Abstract
Women are advised not to attempt pregnancy while on hydroxyurea (HU) due to the teratogenic effects of this agent, based on results obtained from animal studies. Several case reports suggest that HU may have minimal or no teratogenic effects on the developing human fetus. Fourteen cases of HU therapy in pregnant patients diagnosed with acute or chronic myelogenous leukemia, primary thrombocythemia, or sickle cell disease (SCD) have been reported. Three pregnancies were terminated by elective abortion; 1 woman developed eclampsia and delivered a phenotypically normal stillborn infant. All other patients delivered live, healthy infants without congenital anomalies. We contend that case studies such as these have too few patients and cannot effectively address the adverse effect of HU on preimplantation embryo or fetuses. The objective of this study was to assess the risks associated with a clinically relevant dose of HU used for the treatment of SCD, on ovulation rate and embryo development, using adult C57BL/6J female mice as a model. In Experiment 1, adult female mice were randomly assigned to a treatment or a control group (N = 20/group). Treatment consisted of oral HU (30 mg/kg) for 28 days; while control mice received saline (HU vehicle). Five days to the cessation of HU dosing, all mice were subjected to folliculogenesis induction with pregnant mare serum gonadotropin (PMSG). Five mice/group were anesthetized at 48 hours post PMSG to facilitate blood collection via cardiac puncture for estradiol-17β (E2) measurement by RIA. Ovulation was induced in the remaining mice at 48 hours post PMSG with human chorionic gonadotropin (hCG) and immediately caged with adult males for mating. Five plugged female mice/group were sacrificed for the determination of ovulation rate. The remaining mated mice were sacrificed about 26 hours post hCG, ovaries excised and weighed and embryos harvested and cultured in Whitten’s medium (WM) supplemented with CZBt. In Experiments 2 and 3, (N = 10/Experiment) folliculogenesis and ovulation were induced in untreated mice followed by mating. Recovered embryos were either exposed continuously (Experiment 2) or intermittently (Experiment 3) to bioavailable HU (18 μg HU/mL of WM + CZBt) or WM + CZBt only (control). Treated mice sustained decreased ovarian wt, ovulation rate and circulating E2 compared with controls (P < 0.05). Fewer embryos retrieved from HU-treated mice developed to blastocyst stage (32%) compared with those from controls (60%; P < 0.05). Furthermore, continuous or intermittent in vitro exposures of embryos to HU also resulted in reduced development to blastocyst stage (continuous HU, 9 vs. control, 63%; P < 0.05; intermittent HU, 20 vs. control, 62%; P < 0.05) with embryos exposed continuously to HU in vitro fairing worse. Even though HU is well tolerated, our data suggest that it compromises folliculogenesis and the ability of generated embryos to develop. Therefore, designed studies with larger numbers of patients receiving HU during pregnancy, with longer follow-up of exposed children and more careful assessment of embryo/fetotoxic effects, are required before this agent can be promoted as safe in pregnancy.
Highlights
Hydroxyurea (HU) is a low molecular weight nonalkylating myelosuppressive agent that impairsDNA synthesis through the inhibition of ribonucleotide reductase [1]
The reduction in mean ovarian weight among HU treated mice was accompanied by concomitant reductions in serum E2 concentrations (P < 0.05; Figure 3) and ovulation rate (P < 0.05; Figure 4)
In vitro culture of in vivo generated 2-cell embryos (60 embryos/group) revealed that fewer (P < 0.05) in vivo HU-exposed embryos developed to blastocyst stage (19 [32%]); Figure 5 compared with 36 (60%) of their control counterparts that progressed to blastocyst stage of development in vitro (Figure 6)
Summary
Hydroxyurea (HU) is a low molecular weight nonalkylating myelosuppressive agent that impairsDNA synthesis through the inhibition of ribonucleotide reductase [1]. Even though the therapeutic use of HU may be declining in patients with chronic myeloid leukemia [4], its use for the treatment of patients with sickle cell disease (SCD; [5]) is gaining acceptance. In the latter patients, HU alleviates the classical symptoms of the SCD not by its antimitotic effect but by provoking increased production of fetal hemoglobin which has a higher oxygen carrying capacity than sickle cell hemoglobin. HU is used investigatively for the treatment of human immunodeficiency virus (HIV) infection [6,7] In the latter treatment, HU does not have a direct anti-virus activity; rather, it inhibits the cellular enzyme ribonucleotide reductase and as a consequence, reduces deoxynucleotide triphosphates (dNTPs) that are necessary for DNA synthesis
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