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