Hydroxycarbamide in the general population with SCD

• Hydroxycarbamide is the most-studied disease-modifying medication for SCD. It has been shown to increase the synthesis of fetal haemoglobin, which inhibits sickling by interfering with the formation of rigid, rod-like polymers of deoxygenated haemoglobin S molecules (95). There is evidence that it reduces the frequency of pain and vaso-occlusive crises (96). Safety of hydroxycarbamide during pregnancy
• While it is a first-line treatment in the general SCD population, hydroxycarbamide has historically been contraindicated in pregnancy due to teratogenic effects in animal (rat and rhesus monkey) studies (97, 98). It has been noted, however, that the doses used in the studies were 10- to 100-fold higher than therapeutic doses (99).
• Recent non-randomized studies identified through the systematic review commissioned to inform this guideline suggest that the odds of teratogenicity may not be increased (100, 101). The authors of one study, however, reported links with miscarriage, stillbirth and low birthweight after controlling for potential confounders (100). The GDG noted that the study was at high risk of bias, with many pregnancy outcomes being self-reported without medical-record confirmation. A retrospective study on the safety of hydroxycarbamide in the second trimester of pregnancy is currently ongoing (102).
• Guidance from the WHO African region is that hydroxycarbamide treatment be suspended during pregnancy, however timing of treatment suspension is not specified (23). As noted above, the studies suggesting teratogenicity were animal studies (97, 98), used higher doses than those considered therapeutic in humans (99), and teratogenic effects in rats and rhesus monkeys are not proof of teratogenicity in humans (103). Approaches to use of hydroxycarbamide in pregnancy
• Fetal organs are formed by the end of the first trimester, thus theoretical teratogenic potential is highest during this period. However, the potential risk of miscarriage and stillbirth as well as low birth weight remain throughout pregnancy. Given that hydroxycarbamide is the best studied and often only feasible disease-modifying agent for SCD, the GDG considered it unethical to make a blanket recommendation for withholding the medication for the duration of pregnancy. In the context of limited data, the benefits of hydroxycarbamide for symptom control need to be weighed against the potential fetal risks.
• In the context of shared decision making, pregnant women with SCD who have controlled their condition with hydroxycarbamide outside of pregnancy or who are not candidates for transfusion may benefit from counselling on the current state of knowledge regarding its use in pregnancy, including what is both known and unknown, to assist them in making an informed decision about its use.