Disease-severity in subsequent pregnancies with RhD
immunization: a nationwide cohort
Carolien Zwiers, MD PhD, Department of Obstetrics, Leiden University
Medical Center, Leiden, the Netherlands; Department of Experimental
Immunohematology, Sanquin Research and Landsteiner Laboratory, Academic
Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
Yolentha M. Slootweg, MD, Department of Obstetrics, Leiden University
Medical Center, Leiden, the Netherlands;
Joke M. Koelewijn, MD PhD, Department of Experimental Immunohematology,
Sanquin Research and Landsteiner Laboratory, Academic Medical Center,
University of Amsterdam, Amsterdam, the Netherlands; Department of
Immunohematology Diagnostic Services, Sanquin, Amsterdam, the
Netherlands.
Peter C. Ligthart, MSc, Department of Immunohematology Diagnostic
Services, Sanquin, Amsterdam, the Netherlands.
Johanna G. van der Bom, MD PhD, Center for Clinical Transfusion
Research, Sanquin Research, Leiden, the Netherlands; Department of
Clinical Epidemiology, Leiden University Medical Center, Leiden, the
Netherlands.
Inge L. van Kamp, MD PhD, Department of Obstetrics, Leiden University
Medical Center, Leiden, the Netherlands.
Enrico Lopriore, MD PhD, Department of Pediatrics, Leiden University
Medical Center, Leiden, the Netherlands.
C. Ellen van der Schoot, MD PhD, Department of Experimental
Immunohematology, Sanquin Research and Landsteiner Laboratory, Academic
Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
Dick Oepkes, MD PhD, Department of Obstetrics, Leiden University Medical
Center, Leiden, the Netherlands.
Masja de Haas, MD PhD, Department of Immunohematology and Blood
Transfusion, Leiden University Medical Center, Leiden, the Netherlands;
Immunohematology Diagnostic Services, Sanquin Blood Supply, Amsterdam,
the Netherlands.
Corresponding author: Carolien Zwiers, Department of Obstetrics, Room
K6-034, Leiden University Medical Center, PO box 9600, 2300 RC Leiden,
the Netherlands,
c.zwiers@lumc.nl,
+31612766799, fax number +31715266741.
Running title: HDFN severity in subsequent pregnancies.
ABSTRACT
OBJECTIVE(S): to evaluate the severity of HDFN in subsequent
pregnancies with RhD immunization and to identify predictive factors for
severe disease.
DESIGN: prospective cohort.
SETTING: the Netherlands.
POPULATION: nationwide selection of all pregnant women with RhD
antibodies.
METHODS: women with two subsequent RhD immunized pregnancies
with RhD-positive children after antibodies were detected were included.
MAIN OUTCOME MEASURE: the severity of HDFN in the first and
subsequent pregnancy at risk.
RESULTS: 62 RhD immunized women with a total of 150
RhD-positive children were included. The severity of HDFN increased
significantly in the subsequent pregnancy (P <.001),
although it remained equal or even decreased in 44% of women. When
antibodies were already detected at first trimester screening in the
first immunized pregnancy, severe HDFN in the next pregnancy was
uncommon (22%), especially when no therapy or only non-intensive
phototherapy was indicated during the first pregnancy (6%), or if the
ADCC result remained <10%. Contrarily, women with antibodies
detected during the first pregnancy of a RhD positive child
(>= 27th week), most often before they
had ever received RhIg prophylaxis, were most prone for severe disease
in a subsequent pregnancy (48%).
CONCLUSION(S): RhD-mediated HDFN in a subsequent pregnancy is
generally more severe than in the first pregnancy at risk and can be
estimated using moment of antibody
detection and severity in the first immunized pregnancy. Women
developing antibodies in their first pregnancy of a RhD-positive child
are at highest risk of severe disease in the next pregnancy.
FUNDING: grant from Sanquin Blood Supply (L2181).
KEYWORDS: Alloimmunization in pregnancy, Foetal anaemia, Foetal
hydrops, Haemolytic disease of the foetus and newborn, Intra-uterine
transfusion, Natural course of disease, Pregnancy complications, Red
cell immunization in pregnancy.
TWEETABLE ABSTRACT
The moment of RhD antibody detection and previous HDFN severity help to
predict HDFN severity in a next pregnancy.
INTRODUCTION
Haemolytic disease of the foetus and newborn (HDFN) is a serious, and
nowadays rare condition, caused by maternal alloantibodies against
foetal red cells. The subsequent haemolysis may result in neonatal
anaemia and hyperbilirubinemia, evoking the need for phototherapy, red
cell transfusions or exchange transfusions. In severe cases, anaemia
occurs prenatally and intervention with intrauterine transfusion(s)
(IUT) is needed. Although the introduction of RhIg-prophylaxis has
greatly reduced the RhD immunization-rate, it still has remained the
major cause of severe HDFN cases.1
As blood transfusions are nowadays always ABO- and RhD-matched, RhD
alloimmunization is mostly the result of maternal exposure to foetal red
cell antigens, inherited from the father.2 The risk of
alloimmunization depends on the duration and amount of foetomaternal
haemorrhage, characteristics of the maternal immune system and of the
red blood cell antigens.3
A generally accepted idea is that the severity of HDFN increases in
every subsequent pregnancy, as a rise in the amount of stillbirths in
every following pregnancy affected with HDFN was already reported in
1957, before the introduction of RhIg.4, 5 As the
administration of RhIg is thought to have a long lasting suppressive
effect on the strength of the immune response,6, 7this generally accepted idea cannot simply be applied to the current
setting.
The aim of this study is to assess the severity of HDFN in consecutive
pregnancies with RhD immunization and RhD-positive foetuses, in the
presence of routine antenatal and postnatal RhIg prophylaxis, in order
to properly counsel and manage women after a first RhD immunized
pregnancy. Furthermore, we evaluated which factors from the first
immunized pregnancy are associated with severe disease in a subsequent
pregnancy at risk.
METHODS