Antineoplastic/Vitamin
PREGNANCY RECOMMENDATION: Contraindicated—1st Trimester
BREASTFEEDING RECOMMENDATION: No Human Data—Probably Compatible
PREGNANCY SUMMARY
Tretinoin (all-trans retinoic acid; retinoic acid; vitamin A acid) is a retinoid and vitamin A (retinol) metabolite that is available both as a topical formulation (see Tretinoin [Topical]) and as an oral antineoplastic for the treatment of acute promyelocytic leukemia. As with other retinoids, all-trans retinoic acid is a potent teratogen when taken systemically during early pregnancy (see Etretinate, Isotretinoin, and Vitamin A), producing a pattern of birth defects termed retinoic acid embryopathy (CNS, craniofacial, cardiovascular, and thymic anomalies). The teratogenic effect of all-trans retinoic acid is dose-dependent because an endogenous supply of the vitamin is required for normal morphogenesis and differentiation of the embryo, including a role in physiologic developmental gene expression (1). A low serum concentrations or frank deficiency of vitamin A and all-trans retinoic acid is also teratogenic (see Tretinoin [Topical]).
FETAL RISK SUMMARY
The teratogenicity of all-trans retinoic acid in animals is summarized under the topical formulation as is the reported human pregnancy experience following topical use.
A number of reports have described the use of systemic tretinoin (45 mg/m2/day in 10 cases, 70 mg/day in 1) for the treatment of acute promyelocytic leukemia during pregnancy (2–12). In one case treatment was started during the sixth week of gestation (about 36 days from the last menstruation) (2); in six cases (one set of twins), treatment was started during the 2nd trimester (3–8); and in four cases, treatment was started during the 3rd trimester (9–12). No congenital abnormalities were observed in the 12 newborns, although 10 were premature. The growth and development in nine of the infants (postnatal examinations not reported in two cases) were normal in the follow-up periods ranging up to 4 years.
BREASTFEEDING SUMMARY
Vitamin A and, presumably, tretinoin (all-trans retinoic acid) are natural constituents of human milk. There are no data available on the amount of all-trans retinoic acid excreted into breast milk following the doses used for the treatment of promyelocytic leukemia or the risk, if any, this may present to a nursing infant.
References
1.Morriss-Kay G. Retinoic acid and development. Pathobiology 1992;60:264–70.
2.Simone MD, Stasi R, Venditti A, Del Poeta G, Aronica G, Bruno A, Masi M, Tribalto M, Papa G, Amadori S. All-trans retinoic acid (ATRA) administration during pregnancy in relapsed acute promyelocytic leukemia. Leukemia 1995;9:1412–3.
3.Stentoft J, Lanng Nielsen J, Hvidman LE. All-trans retinoic acid in acute promyelocytic leukemia in late pregnancy. Leukemia 1994;8(Suppl 2):S77–80.
4.Harrison P, Chipping P, Fothergill GA. Successful use of all-trans retinoic acid in acute promyelocytic leukaemia presenting during the second trimester of pregnancy. Br J Haematol 1994;86:681–2.
5.Lin C-P, Huang M-J, Liu H-J, Chang IY, Tsai C-H. Successful treatment of acute promyelocytic leukemia in a pregnant Jehovah’s Witness with all-trans retinoic acid, rhG-CSF, and erythropoietin. Am J Hematol 1996;51:251–2.
6.Incerpi MH, Miller DA, Posen R, Byrne JD. All-trans retinoic acid for the treatment of acute promyelocytic leukemia in pregnancy. Obstet Gynecol 1997;89:826–8.
7.Morton J, Taylor K, Wright S, Pitcher L, Wilson E, Tudehope D, Savage J, Williams B, Taylor D, Wiley J, Tsoris D, O’Donnell A. Successful maternal and fetal outcome following the use of ATRA for the induction APML late in the first trimester (abstract). Blood 1995;86(Suppl 1):772a.
8.Giagounidis AAN, Beckman MW, Giagoundis AS, Aivado M, Emde T, Germing U, Riehs T, Heyll A, Aul C. Acute promyelocytic leukemia and pregnancy. Eur J Haematol 2000;64:267–71.
9.Watanabe R, Okamoto S, Moriki T, Kizaki M, Kawai Y, Ikeda Y. Treatment of acute promyelocytic leukemia with all-trans retinoic acid during the third trimester of pregnancy. Am J Hematol 1995;48:210–1.
10.Nakamura K, Dan K, Iwakiri R, Gomi S, Nomura T. Successful treatment of acute promyelocytic leukemia in pregnancy with all-trans retinoic acid. Ann Hematol 1995;71:263–4.
11.Lipovsky MM, Biesma DH, Christiaens GCML, Petersen EJ. Successful treatment of acute promyelocytic leukaemia with all-trans-retinoic-acid during late pregnancy. Br J Haematol 1996;94:699–701.
12.Consoli U, Figuera A, Milone G, Meli CR, Guido G, Indelicato F, Moschetti G, Leotta S, Tornello A, Poidomani M, Murgano P, Pinto V, Giustolisi R. Acute promyelocytic leukemia during pregnancy: report of 3 cases. Int J Hematol 2004;79:31–6.