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QUESTION

HOW DO I FOLLOW A PATIENT WHO HAS DIABETES AND BECOMES PREGNANT? WHAT TESTS CAN I DO?

Judy E. Kim, MD
Alessa Crossan, MD

Pregnancy complicates the ophthalmic management of patients with preexisting diabetes. Patients who develop gestational diabetes do not develop diabetic retinopathy during pregnancy. Historically, studies have focused on patients with Type 1 diabetes; we presume results can be extrapolated to patients with Type 2 diabetes.

Diabetic retinopathy worsens during pregnancy, although the reasons for this are still debated. Up to 27% of diabetic pregnancies will have diabetic retinopathy at some point.¹ Both clinically significant diabetic macular edema (DME) and proliferative diabetic retinopathy (PDR) may worsen or develop de novo during pregnancy.^2,3 Though proliferative disease attracts the most attention, case series have reported severe vision loss from DME.³ Rates of progression toward PDR have varied widely in the literature. In case series, anywhere from 8% to 70% of patients have shown progression during pregnancy.¹ There is a common and dangerous misconception that retinopathy progression to proliferative disease during pregnancy reverses after delivery. One study found that only 54% of patients improve postpartum,² and another detailed a series of patients who demonstrated severe progression following delivery.⁴ The risk of progression has been correlated with the duration of diabetes prior to pregnancy, rapid glucose normalization during pregnancy, severity of diabetes at baseline, baseline glycemic control, hypertension, and eclampsia.² Therefore, patients with these risk factors should be closely monitored and educated before, during, and even after pregnancy.

Preconception counseling regarding glycemic control and the potential for progression of diabetic retinopathy is key.5 Preconception baseline examination is highly recommended to establish the patient’s baseline diabetic retinopathy. The actual clinical examination should be equivalent for pregnant and non-pregnant diabetic patients. This should include examination of visual acuity, intraocular pressure, and a thorough anterior segment examination with gonioscopy if necessary to evaluate for neovascularization of the iris and angle. A dilated fundus examination is necessary, since undilated examination may fail to diagnose up to 50% of cases of diabetic retinopathy.⁶ Dilating agents, such as cyclopentolate, tropicamide, and phenylephrine, are category C for use in pregnancy, although used frequently with no reported evidence of adverse events for the pregnant patient or the fetus. Nonetheless, it may be prudent to use lower concentrations or to consider punctal occlusion to reduce systemic exposure to these drugs.

Regarding ancillary tests, fundus photography and optical coherence tomography (OCT) clearly pose no adverse risk to the pregnancy. Fundus photography may have varying levels of sensitivity and specificity for detection of retinopathy depending on imaging modality, patient cooperation, and the photographer. There has been an increased use of ultra-widefield fundus photographs in recent years, and it is a good way to noninvasively, quickly, and easily detect, document, and monitor posterior pole disease as well as peripheral lesions. Widefield red free or autofluorescence images may highlight areas of retinal neovascularization. OCT images are the best way to detect even the most subtle intraretinal or subretinal fluid due to DME and help determine areas and the magnitude of retinal thickening. Treatment of DME is often guided by OCT images both in pregnant and non-pregnant diabetic patients, given its noninvasiveness, rapid image capture, quantitative and qualitative information, and registration of images that allow comparison between visits and treatment effects.

While fluorescein angiography (FA) is helpful to evaluate areas of vascular abnormalities, such as microaneurysms, leakage, nonperfusion, and neovascularization, it is usually not performed on pregnant patients due to unknown effects on the fetus. Even in non-pregnant patients, FA is not benign because there is a 1/200,000 chance of a serious adverse event or death.⁶ Fluorescein dye has no known risks or teratogenic effects in pregnancy, but neither has it been conclusively determined to be safe. Fortunately, FA is not absolutely necessary to diagnose or treat diabetic retinopathy. It is possible that newer noninvasive imaging modalities, such as OCT angiography, may play a role in assessment and treatment of diabetic patients in the future.

How Often Do I Follow These Patients?

It would be best for any diabetic patients who are contemplating pregnancy to have a baseline ocular examination prior to conception to determine presence of any treatable diabetic retinopathy. This will allow safe use of various agents and treatment modalities without the added concern for the fetus. After the baseline examination prior to conception that incorporates any necessary care, an eye examination during the first trimester is usually recommended.⁵ Subsequent follow-up visits depend on the assessed risk of progression based on the severity of retinopathy. Several different follow-up schedules have been suggested in the literature. Second and third trimester examinations are recommended by health organizations in most countries; frequency of exam is dictated by severity and presence of retinopathy.

The most recent publication of the “Preferred Practice Patterns” by the American Academy of Ophthalmology for diabetic retinopathy suggests that pregnant patients found on initial exam to have no retinopathy to mild or moderate nonproliferative diabetic retinopathy (NPDR) have examinations every 3 to 12 months; patients with severe NPDR or worse may need examination every 1 to 3 months.6 Other sources suggest at least every 3 months⁷ or every 4 to 6 weeks.⁸ Interestingly, some case series in the literature have followed patients every 2 weeks.^1,4 Follow-up should continue in the postpartum period as well.¹

Both proliferative disease and any retinopathy with DME require attention during pregnancy. Case series by Rahman and colleagues¹ and Chan and colleagues⁴ suggest a cautious follow-up schedule. Patients with more severe disease at baseline were more likely to progress and progressed earlier in their pregnancy. Those with no retinopathy had a 9% rate of progression, while those with early, untreated proliferative disease had a 75% rate of progression. Prior treatment did not completely safeguard against progression; 1 of 4 patients with prior panretinal photocoagulation required further treatment. Rahman and colleagues¹ do concede that their study population probably had a lower rate of treatment compliance and pregestational diabetic care than other groups in the literature. Chan and colleagues⁴ specifically looked at patients with progression of retinopathy. The key conclusion one can draw from their paper is to treat pregnant patients with proliferative disease and even those with severe NPDR with laser photocoagulation, as it will likely progress during pregnancy and may not regress after delivery, leading to extremely poor visual outcomes.⁴ The concept that those with minimal baseline diabetic retinopathy are unlikely to progress to visually threatening changes and those with moderate to more severe retinopathy are at higher risk of sight threatening progression has been borne out by other cohort studies as well.^9,10 The natural history of DME in pregnancy has not been well studied. The possibility for spontaneous remission after delivery implies less urgency relative to proliferative disease.¹¹

How Do I Treat These Patients?

As in all diabetic patients, optimal systemic management of blood pressure, blood sugar, and lipids is essential. Laser photocoagulation is the mainstay of treatment for diabetic retinopathy in pregnant patients due to no known adverse effects on the fetus, with the same protocols and indications as for non-pregnant diabetic patients.⁵ While some have used intravitreal injections of steroids for management of severe DME during pregnancy, given theoretical safety, there is very little information in the literature regarding its use during pregnancy. Steroids available for use in the eye for treatment of DME include off-label use of Kenalog (triamcinolone acetate), off-label use of preservative-free Triesence (triamcinolone acetonide), on-label use of Ozurdex implant (dexamethasone), and on-label use of Iluvien implant (fluocinolone). However, these drugs are all category C for use during pregnancy. A recent case series reports use of a dexamethasone implant for management of DME in 5 pregnant patients with improvement in vision and no known complications to the baby.¹² However, the follow-up was limited to the immediate postpartum period.⁹ Further reports on the use of these drugs in pregnancy will likely guide subsequent treatment recommendations.

Anti-vascular endothelial growth factor (anti-VEGF) agents such as Avastin (bevacizumab), Lucentis (ranibizumab), and Eylea (aflibercept) are currently the first-line treatment for eyes with DME. They can be also used for the treatment of proliferative disease in diabetic patients. Because all these medications are Category C for use during pregnancy, current literature on the use of anti-VEGF agents in pregnancy is quite limited. Reports exist of miscarriage and preeclampsia after use of bevacizumab; however, the paucity of cases limits our understanding of anti-VEGF’s adverse effects.¹³ Currently, pregnancy is a contraindication for anti-VEGF agents in our practice due to safety concerns. It may be prudent to consider pregnancy testing in women of child bearing age who are starting anti-VEGF treatment. Review of published cases of anti-VEGF therapy and pregnancy indicates 50% of women discovered that they were pregnant only after anti-VEGF treatment was initiated.¹¹

1.     Rahman W, Rahman FZ, Yassin S, Al-Suleiman SA, Rahman J. Progression of retinopathy during pregnancy in type 1 diabetes mellitus. Clin Experiment Ophthalmol. 2007;35(3):231-236.

2.     Soubrane G, Coscas G. Influence of pregnancy on the evolution of diabetic retinopathy. Int Ophthalmol Clin. 1998;38(2):187-194.

3.     Sinclair SH, Nesler C, Foxman B, Nichols CW, Gabbe S. Macular edema and pregnancy in insulin-dependent diabetes. Am J Ophthalmol. 1984;97(2):154-167.

4.     Chan WC, Lim LT, Quinn MJ, Knox FA, McCance D, Best RM. Management and outcome of sight-threatening diabetic retinopathy in pregnancy. Eye. 2004;18(8):826-832.

5.     Morrison JL, Hodgson LA, Lim LL, Al-Qureshi S. Diabetic retinopathy in pregnancy: a review. Clin Exp Ophthalmol. 2016; 44:321-334.

6.     American Academy of Ophthalmology Retina Panel. Preferred Practice Pattern: Diabetic Retinopathy. San Francisco, CA: American Academy of Ophthalmology; 2016.

7.     American Academy of Ophthalmology. Basic and Clinical Science Course: Retina and Vitreous. Section 12. 2004-2005. San Francisco, CA: American Academy of Ophthalmology; 2004.

8.     Chatterjee S, Tsaloumas MD, Gee H, Lipkin G, Dunne FP. From minimal background diabetic retinopathy to profuse sight-threatening vitreoretinal haemorrhage: management issues in a case of pregestational diabetes and pregnancy. Diabet Med. 2003;20(8):683-685.

9.     Egan AM, McVicker L, Heerey A, Carmody L, Harney F, Dunne F. Diabetic retinopathy in pregnancy: a population-based study of women with pregestational diabetes. J Diabetes Res. 2015;2015:310239. doi: 10.1155/2015/310239.

10.   Toda J, Kato S, Sanaka M, Kitano S. The effect of pregnancy on the progression of diabetic retinopathy. Jpn J Ophthalmol. 2016;60 (6): 454-458.

11.   Pescosolido N, Campagna O, Barbato A. Diabetic retinopathy in pregnancy. A. Int Ophthalmol. 2014;34:989-997. doi:10.1007/s10792-014-9906-z

12.   Concillado M, Lund-Andersen H, Mathiesen E, Larsen M. Dexamethasone Intravitreal Implant for diabetic macular edema during pregnancy. Am J Ophthalmol. 2016;165:7-15.

13.   Polizzi S, Mahajan VB. Intravitreal Anti VEGF Injections in Pregnancy. Case Series and Review of Literature. J Ocul Pharmacol Ther. 2015;31(10):605-610.

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