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Title: Management of Glaucoma During Pregnancy
Author: Angelo P. Tanna
Department of Ophthalmology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
Division of Ophthalmology, Ann & Robert H. Lurie Children’s Hospital of Chicago, Chicago, Illinois, USA
Conflicts of Interest Disclosure:
APT: Consultant to Ivantis, Sandoz, and Zeiss
APT is supported by an unrestricted departmental grant from Research to Prevent Blindness, NY, NY
Angelo P. Tanna, M.D.
Department of Ophthalmology
Northwestern University Feinberg School of Medicine
645 N. Michigan Ave., Suite 440
Chicago, IL 60611
I read with interest the work of Doctor Hashimoto and colleagues on the risk of adverse neonatal outcomes (congenital anomalies, preterm birth, low birth weight) associated with maternal exposure to intraocular pressure-lowering medications during pregnancy.1 They used a large Japanese claims database and state-of-the-art statistical methodology to evaluate the frequency of adverse events in a cohort of live births of 91 women who had “at least one dispensation of IOP-lowering medications during the first trimester,” compared to that observed in 735 women with glaucoma or...
I read with interest the work of Doctor Hashimoto and colleagues on the risk of adverse neonatal outcomes (congenital anomalies, preterm birth, low birth weight) associated with maternal exposure to intraocular pressure-lowering medications during pregnancy.1 They used a large Japanese claims database and state-of-the-art statistical methodology to evaluate the frequency of adverse events in a cohort of live births of 91 women who had “at least one dispensation of IOP-lowering medications during the first trimester,” compared to that observed in 735 women with glaucoma or suspicion of glaucoma who did not have such an exposure.
The authors discuss the previously used and outdated United States Food and Drug Administration (FDA) risk classification system for drugs used during pregnancy. The FDA required the removal of the pregnancy letter categories – A, B, C, D, and X from all drug product labels in 2015. Instead, for systemically absorbed drugs (which includes all ocular hypotensive medications), the FDA requires labeling to include a summary of the risks of using a drug during pregnancy as well as “risk statements based on data from all relevant sources (human, animal, and/or pharmacologic), that describe, for the drug, the risk of adverse developmental outcomes.”2
The investigators observed any adverse outcome in 17.6% of neonates with and in 13.3% without fetal exposure to IOP-lowering medications. The authors concluded that after propensity score adjustment, IOP-lowering medications were not significantly associated with more frequent adverse events. For example, the adjusted odds ratio for congenital anomalies was 1.43 (95% CI, 0.66 to 3.12).
The investigators only evaluated live births; therefore, the potentially increased risk of spontaneous abortion or fetal demise associated with the use of these agents during pregnancy cannot be known from this analysis. It is possible some of the women in the control cohort may have been exposed to ocular hypotensive agent(s) during the first trimester, using medication already in their possession, without necessarily having been dispensed any such agent during the first trimester. This could confound the comparative analysis.
Finally, the authors report their study had a power > 80% for detecting a two-fold increase in the composite outcome (i.e., the risk of any of the adverse neonatal outcomes studied). This begs the question: How much increased risk is a pregnant woman willing to accept? I believe a much lower threshold is necessary to arrive at a meaningful conclusion. In my experience, many women would reject even a 1% increase in the risk of a congenital anomaly. So then, the concluding message in the abstract that “IOP-lowering medications during the first trimester were not significantly associated with increase in congenital anomalies, preterm birth or low birth weight” is not meaningfully supported by the data. The study only supports the concept that the use of these medications is probably not associated with a doubling of the risk. Patients and society are interested in a higher threshold of safety.
Fortunately, pregnancy is often associated with a spontaneous reduction in intraocular pressure (IOP)4; therefore, continued treatment may not be required. Selective laser trabeculoplasty is also an option to consider for some patients. Moreover, many young patients with glaucoma can tolerate nine months of higher IOP.
Glaucoma in pregnancy is a complex problem that requires complex, collaborative decision-making. Pregnant women, their ophthalmologists and obstetricians must evaluate the potential risks associated with continued use of ocular hypotensive agents during pregnancy and weigh those against the risks of modifying or stopping therapy. I congratulate the authors on exploring this important topic and encourage others to conduct similar studies. Eventually, a meta-analysis may yield evidence that can guide clinical decision-making.
1. Hashimoto Y, Michihata N, Yamana H, Shigemi D, Morita K, Matsui H, Yasunaga H, Aihara M. Intraocular pressure-lowering medications during pregnancy and risk of neonatal adverse outcomes: a propensity score analysis using a large database. Br J Ophthalmol. 2021 Oct;105(10):1390-1394. doi: 10.1136/bjophthalmol-2020-316198. Epub 2020 Sep 9. PMID: 32907812.
2. Content and Format of Labeling for Human Prescription Drug and Biological Products;
Requirements for Pregnancy and Lactation Labeling. Department of Health and Human Services. Food and Drug Administration 21 CFR Part 201 [Docket No. FDA-2006-N-0515] RIN 0910-AF11. Available online at http://federalregister.gov/a/2014-28241.
3. Mezawa H, Tomotaki A, Yamamoto-Hanada K, Ishitsuka K, Ayabe T, Konishi M, Saito M, Yang L, Suganuma N, Hirahara F, Nakayama SF, Saito H, Ohya Y. Prevalence of Congenital Anomalies in the Japan Environment and Children's Study. J Epidemiol. 2019 Jul 5;29(7):247-256. doi: 10.2188/jea.JE20180014. Epub 2018 Sep 22. PMID: 30249945; PMCID: PMC6556438.
4. Ziai N, Ory SJ, Khan AR, Brubaker RF. Beta-human chorionic gonadotropin, progesterone, and aqueous dynamics during pregnancy. Arch Ophthalmol. 1994 Jun;112(6):801-6. doi: 10.1001/archopht.1994.01090180099043. PMID: 8002840.