Early loss of pregnancy after intravitreal bevacizumab injection

Abstract

e report two cases of womenwho suffered an early loss ofpregnancy (at 7 and 10 days, respec-tively) following intravitreal bev-acizumab injection.Case 1: A 29-year-old Whitewoman presented to our departmentwith a sudden deterioration of visionin the left eye (LE). She was a knowntype 1 diabetes subject under regularinsulin injections with well-controlleddiabetes (glycosylated haemoglobin[HbA1c] = 6%, normal lipid profile)and no diabetes-related complications.Her past medical and gynaecologicalhistory was otherwise unremarkable.She was the mother of a 9-month-oldboy (non-breast feeding). She hadundergone a full panretinal photoco-agulation (PRP) in the right eye (RE)and some sessions of PRP in the LEfor bilateral proliferative diabetic reti-nopathy.On examination, best correctedvisual acuity (BCVA) was 6⁄12 REand 6⁄36 LE. Anterior segment exam-ination was unremarkable and dil-ated fundoscopy revealed an inferiorvitreous haemorrhage in the LE.Bevacizumab was administered intra-vitreally (1.25 mg) with a view tocontinuing the PRP therapy in theinferior retina 2–4 weeks following theinjection. Five days later, gynaecologi-cal examination including bHCG(b-human chorionic gonadotrophin)(2750) and ultrasound confirmed a5-week pregnancy of which the patientwas unaware. Seven days after thebevacizumab injection, she suffered anearly loss of pregnancy.Case 2: A 25-year-old healthymyope () 10 D LE, ) 7 D RE) pre-sented with blurred vision in the LEand BCVA of 20⁄25 in the RE and20⁄50 LE. Fundus examination dem-onstrated an elevated subfoveal lesionin the LE and myopic chorioretinaland peripapillary atrophies bilaterally.Fundus fluorescein angiography andindocyanine green angiography con-firmed choroidal neovascularization inthe LE. Bevacizumab was adminis-tered intravitreally (1.25 mg). Oneweek later the subject underwent agynaecological examination. ElevatedbHCG levels and ultrasound wereconsistent with a 4-week pregnancy ofwhich the patient was unaware. Tendays after the intravitreal injection,she suffered a miscarriage.Over recent years, the use of bev-acizumab has expanded to include thetreatment of diabetic retinopathy(Avery et al. 2006). Systemic bev-acizumab is teratogenic in rabbits atdoses twice the recommended i.v.human dose (US Food and DrugAdministration 2005) and althoughsystemic absorption (when adminis-tered intravitreally) is believed to beminimal, recent research has demon-strated that intravitreal 1.25 mg bev-acizumab may reach the systemiccirculation in plasma concentrationsof 100 ng⁄ml (Csaky 2007).Recently, Rosen et al. (2009)reported the absence of fetal side-effects after exposure to intravitrealbevacizumab during the second tri-mester. Although the latter representsan important observation, the effectof bevacizumab exposure during thefirst trimester is unknown. Moreover,a case of metrorrhagia 2 weeks afterintravitreal Avastin injection has beenreported (Rodrigues et al. 2007).Once it is in the circulation, bev-acizumab, although it is incapable ofcrossing the placenta barrier, may acton placenta circulation by inhibitingVEGF-A. This would explain its tera-togenic effect. The short periodbetween the intravitreal injection andthe spontaneous abortion, as well asthe lack of risk factors for miscarriagein both our patients (age 35 years, prior miscarriage,prior elective termination of preg-nancy, prior ectopic pregnancy, priorpelvic surgery, infection etc.) comprisethe main reasons for suspicion of anaetiological correlation between bev-acizumab injection and early loss ofpregnancy.Although such a correlation cannotbe established unless further studiesare performed, we believe that pre-treatment counselling should include adiscussion with all premenopausalwomen outlining the possible risk ofmiscarriage.