Antineoplastic
PREGNANCY RECOMMENDATION: Limited Human Data—Animal Data Suggest Moderate Risk
BREASTFEEDING RECOMMENDATION: No Human Data—Potential Toxicity
PREGNANCY SUMMARY
Six reports describing the use of bevacizumab in human pregnancy have been located. All of these reports involved intravitreal injections. Three of the exposures involved unknown pregnancies. The outcomes of the pregnancies were two spontaneous abortions and seven healthy, term infants. The animal reproduction data, although involving only one species, suggest risk. Angiogenesis is critical to fetal development (1), so the drug is best avoided in pregnancy (2). Because of the very long elimination half-life, it could take as long as 100 days (range 55–250 days) to eliminate 97% of the drug from the plasma. If a pregnant woman requires treatment with bevacizumab, she should be advised of the potential risks to the embryo–fetus that include growth restriction, structural anomalies, and death.
FETAL RISK SUMMARY
Bevacizumab is a recombinant humanized monoclonal IgG1 antibody. It is indicated, in combination with IV 5-fluorouracil-based chemotherapy, as first- or second-line treatment of patients with metastatic carcinoma of the colon or rectum. Bevacizumab binds and inhibits the histologic activity of human vascular endothelial growth factor (VEGF). This effect prevents the formation of new blood vessels (angiogenesis). The drug is given as an IV infusion every 2 weeks. The estimated elimination half-life is about 20 days (range 11–50 days) (1). No information is available on metabolism.
Reproduction studies have been conducted in rabbits. Doses that approximated the human dose based on body weight were associated with developmental toxicity, including reduced maternal and fetal body weights, an increased number of fetal resorptions, and an increased incidence of specific gross and fetal skeletal alterations. Adverse fetal outcomes were observed at all doses tested (1).
Carcinogenic and mutagenic studies have not been conducted with bevacizumab. Bevacizumab may impair fertility. Female cynomolgus monkeys were given doses that were equal to or 5 times the human 10 mg/kg dose for 13 or 26 weeks. Following recovery, dose-related decreases in ovarian and uterine weights, endometrial proliferation, number of menstrual cycles, and arrested follicular development or absent corpora lutea were observed (1).
It is not known if bevacizumab crosses the human placenta. Although antibodies are large molecules, the molecular weight of bevacizumab is about 149,000, some immune globulins are transported across the placenta to the embryo–fetus (e.g., see Immune Globulin Intravenous).
A brief 2009 report described the use of bevacizumab and verteporfin in a pregnant woman treated for choroidal neovascularization (CNV) secondary to punctate inner choroidopathy (3). She received photodynamic therapy with IV verteporfin about 1–2 weeks postconception. At 3-months postconception, she underwent intravitreal injection of 1.25 mg bevacizumab. The patient delivered a healthy infant at term with no evidence of congenital anomalies at birth or at 3-months of age (3).
A 2009 report described the use of intravitreal 1.25 mg bevacizumab in two early pregnancies, one at about 4 weeks in a 29-year-old and the other at about 3 weeks in a 25-year-old (4). Both pregnancies were spontaneously aborted 7 and 10 days, respectively, after the intravitreal injection. The authors cited a website stating that a 1.25-mg bevacizumab intravitreal injection achieves high systemic concentrations (100’s ng/mL) and that blood levels have been detected for up to a month after injection (5). The authors speculated that the abortions resulted from the VEGF action of the drug (4).
In a 2010 case report, a woman with CNV received bevacizumab 1.25-mg intravitreal injection in both eyes, performed 1 week apart, and 6 weeks later, received a second 1.25-mg dose in the left eye (total dose 3.75 mg) (6). Three weeks later, she was diagnosed with a 5-week pregnancy. After an uneventful pregnancy, she gave birth at term to a healthy 3.17-kg female infant. No developmental abnormalities were observed in the infant who was doing well at 12 months of age (6).
Four pregnant women were treated with bevacizumab for CNV in a 2010 report (7). The women received a mean 2.6 injections (range 1–6) during pregnancy. All delivered healthy full-term infants who remained healthy with normal growth and development during infancy (7).
A 2012 report described the pregnancy outcome of a 35-year-old woman with CNV who was treated with bevacizumab (dose not specified) in her 7th gestational week (8). She delivered vaginally a healthy 3.75-kg male infant at term with Apgar scores of 10 and 10. The infant had no congenital anomalies and had normal visual behavior. His growth and development were normal in his first 12 months (8).
BREASTFEEDING SUMMARY
No reports describing the use of bevacizumab during human lactation have been located. Although antibodies are large molecules (the molecular weight of bevacizumab is about 149,000), some immune globulins are excreted into breast milk. Of importance, human IgG is excreted into milk (1). Therefore, the excretion into milk of the closely related bevacizumab should be expected. The effects of this exposure on a nursing infant are unknown, but the toxicity could be severe. Thus, the best course is to not breastfeed if the woman is receiving bevacizumab therapy.
References
1.Product information. Avastin. Genentech, 2007.
2.Kumar N, Sebastian R, Harding S, Pearce I. Bevacizumab: a word of caution. Can J Ophthalmol 2007;42:760–1.
3.Rosen E, Rubowitz A, Ferencz JR. Exposure to verteporfin and bevacizumab therapy for choroidal neovascularization secondary to punctate inner choroidopathy during pregnancy. Eye (Lond) 2009;23:1479.
4.Petrou P, Georgalas I, Giavaras G, Anastasiou E, Ntana Z, Petrou C. Early loss of pregnancy after intravitreal bevacizumab injection. Acta Ophthalmol 2010;88:e136.
5.Cousins SW. Safety surveillance in the anti-VEGF era: myths and misconceptions. Available at http://www.osnsupersite.com/view.aspx?rid=19510. Accessed May 9, 2010.
6.Wu Z, Huang J, Sadda S. Inadvertent use of bevacizumab to treat choroidal neovascularization during pregnancy: a case report. Ann Acad Med Singapore 2010;39:143–5.
7.Tarantola RM, Folk JC, Boldt HC, Mahajan VB. Intravitreal bevacizumab during pregnancy. Retina 2010;30:1405–11.
8.Introini U, Casalino G, Cardani A, Scotti F, Finardi A, Candiani M, Bandello F. Intravitreal bevacizumab for a subfoveal myopic choroidal neovascularization in the first trimester of pregnancy. J Ocul Pharmacol Ther 2012;28:553–5.