HYDROXYUREA

Fetal Risk Summary

Hydroxyurea, an antineoplastic agent, is teratogenic in animals. Shepard reviewed nine studies describing the effects of this agent on the embryos and fetuses of a variety of animal species (1). Anomalies observed included defects of the central nervous system, palate, and skeleton, depressed DNA synthesis, extensive cell death in limb buds and central nervous system, impaired postnatal learning, and decreased body and brain growth (rats), beak defects (chick embryos), and neural tube and cardiac defects (hamsters) (1). A 1999 report, evaluating the combined prenatal toxicity of hydroxyurea and 6-mercaptopurine riboside in mice, determined that the NOAEL (no observed adverse effect level) of a single, intraperitoneal dose of hydroxyurea administered on day 11 of gestation was 250 mg/kg (2). An increase in gross structural abnormalities was observed at the 300- and 350-mg/kg dose levels.

Published human pregnancy experience with hydroxyurea is limited to 19 cases, 5 of which were electively terminated and 1 ended in a stillbirth (3,4,5,6,7,8,9,10,11,12,13,14,15 and 16). Two women, both with acute myelocytic leukemia, were treated with five-drug chemotherapy regimens at 17 and 27 weeks' gestation, respectively (3). In both cases, hydroxyurea (8 mg) was given as an initial, single IV dose. One woman underwent an elective abortion of a grossly normal fetus 4 weeks after the start of chemotherapy. The second patient delivered a premature infant at 31 weeks with no evidence of birth defects, again 4 weeks after the start of therapy. Follow-up at 13.5 months revealed normal growth and development.

A 1991 report described the use of oral hydroxyurea, 0.5–1.0 g/day, throughout gestation in a woman with chronic myelocytic leukemia (CML) (4). A spontaneous vaginal delivery at 36 weeks' gestation resulted in the birth of a normal, healthy 2670-g male infant with normal blood counts. The infant's growth and development have been normal through 26 months of age. A subsequent brief report described a similar patient treated with 1–3 g/day orally before and throughout gestation (5). Hydroxyurea therapy was stopped (to prevent a potential cytopenia in the fetus) 1 week before a planned cesarean section at 38 weeks' gestation. A healthy 3100-g male infant was delivered, without evidence of hematologic abnormalities, whose growth and development remain normal at 32 months of age. A 1992 report listed a pregnant woman with CML who was treated in the 1st trimester with hydroxyurea and three other agents (6). She elected to terminate her pregnancy.

Four other studies have reported on the use of hydroxyurea for CML during pregnancy (7,8,9 and 10). A 1992 publication described two women who were treated before and throughout gestation with oral doses of 1.5 g/day (7). Eclampsia developed at 26 weeks' gestation in one woman resulting in the delivery of a stillborn male fetus without gross abnormalities who had a normal phenotype. The second patient had a vaginal delivery at 40 weeks of a healthy 3.2-kg male infant with normal phenotype. No follow-up evaluation of the infant was mentioned. The clinical course of a pregnant woman with CML was discussed in a 1993 report (8). She required 1.5–3 g/day during pregnancy for her disease. At 37 weeks' gestation, she delivered a healthy baby girl who had normal blood counts and no evidence of congenital defects. A second 1993 report described a woman with CML treated unsuccessfully with interferon alfa before pregnancy and then with hydroxyurea (9). At the patient's request, all therapy was stopped before conception. Hydroxyurea therapy (dose not specified) was reinstituted during the 2nd trimester and continued until 1 month before the delivery of a normal, term, 3.4-kg, male infant. The infant was developing normally at approximately 11 months of age. In another case, a woman received hydroxyurea, 1.5–2.5 g/day, throughout gestation and delivered a term, 3.44-kg female infant who was normal at age 6 weeks (10).

A 1994 report described a woman with primary thrombocythemia who had lost two previous pregnancies from stillbirths (11). She was treated with hydroxyurea (1–2 g/day) prior to and during the first 6 weeks of her third pregnancy. She delivered a healthy male infant at 35 weeks' gestation. Two other publications have also reported the use of hydroxyurea in pregnant women with essential thrombocythemia (12, 13). In one case, the dose and exposure time was not specified but the pregnancy was elective terminated due to maternal complications (12). In the other case, 0.5–1.0 g/day was used from 18 to 28 weeks' gestation and a healthy male infant was delivered at 37 weeks' gestation (13).

Three reports have described the use of hydroxyurea for the management of sickle cell disease in pregnant women (14,15 and 16). In a study published in 1995, three women conceived while receiving the drug (14). All stopped the therapy when pregnancy was diagnosed. One delivered a normal, full-term infant, and two had elective pregnancy terminations. A 1999 report described one woman with sickle cell disease who had received hydroxyurea (1 g/day) and folic acid (5 mg/day) for 3 years before pregnancy (15). She discontinued hydroxyurea when pregnancy was confirmed at 9 weeks' gestation and delivered a normal male baby at 39 weeks' with Apgar scores of 8 and 10 at 1 and 5 minutes, respectively. The 3.24-kg newborn, length 55 cm and head circumference 31 cm, was developing normally at 15 months. Another 1999 publication reported two pregnancies that were exposed to hydroxyurea very early in gestation (16). Both women were being treated for sickle cell disease with the drug (1g/day and 0.5 g/day), in addition to folic acid and other drugs, and both discontinued hydroxyurea when pregnancy was confirmed at approximately 5 and 4 weeks, respectively. One woman delivered a 2750-g, male infant at 37 weeks' gestation with Apgar scores of 8 and 9 at 1 and 5 minutes, respectively. The infant was developing normally at age 17 months. The second woman delivered a premature, 1365-g, male baby at 32.5 weeks' gestation with Apgar scores of 8 and 9 at 1 and 5 minutes, respectively. Because of his prematurity, the infant required treatment for respiratory distress syndrome, hyperbilirubinemia, patent ductus arteriosus, and sepsis during the first 6 weeks, but was developing normally at age 21 months (16).

The outcomes of pregnancies exposed to chemotherapy gestational trophoblastic disease before conception were evaluated two reports, one in 1984 and the other in 1998 (17,18). In 436 long-term survivors treated with chemotherapy between 1958 and 1978, 69 (16%) received hydroxyurea as part of their treatment regimens (17). Of the 69 women, 14 (20%) had at least one live birth (numbers in parentheses refer to mean/maximum hydroxyurea dose in grams) (3.6/8.0), 3 (4%) had no live births (6.3/16.0), 3 (4%) failed to conceive (3.0/6.0), and 49 (71%) did not try to conceive (9.4/47.0). Additional details, including congenital anomalies observed, are described in the monograph for methotrexate (see Methotrexate) (17). In the 1998 report, 336 women, who had tried to conceive, had previously received various combinations of chemotherapeutic agents, some of which included hydroxyurea (18). In comparison to a group receiving single-agent therapy (N=392; methotrexate), no differences in pregnancy outcome were observed in the number of live births, unsuccessful pregnancies, and an inability to become pregnant. Only 18 major or minor congenital abnormalities (affecting 1.7% of the births) were reported. However, the stillbirth rate in all women treated for gestational trophoblastic disease was significantly higher than that of the general population (odds ratio 2.87; 95% confidence interval 2.44–3.03; p<0.001) (18). One woman treated for acute lymphoid leukemia with a combination of nine antineoplastic agents, one of which was hydroxyurea, conceived two pregnancies, 2 and 4 years after chemotherapy was stopped (19). Apparently normal term infants, a 3850-g male and a 3550-g female, resulted and both were doing well at 7 and 4.5 years, respectively.

Occupational exposure of the mother to antineoplastic agents during pregnancy may present a risk to the fetus. A position statement from the National Study Commission on Cytotoxic Exposure and a research article involving some antineoplastic agents are presented in the monograph for cyclophosphamide (see Cyclophosphamide).

In summary, although hydroxyurea is teratogenic in animals, no fetal anomalies have been observed in 13 human pregnancies that resulted in live infants in which the drug was used to treat maternal disease. In some of these cases, however, hydroxyurea was discontinued very early in gestation. Therefore, the data are too limited to draw conclusions about the safety of this agent during pregnancy or about the long-term growth and development of children exposed in utero.

Breast Feeding Summary

Hydroxyurea is excreted into human milk. A 29-year-old breast-feeding woman with recently diagnosed chronic myelogenous leukemia was treated with hydroxyurea, 500 mg orally 3 times daily (20). Breast feeding was halted before initiation of the chemotherapy. Milk samples were collected 2 hours after the last dose for 7 days. Because of technical difficulties with the analysis, milk concentrations of hydroxyurea could only be determined on days 1, 3, and 4. The mean level of hydroxyurea was 6.1 µg/mL (range 3.8–8.4 µg/mL). Serum concentrations were not measured. Although these concentrations are low, the potential for adverse effects in the infant indicates that nursing should be considered contraindicated during hydroxyurea therapy.

References

1. Shepard TH. Catalog of Teratogenic Agents. 7th ed. Baltimore, MD:Johns Hopkins University Press, 1992:206–7.
2. Platzek T, Schwabe R. Combined prenatal toxicity of 6-mercaptopurine riboside and hydroxyurea in mice. Teratogenesis Carcinog Mutagen 1999;19:223–32.
3. Doney KC, Kraemer KG, Shepard TH. Combination chemotherapy for acute myelocytic leukemia during pregnancy: three case reports. Cancer Treat Rep 1979;63:369–71.
4. Patel M, Dukes IAF, Hull JC. Use of hydroxyurea in chronic myeloid leukemia during pregnancy: a case report. Am J Obstet Gynecol 1991;165:565–6.
5. Tertian G, Tchernia G, Papiernik E, Elefant E. Hydroxyurea and pregnancy. Am J Obstet Gynecol 1992;166:1868.
6. Zemlickis D, Lishner M, Degendorfer P, Panzarella T, Sutcliffe SB, Koren G. Fetal outcome after in utero exposure to cancer chemotherapy. Arch Intern Med 1992;152:573–6.
7. Delmer A, Rio B, Bauduer F, Ajchenbaum F, Marie J-P, Zittoun R. Pregnancy during myelosuppressive treatment for chronic myelogenous leukaemia. Br J Haematol 1992;82:783–4.
8. Jackson N, Shukri A, Ali K. Hydroxyurea treatment for chronic myeloid leukaemia during pregnancy. Br J Haematol 1993;85:203–4.
9. Fitzgerald JM, McCann SR. The combination of hydroxyurea and leucapheresis in the treatment of chronic myeloid leukaemia in pregnancy. Clin Lab Haematol 1993;15:63–5.
10. Szanto F, Kovacs L. Successful delivery following continuous cytostatic therapy of a leukemic pregnant woman. Ovr Hetil 1994;134:527–9. (Hungarian). As cited by Diav-Citrin O, Hunnisett L, Sher GD, Koren G. Hydroxyurea use during pregnancy: a case report in sickle cell disease and review of the literature. Am J Hematol 1999;60:148–50.
11. Cinkotai KI, Wood P, Donnai P, Kendra J. Pregnancy after treatment with hydroxyurea in a patient with primary thrombocythaemia and a history of recurrent abortion. J Clin Pathol 1994;47:769–70.
12. Fernandez H. Essential thrombocythemia and pregnancy. J Gynecol Obstet Biol Reprod 1994;23:103–4. (French). As cited by Diav-Citrin O, Hunniset L, Sher GD, Koren G. Hydroxyurea use during pregnancy: a case report in sickle cell disease and review of the literature. Am J Hematol 1999;60:148–50.
13. Dell'Isola A, De Rosa G, Catalano D. Essential thrombocythemia in pregnancy. A case report and general considerations. Minerva Ginecol 1997;49:165–72. (Italian). As cited by Diav-Citrin O, Hunnisett L, Sher GD, Koren G. Hydroxyurea use during pregnancy: a case report in sickle cell disease and review of the literature. Am J Hematol 1999;60:148–50.
14. Charache S, Terrin ML, Moore RD, Dover GJ, Barton FB, Eckert SV, McMahon RP, Bonds DR, and the Investigators of the Multicenter Study of Hydroxyurea in Sickle Cell Anemia. Effect of hydroxyurea on the frequency of painful crises in sickle cell anemia. N Engl J Med 1995;332:1317–22.
15. Diav-Citrin O, Hunnisett L, Sher GD, Koren G. Hydroxyurea use during pregnancy: a case report in sickle cell disease and review of the literature. Am J Hematol 1999;60:148–50.
16. Byrd DC, Pitts SR, Alexander CK. Hydroxyurea in two pregnant women with sickle cell anemia. Pharmacotherapy 1999;19:1459–62.
17. Rustin GJS, Booth M, Dent J, Salt S, Rustin F, Bagshawe KD. Pregnancy after cytotoxic chemotherapy for gestational trophoblastic tumours. Br Med J 1984;288:103–6.
18. Woolas RP, Bower M, Newlands ES, Seckl M, Short D, Holden L. Influence of chemotherapy for gestational trophoblastic disease on subsequent pregnancy outcome. Br J Obstet Gynaecol 1998;105:1032–5.
19. Pajor A, Zimonyi I, Koos R, Lehoczky D, Ambrus C. Pregnancies and offspring in survivors of acute lymphoid leukemia and lymphoma. Eur J Obstet Gynecol Reprod Biol 1991;40:1–5.
20. Sylvester RK, Lobell M, Teresi ME, Brundage D, Dubowy R. Excretion of hydroxyurea into milk. Cancer 1987;60:2177–8.