Sickle Cell Raises Risk for Stillbirth

Heidi Splete

November 30, 2021

Both sickle cell trait and sickle cell disease were significantly associated with an increased risk of stillbirth, based on data from more than 50,000 women.

Pregnant women with sickle cell disease (SCD) are at increased risk of complications, including stillbirth, but many women with the disease in the United States lack access to specialty care, Silvia P. Canelón, PhD, of the University of Pennsylvania, Philadelphia, and colleagues wrote. Sickle cell trait (SCT), defined as one abnormal allele of the hemoglobin gene, is not considered a disease state because many carriers are asymptomatic, and therefore even less likely to be assessed for potential complications. "However, it is possible for people with SCT to experience sickling of red blood cells under severe hypoxia, dehydration, and hyperthermia. This condition can lead to severe medical complications for sickle cell carriers, including fetal loss, splenic infarction, exercise-related sudden death, and others," they noted.

In a study published in JAMA Network Open, the researchers reviewed data from 63,334 deliveries in 50,560 women between Jan. 1, 2010, and Aug. 15, 2017, at four quaternary academic medical centers in Pennsylvania. Of these, 1,904 had SCT but not SCD, and 164 had SCD. The mean age of the women was 29.5 years, and approximately 56% were single at the time of delivery. A majority (87%) of the study population was Rhesus-factor positive, 47.0% were Black or African American, 33.7% were White, and 45.2% had ABO blood type O.

Risk factors for stillbirth used in the analysis included SCD, numbers of pain crises and blood transfusions before delivery, delivery episode (to represent parity), history of cesarean delivery, multiple gestation, age, marital status, race and ethnicity, ABO blood type, Rhesus factor, and year of delivery.

Overall, the prevalence of stillbirth in women with SCT was 1.1%, compared with 0.8% in the general study population, and was significantly associated with increased risk of stillbirth after controlling for multiple risk factors. The adjusted odds ratio was 8.94 for stillbirth risk in women with SCT, compared with women without SCT (P = .045), although the risk was greater among women with SCD, compared with those without SCD (aOR, 26.40).

"In addition, the stratified analysis found Black or African American patients with SCD to be at higher risk of stillbirth, compared with Black or African American patients without SCD (aOR, 3.59)," but no significant association was noted between stillbirth and SCT, the researchers wrote. Stillbirth rates were 1.1% in Black or African American women overall, 2.7% in those with SCD, and 1.0% in those with SCT. Overall, multiple gestation was associated with an increased risk of stillbirth (aOR, 4.68), while a history of cesarean delivery and being married at the time of delivery were associated with decreased risk (aOR, 0.44 and 0.72, respectively).

The lack of association between stillbirth and SCT in Black or African American patients supports some previous research, but contradicts other studies, the researchers wrote. "Ultimately, it may be impossible to disentangle the risks due to the disease and those due to disparities associated with the disease that have resulted from longstanding inequity and stigma," they said. The findings also suggest that biological mechanisms of SCT may contribute to severe clinical complications, and therefore "invite a more critical examination of the assumption that SCT is not a disease state."

The study findings were limited by several factors including the lack of assessment of SCT independent of other comorbidities, such as hypertension, preeclampsia, diabetes, and obesity, and by the use of billing codes that could misclassify patients, the researchers noted.

However, the results support some findings from previous studies of the potential health complications for pregnant SCT patients. The large study population highlights the need to identify women's SCT status during obstetric care, and to provide both pregnancy guidance for SCT patients and systemic support of comprehensive care for SCD and SCT patients, they concluded.

Disparities May Drive Stillbirth in Sickle Cell Trait Women

"There is a paucity of research evaluating sickle cell trait and the risk of adverse pregnancy outcomes such as stillbirth," Iris Krishna, MD, of Emory University, Atlanta, said in an interview. "Prior studies evaluating the risk of stillbirth have yielded mixed results, and an increased risk of stillbirth in women with sickle cell trait has not been established. This study is unique in that it attempts to address how racial inequities and health disparities may contribute to risk of stillbirth in women with sickle cell trait."

Although the study findings suggest an increased risk of stillbirth in women with sickle cell trait, an analysis stratified for Black or African American patients showed no association, Krishna said. "The prevalence of stillbirth was noted to be 1% among Black or African American patients with sickle cell trait compared to the prevalence of stillbirth of 1.1% among Black or African American women with no sickle cell trait or disease. Although, sickle cell trait or sickle cell disease can be found in any racial or ethnic group, it disproportionately affects Black or African Americans, with a sickle cell trait carrier rate of approximately 1 in 10. The mixed findings in this study amongst racial/ethnic groups further suggest that there is more research needed before an association between stillbirth and sickle cell trait can be supported."

As for clinical implications, "it is well established that for women with sickle cell trait there is an increased risk of urinary tract infections in pregnancy," said Krishna. "Women with sickle cell trait should have a urine culture performed at their first prenatal visit and each trimester. At this time, studies evaluating risk of stillbirth in women with sickle cell trait have yielded conflicting results, and current consensus is that women with sickle cell trait are not at increased risk. In comparison, women with sickle cell disease are at increased risk for stillbirth and adverse pregnancy outcomes. Women with sickle cell disease should be followed closely during pregnancy and fetal surveillance implemented at 32 weeks, if not sooner, to reduce risk of stillbirth.

"Prior studies evaluating risk of stillbirth in women with sickle cell trait consist of retrospective cohorts with small study populations," Krishna added. Notably, the current study was limited by the inability to adjust for comorbidities including diabetes, hypertension, and obesity, that are not only associated with an increased risk for stillbirth, but also disproportionately common among Black women.

"More studies are needed evaluating the relationship between these comorbidities as well as studies specifically evaluating how race affects care and pregnancy outcomes," Krisha emphasized.

The study was funded by the University of Pennsylvania department of biostatistics, epidemiology, and informatics. Lead author Canelón disclosed grants from the Centers for Disease Control and Prevention, Clinical and Translational Science Awards, and grants from the National Institutes of Health outside the submitted work. Krishna had no financial conflicts to disclose, but serves on the editorial advisory board of Ob.Gyn News.

This article originally appeared on, part of the Medscape Professional Network.


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