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.