Glaucoma management during pregnancy and postpartum is a unique clinical challenge that requires balancing maternal visual protection with avoidance of fetal and neonatal drug risks 1). Although glaucoma is more common in individuals over 40, women of childbearing age may have congenital glaucoma, anterior segment dysgenesis, or glaucoma secondary to uveitis, diabetes, etc. 1).
The basic principles of management include the following 3)7):
Intraocular pressure (IOP) tends to decrease during pregnancy 1). The mean IOP in the first trimester is about 2 mmHg higher than in the third trimester 1). Proposed mechanisms for IOP reduction include improved aqueous humor outflow due to increased progesterone and relaxin, decreased episcleral venous pressure due to reduced upper extremity venous pressure, and gestational metabolic acidosis 1).
However, in a study of 15 women with pre-existing glaucoma, 57% showed no IOP elevation or visual field progression, while 18% had progressive visual field defects and another 18% had IOP elevation without visual field progression (mean increase of 10 mmHg) 1). Monitoring should be performed at least once per trimester during pregnancy 1).
Intraocular pressure tends to decrease naturally during pregnancy 1). This is related to improved aqueous humor outflow due to progesterone and relaxin. However, about 18% of glaucoma patients experience IOP elevation during pregnancy, which may require additional treatment 1). Therefore, regular monitoring every trimester is important.
The safety of glaucoma medications during pregnancy has been classified based on the FDA pregnancy risk categories (A to X) 4)5)7).
| Category | Definition |
|---|---|
| A | No fetal risk in human pregnant women |
| B | No risk in animal studies or safe in humans |
| C | Adverse effects in animals, but no human studies |
Category D indicates risk to the human fetus, and X means contraindicated 4). No glaucoma medication falls into Category A 1). In 2015, the FDA abolished the ABCDX classification and changed to individual descriptive labeling 4)5). Therefore, Rho kinase inhibitors have not been assigned a category 4)5).
Beta-blockers
FDA Category: C1)4)
Risk during pregnancy: Fetal bradycardia and arrhythmia due to placental transfer 1)3)
During breastfeeding: Reports indicate breast milk concentration is 6 times that of plasma 7). Cardiorespiratory monitoring of the infant is necessary 1)
Status: Long-term experience exists and they are considered relatively safe 3)6). Punctal occlusion can reduce systemic absorption by approximately 40% 1)
Brimonidine (alpha-2 agonist)
FDA Category: B1)4)7)
Risk during pregnancy: No significant effects in animal studies 1)
Neonatal risk: Crosses the blood-brain barrier, causing central nervous system depression and apnea 1)3)
Status: Can be used in the first and second trimesters, but should be discontinued before delivery and during breastfeeding 1)3)6)
Prostaglandin analogs: FDA Category C 1)4). High rates of miscarriage have been reported in animal studies 3). They stimulate uterine contractions and pose a risk of preterm labor, but it is unclear whether this effect occurs at the low systemic concentrations from eye drops 1). In 11 pregnant women exposed to latanoprost, no congenital anomalies were observed 4)5). Generally avoided during pregnancy, but considered usable during breastfeeding 3)6).
Carbonic anhydrase inhibitors (CAIs): Both topical and systemic formulations are FDA category C 1)4). In animal studies, dorzolamide has been associated with vertebral malformations, and high-dose oral acetazolamide has been reported to cause forelimb abnormalities 1)6). The first trimester carries the highest risk of teratogenicity 3)6). During breastfeeding, use is approved by the American Academy of Pediatrics (AAP) 4)5)6).
Rho kinase inhibitors (netarsudil): FDA category not assigned 4)5). Animal studies have not shown clear teratogenicity, but there are insufficient clinical data, and use during pregnancy is not recommended 1)3). Because netarsudil has very low systemic exposure, effects on nursing infants are not expected, but relevant data are insufficient 3).
In Japan, the incidence of congenital anomalies at birth is 1.7–2.0%, and drug-induced anomalies account for only 2–3% of external factors 7). A recent large-scale database study in Japan reported no association between the use of glaucoma eye drops in early pregnancy and adverse neonatal outcomes 7).
No glaucoma medication has been established as completely safe 3)7). Brimonidine, an FDA category B drug, can be used in the first and second trimesters, but it is contraindicated before delivery and during breastfeeding due to the risk of neonatal apnea 1)3). Beta-blockers are considered relatively safe based on long-term experience, and it is advisable to use punctal occlusion to reduce systemic absorption 3)6). If use is unavoidable, the lowest effective dose should be used, and collaboration with an obstetrician and neonatologist is essential.
The medications that can be used safely differ depending on the stage of pregnancy 1).
| Drug | First Trimester | Second Trimester | Breastfeeding |
|---|---|---|---|
| Brimonidine | First choice | Discontinue in later half | Contraindicated |
| Beta-blockers | First- to second-line | Can be continued | Can be used |
| Prostaglandin-related drugs | Third-line | Second-line | First-line |
Topical CAIs can be used as third-line in the first trimester and as second-line from the second trimester onward, but should be combined with punctal occlusion 1). Systemic CAIs are used only for short periods in cases of acute intraocular pressure elevation 1).
Laser treatment is a safe alternative during pregnancy1)4).
However, trabeculoplasty tends to be less effective in younger patients, and congenital glaucoma variants and juvenile open-angle glaucoma are often resistant to treatment1).
If intraocular pressure is poorly controlled with medication and laser treatment, surgery is considered1)2).
Principles of Surgery
Optimal timing: The second trimester offers the best balance of potential risks to mother and child1)
Contraindicated agents: Mitomycin C (MMC) and 5-FU (FDA Category X)1)
Anesthesia: Local anesthesia (lidocaine) is recommended. Bupivacaine has been associated with fetal bradycardia1)
Position: After the second trimester, supine position carries a risk of great vessel compression; consider left lateral decubitus position1)
Choice of Procedure
Trabeculectomy: Can be performed without antimetabolites, using non-pharmacological adjuncts such as collagen matrix1)
Tube shunt surgery: Use of Ahmed, Baerveldt, etc. has been reported1)
Minimally Invasive Glaucoma Surgery (MIGS): Can be performed under local anesthesia, with small incisions and short operative time, potentially reducing risks1)
Pol et al. reported a case of a 36-year-old primigravida (10 weeks gestation) who developed acute angle-closure glaucoma (IOP 40 mmHg). YAG laser iridotomy and antiglaucoma medications failed to control intraocular pressure, so trabeculectomy was performed in both eyes. Postoperative intraocular pressure normalized, no structural abnormalities were observed in the fetus, and a healthy infant was delivered at full term2).
It is possible, but the first trimester should be avoided due to risks of teratogenicity and miscarriage1). If surgery is necessary, the second trimester is considered safest. Antimetabolites such as mitomycin C and 5-FU are contraindicated (FDA Category X)1), and alternative materials such as collagen matrix should be used. Local anesthesia with lidocaine is recommended1). In recent years, minimally invasive glaucoma surgery has been reported as a new option1).
Prostaglandin F2α analogs bind to the prostaglandin F2 receptor, stimulating luteolysis and oxytocin release1). In rodent models, latanoprost, travoprost, and bimatoprost showed contractile activity in non-pregnant uteri1). Travoprost has been confirmed to be teratogenic at intravenous exposures 250 times the maximum recommended human ophthalmic dose1). Oral and vaginal use of the abortifacient misoprostol is associated with risks of Möbius syndrome and terminal transverse limb defects, but it is unknown whether these occur with the low systemic concentrations of ophthalmic prostaglandins1).
Timolol crosses the placental barrier1). In a 3-week-old infant, plasma timolol concentration was reported to reach 34 ng/ml (compared to 3.5 ng/ml in a 5-year-old)1). Neonatal effects include bradycardia, arrhythmia, and respiratory depression3)6). Beta-blockers in breast milk have been reported to be concentrated up to 6 times the plasma concentration, but the clinical impact on infants remains largely unknown7).
High-dose oral acetazolamide causes forelimb abnormalities in rodents1)6). In humans, there is a case report of neonatal sacrococcygeal teratoma1). Topical dorzolamide was associated with vertebral malformations in rabbits, but brinzolamide showed no organ malformations even at 375 times the human ophthalmic dose1). On the other hand, no adverse fetal effects were reported in 12 cases of oral acetazolamide use for idiopathic intracranial hypertension1).
Benzalkonium chloride (BAK) is present in glaucoma eye drops at concentrations of 0.004–0.02%1). Animal studies have confirmed dose-dependent fetal toxicity, with mild sternal defects observed after a single dose of 100–200 mg/kg1). Although the BAK concentration in ophthalmic preparations is extremely low compared to animal studies, preservative-free formulations are recommended1).
Hormonal factors are involved in the decrease in intraocular pressure during pregnancy1). Increases in progesterone and relaxin enhance aqueous humor outflow1). Additionally, a decrease in episcleral venous pressure due to reduced peripheral vascular resistance and metabolic acidosis also contribute to lower intraocular pressure1). The Valsalva maneuver during delivery causes a transient increase in intraocular pressure, but it returns to pre-delivery levels within 72 hours after delivery1).
In a review by Kumari et al., a case was reported in which XEN Gel Stent (without antimetabolites) was sequentially implanted in both eyes during pregnancy, achieving good intraocular pressure reduction1). Minimally invasive glaucoma surgery has a short operative time, preserves the conjunctiva, and is advantageous if additional surgery is needed postpartum1).
A case series of pregnant women with juvenile open-angle glaucoma (JOAG) who underwent orphan trabeculectomy or Ahmed/Baerveldt tube shunt in both eyes during the second trimester with good outcomes has also been reported1).
In a propensity score analysis using a large Japanese database by Hashimoto et al., no association was found between the use of glaucoma eye drops in early pregnancy and the occurrence of neonatal adverse events7). However, due to limitations in sample size, subgroup analysis was difficult, and further research is needed on the safety of individual drugs.
Regarding glaucoma management during pregnancy, conducting randomized controlled trials is difficult due to ethical constraints1). Future progress is expected in the following directions.
