Optimizing hemolytic disease management with third-trimester screening


Dutch researchers reviewed data from 62,000 Rh-negative women to determine how to best detect and treat severe hemolytic disease of the fetus and newborn.

Third-trimester red blood cell (RBC) antibody screening in pregnant women who are Rhc-negative contributes to the timely detection and treatment of severe hemolytic disease of the fetus and newborn (HDFN). It also likely leads to a decrease in the incidence of severe HDFN, according to researchers who analyzed data from the Dutch national screening program.

The nationwide cohort study reviewed data prospectively collected between October 1, 2011 and October 1, 2013 from 62,096 Rhc-negative women without RBC antibodies at first trimester screening and their offspring.1 Late alloimmunization (presence of newly detected, clinically relevant RBC antibodies at week 27 of pregnancy) occurred in 99 women (0.16%), of whom 91% developed c and/or E antibodies.

There were 22 cases of HDFN in the overall population, of which 2 (0.003%) were severe (disease needing intervention with intrauterine transfusion and/or neonatal exchange or blood transfusions in the first week after birth) and 20 (0.032%) were moderate (need for treatment of neonatal jaundice with phototherapy only). Rates of severe and moderate HDFN in the late alloimmunization subgroup were 2% and 22.5%, respectively.

There were no fetal or neonatal deaths in the series. The number needed to screen to detect one case of HDFN was calculated to be 2823, and the number needed to screen to detect one severe HDFN case was 31,048.

 “In the Netherlands, the current alloimmunization screening protocol for pregnant women involves a first trimester assay for RBC antibodies and repeat screening at 27 weeks’ gestation for RhD-negative and Rhc-negative women. The second screening of Rhc-negative women, who account for almost 20% of the population, was implemented in July 2011 after it was recognized that four cases of severe HDFN were missed with the first trimester screening annually due to late Rhc immunization,” explained Yolentha Slootweg, MSc, department of obstetrics, Leiden University Medical Centre, Leiden, the Netherlands.



“To our knowledge, this is the first prospective nationwide study on the effect of a second antibody screening in Rhc-negative women, and the results of the study corroborate the benefit of the second screening.”

The investigators also sought to identify potential risk factors for late alloimmunization among Rhc-negative pregnant women by conducting a case-control study comparing 54 Rhc-negative women with late alloimunization and 104 matched controls without late alloimmunization. The analyses found that blood transfusion, parity, and chorionic villus sampling/amniocentesis in the current pregnancy were independent predictors.

Also read: IV Drug Abuse Linked to Alloimmunization

“These findings are consistent with the hypothesis that the primary immune response occurs in or following a previous pregnancy. Subsequently, antibody levels fall and are too low to be detected at first trimester screening, but rise again during pregnancy after the maternal immune system has renewed contact with fetal RBCs. The potential for such renewed contact to occur after invasive diagnostic procedures associated with fetomaternal hemorrhage underlines the importance of noninvasive prenatal testing,” said Ms Slootweg.

“Our analysis also underlines a restrictive blood transfusion policy, as well as the use of Rhc- and RhE-matched donor blood, according to current Dutch guidelines.”


1. Slootweg YM, Koelewijn JM, van Kamp IL, et al. Third trimester screening for alloimmunisation in Rhc-negative pregnant women: evaluation of the Dutch national screening programme. BJOG. 2016;123(6):955–963.

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