Ethical and Clinical Considerations in the Use of Hydroxyurea in Pregnant Women with Sickle Cell Disease

Keywords:

• Sickle cell disease
• hydroxyurea
• pregnancy

Letter to the editor

Sickle cell disease (SCD) is an inherited blood disorder characterized by the tendency of red blood cells to become sickle-shaped and block capillaries, leading to vaso-occlusion and anemia [1, 2]. Pregnant women with SCD have an increased risk for adverse maternal, fetal and neonatal outcomes [3–6]. The risk of maternal death is ten times higher compared to normal pregnancies [4, 7]. The risk of maternal death was 30 times higher in our cohort of pregnant women with the disease. Additionally, pregnant women with SCD have a multifold higher risk of intrauterine growth restriction, intrauterine fetal death (IUFD), stillbirth, anemia, low birth weight (LBW), and preeclampsia/eclampsia [4].

The standard of antenatal care in pregnancy with SCD is low-dose aspirin, folic acid supplementation, treatment by a multidisciplinary team, frequent antenatal care visits, regular sonographies, education of the patient and family members, and tertiary level care in case of complications [8, 9]. Top-up blood transfusion is recommended for acute anemia. However, prophylactic blood transfusion is not universally recommended and is quite challenging in low- and middle-income countries [9]. Despite providing the standard of care, maternal and fetal outcomes have been unfavorable in a variety of clinical settings, even in high-income countries [6].

Hydroxyurea (HU) is an antimetabolite that is used in nonpregnant patients with SCD to decrease the incidence/risk of complications, including acute chest syndrome (ACS), vaso-occlusive crisis, and stroke [8]. HU is approved for the treatment of SCD among nonpregnant patients by many drug regulatory authorities, including in India. It is included in the national guidelines in India and other countries for the treatment of SCD [10, 11].

Therefore, there is a growing interest in exploring the use of HU during pregnancy in women with SCD [12, 13]. There are a few reasons to justify the role of HU during pregnancy. First, HU reduces the incidence of acute chest syndrome, stroke and vaso-occlusive crisis among non-pregnant patients [14, 15]; these are the major causes of maternal deaths and morbidity in SCD. Placental studies among women with SCD have revealed microthrombi, sickle-shaped cells and infarcts. HU tends to reduce sickling of red blood cells. Thus, it is plausible that HU may reduce the risk of stillbirth, IUFD, LBW and preterm deliveries although there are no human studies.

HU is currently not recommended in pregnancy. Patients are advised to stop the drug before planning a pregnancy [16]; based on it being an antimetabolite. Some animal studies have reported congenital anomalies among fetuses, such as partially ossified cranial bones, absence of eye sockets, hydrocephaly, bipartite sternebrae, and missing lumbar vertebrae. Although the dose used in these animal studies was much higher than the currently recommended doses used in humans [17–19].

However, there have been more than 300 pregnancies in which hydroxyurea was administered during pregnancy as reported in case series and cohort studies globally. These studies reported no increased risk of fetal malformation more than the baseline risk in the general population [20–24]. The use of HU in pregnancy may be considered in second and third trimester as per one such study [13]. The British Haematological Society has recommended that HU might be considered in those pregnant women where the risk of stopping the drug outweighs the risk of continuing it after explaining the risks and benefits to the patients [13]. However, no trials have looked at the effectiveness of HU on maternal, fetal and neonatal outcomes.

There are other drugs belonging to category D and category X like valproic acid, warfarin, carbamazepine, propylthiouracil, etc. with an established risk of fetal malformations [25–27]. However, it is standard of care to use these category D/X drugs during pregnancy when maternal benefits outweigh fetal risks. For example, it is standard of care to use warfarin in pregnant patients with mechanical heart valves and propylthiouracil to treat hyperthyroidism during pregnancy [28].

Therefore, a risk-benefit analysis would greatly enhance the ethical and clinical debate about using HU in pregnancy. If there are good quality studies to document the risk and benefits of using HU during pregnancy, then regulators, clinicians and patients may be able to make an informed decision. Considering the very high risk of maternal and fetal outcomes during pregnancy in women with SCD, there is a strong ethical argument to generate good quality evidence about the risks and benefits of using HU during pregnancy with SCD. A well-designed randomized control trial among consenting women might offer such good quality evidence. Unfortunately, no such randomized control trials or even quasi-experimental studies have been conducted so far.

Therefore, we urge researchers to conduct rigorous studies documenting the effectiveness and risks of using HU among pregnant women with SCD. We also propose to the ethics committees to approve the experimental use of HU among pregnant women in a trial setting [29]. However, it would be important for the trialists to follow universal ethical standards. Additionally, the patients should be informed about the risks and benefits of HU, and the patients should be enrolled for the study only after informed consent is received. The investigators should closely follow fetal outcomes through serial sonography for the early detection of any fetal abnormalities. It is preferable to start HU after the completion of the first trimester and once organogenesis is completed; thus, it may further reduce the risk of fetal anomalies with HU. Standard care should be provided to both arms equally to study the effect of HU. A data safety and monitoring board should closely follow the benefits and harms. The ethics committees may allow such trials if the team of investigators takes aforementioned precautions.

In conclusion, we believe that there is a strong ethical and clinical case for conducting a randomized control trial to evaluate the effectiveness of HU toward improving maternal and fetal outcomes of pregnancies in patients with SCD and assess any associated risk.

Disclosure statement

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article.

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Funding

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