Hydroxyurea Use During Pregnancy Raises Risk of Miscarriage, Stillbirths

Patricia Inácio, PhD avatar

by Patricia Inácio, PhD |

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Treatment with hydroxyurea at the time of conception may be safe, but its use by women with sickle cell disease (SCD) during pregnancy was linked to twofold higher risks of both miscarriage and stillbirth, a U.S. study reported.

Pregnant women taking hydroxyurea — used to reduce the frequency of vaso-occlusive crises (VOCs) in SCD — also had a nearly threefold higher risk of having a baby with a low weight at birth, the analysis showed.

These results highlight the need for clinicians to continue cautioning patients about hydroxyurea use during pregnancy, according to researchers.

“Our findings support advising women who become pregnant while on hydroxyurea to discontinue the medication during the pregnancy, if possible, and to use alternative approaches to prevent sickle cell disease complications during this time,” the team wrote.

Notably, they said that using hydroxyurea at conception “was not associated with miscarriage or stillbirth.”

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The study, “Pregnancy Outcomes with Hydroxyurea Use in Women with Sickle Cell Disease” was published in the American Journal of Hematology.

Hydroxyurea is an oral therapy that boosts the levels of hemoglobin F, also known as fetal hemoglobin. This form of hemoglobin carries oxygen in a developing baby, but its production normally ceases after birth. Moreover, it is more effective at transporting oxygen through the body than the adult form of hemoglobin.

By increasing the levels of hemoglobin F, hydroxyurea improves oxygen transport in SCD patients and lowers the frequency of pain crises, as well as the need for blood transfusions.

Pregnant women with SCD have been found to face a greater risk of both fetal and maternal adverse outcomes when compared with women without the disorder.

Few studies, however, have assessed the safety of hydroxyurea during pregnancy. Data from preclinical studies in animals suggest that it may have detrimental outcomes, particularly in regard to increasing the risk of fetal abnormalities.

Better assessing the effects of hydroxyurea at the time of conception and during pregnancy — as well as on fetal outcomes — is one of the goals of the Sickle Cell Disease Implementation Consortium (SCDIC) Registry. The SCDIC was established in the U.S. in 2016 to identify and address barriers to care for SCD patients.

Now, the consortium presented an analysis of self-reported pregnancy histories, hydroxyurea use, and pregnancy outcomes. The report involved 1,285 women with SCD, ages 18–45, who are enrolled in the registry.

More than half of the women (57.4%, 737 patients) reported they had become pregnant at least once, while 42.6% (548) were never pregnant. A total of 1,788 pregnancies were reported.

The proportion of women who reported being pregnant was higher for those not taking hydroxyurea at enrollment as compared with those taking the medication (62.2% vs. 51.6%).

The majority of women who reported at least one pregnancy were age 25 or older, and were not married. Most had a high school degree, and the majority had been unemployed, with an annual household income of $25,000 or less.

Nearly three-quarters (70%) had severe SCD, but 82% reported no history of chronic kidney disease or pulmonary hypertension.

Also, women who reported at least one pregnancy were significantly more likely to have sought medical attention for pain in the previous year. They were, however, less likely to currently be taking hydroxyurea.

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Of the 1,788 reported pregnancies, over half (60.3%) were live births, and only a minority (2.2%) were stillbirths. Around a fifth (22%) resulted in a miscarriage and even fewer (11.6%) were elective abortions. A total of 48 pregnancies (2.7%) were ongoing, and 20 (1.1%) had undefined outcomes.

Among the 680 women who reported a live birth, miscarriage, or stillbirth, almost a quarter (24.6%) said that they were on hydroxyurea at the time of conceiving at least one pregnancy.

Statistical analysis revealed several factors with a significant association with a higher rate of miscarriages or stillbirths. These included having more than three pregnancies, severe SCD, history of stillbirth or miscarriage, and chronic kidney disease.

After adjusting the analysis for potential confounding effects, including disease severity, the analysis showed that the use of hydroxyurea at the time of conception and during pregnancy was linked to a 2.21-times higher risk of miscarriage or stillbirth.

Researchers noted that a higher number of hospital visits for acute pain in the previous year was associated with lower risks of miscarriage or stillbirth.

When the team analyzed live birth outcomes (a total of 1,079 births), results showed that hydroxyurea use during conception and pregnancy was associated with a 2.98-times higher risk of low birth weight (below 5.5 lbs) in full-term infants. No association was seen for premature births or serious medical birth problems, including birth defects.

“The use of hydroxyurea up to the time of conception does not seem to have an adverse effect on the fetus and may be considered safe,” the researchers wrote. “On the other hand, women that continue taking hydroxyurea during pregnancy may have an increased risk of low fetal viability or low infant birth weight.”