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