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Breastfeeding reduces anti-NIMA immune response
Table 3. Variables associated with red blood cell antibody formation after mismatched antigen exposures, by categorized and dichotomized breast- feeding periods, multivariate analysis.*
BF duration
Breastfeeding
aOR 95% CI
NIMA exposure** aOR 95% CI
3.28 1.38-7.80
1.81 0.68-4.79
1.78 0.71-4.41
3.34 1.55-7.24
2.49 1.23-5.06
1.77 0.92-3.39
1.55 0.83-2.92
3.57 1.47-8.70
1.15 0.36-3.69
NIMA by months BF aOR 95% CI
0.66 0.48-0.93
0.77 0.23-2.53
0.78 0.24-2.48
0.12 0.03-0.42
0.41 0.03-0.59
0.37 0.07-1.98
0.86 0.13-5.61
0.11 0.02-0.51
0.35 0.07-1.80
Categorized
0,1,2,3,4-6,>6 1.17 Dichotomized
0 vs.>0 1.11 ≤1 vs.>1 1.15 ≤2 vs.>2 2.39 ≤3vs>3 1.95 ≤4 vs. >4 1.34 ≤6 vs. >6 1.08 <2 vs. >3 2.37
2and3vs.>3 1.11
0.97-1.43
0.54-2.26
0.56-2.33
1.12-5.13
0.83-4.59
0.53-3.43
0.35-3.32
0.93-6.05
0.41-2.96
*The complete table 3, including results from the variables, Immunogenicity, Number of IUTs,Year of IUT and the interaction term NIMA by Immunogenicity are in the Online Supplementary Appendix. BF: breastfeeding; NIMA: non-inherited maternal antigen; aOR: adjusted odds ratio; CI: confidence interval; **The reference is incidence of antibodies after exposure not as a NIMA.
Figure 2. Study flowchart of 125 mothers exposed to 330 non-D RBC antigens and antibody response. RBC: red blood cell; NIMA: non-inherited maternal anti- gen; HDFN: hemolytic disease of the fetus and newborn.
others do not, despite multiple exposures to mismatched RBC antigens (nonresponders), has yet to be unravelled and considered to be multifactorial. Factors such as anti- gen immunogenicity and dose, route of exposure, race, age, co-existence of inflammation during RBC antigen exposure, genetic factors (such as HLA and immunoregu- latory gene polymorphisms), and medical (immunosup- pressive) conditions have all been reported to enhance or ameliorate RBC alloantibody formation.38-42 The duration of exposure to NIMA by BF adds a new aspect to this already complex question.
Limitations
Firstly, our study cohort - similar to the HLA immunized cohort on the renal transplant waiting list, mentioned before8 - consisted of highly immunized individuals, already possessing at inclusion at least one strong RBC antibody causing HDFN. We previously showed that once individuals produced an RBC antibody, there is over a 20% risk of forming additional antibodies upon subse- quent exposures.21,43 The results in these extensively allo-
exposed young women, of which 80% formed antibodies against multiple RBC antigens after delivery, may not be generalizable for first RBC antigen encounter and for immune-compromised patients. Secondly, unidentified or unknown antigen exposures that had not resulted in RBC antibodies may have been missed; however, it is likely that these were equally distributed in the distinct BF peri- ods. Thirdly, Owen and colleagues evaluated anti-D for- mation in relation to the D-NIMA. As a result of RhD immunoprophylaxis, we could not repeat Owen’s design, however we did find support for a grandmother effect to non-D NIMAs after oral exposure by more than two months BF. Fourthly, the duration of BF was assessed through a questionnaire. BF was given decades before this study, and memory may not be exactly accurate. Lastly, in agreement with Owen, our study is hypothesis-generat- ing and needs corroboration before drawing any definitive conclusion.
In conclusion, in women with HDFN-affected children, prolonged oral exposure to non-D NIMA by BF was asso- ciated with a significantly lower incidence of antibody production when later challenged to these NIMAs com-
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