Glaucoma treatment in pregnant patients presents a unique challenge, wherein adequate treatment of maternal disease must be balanced with reduction of adverse effects to the fetus. Although glaucoma is less common in individuals of childbearing age, estimated prevalence ranges from 0.16%¹ to 0.73%,² making it possible, and indeed likely, for a provider to encounter such patients over the course of a career. There is nevertheless uncertainty in regard to treating glaucoma in this population, as evidenced by a survey in which 31% of consulting ophthalmologists reported being unsure of how to treat a pregnant woman with elevated intraocular pressure (IOP).³

Evidence for maternal and fetal safety of glaucoma treatments is limited largely to animal studies and clinical case reports due to the ethical constraints of enrolling pregnant patients in clinical trials. This evidence will be summarized with the goal of highlighting glaucoma treatment principles that promote safety of mother and fetus. It is not our hope to provide treatment guidelines but rather a framework to be utilized by treating physicians based on their own judgement, in close consultation with patients’ obstetricians and neonatologists.

General Principles

The US Food and Drug Administration (FDA) has categorized medications based on their safety to the fetus.⁴ Category A medications are established as safe in human studies. Category B medications are presumed safe based on animal studies. Brimonidine is a category B drug. Category C medications have shown adverse effects in animals with no human data available. Prostaglandin analogs, beta blockers, carbonic anhydrase inhibitors (CAIs), and cholinergics are category C drugs. Category D medications demonstrate risks to the fetus that may be outweighed by maternal benefits. Category X medications demonstrate risks to the fetus that outweigh any maternal benefits. Mitomycin C and 5-fluorouracil are category X drugs.

When medications are employed, the fewest number of drugs, drugs with the lowest concentration, and drugs least likely to be systemically absorbed (eg, gel-forming solution) should be used where possible. Systemic absorption of medications can be further minimized by instructing patients on punctal occlusion⁵ or placing punctal plugs.

Preconception

Providers should initiate preconception counseling in glaucomatous patients of childbearing age, the purpose of which is twofold. First, the patient can be informed of potential fetal risks from any present, and potential future, treatment options. Second, the patient can be educated on the importance of notifying her provider once pregnancy is confirmed, so therapy can be modified to promote fetal safety throughout pregnancy.

Management of glaucoma in the preconception period should be guided by the severity of the patient’s glaucoma. Mild glaucoma may be effectively managed with brimonidine, either as initial therapy or as substitute for an existing medication, because brimonidine has the lowest fetal risk categorization (category B) among all glaucoma medications. Laser trabeculoplasty may also be considered to reduce medication burden throughout pregnancy. In contrast, patients with IOP that is uncontrolled, or controlled only with numerous medications, may be candidates for surgery in the preconception period. Surgery may reduce medication burden and its potential fetal toxicity during pregnancy, as well as avoid the risks, to both mother and fetus, of surgery during pregnancy.

First Trimester

The first trimester is a period of major organogenesis and therefore carries the greatest risk of medication-induced teratogenesis.⁶ Brimonidine is the preferred medication in the first trimester given that it is category B, the lowest fetal risk category among glaucoma medications.

Beta blockers may be a reasonable second-line therapy. Although there is a case report of fetal bradycardia in a patient using a topical beta blocker for glaucoma,⁷ many other retrospective cohort and case-control studies have shown that pregnant women using topical beta blockers had no increased incidence of fetal adverse events, including low birth weight or miscarriage.^8-10 Additionally, obstetricians commonly use systemic beta blockers to control hypertension in pregnancy,^11,12 further supporting the safety of topical beta blockers in pregnancy.

Prostaglandin analog safety was examined in a case series of 10 pregnant patients who used the medication for treatment of glaucoma.¹³ Nine patients experienced no fetal adverse events. One patient experienced a miscarriage, although the authors suggest it was less likely attributable to the prostaglandin analog and more likely attributable to the patient’s advanced age of 46, which placed her at high reproductive risk. Nevertheless, prostaglandin analogs have been shown to induce uterine contraction in rodent in vitro studies,¹⁴ and the theoretical risk of topical forms inducing premature contraction in humans makes them less preferred in the first trimester.

The evidence for fetal safety of topical CAIs in pregnancy is mixed. Some studies have shown no adverse fetal effect.⁸ However, others demonstrated a trend toward low birth weight,⁹ although these children had normal physical and mental status within 2 years of birth.¹⁵ It is important to note that patients in these studies were not on monotherapy with topical CAIs, but rather were taking multiple glaucoma medications, making it unclear whether the low birth weight was related to CAIs, another medication, or the combination of the medications. Overall, topical CAIs may be appropriate as third-line therapy in pregnant patients.

Systemic CAIs are known to produce forelimb abnormalities in animals.^16-18 In humans, there are single case reports of possible associations between systemic CAIs and sacrococcygeal teratoma,¹⁹ transient renal tubular acidosis,²⁰ and skeletal malformations.²¹ However, no increased rate of adverse fetal events was noted in an observational case series of 12 pregnant pseudotumor cerebri patients using acetazolamide,²² nor in a case-control series in which acetazolamide was either used or not among 101 pregnant pseudotumor cerebri patients.²³ Furthermore, the Collaborative Perinatal Project reported that 1,024 women exposed to acetazolamide in pregnancy, including 12 in the first trimester, had no increased risk in fetal malformations.²⁴ Overall, systemic CAIs may be reserved for urgent short-term IOP lowering in the first trimester.

Rho kinase inhibitors have been only recently approved for use in glaucoma treatment, and their fetal safety profile is unsurprisingly not well understood. Findings in in vitro studies suggest Rho kinase inhibitors weaken uterine contraction.^25,26 However, there are no available in vivo safety data to date, and no FDA pregnancy category has yet been assigned. Overall, the available data do not allow an informed judgement on the safety of Rho kinase inhibitors in pregnancy.

Finally, the cholinergic agent pilocarpine was found to have no increased association with congenital abnormalities when used in pregnant patients. Therefore, pilocarpine is a potential third-line treatment.²⁷

Second Trimester

The risk of serious teratogenesis decreases after the first trimester as major organogenesis completes. The principles guiding medication selection in the first trimester are generally applicable in the second trimester.

While surgery in pregnancy is not ideal, it may be most appropriate to consider during the second trimester if IOP remains uncontrolled with medications and laser trabeculoplasty.²⁸ The fetus is generally at greatest risk in the first trimester due to the potentially teratogenic effects of anesthetics and sensitivity to intraoperative hypoxemia. The mother is generally at greatest risk in the third trimester due to changes in maternal physiology, including compression of the great vessels in the supine position by the enlarging fetus, altered sphincter tone causing increased risk of gastroesophageal reflux and aspiration, and laryngeal edema increasing intubation difficulty.

Special consideration must also be given to the type of surgery performed in pregnant patients. Antimetabolites, such as mitomycin C and 5-fluorouracil, are category X medications, and they are absolutely contraindicated in pregnancy. This precludes the use of trabeculectomy or Xen gel stent (Allergan) to control IOP. The ideal surgery would minimize operative time, as well as postoperative hypotony, which could increase the risk of ocular complications during labor-associated Valsalva maneuver. Cyclophotocoagulation has been used successfully in lieu of incisional surgery in some instances, with benefits including short operative time and relaxed positioning requirements.²⁹ Erythromycin (category B) and prednisolone acetate (category C) may be used in the postoperative period.

Third Trimester

A pregnant patient’s glaucoma medication regimen must be modified in the third trimester to ensure the fetus thrives once delivered. Brimonidine should be discontinued, because it readily penetrates the blood-brain barrier of infants, causing central nervous system depression and apnea.^30,31 Prostaglandins, withheld in earlier trimesters due to the theoretical risk of premature labor, may be more safely employed given the greater postpartum viability of a third trimester fetus. Rare reports of bradycardia and respiratory distress in infants exposed to topical beta blockers³² may make it prudent to discontinue beta blocker therapy in the days before delivery where possible, or otherwise closely monitor neonatal heart rate. A case report of metabolic acidosis in an infant exposed to topical dorzolamide³³ may likewise make it worthwhile to discontinue CAIs in the days before delivery where possible, or otherwise ensure the neonate’s electrolytes are normal once delivered. Finally, consideration should be given to discontinuing cholinergic agents prior to delivery, given rare reports of hyperthermia, restlessness, seizures, and meningitis-like symptoms in infants born to mothers using pilocarpine.³⁴

Postpartum

A nursing mother’s glaucoma medication regimen must be modified given the possibility of excretion of some medications into the breast milk. In all cases, medication should be instilled promptly after, rather than before, breastfeeding where possible, to allow diminishment of systemic and breast milk medication concentrations by the time of next breastfeeding.

Brimonidine has no human data available on transfer into breast milk, though animal studies have shown it to be excreted in breast milk.³⁵ It is therefore important to discontinue brimonidine while breastfeeding given brimonidine’s known complications of central nervous system depression and apnea in infants. Animal studies have also shown topical CAIs to be excreted in breast milk,³⁵ though there is no evidence available to suggest it adversely affects the infant. Systemic CAIs have been detected in human breast milk, but at concentrations too low to adversely affect an infant.³⁶ Neither animal nor human studies have elucidated whether prostaglandin analogs are excreted in breast milk,³⁵ but their short half-lives (eg, 17 minutes for latanoprost)³⁷ suggest that clinically insignificant amounts are passed to the infant. Beta blockers are known to be excreted in human breast milk,³⁸ albeit at concentrations unlikely to cause adverse effects in the infant.³⁹ Nevertheless, infants with preexisting cardiopulmonary disease may warrant monitoring for signs of beta blockade. Finally, it remains unknown whether cholinergic agents are excreted in breast milk,³⁵ but the finding of meningitis-like symptoms, albeit rare, in infants born to mothers using pilocarpine may warrant its discontinuation while breastfeeding.³⁴

Conclusion

Managing glaucoma in pregnancy requires the delicate balance of adequate maternal disease treatment and maintenance of fetal safety. Medications used from preconception to the postpartum period should be tailored at each stage to minimize fetal risk based on the available, albeit limited, safety data. Laser trabeculoplasty can be employed to reduce medication burden at any stage of pregnancy, from preconception to postpartum period. Surgery should be considered in the preconception period for IOP uncontrolled by medication and laser trabeculoplasty, reserving surgery during pregnancy for dire cases after careful consideration of benefits and risks to mother and fetus. Optimal outcomes are achievable by partnering with patients, as well as their obstetricians and neonatologists, to determine the best and safest course of treatment. GP

Robert J. Purgert, MD, PhD, is with Ophthalmic Consultants and Surgeons of Cleveland in Cleveland, Ohio. He reports no related disclosures.

Marlene R. Moster, MD, is with the Wills Eye Hospital Glaucoma Service. She reports no related disclosures. Reach her at mmoster@oppdoctors.com.

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