Clinical trial NCT04093986: Hydroxyurea Exposure Limiting Pregnancy and Follow-Up Lactation
Official title: Hydroxyurea Exposure Limiting Pregnancy and Follow-Up Lactation
Study type: OBSERVATIONAL
Overall status: RECRUITING
Conditions: Sickle Cell Disease
Sickle Cell Anemia
Keywords: Hydroxyurea
Lead sponsor: Children's Hospital Medical Center, Cincinnati
Sponsor class: OTHER
Collaborators: name: University of Connecticut
name: University of Colorado, Denver
name: Guy's and St Thomas' NHS Foundation Trust
name: Duke University
name: Children's Hospital of Philadelphia
First posted: 2019-09-18
Enrollment: 200
Sex: ALL
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: CASE_ONLY
Time perspective: RETROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Clinical and laboratory data on up to 200 women with SCD with hydroxyurea exposure during either gestation or lactation.

Brief summary: The purpose of this research study is to document and understand the effects of hydroxyurea exposure for women with SCD and their babies, during both gestation and lactation.

Detailed description: 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.

Eligibility criteria: Inclusion Criteria:

* Medical records or data available from previous clinical care prior to June 20, 2019 of pregnant females with SCD, including women who miscarried, had a still birth, or completed labor at any gestational stage, with any hydroxyurea exposure during either pregnancy and/or while breastfeeding.
* Medical records or data available from previous clinical care prior to June 20, 2019 about pregnancy and breastfeeding outcomes, both for babies with hydroxyurea exposure and other babies by these same women.

Exclusion Criteria:

* Unavailable medical records or lack of information about hydroxyurea exposure.

Primary outcomes:
measure: How long pregnant women with Sickle Cell Disease (SCD) were exposed to Hydroxyurea.
timeFrame: Through completion of pregnancy, an average of 2 years
measure: Dose of hydroxyurea taken during pregnancy.
timeFrame: Through completion of pregnancy, an average of 2 years
measure: How long infants were exposed to Hydroxyurea.
timeFrame: Through study completion, an average of 2 years
measure: Dose of hydroxyurea exposure in infants.
timeFrame: Through study completion, an average of 2 years
measure: Health outcomes of infants exposed to Hydroxyurea.
timeFrame: Through study completion, an average of 2 years
measure: Pregnancy in Sickle Cell Disease (SCD).
timeFrame: Start of pregnancy until June 2019
measure: Comparative analysis of congenital malformations or medical conditions in infants
timeFrame: Through study completion, an average of 2 years
Secondary outcomes:
Other outcomes:
Locations:
city: Cincinnati
country: United States
facility: Cincinnati Children's Hospital Medical Center
state: Ohio
Study officials:
affiliation: Children's Hospital Medical Center, Cincinnati
name: Russell Ware, MD
role: PRINCIPAL_INVESTIGATOR
References: