Oman Journal of Ophthalmology

REVIEW ARTICLE
Year
: 2018  |  Volume : 11  |  Issue : 3  |  Page : 195--199

Glaucoma medications in pregnancy


M Reza Razeghinejad 
 Glaucoma Service, Wills Eye Hospital, Philadelphia, PA, USA

Correspondence Address:
Dr. M Reza Razeghinejad
840 Walnut Street, Suite 1140, Philadelphia, PA 19107
USA

Abstract

Glaucoma is a chronic, progressive disease of the optic nerve which is relatively uncommon in childbearing age; however, its management is a real challenge. Although the intraocular pressure decreases in pregnancy, many glaucoma patients continue to require treatment. In addition to the side effects, antiglaucoma medications on the mother, the possible side effects of drugs on the fetus must be taken into account. The only antiglaucoma medication categorized in Category B is brimonidine, and all others are in Category C. Most evidence on glaucoma medications in pregnancy comes from single case reports or animal studies with the limitations that these impose. Theoretically, glaucoma medications may damage the fetus; however, they may not have substantial clinical significance with routine dosages and no topical antiglaucoma agents have strong evidence of safety to the fetus based on the human studies. When discussing possible options for glaucoma management with the pregnant patient, it is important to emphasize the lack of definitive studies and the patient may be involved in the therapeutic decision-making process.



How to cite this article:
Razeghinejad M R. Glaucoma medications in pregnancy.Oman J Ophthalmol 2018;11:195-199


How to cite this URL:
Razeghinejad M R. Glaucoma medications in pregnancy. Oman J Ophthalmol [serial online] 2018 [cited 2018 Dec 14 ];11:195-199
Available from: http://www.ojoonline.org/text.asp?2018/11/3/195/244318


Full Text



 Introduction



The coincidence of glaucoma and pregnancy is thought to be rare; however, we need to improve our understanding about glaucoma management in this very challenging group of patients. It is now commonplace for women to choose to start families later in life; thus, the frequency of glaucoma during pregnancy seems to be on the rise. The management of the pregnant woman with glaucoma requires a balance between the treatment's risk to the fetus and the mother. The intraocular pressure (IOP) typically decreases during pregnancy; however, many glaucoma patients continue to require medical treatment for glaucoma and some may experience IOP elevation during pregnancy while have controlled glaucoma before conception.[1],[2],[3] In a retrospective study on 28 eyes of 15 pregnant glaucoma patients with varying severity and types of glaucoma, the IOP remained controlled without any change in visual field in 16 eyes. In five eyes, there was progression in the visual field while the level of IOP remained stable or increased, and in five eyes, the level of IOP increased; however, there was no change in the visual field. The data of two patients were inconclusive. Glaucoma medications were used to control the IOP in 13 out of 15 patients.[3] A 28-year-old woman had a controlled IOP with latanoprost for 5 years, but after conception, the IOP increased to 30 mmHg even after adding timolol and dorzolamide and receiving laser trabeculoplasty.[4] There is a general level of uncertainty regarding medical management among ophthalmologists in managing a pregnant glaucoma patient.[5] In a survey of ophthalmologists in the UK, 26% had previously treated pregnant women with glaucoma. Interestingly, 31% were unsure how to treat a pregnant woman who had uncontrolled IOP; 40% used topical treatment. Of those who prescribed medical treatment, 45% used topical beta-blockers first, 33% used topical prostaglandin analogs first, and 22% used other medications first.[5] In this review, the side effects an precautions of glaucoma medications during pregnancy is discussed based on the information obtained through a literature search on the PubMed database and including all relevant studies.

 Medications



The Food and Drug Administration (FDA) classification of drugs safety in pregnancy includes:

Category A: Safety established using human studiesCategory B: Presumed safety based on animal studies, but no human studiesCategory C: Uncertain safety, with no human studies and animal studies showing adverse effectCategory D: Unsafe; evidence of risk that in certain clinical circumstances may be justifiableCategory X: Definitely unsafe, with the risk of use outweighing any possible benefit.

In general, <20% of all drugs classified by the FDA fall into categories A or B. Most topical antiglaucoma drugs belong to Category C, and none are placed in Category A or X.[6] Category A indicates that controlled studies in women fail to demonstrate a risk to the fetus and the medications have a low risk for causing fetal harm while Category X is definitely unsafe.[1] The only glaucoma medications in Category B are brimonidine and dipivefrine. The presumed safety of brimonidine and dipivefrine is based on animal studies only.[6] Nasolacrimal occlusion, eyelid closure, or blotting the excess drops away during administration, and punctual plugging should be discussed with pregnant women on topical antiglaucoma medications.[7] By employing punctual occlusion after drug application, the amount of medication which is absorbed into the blood can be reduced by up to two-thirds. For the fetal safety, the fewest number, the lowest concentration, the least number of times each day the drops should be used.

 Beta-Blockers



Timolol, carteolol, levobunolol, and metipranolol are nonselective beta-blockers, and betaxolol is a beta-1 blocker. Some reports state that while beta-blockers are teratogen, the obstetricians are most comfortable with their oral use to control hypertension during pregnancy.[8] If a patient is given timolol 0.5% once a day and the entire drop is absorbed, the total daily systemic exposure would be approximately 300 μg. Thus, the systemic burden of timolol 0.5% used in both eyes once daily is <3% of a 20 mg oral dose of timolol.[9] One report described arrhythmia and bradycardia in the fetus of a pregnant glaucoma patient using timolol. The baby developed postpartum arrhythmia, and the authors speculated that the cause of the heart conduction defect was timolol.[10] However, other reports detected no specific problem in the newborns of women on topical timolol.[7],[11] The reported adverse effect of systemic beta-blockers on the fetus and neonate includes premature labor pain, intrauterine growth retardation, bradycardia, polycythemia, apnea at birth, hypoglycemia, and hyperbilirubinemia.[12]

In a population-based study, 244 pregnant women on topical antiglaucoma medications were compared with 1952 pregnant women matched for age, year of delivery, maternal hypertension, and gestational diabetes. The majority of pregnant women (77.5%) were prescribed beta-blockers. There was no significant difference in the risk of low birth weight infants between mothers prescribed beta-blockers and the control group; however, the risk of a low birth weight infant was higher in mothers prescribed topical antiglaucoma medications other than beta-blockers. The authors concluded that beta-blockers can be the first-line drug when considering glaucoma medical treatment in pregnant women.[13] With respect to the available data, there is no definite evidence to restrict beta-blockers use in pregnancy. There are reports of respiratory problems in the newborns exposed to systemic beta-blockers near delivery. Thus, newborns exposed to timolol before birth should be closely observed during the first 2 days after birth for bradycardia and other symptoms.[14],[15] These agents should be discontinued 2–3 days before delivery to avoid beta-blockade in the infant.[16]

 Parasympathomimetics



Cholinergic drugs act either directly by stimulating cholinergic receptors (pilocarpine and carbachol) or indirectly by inhibiting the enzyme cholinesterase (echothiophate and demecarium). These medications are categorized as Group C by FDA for use in pregnancy. Although pilocarpine and carbachol have demonstrated teratogenic and adverse fetal effects in animals,[17] a large collaborative study examining the use of systemic cholinergic drugs found no association between their use during the first 4 months of gestation and congenital abnormalities.[18] Cholinergic agents have been associated with neonatal hyperthermia, restlessness, seizures, and diaphoresis when given to women near term and mimicked the signs of meningitis.[19],[20] Regarding the local and systemic side effects of this class of antiglaucoma medications and the emergence of the more potent drugs with fewer local and systemic side effects, these are not a good choice for treating a pregnant glaucomatous patient.

 Carbonic Anhydrase Inhibitors



Topical

Dorzolamide and brinzolamide are classified as Category C for use in pregnancy. Although there are reports of association between the use of oral carbonic anhydrase inhibitors and sacrococcygeal teratoma and transient renal tubular acidosis in neonates,[21],[22] no adverse effects associated with the use of topical carbonic anhydrase inhibitors during pregnancy, have been reported. In the only reported study on five pregnant patients who received dorzolamide, no problems were observed in the neonates up to 2 years after birth.[7] In a study, two of the seven mothers on topical carbonic anhydrase inhibitors (28.6%) had low birth weight infants that were higher than that for the control group (6.2%).[13] However, no fetal side effects were observed in nine patients that received topical carbonic anhydrase inhibitors.[3],[7]

Oral

The available oral forms of carbonic anhydrase inhibitors are acetazolamide and methazolamide. Both are in Category C for use in pregnancy. Although there are reports indicating an association between the use of oral carbonic anhydrase inhibitors and sacrococcygeal teratoma and transient renal tubular acidosis in neonates,[21],[22] no evidence was found to suggest a relationship to major or minor fetal anomalies in the infants of 1024 women exposed to acetazolamide at any time during pregnancy.[23] In a study on rats, acetazolamide with >20 times, the usual therapeutic dose was associated with forelimb deformities. An unexplained aspect of this work was the unilaterality (right side) of the lesion in 95% of the participants. Only 5% had bilateral lesions, but never the left side lesion alone.[24] In a study, 12 pregnant patients receiving acetazolamide for pseudotumor cerebri, no adverse pregnancy outcomes was observed.[25] Although many suggest that acetazolamide be avoided in pregnancy, especially in the first trimester, there is little clinical evidence to support this recommendation and it may have a more medicolegal than medical rationale. Ellison and Maren demonstrated the evidence for potassium depletion in rats treated with acetazolamide and concluded that replacement therapy with potassium resulted in partial to complete protection of developing embryos.[26] It is clear that results from teratogenesis studies in laboratory animals cannot be extrapolated to humans, but to prevent the possible fetal or neonatal hypokalemia, acidosis, and risk of teratogenesis, monitoring the plasma potassium level is recommended while modifying the diet in pregnant patients on these agents. If the clinical situation warrants the use of acetazolamide, the drug probably could be administered with appropriate informed consent.[25]

 Prostaglandins



The available prostaglandin analogs are as follows: latanoprost, travoprost, bimatoprost, and unoprostone. Prostaglandin analogs are classified into Category C in pregnancy. There have been no systemic side effects attributed to topical prostaglandins in any of the clinical trials. It may be due to the short halflife of 17 min.[9],[27],[28],[29] No adverse embryo effects were reported by the manufacturer when exposure was up to 15 times the human dosage.[30] Of 10 pregnant women who received latanoprost in the first trimester, one patient had a miscarriage. The patient was a 46-year-old primigravida who had enhanced reproductive risk related to her advanced age. All other nine patients had a normal pregnancy course and outcome without neonatal malformations.[31] Theoretically, prostaglandins increase uterine tone and may lead to premature labor. Interestingly, the dosage used to stimulate abortion would be the equivalent of 400 cc of the ocular formulation of latanoprost.[9] At present, there are debates regarding the use of this group of medications in pregnancy. It has been claimed that ocular prostaglandin analogs have insufficient active ingredients to induce adverse effects on the fetus.[32] However, some believe that its use is contraindicated in pregnant women.[33],[34] There is no compelling evidence to withheld this group of medications in pregnant glaucomatous patients. Since prostaglandins increase uterine tone and can cause reduced perfusion to the fetus, general caution is advised.

 Osmotic Agents



The osmotic agents include mannitol, urea, isosorbide, and glycerol. Isosorbide for oral administration is no longer available. Mannitol and glycerol have been assigned to pregnancy Category C. Animal studies have not been reported on these agents, and there is no human pregnancy study.[9] However, among the medical methods of inducing the second trimester, abortion is intra-amniotic administration of mannitol and urea.[35] Mannitol and glycerol may be used during pregnancy when the benefits outweigh risks.

 Alpha-2 Agonists



The alpha-2 agonists available clinically include clonidine, apraclonidine, and brimonidine.[9] Brimonidine is categorized as B for use in pregnancy. However, in a study of 20 pregnant glaucoma patients receiving brimonidine, two (10%) had low birth weight infants.[13] There are warnings about the use of brimonidine in infants and young children because it has some central nervous system effects such a apnea and hypotension.[20] Thus, if this drug is used in pregnancy a wise decision is stopping the drug days before delivery because it penetrates the placenta and blood–brain barrier and can result in neonatal central nervous system depression.

 Preservative of Antiglaucoma Eyedrops



The most commonly used preservatives in eye drop formulations is benzalkonium chloride. The two other preservatives used in the glaucoma medications are SofZia and purite. SofZia is an ionic buffer containing borate, sorbitol, propylene glycol, and zinc that break up into harmless ingredients after application. It is used as the preservative in the Travatan-Z. Purite, stabilized oxychloro complex, is an oxidative-type preservative used in Alphagan-p and breaks down on contact with the air. Although purite is a chemical oxidant, there is no in vivo or in vitro evidence of its mutagenicity or carcinogenicity.[36],[37] Benzalkonium chloride causes bronchoconstriction through a combination of mast cell activation and stimulation of neural pathways, especially in patients who receive more than one antiglaucoma drug.[38] For patients who require more than one topical antiglaucoma agent, fixed-combination products offer less exposure to preservatives. Plasma timolol concentration values were 20% lower in the fixed-combination timolol/brimonidine treatment group than in the timolol only group. The finding was attributed to a slower absorption of timolol due to a difference in benzalkonium chloride concentrations.[39] Timolol/brimonidine fixed-combination may be a suitable treatment regimen in patients who need to use two medications including a beta-blocker. Whether benzalkonium chloride can affect the fetal lung maturation has not been determined. In a study of rats, a dose-related increase in fetal resorption, death, and reduction in litter size and weight were observed after exposure to benzalkonium chloride. However, it was not associated with any discernible visceral malformations although minor sternal defects occurred in fetuses exposed to a single dose of 100 and 200 mg/kg.[40] The concentration of BAK in antiglaucoma eye drops is miniscule compared to the above study. The preservative free forms of the following antiglaucoma medications are available and seem to be a better choice in pregnant patient compared to the preservative containing compounds: timolol, dorzolamide-timolol, and tafluprost.

 Conclusion



The highest risk of fetal damage is during the first trimester, and since women often do not know for several weeks if they are pregnant or not, it is crucial to inform glaucomatous patients about unplanned pregnancies. In glaucomatous women at childbearing age, if possible, the treatment plan should be discussed before they get pregnant, allowing for discussion of treatment options, and possible risks. With this strategy, the adverse effects of medications can be prevented during the organogenesis period. In addition, alternate effective IOP lowering methods including surgery can be explored or achieved before the beginning of the pregnancy.

Every woman in the general population has a 3%–5% risk of having a child with a birth defect or cognitive impairment. Drug and chemical exposure during pregnancy accounts for only about 1% of congenital malformations.[41] All glaucoma patients fear blindness throughout their lives, and when a woman gets pregnant, the baby's health issue is added to the mother's stresses. A population-based sample of mothers showed that maternal life stress during pregnancy may be a common risk factor for impaired child health.[42] Initiation of medical therapy should involve a discussion with the patient about the benefits, risks, and the more common potential side effects of therapy, especially during the first 12 weeks of gestation (organogenesis).[43] The last month of pregnancy is also important because the drugs pass through the placenta and reach the fetal circulation and may affect the newborn's cardiac, respiratory, and neurologic systems functions. No topical antiglaucoma agents have strong evidence of safety to the fetus based on the human studies.[1] Most evidence comes from single case reports or animal studies with the limitations that these impose. When discussing possible options for glaucoma management with a pregnant patient, it is important to emphasize the lack of definitive studies. The patient may be involved in the therapeutic decision-making process.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

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