The LOTUS study

LOng Term follow- Up after intra-uterine transfusion S


The mainstay for the treatment of fetal anemia is intrauterine blood transfusion. The Leiden University Medical Center is the single national referral center in the Netherlands for the management of pregnancies complicated by severe fetal anemia. The main causes of fetal anemia are maternal red blood cells (RBC) alloimmunization and, less frequent, Parvo B19 infection and feto-maternal hemorrhage.

Alloimmunization is a major transfusion problem and deliberate transfusions may induce multiple (HLA, HPA, RBC) alloantibodies. Intra-uterine transfusions (IUT) for alloimmune hemolytic disease (HDFN) are associated with a high immunization rate despite the usually small volumes of the feto-maternal hemorrhage (FMH) of just a few milliliters. Although it has not been systematically studied, pregnancy-induced antibodies, in contrast to transfusion-induced RBC antibodies, can persist for many years. These antibodies complicate both transfusion therapy and future pregnancies. Patients who develop RBC antibodies are high responders with a more than 20-fold increased risk for additional antibody formation.

Most study groups report perinatal survival rates in RBC alloimmunization treated with IUTs above 90%. To date only a few small studies have reported on the long-term neurodevelopmental outcome. The main limitation of these studies is the small number of patients included (range 16 to 69).


Some transfusion recipients seem more susceptible for alloimmunization, but with respect to red cell antibodies the mechanisms have hardly been investigated. IUTs are associated with increased FMH, transmitting not only donor red cells but also viable HLA-haplo-identical fetal blood cells. After IUT treatment more than 20% of mothers have formed new RBC antibodies and more than 70% have multiple antibody specificities. Although data are lacking, immunological changes in pregnancy may enhance antibody formation. It is not known whether a combination of factors enhances antibody formation and whether post-pregnancy chimerism contributes to maintenance of antibody production.

As perinatal survival is improving, attention is now shifting towards short-term and long-term outcome in surviving children. Although hydrops fetalis has been reported to be associated with increased mortality, not much is known on the association between the severity of fetal anemia and long-term neurodevelopmental outcome.


The first part of this study addresses several putative mechanisms associated with blood group alloimmunization in these mothers. The second part of this study determines the incidence of long-term neurodevelopment impairment (NDI) and associated risk factors in children treated with IUT.

Study design

Observational cohort study.

Study population

All mothers and their children who were treated with intra-uterine RBC transfusions over the past 20 years.


One-time visit to the LUMC for sampling, examination and questionnares

Main study parameters/endpoints



Procedure of the research (study protocol)

Patients and their off-springs will be asked to come to the LUMC where a one-time blood sample, mouth swap or saliva sample will be taken.
Maternal health and childrens’ neuromotor development will be assessed by questionnares and neurological and psychosocial examination.

Exclusion criteria

Women with no live-born ‘IUT’-children.

Time schedule

Not applicable


H. Schonewille PhD
A. Brand MD PhD
I.I.N Doxiadis MD PhD
E. Lopriore MD PhD
D. Oepkes MD PhD

Participating hospitals

Leiden University Medical Center (LUMC), Leiden, The Netherlands; Departments of  Immunohematology and Blood Transfusion, Pediatrics and Obstetrics.


H. Schonewille PhD


Last edited on: 29 August 2013