Pregnant women with diabetes are at high risk for the development and progression of retinopathy, as multiple studies, most notably the Diabetes Control and Complications Trial (DCCT) and the Diabetes in Early Pregnancy study (DIEP), have reported.1-5 A Danish study found that 16 percent of type I diabetics had macular edema at their baseline exam in early pregnancy, with another 10 percent developing macular edema as the pregnancy progressed.4
So what are the treatment options for these patients with diabetic macular edema (DME)? For the past 30 years, the recommended treatment of DME in pregnancy has remained essentially unchanged despite great progress in the management of DME. In addition to the standard laser option, newer treatment options include subthreshold laser, such as the MicroPulse (Iridex) or Endpoint Management (Topcon Medical Systems) lasers, intravitreal corticosteroids and even intravitreal inhibitors of vascular endothelial growth factor therapies (VEGF).
Observation and Laser
If a pregnant patient presents initially with mild to moderate DME, then it’s reasonable to recommend close observation with an emphasis on blood glucose control. In a report from Copenhagen University Hospital,5 two diabetic patients early in their pregnancies presented with macular edema between 500 and 1,500 μm from the fovea. With good blood glucose control, both had improvement and required no further intervention.
Although observation is a reasonable option, it is important to monitor these patients more closely than one would a normal adult because pregnancy can accelerate the severity of the retinopathy and edema.
If DME does not improve after a period of observation, the first treatment option should be laser. As reported in the Early Treatment Diabetic Retinopathy Study (ETDRS), grid or focal laser for clinically significant macular edema is effective in preventing future vision loss.6,7 In another study out of Copenhagen,4 two pregnant patients with type 1 diabetes and macular edema received focal laser and required no further treatment for the term of their pregnancies.
When foveal involvement precludes the safe use of conventional laser, subthreshold MicroPulse or Endpoint Management could be considered. Investigators at the University of Genoa, Italy,8 demonstrated significant short-term improvement in DME and vision after treatment with the MicroPulse laser.
However, not all patients with macular edema are good candidates for laser. In a case report by Elisabet Agardh, MD, in Sweden, a pregnant woman with type 1 diabetes developed bilateral macular edema and high-risk nonproliferative diabetic retinopathy (NPDR) at week 19 of gestation.9 As the pregnancy progressed, the persistent macular edema involved the fovea and Dr. Agardh determined it was too extensive for conventional laser. She observed the patient instead.
Ultimately, the patient received macular grid laser therapy in the right eye during the postpartum period and observation in the left eye. Final visual acuities were 20/40 and 20/50 in the right and left eyes, respectively, vs. 20/20 in both eyes at baseline. What other options were available even if this patient had been refractory to conventional laser during her pregnancy?
When Laser Won’t Work
For DME refractory to laser, intravitreal steroids are thought to be a safe option during pregnancy. The Diabetic Retinopathy Clinical Research Network (DRCR.net), which found laser to be superior to intravitreal triamcinolone for treatment of DME at three years, actually found steroids to be more efficacious than laser after four months in terms of visual acuity and retinal thickening.10,11
Although long-term outcomes are generally the primary focus of any treatment, in pregnancy, which spans a finite period of time, short-term outcomes are equally, if not more, important.
A 2011 case report described a 23-year-old woman with type 1 diabetes who had injections of 0.05 ml triamcinolone acetonide.12 She presented with NPDR and bilateral fovea-involving DME with central macular thicknesses of 578 μm and 667 μm in the right and left eyes, respectively, and 20/40 vision in both eyes. After consultation with the obstetrician, the patient had the injections in each eye one week apart.
Six weeks later, the retinal thickness measurements were 159 μm and 202 μm and Snellen visual acuities were 20/20 and 20/25 in the right and left eyes, respectively. The patient had no related complications such as glaucoma or cataract, and she delivered a healthy baby.
It is noteworthy that some studies have associated first trimester systemic corticosteroid use with oral clefts13 and topical corticosteroids with low birth weight.14 However, the systemic absorption of intravitreal triamcinolone has been shown to be minimal.15
On the other hand, intravitreal steroids have been shown to cause increased intraocular pressure and the development of cataracts.16 Although this is the only reported case of intravitreal triamcinolone administered during pregnancy, it is an effective option that should be considered safe in patients with refractory DME.
Role of Anti-VEGF Therapy
In the modern practice of medical retina, no discussion is complete without the mention of anti-VEGF therapy.
|Dr. Rosenfeld is a professor at Bascom Palmer Eye Institute, University of Miami Miller School of Medicine. He has been the principal investigator and study chair for several clinical trials. Dr. Peracha is a medical retina fellow at Bascom Palmer.|
In a patient with foveal involving DME with a contraindication to steroids, anti-VEGF could be considered. As the DRCR.net study demonstrated comparing anti-VEGF plus laser vs. laser alone, anti-VEGF therapies are very effective in the treatment of DME.17
Although there are no reports of anti-VEGF use in pregnancy for DME, there have been reports of its use in pregnancy for other indications. To date, there have been 21 reported intravitreal injections of anti-VEGF drugs into the eyes of pregnant women.18 Overall, 20 unique patients have been treated, with one patient having received treatment during two separate pregnancies.
Within this group, three pregnancies resulted in fetal demise during the first month of gestation and one had a complicated birth at 29 weeks in the setting of preeclampsia.18 Although the three cases of fetal demise are concerning, it’s important to keep in mind that the rate of spontaneous miscarriage is between 15 and 20 percent. As a result, it’s difficult to know if anti-VEGF therapy played a role.19
Regarding the complicated birth in the setting of preeclampsia, the mother had a significant medical history that included diabetes, hypertension and a prior emergent Cesarean section for fetal distress. Although anti-VEGF therapy has not been proven to be unsafe in pregnancy, much more investigation is needed before this can become a routine treatment option.
First-line treatments for DME in pregnancy are and should remain blood glucose control and laser. In severe instances of DME that are refractory to those approaches, intravitreal steroids can be considered. Treatment should be offered only in the second or third trimesters and the risks of intraocular pressure elevation and cataract development, and the remote risk of fetal harm, should be fully discussed with the patient.
Finally, only consider anti-VEGF therapy as a last resort due to the lack of long-term safety data in pregnancy and preferably within the third trimester of pregnancy. Caring for a pregnant mother and her fetus presents a great responsibility and, as a result, we as physicians appropriately act with great caution. However, it is our duty to inform patients of all available treatment options and allow them to fully participate in the decision-making process. RS
2. Chew EY, Mills JL, Metzger BE. Metabolic control and progression of retinopathy. The Diabetes in Early Pregnancy Study. National Institute of Child Health and Human Development Diabetes in Early Pregnancy Study. Diabetes Care. 1995;18;631-637.
3. Klein B E, Moss S E, Klein R. Effect of pregnancy on progression of diabetic retinopathy. Diabetes Care. 1990;13:34-40.
4. Vestgaard M, Ringholm L, Laugesen CS, Rasmussen KL, Damm P, Mathiesen ER. Pregnancy-induced sight-threatening diabetic retinopathy in women with Type 1 diabetes. Diabet Med. 2010;27:431-435.
5. Rasmussen KL, Laugesen CS, Ringholm L, Vestagaard M, Damm P, Mathiesen ER. Progression of diabetic retinopathy during pregnancy in women with type 2 diabetes. Diabetologia. 2010;53:1076-1083.
6. Photocoagulation for diabetic macular edema. Early Treatment Diabetic Retinopathy Study report number 1. Early Treatment Diabetic Retinopathy Study research group. Archives of ophthalmology 103, 1796-1806 (1985).
7. Dedania V S, Bakri S J. Novel pharmacotherapies in diabetic retinopathy. Mid E African J Ophthalmol. 2015;22:164-173.
8.Nicolo M, Musetti D, Traverso CE. Yellow micropulse laser in diabetic macular edema: a short-term pilot study. Euro J Ophthalmol. 2014; 24:885-889, doi:10.5301/ejo.5000495 (2014).
9. Agardh E. A case of progression of diabetic retinopathy during pregnancy. Acta ophthalmologica Scandinavica 80, 524-530 (2002).
10. Diabetic Retinopathy Clinical Research Network. A randomized trial comparing intravitreal triamcinolone acetonide and focal/grid photocoagulation for diabetic macular edema. Ophthalmology. 2008;115:1447-1449.
11. Diabetic Retinopathy Clinical Research Network. Three-year follow-up of a randomized trial comparing focal/grid photocoagulation and intravitreal triamcinolone for diabetic macular edema. Arch Ophthalmol. 2009;127:245-251.
12. Fazelat A, Lashkari K. Off-label use of intravitreal triamcinolone acetonide for diabetic macular edema in a pregnant patient. Clin Ophthalmol. 2011;5:439-441.
13. Oren D, Nulman I, Makhija M, Ito S, Koren G. Using corticosteroids during pregnancy. Are topical, inhaled, or systemic agents associated with risk? Can Fam Phys. 2004;50:1083-1085.
14. Chi CC, Wang SH, Kirtschig G, Wojnarowska F. Systematic review of the safety of topical corticosteroids in pregnancy. J Am Acad Dermatol. 2010;62:694-705.
15. Degenring R F, Jonas JB. Serum levels of triamcinolone acetonide after intravitreal injection. Am J Ophthalmol. 2004;137:1142-1143.
16. Scott IU, Ip MS, VanVeldhuisen PC, et al. A randomized trial comparing the efficacy and safety of intravitreal triamcinolone with standard care to treat vision loss associated with macular edema secondary to branch retinal vein occlusion: the Standard Care vs Corticosteroid for Retinal Vein Occlusion (SCORE) study report 6. Arch Ophthalmol. 2009;127:1115-1128.
17. Diabetic Retinopathy Clinical Research Network. Randomized trial evaluating ranibizumab plus prompt or deferred laser or triamcinolone plus prompt laser for diabetic macular edema. Ophthalmology. 2010;117:1064-1077.
18. Polizzi S, Mahajan VB. Intravitreal anti-VEGF injections in pregnancy: Case series and review of literature. J Ocul Pharmacol Ther. 2015 Aug 24. Epub ahead of print.
19. Robinson GE. Pregnancy loss. Best Prac Res Clin Obstet Gynaecol. 2014;28: 169-178.