Figure 1. Fluorescein image of a developing embryo’s complex vasculature, compared to the size of a jellybean.
Managing patients with diabetic retinopathy and treating their ophthalmic conditions before and during pregnancy, can be challenging but highly rewarding, as Drs Dov Hersh and Brighu Swamy explain with a case study.
In Australia and worldwide, the prevalence of diabetes in pregnancy is increasing. In this cohort there has been a corresponding increase in the rates of both newly diagnosed diabetic retinopathy and an increased risk of disease progression in patients with established retinopathy. Because many of the usual treatments for diabetic retinopathy and maculopathy are contraindicated in patients who are pregnant or in the perinatal period, management of diabetic eye disease poses specific challenges in this cohort.
Adding to the challenge is the paucity of evidence to guide clinicians in the use of treatments, as pregnant patients are often not included in clinical trials of medications due to the potential risk to the foetus. Therapeutically endorsed optometrists are able to prescribe a range of ocular medications and it is important to understand the safety of specific treatments in this cohort.
BACKGROUND
The prevalence of diabetes mellitus in the general population is increasing. In Australia, the incidence of diabetes has more than doubled in the past 20 years from 4% to 8% of the population. This trend is exacerbated in pregnancy where rates of pre-existing type 1 or type 2 have doubled in seven years. In Aboriginal and Torres Strait Islander women, the rate of diabetes in pregnancy is 10 times higher than non-Indigenous Australians. Along with the increasing numbers of patients with diabetes in pregnancy, the prevalence and progression of diabetic retinopathy (DR) in pregnancy has significantly increased. DR affects approximately 15% of women with established diabetes in pregnancy, with the rates of progression similar for both type 1 and type 2 diabetes. In patients with established non-proliferative diabetic retinopathy (NPDR), progression occurs in 30% of patients. The increased risk of worsening DR can persist for up to 12 months postpartum. National Health and Medical Research Council (NHMRC) studies have shown that type 2 diabetes in pregnancy has equivalently poor outcomes as type 1, both in terms of foetal complications and maternal retinopathy. It is important to distinguish patients with established type 1 or type 2 diabetes from those who develop gestational diabetes mellitus. Due to the transient nature of gestational diabetes, these patients are less likely to develop DR when compared with patients with known DR prior to pregnancy. However, it is important to keep in mind that around 20% of patients diagnosed with gestational diabetes will go on to be diagnosed with type 2 diabetes.
The progression of DR during pregnancy is multifactorial and often a result of altered metabolic and hormonal states. Pregnancy itself has been found to be an independent risk factor for worsening of DR. Coexisting hypertension has been found to compound the risk of progression of DR in diabetic pregnancies. Paradoxically, rapid and tight metabolic control during pregnancy in women with previously poor metabolic control can result in worsening of DR.
Management of DR during pregnancy poses several unique challenges including increased risk of progression during pregnancy, inability to administer anti- VEGF agents due to the possible foetal risk, and logistical difficulties caused by multiple medical appointments. As mentioned in the introduction, evidence evaluating the safety and efficacy of medications used for treatment of DR in pregnant patients is lacking due to the medical and ethical issues involved in enrolment of pregnant women in clinical trials and potential harm to the foetus. Nonetheless, we need to and do manage patients who are in the perinatal period including: trying for conception, pregnancy, and breastfeeding.
In treating pregnant patients there are two overarching principals. First the need to adopt a multidisciplinary approach involving the patients’ health clinicians, which may include a patient’s ophthalmologist, obstetrician, endocrinologist, and general practitioner. Secondly, treatments should only be administered during pregnancy if the potential benefit justifies the risk to the foetus.
SCREENING
In the perinatal period, women with type 1 and type 2 diabetes should be appropriately counselled regarding the effect of pregnancy on DR and optimal glycaemic control should be encouraged. Most guidelines (NHMRC in Australia, American Academy of Ophthalmology in the United States, and The National Institute for Health and Care Excellence in the United Kingdom) recommend an eye examination is performed prior to pregnancy or in the first trimester. Follow-up in the second and third trimesters is dependent on clinical findings and evaluation of other risk factors including glycaemic control, pre-eclampsia, and longer duration of diabetes. Pregnant women found to have diabetic retinopathy should be referred to an ophthalmologist for review and follow-up. Because the increased risk of DR progression in pregnancy can continue for up to a year postpartum, follow-up should continue for this time, with intervals determined by the factors outlined above.
It is interesting to note that retinal screening is not recommended in women without a prior history of diabetes who are diagnosed with gestational diabetes mellitus. This is because DR rarely occurs during pregnancy in this group of patients. However, some studies note that 5–10% of women diagnosed with gestational diabetes will have previously undiagnosed type 2 diabetes and appropriate follow-up of this group is important.
MEDICATION USE IN PREGNANCY
Most medicines cross the placenta. The Therapeutic Goods Administration (TGA) evaluates all medications available in Australia and issues guidelines regarding the safety of prescribing medicines in pregnancy. The system outlined in Table 1 takes into account harmful effects of medicines on the developing baby, including the potential to cause birth defects, unwanted pharmacological effects in the perinatal period, and potential problems in later life. The system uses categories A–D and X with the risks increasing as we move through the alphabet.
ANTI-VEGF MEDICATIONS AND PREGNANCY
Vascular endothelial growth factor (VEGF) is key to angiogenesis in embryo-foetal development. Figure 1 displays the fluorescein image of a developing embryo’s complex vasculature, compared to the size of a jellybean.
The anti-VEGF medications: Avastin (bevacizumab, Genentech), Lucentis (ranibizumab, Novartis), and Eylea (aflibercept, Bayer), and anti-VEGF/anti- Angio 2 (Vabysmo, faricimab-svoa, Roche) are classified as category D. Although intravitreal administration limits systemic exposure, the mechanism of action of anti- VEGF medications suggests treatment may pose a risk to embryo–foetal development. Animal studies, when dosed at levels higher than recommended in humans, have shown malformations and foetal abnormalities. As such, these medications are not recommended for use in patients who are pregnant. To allow for an adequate washout period, it is recommended that women wait at least three months after their last treatment with these agents prior to conceiving.
In rare cases, the authors have administered anti-VEGF treatments in pregnant patients. These have been administered in the third trimester and in patients where the only functioning eye was at risk of loss of vision secondary to neovascular pathology e.g., a uniocular patient with choroidal neovascularisation secondary to punctate inner chorioretinopathy (PIC). Case reports are available in the medical literature outlining similar treatments for uniocular patients where the vision would be at risk without active treatment. When the decision is made to treat with anti-VEGF agents in pregnancy, ranibizumab and aflibercept remain the agents of choice given their shorter half-life and faster plasma clearance compared with bevacizumab. In these rare circumstances, decisions should be individualised to each patient after a thorough evaluation and discussion of risks and benefits.
AN ILLUSTRATIVE CASE
The following is an illustrative case managed by the authors outlining some of the decisions and treatment options for patients with DR in the perinatal period. As each patient’s diabetic control and ophthalmic status is different, not all the interventions used in our case will be appropriate to an individual pregnant patient, and not all treatment options available are discussed in this case, however it does provide real life examples outlining the principals of treating pregnant patients who develop or experience progression of DR during pregnancy.
Presentation
Leah Myles,* a 34-year-old female, presented with gradual blurring of vison in both eyes over a three-month period. Her past medical history was significant for a 24-year history of type 1 diabetes, which was sub-optimally controlled (HbA1c 8.8%). Ms Myles was a moderate myope at -2.00 in each eye. She worked as an interior architect and wore a full myopic script in her glasses. She had no history of hypertension or other systemic health concerns.
At presentation, Ms Myle’s visual acuity was RE 6/18, LE 6/12; intraocular pressure (IOP) was RE 20, LE 20. Both eyes displayed bilateral diabetic maular oedema (DMO) and proliferative diabetic retinopathy (PDR) with Optos widefield fundus imaging and fundus fluorescein angiogram (FFA) (Figure 2).
Ms Myle’s PDR was treated with three sessions of argon pan retinal photocoagulation (PRP) laser to each eye, and intravitreal Lucentis, initially monthly to treat the existing DMO and reduce the likelihood of worsening DMO that can occur secondary to PRP laser. In addition, she commenced using a digital glucose insulin monitor and insulin pump and achieved a significantly improved blood sugar level control.
At the eight-month mark, Ms Myles’ vision returned to 6/6 in each eye, with the DMO controlled on a Lucentis eight-weekly interval (Figure 3).
The Question
Two years post her initial presentation, Ms Myles’ vision remained stable at 6/6 in each eye, with bilateral Lucentis eight-weekly required to control her DMO. It was then that she asked an unexpected question: “My husband and I want to try to have a baby, but I don’t want to go blind, and I don’t want to risk my baby having an abnormality because of my eye treatment. What should we do?”
Obstetric advice is not something most ophthalmologists expect to encounter in their careers.
Considerations
Anti-VEGF agents are classified as category D and therefore are contraindicated in pregnancy. For Ms Myles to make an informed decision, we needed to establish a plan that would address any worsening of her diabetic eye disease without the use of anti- VEGF agents during pregnancy.
The plan involved three steps:
- Optimising management of Ms Myles’ type 1 diabetes and blood pressure in the antenatal period and during pregnancy.
We established a multidisciplinary team and open communication between Ms Myles’ obstetrician, endocrinologist, general practitioner, and ophthalmologists. All efforts were made to optimise her sugar control and monitor for pre-eclampsia. To allow for an adequate anti-VEGF washout, a three-month anti-VEGF free period was undertaken prior to trying to conceive.
- Management of DMO recurrence.
Ms Myles was aware that the decision to stop the current treatment of Lucentis eight-weekly in the lead-up and during pregnancy risked recurrence of her DR and DMO. From the DRCR Net Protocol V study, we know that in patients with centre involving DMO and good vision (6/7.5 or better), observation without treatment is a reasonable strategy. If Ms Myles’ centre involving DMO recurred with a decrease in vision of 6/9 or worse, the plan was to treat with intravitreal Ozurdex (Dexamethasone 700 μg, Allergan). Ozurdex is efficacious in the treatment of DMO and has a longer treatment effect compared with anti-VEGF medications. However, anti-VEGF agents are generally preferred over intravitreal steroids because of the potential side effects of steroid, which include the risk of increased intraocular pressure via a ‘steroid response’ and formation of cataracts.
For use in pregnancy, Ozurdex is classified as category B3, however systemic dexamethasone is classified as category A. The difference in categorisation between systemic and intravitreal dexamethasone use in pregnancy is due to the fact that Maxidex (dexamethasone) drops are classified as B3.
In collaboration with Ms Myles’ endocrinologist and obstetrician, we decided that given systemic dexamethasone is classified as category A for use in pregnancy, intravitreal Ozurdex could be administered safely should treatment be required for her DMO while pregnant. We made sure that Ms Myles understood the potential ocular side effects of increased IOP and cataract with Ozurdex. Her IOP was 18 in each eye and her optic nerves were healthy with a cup to disc ratio of 0.3 in both eyes.
- Management of reactivation of DR.
Both stopping Lucentis treatment and pregnancy were risk factors for progression of Ms Myles’ DR. At initial presentation two years prior, she had undergone bilateral PRP making this less likely. If DR did worsen, then further PRP treatment could be used safely in pregnancy.
With the above plan and a tailored monitoring schedule by Ms Myles’ health care professionals, a decision was made to withhold intravitreal treatment with Lucentis and for Ms Myles to try to conceive after a three-month washout period.
Progress
At eight weeks’ gestation: Ms Myles fell pregnant relatively soon after the washout period, and at eight weeks gestation presented for review. Her last intravitreal injection was six months prior. Her glycaemic levels and blood pressure were well controlled. Visual acuity was RE 6/7.5 LE 6/6. Both eyes displayed mild DMO, and there was no progression of her previously treated mild NPDR. Using the findings of DRCR.net protocol V, we decided to observe with close follow-up.
At 12 weeks’ gestation: Four weeks later, a review displayed an exacerbation of DMO on OCT in both eyes and a corresponding reduction of visual acuity: RE 6/15, LE 6/9. Ms Myles reported that she was having trouble seeing architectural drawings used for her work. As per the plan, bilateral intravitreal injections of Ozurdex were administered (Figure 4).
At 16 weeks’ gestation: At her four-week review post-bilateral intravitreal Ozurdex, the DMO on OCT had resolved in the right eye and reduced in the left eye (Figure 5). Her visual acuity had returned to 6/6 in both eyes.
However, Ms Myles’ IOP measured with Goldmann applanation tonometry (GAT) was RE 34, LE 32. All the current classes of glaucoma medications are classified either category B3 or category C (Table 2).
Taking this into account, and the fact that Ms Myles’ cup to disc ratio was 0.3 in each eye with normal visual fields, we decided to treat her with bilateral selective laser trabeculoplasty (SLT).
At 20 weeks’ gestation: At Ms Myes’ next review, four weeks post-bilateral SLT, her IOP had reduced to R 20, L 22. Visual acuity remained at 6/6 in each eye and there was no recurrence of DMO on OCT.
At 38 weeks’ gestation: Ms Myles delivered a healthy baby girl at term. Her visual acuity had decreased to RE 6/15, LE 6/9. There had been a recurrence of DMO. A decision was made to restart Lucentis in both eyes and for the new baby to be formula fed to mitigate the risk of anti-VEGF crossing over into the breast milk.
Postpartum: At eight weeks’ postpartum, Ms Myles had received two doses of Lucentis in each eye. Her visual acuity had increased in the left eye to 6/6, however the right eye only improved to 6/12, with her symptomatic of the decrease in right visual acuity. OCT displayed dry maculas, with no DMO. Examination of the eye showed that Ms Myles had developed a right posterior sub capsular cataract (PSCC), likely as a side effect of the Ozurdex. She underwent right cataract extraction and, with an intraocular lens implanted, achieved a stable post-operative vision of 6/6.
Eight months’ postpartum: Ms Myles developed a left eye PSCC with decreased visual acuity to 6/12. The DMO was controlled in each eye with injections of Lucentis at eight-week intervals. She opted to undergo left cataract extraction with a monovision intraocular lens implant with an aim of -2.00 to allow reduced spectacle dependence when reading architectural plans.
Four years’ postpartum: Ms Myles’ best corrected distance visual acuity remains 6/6 in each eye with variable centre involving DMO treated with Vabysmo at variable intervals of eight to 12-weeks in the left eye, and six-monthly in the right eye.
CONCLUSION
The prevalence of pregnant patients with coexisting diabetes is increasing. Along with this, there has been an increase in the numbers of pregnant patients presenting with worsening diabetic eye disease. The real-life case described here addresses some of the challenges associated with managing diabetic eye disease in pregnant patients, including the treatment of DMO and progression of DR. The case outlines the need to consider alternative treatments for diabetic eye disease in pregnant patients given the general contraindication for the use of our standard medications during this time. These interventions come with limitations and side effects that need to be understood by the clinician and patient, and appropriately managed. The overriding principles for managing patients with diabetic eye disease during the perinatal period are to adopt a multidisciplinary approach and for individualised treatment where the potential benefit to the patient’s vision justifies any risk to the foetus.
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Dr Dov Hersh BCom (IT) MBBS (Hons) MMed (Ophth) FRANZCO is a Sydney and Central Coast-based ophthalmologist with sub-specialty expertise in diseases of the retina. After completing specialist ophthalmology qualifications at The Sydney Eye Hospital, Dr Hersh undertook rare dual international post-graduate fellowships at Bristol Eye Hospital and Moorfields Eye Hospital, London. Dr Hersh trained with pioneers in the field of medical retina and was appointed as an investigator in an array of multi-national clinical trials, studying emerging treatments for retinal diseases and bringing this expertise to his patients. He remains a Clinical Associate Lecturer at the University of Sydney. Dr Hersh is passionate about patient-centred care, optimal functional outcomes, and quality of life for his patients.
Dr Brighu Swamy BSc (Med) MBBS (Hons) MMed (Oph Sci, Clin Epi) FRANZCO is a medical retina and macula subspecialist. He is a founding director at Sydney Eye Surgeons. His expertise is in the diagnosis, treatment, and care of patients with retinal conditions. Dr Swamy graduated in medicine from the University of New South Wales with Honours, before completing both a Master of Medicine in Ophthalmic Science and a Master of Medicine with merit in clinical epidemiology at the University of Sydney. He undertook ophthalmology training at the Sydney Eye Hospital and subsequently completed the Medical Retina and Uveitis fellowship at the Moorfields Eye Hospital in London.
He is a clinical lecturer at the University of Sydney and a Visiting Medical Officer at Bankstown Hospital, where he is involved in teaching and supervising registrars.
References
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- Kitzmiller, J.L., Block, J.M., Brown, F.M., et al., Managing preexisting diabetes for pregnancy: summary of evidence and consensus recommendations for care. Diabetes Care 2008; 31: 1060–79.
- Rasmussen, K.L., Damm, P., Mathiesen, E.R., et al., Progression of diabetic retinopathy during pregnancy in women with type 2 diabetes. Diabetologia 2010; 53: 1076–83. English.
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- National Health and Medical Research Council. Guidelines for the Management of Diabetic Retinopathy. Canberra: NHMRC, 2008.
- Therapeutic Goods Administration, Australian categorisation system for prescribing medicines in pregnancy (webpage, last updated 4 May 2011), available at: tga.gov.au/australian-categorisation-system-prescribingmedicines- pregnancy [accessed March 2024].
- Novartis Pharmaceuticals Australia Pty Limited. Product information: Lucentis (Ranibizumab). 2015.
- Baker, C.W., Glassman, A.R., Beaulieu, W.T., et al., for the DRCR Retina Network. Effect of initial management with aflibercept vs laser photocoagulation vs observation on vision loss among patients with diabetic macular edema involving the center of the macula and good visual acuity. A randomized clinical trial. JAMA. 2019;321:1880–1894.