Hydroxyurea (hydroxycarbamide) is the primary disease-modifying therapy for individuals
with sickle cell disease (SCD) and is both US FDA- and EMA-approved for SCD treatment.
Decades of research have documented that hydroxyurea reduces morbidity and mortality for
affected patients. Although its primary mechanism of action for SCD is the induction of
fetal hemoglobin (HbF) that prevents erythrocyte sickling, hydroxyurea is also a
ribonucleotide reductase inhibitor with dose-dependent cytotoxic effects. Based on
laboratory data, hydroxyurea is considered to be a potential human mutagen, clastogen,
teratogen, and even carcinogen. However, most of these are theoretical human risks; for
example, teratogenic effects of hydroxyurea are based on in vitro cellular data and
supra-pharmacological dosing of animals, with no documented abnormalities in humans.
Despite the lack of in vivo human data, the package insert for hydroxyurea, sold as
either Hydrea® or Droxia® (Bristol-Myers Squibb), or as Siklos® (Addmedica) lists both
pregnancy and lactation as contraindications for treatment.
This contraindication label is critically important, since women with SCD frequently have
high-risk pregnancies throughout gestation, with increased morbidity and mortality for
both the mother and baby. Acute clinical complications for the mother occur commonly
during gestation, while placental insufficiency through repeated infarctions also leads
to increased fetal morbidity. Protection of the mother's health during pregnancy is
therefore a high priority, which historically has been aided by judicious use of
transfusions and management by a multidisciplinary healthcare team. In the current era,
many women with SCD of child-bearing age are taking daily oral hydroxyurea with an
excellent treatment effect, so its forced discontinuation around the time of pregnancy
represents cessation of effective therapy. Abrupt withdrawal of hydroxyurea is typically
deleterious and may not be justified in this setting. Numerous published case reports and
small series have described the safe use of hydroxyurea as anti-neoplastic therapy during
pregnancy in women with cancer; moreover, anecdotal experience of >100 pregnancies with
hydroxyurea exposure did not document any teratogenicity.
Based on the importance of determining the actual risks and benefits of continuing
hydroxyurea as disease-modifying therapy during pregnancy to protect both mothers and
babies, and the lack of documented in vivo data, the safety of hydroxyurea during
gestation and subsequent lactation was recently identified as an important knowledge gap
by the NHLBI evidence-based SCD guidelines. Further data collection is needed regarding
the actual effects of hydroxyurea for women with SCD during both pregnancy and while
breastfeeding. Accordingly, we will conduct a multinational research project to
retrospectively capture known human exposures to hydroxyurea in the setting of SCD, which
have occurred during gestation and/or lactation, to elucidate the outcomes for the
mothers and their babies. Those outcomes will be compared to pregnancies in these same
women without hydroxyurea exposure.