Diabetic Macular Edema

Diabetic macular edema is a serious complication of Diabetes Milletus, with a prevalence of 6.81% worldwide, affecting 21 million people. The release of Vascular Endothelial Growth Factor, which is thought to be the main factor in the pathogenesis, leads to disruption of blood-retinal barrier, leading to accumulation of sub- and intra- retinal fluid, in the inner and outer plexiform layer. Muller cell, pericyte and glial cell dysfunction also contribute to the development of macular edema.
Macular edema is managed by controlling blood sugar and Laser photocoagulation, Anti-VEGF, and Vitrectomy. Anti-VEGF medications include bevacizumab, known as Avastin, a recombinant humanized monoclonal antibody that blocks angiogenesis by inhibiting vascular
endothelial growth factor A. It has several side effects, including hypertension and proteinuria.
There is a reported case of menorrhagia in a young female after receiving Intra vitreous Avastin, who was investigated and found no gynecological or medical abnormality. So in this study we aim to know if Intra vitreous Avastin is safe for female in reproductive age or not.

Method:
Patients are female who are in reproductive age, diagnosed with diabetic macular edema and received Intra vitreous Avastin for management.
Patients were contacted and interviewed, through a questionnaire that included Age, Ethnicity, Marital status and pregnancies in demographics. Duration of menstrual cycle, flow of mensturation, Painful mensturation and inter-menstural bleeding were recorded pre- and post- Intra vitreous Avastin injection. Time of menarche, Post-coital bleeding and gynecological procedures/surgeries were included as well. Visual acuity, macular volume (OCT) and number of injections were recorded to evaluate the effect of Intra vitreous
injections.

Results:
Bevacizumab (Avastin™) is a monoclonal antibody which is commonly used in certain types of cancers and in ocular diseases.
It was found to be cost-effective in treating diabetic edema. Intravitreal injection of Bevacizumab carries a risk of developing corneal abrasion, chemosis, lense injury, ocular inflammation, retinal pigment epithelial tear and acute vision loss. Intravitreal injection of 1.25 mg Bevacizumab into rabbits' eyes was reported to reach the systemic circulation (Bakri et al. 2007). Systemic adverse effects of Bevacizumab include hypertension, cerebral infarction, facial skin rashes, itchy skin and menstrual irregularity. Reported cases of having polyhypermenorrhea, oligomenorrhea, and menorrhagia after intravitreal injection of Bevacizumab. In our study there were not reported changes in duration, flow, or pain during mensuration after injection of intravitreal Bevacizumab. Patients didn't report any menorrhagia or inter menstrual bleeding. We aim to further evaluate the effect of intravitreal Bevacizumab on mensturation to look for any other
result.
Discussion:
Abnormal mensturation may be idiopathic or caused by a variety of conditions including hormone alterations, and anatomical abnormalities. Even though there is no reported menstural changes in our patients, there is a case of metrorrhagia after receiving intravitreal injection, with absence of hormonal and anatomical dysfunction. That increases the possibility of bevacizumab causing the uterine haemorrhage. Recent research demonstrated that intravitreally injected 1.25 mg bevacizumab may reach systemic circulation in plasma concentrations of 100 ng ⁄ ml; the drug half-life is in the magnitude of several weeks, and drug blood levels are detected for up to 4 weeks (Csaky 2007). When it reaches the circulation, the anti-VEGF agent may reach the human endometrium, Antagonizing the effect of VAGEF-A. VEGEF-A exerts numerous biological actions such as vascular tone control, endometrium growth ⁄shedding and endometrial angiogenesis regulation, as well as interaction with the endometrial coagulation system (Smith 2001). VEGF inhibition may decrease the renewal capacity of endothelial cells, induce endothelial cell dysfunction and enable defects in the interior vascular lining to expose subendothelial collagen with resultant uterine bleeding (Nap et al. 2004). Bevacizumab has also promoted longer and heavier uterine bleeding during menses when used in Cancer patients for chemotherapy. (Hurwitz & Saini 2006; BC Cancer Agency 2006).

The study had few limitations. Number of patients was limited, because most females who received Intravitreal Bevacizumab have passed the reproductive period. The study was retrospective, which may increase the possibility of bias. Plus, there was no control group.
It is recommended that further prospective randomized controlled multicentric trial should be performed.

Conclusion:
Bevacizumab induced menstrual irregularities have been reported, however in our patients we didn't detect any menstrual changes following Intravitreal injection Bevacizumab. We recommend further evaluation regarding this.