PREGNANCY RECOMMENDATION: Limited Human Data Suggest Low Risk
BREASTFEEDING RECOMMENDATION: Limited Human Data—Potential Toxicity
Although hydroxyurea is teratogenic in animals, almost all reported human pregnancy exposures have resulted in normal outcomes. In some of cases, however, hydroxyurea was discontinued very early in gestation or started after organogenesis. The available data prevent a better assessment of the embryo–fetal risk. In addition, although many children exposed in utero have had normal growth and development during their first few years, longer evaluation periods are warranted because the drug might be a human carcinogen. Nevertheless, if the drug is indicated, it should not be withheld because of pregnancy, but avoiding organogenesis would be best.
FETAL RISK SUMMARY
Hydroxyurea is an antineoplastic agent that causes cytotoxic and cytoreductive effects. It is indicated to reduce the frequency of painful crises and to reduce the need for blood transfusions in adult patients with sickle cell anemia with recurrent moderate to severe painful crises. It undergoes partial metabolism. Hydroxyurea is presumed to be a human carcinogen (1). The drug is also used for other indications as discussed below.
Hydroxyurea is teratogenic in several animal species including mice, hamsters, cats, miniature swine, dogs, and monkeys at doses within onefold of the human dose based on BSA (1). Shepard (2) reviewed nine studies describing the effects of this agent on the embryos and fetuses of various animal species. Anomalies observed included defects of the CNS, palate, and skeleton, depressed DNA synthesis, extensive cell death in limb buds and CNS, impaired postnatal learning, and decreased body and brain growth (rats); beak defects (chick embryos); and neural tube and cardiac defects (hamsters) (2). 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 (3). An increase in gross structural abnormalities was observed at the 300- and 350-mg/kg dose levels.
A number of reports have described the use of hydroxyurea in human pregnancy (4–27). Two women, both with acute myelocytic leukemia, were treated with five-drug chemotherapy regimens at 17 and 27 weeks’ gestation, respectively (4). In both cases, hydroxyurea (8 mg) was given as an initial, single IV dose. One woman underwent an elective abortion (EAB) 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 (4).
A 1991 report described the use of hydroxyurea, 0.5–1.0 g/day, throughout gestation in a woman with chronic myelocytic leukemia (CML) (5). 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 (5). A subsequent brief report described a similar patient treated with 1–3 g/day orally before and throughout gestation (6). 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 (6). A 1992 report listed a pregnant woman with CML who was treated in the 1st trimester with hydroxyurea and three other agents (7). She elected to terminate her pregnancy.
Several other studies have reported on the use of hydroxyurea for CML during pregnancy (8–14). A 1992 publication described two women who were treated before and throughout gestation with oral doses of 1.5 g/day (8). 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 (8). The clinical course of a pregnant woman with CML was discussed in a 1993 report (9). 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 (9). A second 1993 report described a woman with CML treated unsuccessfully with interferon alfa before pregnancy and then with hydroxyurea (10). At the patient’s request, all therapies were 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 (10). 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 (11). In a 2011 case report, the therapy of a 24-year-old patient with CML was changed at 10 weeks’ from imatinib to hydroxyurea. She was maintained on the agent (2.0–2.5 g/day) for the remainder of her pregnancy (12). A healthy 2.5-kg female baby was born at 37 weeks. At 1-year follow-up, her growth and development were normal. In a 2006 report, a woman was treated for chronic-phase CML with imatinib before and during the first 6 weeks of gestation until her pregnancy was diagnosed (13). Therapy was stopped until the completion of the 1st trimester, at which time hydroxyurea was started. At 30 weeks’, a fetal ultrasound revealed a meningocele and 4 weeks later the woman delivered a dead fetus. The defect was thought to have been caused by imatinib (13). A brief 2009 case report described the outcome of a 34-year-old woman with CML who was treated with imatinib (400 mg/day) during the first 4 months of an unplanned pregnancy (14). When pregnancy was diagnosed, imatinib was stopped and hydroxyurea was started. At 37 weeks’, she delivered a healthy 3.12-kg infant with Apgar scores of 9 and 10. The child was doing well at 26 months of age (14).
A 1994 report described a woman with primary thrombocythemia who had lost two previous pregnancies from stillbirths (15). She was treated with hydroxyurea (1–2 g/day) before 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 (16,17). In one case, the dose and exposure time were not specified but the pregnancy was electively terminated due to maternal complications (15). 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 (17).
In another 1994 case report, a 28-year-old woman, known to have familial myeloproliferative syndrome, was treated successfully for essential thrombocythemia (ET) with hydroxyurea and aspirin with disappearance of her neurologic symptoms (18). After about 9–10 months of treatment, she was found to be pregnant and all therapy was stopped. About 2–3 months later, her symptoms reappeared and she was treated with interferon alpha and aspirin the remainder of pregnancy. At term, she gave birth to a growth-restricted baby with multiple malformations (ambiguous genitalia, hemivertebrae D6 to D10 with 11 pairs of ribs, and secondary scoliosis) (no other details on the baby were provided) (18).
A 1995 study described the outcomes of 34 pregnancies in 18 women with ET (19). Only one of the pregnancies was treated with hydroxyurea and that pregnancy was terminated by an EAB. In a 2001 study, 43 pregnancies occurred in 20 patients with ET but only were treated with hydroxyurea (20). The pregnancy outcome was “successful” (no further details given). A 2011 report described the pregnancy outcome of a 42-year-old woman with ET who had been treated with hydroxyurea and aspirin during the first 5 months of gestation (21). At term, she delivered a normal 2.7-kg male infant with Apgar scores of 8 and 9.
Four reports have described the use of hydroxyurea for the management of sickle cell disease in pregnant women (22–25). In a study published in 1995, three women conceived while receiving the drug (22). All stopped the therapy when pregnancy was diagnosed. One delivered a normal, full-term infant, and two had EABs. 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 (23). She discontinued hydroxyurea when pregnancy was confirmed at 9 weeks’ gestation and delivered a normal male 3.24-kg baby at 39 weeks’ with Apgar scores of 8 and 10 at 1 and 5 minutes, respectively. The infant was developing normally at 15 months. Another 1999 publication reported two pregnancies that were exposed to hydroxyurea very early in gestation (24). Both women were being treated for sickle cell disease with the drug (1 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 (24).
In a 2009 report from the Multicenter Study of Hydroxyurea in Sickle Cell Anemia, attempts were made to prevent pregnancies during the randomized double-blind placebo-controlled trial (25). Among the 299 study participants, 153 were females and, of these, 77 (50.3%) were in the hydroxyurea group. During the trial, there were six pregnancies in female participants taking the drug. When pregnancy was diagnosed, all were taken off of the drug. The outcomes of the six pregnancies were two live births, three EABs, and one spontaneous abortion (25).
A 2010 case report described the pregnancy outcome of a 25-year-old patient with sickle-β thalassemia who had been treated with hydroxyurea during the first 9 weeks of gestation (26). At that time, hydroxyurea was stopped and other therapy initiated. Although the remainder of her pregnancy was complicated, she eventually gave birth at 38 weeks’ to a healthy 2.68-kg female infant who was growing normally at 1 year of age (26).
The outcomes of pregnancies exposed to chemotherapy for gestational trophoblastic disease before conception were evaluated in two reports (27,28). In 436 long-term survivors treated with chemotherapy between 1958 and 1978, 69 (16%) received hydroxyurea as part of their treatment regimens (27). 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) (27). In the other report, 336 women, who had tried to conceive, had previously received various combinations of chemotherapeutic agents, some of which included hydroxyurea (28). In comparison with 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) (28).
A 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 (29). 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.
Hydroxyurea was used to treat polycythemia vera for 18 months before a 34-year-old woman became pregnant (30). Her pregnancy was diagnosed at 9 weeks’ and hydroxyurea was stopped. Her erythrocytosis was controlled with phlebotomy. At 37 weeks’ she gave birth to normal 2550-g male infant. The infant’s development up to 12 months of age was normal (30).
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).
Hydroxyurea is excreted into human milk. A 29-year-old breastfeeding woman with recently diagnosed chronic myelogenous leukemia was treated with hydroxyurea, 500 mg orally 3 times daily (31). Breastfeeding 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 be determined only on days 1, 3, and 4. The mean level of hydroxyurea was 6.1 mg/L (range 3.8–8.4 mg/L). Based on a milk intake of 600 mL/day, the authors estimated that a nursing infant would have received 3–4 mg/day of the drug. Serum concentrations were not measured (31).
Because the mother’s weight was not provided, a comparison to the maternal weight-adjusted dose could not calculated. Although the concentrations are low, the potential for adverse effects in the infant suggests that nursing should be considered contraindicated during hydroxyurea therapy.
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