner KS, Zimmerman TJ: Antiglaucoma therapy during pregnancy—Part I. Ann Ophthalmol 20:166–9, 1988 25. Kropp BN, Forward RB: The effect of pilocarpine on teeth and salivary glands in the rat embryo. Anat Rec 145:250–7, 1963 26. Laundauer W: The teratogenic activity of pilocarpine, pilcarpidine and their isomers, with special reference to the importance of steric configuration. J Exp Zool 132:39-50, 1956 27. Layton WM, Hallesy DW: Deformity of forelimb in rats: association with high doses of acetazolamide. Science 149:306–8, 1965 28. Lenz W: A short history of thalidomide embryopathy. Teratology 38:203–15, 1988 29. Lien EJ, Kuwahara J, Koda RT: Diffusion of drugs into prostatic fluid and milk. Drug Intell Clin Pharm 8:470, 1987
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JOHNSON ET AL 49. Rosen MA: Management of anesthesia for the pregnant surgical patient [see comments]. Anesthesiology 91:1159–63, 1999 50. Rosenlund EF: The intraocular pressure lowering effect of timolol in gel-forming solution [published erratum appears in Acta Ophthalmol Scand 1996 Aug;74(4):416]. Acta Ophthalmol Scand 74:160–2, 1996 51. Salminen L: Review: systemic absorption of topically applied ocular drugs in humans. J Ocul Pharmacol 6:243–9, 1990 52. Samples JR, Meyer SM: Use of ophthalmic medications in pregnant and nursing women. Am J Ophthalmol 88:120–2, 1979 53. Schneider H, Proegler M: Placental transfer of beta-adrenergic antagonists studied in an in vitro perfusion system of human placental tissue. Am J Obstet Gynecol 159:42–7, 1988 54. Shammas HJ, Milkie M, Yeo R: Topical and subconjunctival anesthesia for phacoemulsification: prospective study. J Cataract Refract Surg 23:1577–80, 1997 55. Smith RB, Linn JG Jr: Retrobulbar injection of bupivacaine (marcaine) for anesthesia and akinesia. Invest Ophthalmol 13:157–8, 1974 56. Soderman P, Hartvig P, Fagerlund C: Acetazolamide excretion into human breast milk. J Clin Pharmacol 17:599, 1965 57. Stamper RL, Lieberman MF, Drake MV (eds): Becker-Shaffer’s Diagnosis and Therapy of the Glaucomas, Chapter 36, Surgery to relieve outflow block: filtering procedures. St Louis, MO, CV Mosby, 1999, ed 7, p 591 58. Tamagawa M, Numoto T, Tanaka N, Nishino H: Reproduction study of carteolol hydrochloride in mice. Part 2. Periand postnatal toxicity. J Toxicol Sci 4:59–77, 1979 59. Tanaka N, Shingai F, Tamagawa M, Nakatsu I: Reproduction study of carteolol hydrochloride in mice. Part I. Fertility and reproductive performance. J Toxicol Sci 4:47–58, 1979 60. Wilke L: Episcleral venous pressure and pregnancy [proceedings]. Acta Ophthalmol 125 (Suppl):40–1, 1975 61. Worsham F Jr, Beckman EN, Mitchell EH: Sacrococcygeal teratoma in a neonate. Association with maternal use of acetazolamide. JAMA 240:251–2, 1978 62. Ziai N, Ory SJ, Khan AR, Brubaker RF: Beta-human chorionic gonadotropin, progesterone, and aqueous dynamics during pregnancy. Arch Ophthalmol 112:801–6, 1994 63. Zimmerman TJ, Kooner KS, Kandarakis AS, Ziegler LP: Improving the therapeutic index of topically applied ocular drugs. Arch Ophthalmol 102:551–3, 1984
The authors have no proprietary or commercial interest in any product or concept discussed in this article. Reprints are not available.
Abstract. A 30-year-old pregnant woman with glaucoma is presented. The management of her case is used as a basis for a discussion of the use of glaucoma medications, including newer formulations, during pregnancy and lactation. (Surv Ophthalmol 45:449–454, 2001. © 2001 Elsevier Science Inc. All rights reserved.) Key words. beta blockers • glaucoma • intraocular pressure • lactation • pilocarpine • pregnancy • trabeculoplasty