BOptom(Hons) BSc MPH FAAO
PhD Candidate, Centre for Eye Health
Dr Alex Hui
OD PhD FAAO
Lecturer, School of Optometry and Vision Science, UNSW Sydney
In the majority of cases, glaucoma in pregnant women is managed with topical anti-glaucoma medications. Unfortunately, there is currently a lack of a strong evidence base to provide guidance on the best course of action for clinicians when managing glaucoma in these patients.
Glaucoma in women of child-bearing age also tends to be due to disorders acquired early in life, such as congenital malformations, anterior segment dysgenesis and cataracts, or secondary to coexisting conditions such as uveitis or diabetes rather than the primary open angle glaucoma more prevalent in older age groups.1,2 These types of glaucoma usually require aggressive intraocular pressure (IOP) interventions to preserve vision and therefore treatment discontinuation is not an option during the pregnancy and lactating period.3
Topical glaucoma therapy options in pregnancy
One frequent comment regarding medical therapy in pregnancy is that there is ‘no clinical data specifically for humans available,’ so most recommendations are based on animal or laboratory studies where the applicability to use in humans is questionable.1,3,4
The recommendations of the Australian Medicines Handbook (AMH), which is looked on as a reliable source of information by clinicians for prescribing in Australia, attempts to synthesise information based on human data as well as clinical experience when prescribing for special populations such as those who are pregnant or breastfeeding, although it is quick to note that absence of data and information does not necessarily suggest medicines or other products are safe.
The AMH also does not currently list the pregnancy categories for medications as deemed by the Australian Therapeutic Goods Administration (TGA) or American Food and Drug Administration (FDA), due to shortfalls of both systems regarding perceived staging of risk and safety (‘higher’ letter codes do not necessarily imply better safety), the inability of these codes to change over time as new data emerge, the lack of reflection of which stage of foetal development specifically is potentially affected by the drug and overall, a lack of specific utility to aid clinical decision-making regarding a balance of risks and benefits to prescribing.5
The FDA is in the process of eliminating pregnancy categories in a gradual process to improve drug labelling with more relevant and useful information.6 The AMH recommendations for use of topical glaucoma medications during pregnancy and/or while breastfeeding, based on the best available evidence at the time of publication, are summarised in Table 1.5
Table 1. Recommendations for use of anti-glaucoma medications during pregnancy and breastfeeding from the Australian Medicines Handbook.5 Note that some medications do not have explicit recommendations under some conditions.
Prostaglandin analogues (PGAs)
While the PGAs are considered the first-line form of medical treatment for the majority of glaucomas, they are currently not the first choice to manage the condition in pregnant patients for a number of reasons. There are concerns regarding abortion and induction of labour with these molecules, especially with their activity on the F2-alpha receptor which is intimately involved in the parturition (birthing) process.7 Indeed, other prostaglandin analogues such as misoprostol are used in practice to induce labour or abortions.8,9 There are also concerns regarding teratogenesis, with oral use of prostaglandins being associated with birth defects.10
Considering their low dose and route of administration, the actual risk of PGA use for glaucoma during pregnancy has been debated. It has been argued that there is an insufficient drug quantity to induce effects on the foetus with typical eye-drop administration, while others have suggested that the potential risks outweigh the benefits.11 Case series have been published which suggest that it is mostly safe for use in the first trimester, with only one case of spontaneous abortion (miscarriage) noted in a 46-year-old patient.12 Causation of this event due to concurrent latanoprost administration could not be established due to the presence of other risk factors in that particular patient; all other patients (90 per cent) within the series displayed no other adverse effects, with three women having continued treatment with latanoprost throughout pregnancy.
As a class, beta-blockers have been reported to cause the following adverse effects during pregnancy and in the neonate: intrauterine growth retardation, maternal and foetal bradycardia, premature labour, delayed neonatal breathing, neonatal hypoglycaemia, and neonatal hyperbilirubinaemia.13 Timolol specifically has been shown to cross the placental barrier and be secreted in breast milk.
Beta blockers are used not only in the management of glaucoma but also for the management of hypertension when administered systemically. Studies in pregnant patients with hypertension treated using systemic beta-blockers have demonstrated mixed results, with some studies demonstrating intrauterine growth retardation and lighter birth weight when oral atenolol was given from early pregnancy.14,15 There are risks for the foetus of developing permanent respiratory or cardiac disorders following delivery. In topical form, timolol, as a lipid-soluble formulation, reaches high concentration in the foetus, with isolated case reports in support and against timolol usage in pregnancy.16,17 Thus, the typical recommendation is to avoid beta-blockers in early pregnancy, in late pregnancy and during lactation.
Of the two alpha2-agonists available for glaucoma, brimonidine is routinely recommended over apraclonidine for use during pregnancy. Brimonidine is considered by the US FDA to be the safest anti-glaucoma medication based on animal studies demonstrating little to no risk to developing foetus (FDA Pregnancy Category B).4 However, it should be noted that brimonidine readily penetrates the blood brain barrier and can cause central nervous system depression, including apnoea.18
Because breast milk is produced in late pregnancy, it is typically recommended that brimonidine use be ceased before labour and during breastfeeding to reduce transmission to the infant. In contrast, apraclonidine use in high doses during gestation and lactation in animals can lead to poor weight gain and embryotoxicity.19 With the availability of brimonidine this renders apraclonidine to be not routinely recommended for use during pregnancy.
Carbonic anhydrase inhibitors (CAIs)
The concerns with use of CAIs during pregnancy are teratogenesis and electrolyte imbalances in the foetal bloodstream. Animal studies with systemic carbonic anhydrase inhibitors have shown potential teratogenesis at high doses. There have also been studies regarding potassium depletion and its effects on limb development in rats, which was readily treated with potassium replacement therapy.20
Teratogensis with CAIs used in pregnancy has been observed only rarely in humans. A higher dose of oral acetazolamide used in the management of intracranial hypertension (1 g/day) compared to the typical dose in glaucoma (250-500 mg/day) led to no maternal or foetal complications in a group of 12 women.21 However, other case reports have shown complications in the new-born following treatment with acetazolamide during pregnancy.22-24 Notably, administration of oral acetazolamide in these cases were all throughout pregnancy, beginning from the first trimester.
Topical carbonic anhydrase inhibitors for glaucoma therapy, on the other hand, have not been demonstrated to lead to foetal complications, except for one reported case of low birth weight and reduced renal function.25 In animals, high doses of dorzolamide and brinzolamide have been shown to lead to decreased weight gain in the new-borns of lactating rats. Therefore, it is suggested that topical carbonic anhydrase inhibitors at the typical glaucoma dosage may be an appropriate option for pregnant patients.
Parasympathomimetics have been shown to have teratogenic and adverse effects on the foetus in animal studies, particularly in early stages of development.26-28 Pilocarpine is also a tertiary cholinergic anime with a weak base, which facilitates membrane penetration. Local side-effects of parasympathomimetics such as ciliary spasm and miosis are also poorly tolerated in a younger cohort. In combination, this precludes recommendation of pilocarpine for use in pregnant women.
The NHMRC guidelines for the management of patients with glaucoma suggest the following order (most preferred to least preferred) for topical medications in the management of glaucoma in pregnant or lactating patients: beta-blockers, AAs, cholinergics, CAIs then PGAs.29 However, based on the most recently available evidence, customising the selection of agent and dose based on the particular stage of pregnancy and foetal development3,11 has been suggested:
• First trimester: brimonidine, PGAs; avoid BBs and CAIs
• Second trimester and early third trimester: brimonidine, CAIs, BBs; PGAs only with caution
• Late third trimester and during lactation: CAIs or a lower dose of BBs seem to be preferred; avoid brimonidine; PGAs may trigger premature labour.
Overall, the recommendations would be to consult with the patient’s entire medical team, including but not limited to: ophthalmologist, general physician, obstetrician/gynaecologist, paediatrician and endocrinologist. Decisions on medication use during pregnancy and breastfeeding should be carefully considered and discussed based on the relative risks and benefits for the patient and developing foetus or child.
The clinician is reminded of the detailed advice which is available through Pregnancy Drug Information Centres which can be contacted to discuss specific recommendations based on particulars of a specific case. Clinicians are also advised to discuss with patients of childbearing age being treated for glaucoma the alternatives such as glaucoma surgery which can be initiated prior to becoming pregnant to avert concurrent medication use. If medications are used during pregnancy, the expectant mother should be informed to expect to have tests at regular intervals to monitor for drug-related adverse effects, and patients should be taught and reminded of punctal occlusion to minimise systemic absorption.
1. Sethi HS, Naik M, Gupta VS. Management of glaucoma in pregnancy: risks or choices, a dilemma? Int J Ophthalmol 2016; 9: 1684-1690.
2. Kapetanakis VV, Chan MP, Foster PJ, et al. Global variations and time trends in the prevalence of primary open angle glaucoma (POAG): a systematic review and meta-analysis. Br J Ophthalmol 2016; 100: 86-93.
3. Razeghinejad MRM, Masoumpour MM, Eghbal MHM, et al. Glaucoma surgery in pregnancy: a case series and literature review. Iran J Med Sci 2016; 41: 437-445.
4. Salim S. Glaucoma in pregnancy. Curr Opin Ophthalmol 2014; 25: 93-97.
5. Australian Medicines Handbook. Adelaide, South Australia: Australian Medicines Handbook; 2017.
6. FDA. Pregnancy and Lactation Labelling (Drugs) Final Rule. 2014 [updated 2014. Available at: https://www.fda.gov/drugs/developmentapprovalprocess/developmentresources/labeling/ucm093307.htm. Accessed: April 10, 2017].
7. Olson DM. The role of prostaglandins in the initiation of parturition. Best Pract Res Clin Obstet Gynaecol 2003; 17: 717-730.
8. Brabec W. [Priming of the cervix with prostaglandins in the first and second trimester]. Wien Klin Wochenschr 1982; 94: 554-548.
9. Neeb U. [Effectiveness and side-effects of intracervical application of prostaglandin F2-alpha-gel in the early weeks of pregnancy (author’s transl)]. Geburtshilfe Frauenheilkd 1980; 40: 901-903.
10. da Silva Dal Pizzol T, Knop FP, Mengue SS. Prenatal exposure to misoprostol and congenital anomalies: systematic review and meta-analysis. Reprod Toxicol 2006; 22: 666-671.
11. Razeghinejad MR, Nowroozzadeh MH. Anti-glaucoma medication exposure in pregnancy: an observational study and literature review. Clin Exp Optom 2010; 93: 458-465.
12. De Santis M, Lucchese A, Carducci B, et al. Latanoprost exposure in pregnancy. Am J Ophthalmol 2004; 138: 305-306.
13. Frishman WH, Chesner M. Beta-adrenergic blockers in pregnancy. Am Heart J 1988; 115: 147-152.
14. Butters L, Kennedy S, Rubin PC. Atenolol in essential hypertension during pregnancy. BMJ 1990; 301: 587-589.
15. Lip GY, Beevers M, Churchill D, et al. Effect of atenolol on birth weight. Am J Cardiol 1997; 9: 1436-1438.
16. Blaul G. [Local beta blockaders in pregnancy]. Klin Monbl Augenheilkd 1985; 187: 57-59.
17. Wagenvoort AM, van Vugt JM, Sobotka M, van Geijn HP. Topical timolol therapy in pregnancy: is it safe for the fetus? Teratology 1998; 58: 258-262.
18. Rangan C, Everson G, Cantrell FL. Central alpha-2 adrenergic eye drops: case series of 3 pediatric systemic poisonings. Pediatr Emerg Care 2008; 24: 167-169.
19. Manufacturer’s information: Iopidine monograph. Fort Worth, Texas: Alcon Ophthalmics; 1995.
20. Razeghinejad MR, Tania Tai TY, Fudemberg SJ, Katz LJ. Pregnancy and glaucoma. Surv Ophthalmol 2011; 56: 324-335.
21. Lee AG, Pless M, Falardeau J, et al. The use of acetazolamide in idiopathic intracranial hypertension during pregnancy. Am J Ophthalmol 2005; 139: 855-859.
22. 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: 85-88.
23. Ozawa H, Azuma E, Shindo K, et al. Transient renal tubular acidosis in a neonate following transplacental acetazolamide. Eur J Pediatr 2001; 160: 321-322.
24. Worsham F, Jr., Beckman EN, Mitchell EH. Sacrococcygeal teratoma in a neonate. Association with maternal use of acetazolamide. JAMA 1978; 240: 251-252.
25. Morris S, Geh V, Nischal KK, Sahi S, Ahmed MA. Topical dorzolamide and metabolic acidosis in a neonate. Br J Ophthalmol 2003; 87: 1052-1053.
26. Kropp BN, Forward RB. Effect of pilocarpine on teeth and salivary glands in rat embryo. Anatomical Record 1963; 145: 250.
27. Landauer W. On teratogenic effects of pilocarpine in chick development. J Exp Zoology 1953; 122: 469-483.
28. Landauer W. The teratogenic activity of pilocarpine, pilocarpidine and their isomers, with special reference to the importance of steric configuration. J Exp Zoology 1956; 132: 39-50.
29. NHMRC. Guidelines for the Screening, Prognosis, Diagnosis, Management and Prevention of Glaucoma. Canberra, Australia; 2010.