Marilyn J. Telen, MD
Wellcome Professor of Medicine
Duke Comprehensive Sickle Cell Center and Division of Hematology
Duke University School of Medicine
Andra H. James, MD, MPH
Professor Emerita of Obstetrics & Gynecology, Division of Maternal-Fetal Medicine
Consulting Professor of Medicine, Division of Hematology
Duke University School of Medicine
A 43-year-old male patient is on hydroxyurea (HU) 1,500 mg BID as part of his treatment for sickle cell disease (SCD). His wife recently became pregnant, and he is now requesting pregnancy termination due to fear of abnormal sperm morphology or teratogenicity resulting from HU. His wife has a normal hemoglobin pattern and is not taking any medications aside from a prenatal vitamin. I didn’t find any reported cases of HU causing teratogenicity when used by a male partner, nor did I encounter such a concern during my hematology training. We usually counsel female patients on possible teratogenicity from HU and male patients are counseled on low sperm count. However, I found a statement from the drug manufacturer that advised male patients to stop HU when trying to conceive. I also found information on possible teratogenicity in animals, though no cases have been identified in humans. What would you advise for this patient?
Male patients with SCD who are taking HU are routinely counseled to stop the medication several months before they try to conceive with their partner, as are many female patients, though HU has not been proven to be a teratogen in humans. We have seen female patients conceive while on HU without apparent ill effect. The primary concern with HU is that it can be teratogenic since it is an inhibitor of DNA synthesis in many organisms and in cell culture systems. HU has been shown to induce chromosome damage in some experimental systems and is thought to be teratogenic in mammals,1 although attempts to confirm this effect have not been uniformly successful. Consequently, it is believed to have only limited teratogenic activity, and it is hard to pin down what it does in humans.
A paper on the use of HU in women with SCD and pregnancy outcomes found that its “use during conception and pregnancy, but not during conception only, was associated with an increase in the odds ratio (OR) of miscarriage or stillbirth (OR=2.21, 95% CI 1.40-3.47).”2 Furthermore, “in analyses of live birth outcomes, HU use during conception and pregnancy was associated with birth weight [of less than] 5.5 pounds in full-term infants (OR=2.98, 95% CI 1.09-7.38) but not with prematurity or serious medical problems at birth. These findings suggest that [HU] use may be safe up to the time of conception, but that clinicians should continue to advise caution regarding use during pregnancy.”2 Although the investigators attempted to control for severity of SCD in their comparison of women who were and were not taking HU, our perception and experience is that women who take HU during pregnancy are disproportionately affected by severe disease, thus making any conclusions about HU exposure — rather than disease severity raising the risk of miscarriage, stillbirth, and low birth weight — uncertain.
There is another relevant study that is reassuring on the teratogenic potential of HU.3 In the prospective ESCORT-HU study, more than 1,000 patients across multiple European countries were enrolled and treated with HU. Among these, 125 pregnancies were reported in 101 women taking HU, and no malformations were observed among the neonates. There were also 12 pregnancies in the partners of male patients who were treated with HU. This study did report one case of fatal myelodysplastic syndromes, and a causal association with HU could not be excluded.
In this clinical case, although one would have to extrapolate from these data to assess the risk of paternal HU use, HU could only have affected the pregnancy during conception and therefore seems to present a very low risk of contributing to an unwanted outcome. However, since at least 10 to 20% of pregnancies end in miscarriage in normal, healthy women, outcomes can by no means be guaranteed. Thus, while one could not give the prospective parents absolute reassurance, we think it is quite reasonable to continue the pregnancy. On the other hand, the couple’s choice of termination would not be unreasonable either. The key is to supply the parents with the best information we have, even if it is not completely satisfactory.
- Timson J. Hydroxyurea. Mutat Res. 1975;32(2):115-32.
- Kroner BL, Hankins JS, Pugh N, et al. Pregnancy outcomes with hydroxyurea use in women with sickle cell disease. Am J Hematol. 2022;97(5):603-612.
- de Montalembert M, Voskaridou E, Oevermann L, et al. Real-life experience with hydroxyurea in patients with sickle cell disease: results from the prospective ESCORT-HU cohort study. Am J Hematol. 2021;96(10):1223-1231.
NEXT MONTH'S CLINICAL DILEMMA
A 78-year-old male was found to have a leukocytosis with left shift (76% neutrophils, 9% bands, 1.7% monocytes, 1% eosinophils, 6% metamyelocytes, 7% myelocytes, 3% promyelocytes), first noted during an admission for atrial fibrillation with rapid ventricular response. His white blood cell (WBC) count was reported to be 300 × 109/L. After undergoing a bone marrow biopsy, he was started on hydroxyurea and discharged to a rehabilitation center. About a month later, he was hospitalized for a large thigh hematoma, but no intervention was taken. He was found to be anemic and required red blood cell (RBC) transfusion. His bone marrow results came back as myelodysplastic syndromes/myeloproliferative neoplasm-unclassifiable (MDS/MPN-U). The MDS/MPN-U has not been treated, and his WBC count is stable around 100 × 109/L.
The initial report from the biopsy noted that morphology and immunophenotypic features were most consistent with chronic myeloid leukemia (CML). However, subsequent tests were negative for BCR-ABL1. No overt dysplasia in erythroid or myeloid precursors was noted. Megakaryocytes appeared adequate with occasional smaller (relatively hypolobated) forms. Next-generation sequencing identified the following variants: ASXL1 (31.4% variant allele frequency [VAF]), CSF3R T640N (40.1% VAF), CSF3R Q776 (14.7% VAF), FLT3 (4% VAF), GATA2 (46% VAF), SETBP1 (51% VAF), SRSF2 (47% VAF), and CUX1 (48% VAF). The metaphase karyotype was normal.
The patient now requires an RBC transfusion every two to three days. He recently presented with worsening thigh pain, was found to have an active bleed on CT angiogram, and underwent embolization. He is being worked up for an underlying bleeding disorder and his platelet counts are normal. Given the CSF3R mutations present in his disease, would you treat this patient with ruxolitinib or a hypomethylating agent?
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