Interpretation
In this study, severe HDFN occurred more often in subsequent (31%) compared to first immunized (3%) pregnancies, in line with findings of others. For example, Tiblad et al. found 1.7% (5/288) severe HDFN in first immunized pregnancies, according to our definitions, and 19% in the second pregnancy at risk.11 Similar to our findings, mothers that were already immunized during their first ongoing pregnancy (before giving birth to a RhD-positive child) received more treatment for HDFN, although not significantly. Other authors observed 0% severe disease in first immunized pregnancies and 19% in ‘reactivation’ of RhD immunization.12 Our study is however the first study directly comparing the first and subsequent immunized pregnancy of the same woman, which demonstrated that the severity of HDFN did not increase in 44% of the cohort. This challenges the general accepted concept that every next child at risk for HDFN will be more severely affected.
We found that the proportion of severe disease in a subsequent pregnancy of women that developed antibodies during their first pregnancy of a RhD-positive child, before RhIg could even be administered (group A), was as high as 48%. This is twice as much as compared to the subgroup that developed antibodies after giving birth to a RhD-positive child, despite receiving full prophylaxis (group B, 22%), a finding that approached statistical significance (figure 2B and C). Several mechanisms might contribute to this difference in course of disease.
First: women developing antibodies as a result of a large immunizing event (e.g. birth, group A) are ‘low-responders’, as compared to women with an antibody response to a small foetomaternal haemorrhage during pregnancy (group B, potential ‘high-responders). Recent publications revealed associations between the intensity of an antibody response and a combination of genetic risk factors such as carrying HLA-DRB1*1501 and FCRIIC-ORF alleles.13-15 If in the future ‘high responders’ could be identified early, additional anti-D prophylaxis before the conventional antenatal administration might prevent immunization during the first pregnancy at risk. In this study, no association was found in this subgroup between clinical or biochemical (ADCC/titer) disease severity and severe disease in the subsequent pregnancy. Therefore, all women who develop RhD antibodies in their first pregnancy at risk for immunization are to be monitored closely.
Second: the immune response to RhD-antigens is not prevented by anti-D prophylaxis but is merely suppressed, causing a stronger antibody response in women that have never received anti-D (group B), as opposed to women that received prophylaxis at least twice (group A), which has earlier been suggested by others.6, 7, 11, 16
A third hypothesis is that women in group A and B have different IgG-Fc-glycosylation profile of their anti-D antibodies, which correlates with clinical and biochemical (ADCC) HDFN severity.17, 18 Interestingly, we have previously shown that there exists immunological memory for this Fc-glycosylation profile, meaning that this profile is sustained in subsequent pregnancies.18 Already before RhIg was available, disease severity in subsequent pregnancies seemed to be interrelated.4 This correlates with our finding of a persistent tendency to milder disease in the subsequent pregnancy in group A: only one of 16 women with no or mild disease in her first immunized pregnancy developed severe disease, and a low ADCC result in the first immunized pregnancy was the best predicting factor for no severe HDFN in the next pregnancy. These associations were not found in group B, possible reflecting a different IgG-Fc-glycosylation profile.
Lastly, an additional factor influencing the relation between severity in the first and subsequent immunized pregnancies might be the inherited foetal Fc-receptor profiles, as we have previously shown that this profile influences the risk of severe HDFN.15