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Breastfeeding reduces anti-NIMA immune response
breastfed, 80 mothers for a median period of three months (Table 1).
Univariate analyses revealed that antigen immunogenic- ity (OR 17.3; 95% CI 10.0-29.9), number of IUTs (OR 1.22; 95 % CI 1.04-1.43) and IUT-year (OR 0.85; 95% CI 0.68-1.06) were associated (all P<0.2) with antibody for- mation. ABO compatibility, maternal HLA-DRB1*15 genotype and number of pregnancies were regarded not associated (all P>0.5) (Table 2).
Multivariate analysis showed that, high compared to low antigen immunogenicity, increasing number of IUTs and antigen exposure as NIMA compared to exposure not as NIMA were associated with an increased risk of having antibodies (aOR for the latter 3.28; 95% CI 1.38-7.80). A longer BF period showed a trend towards a higher risk for antibodies (OR 1.17; 95% CI 0.97-1.43). The interaction term (NIMA by categorized months BF) revealed that a longer BF period was associated with a decreased risk of antibody formation against NIMA (aOR 0.66; 95% CI 0.48-0.93) compared to antigens not exposed to as NIMA (Table 3).
Sensitivity analyses with dichotomized periods of BF showed that BF for at least two months compared to a shorter period, and NIMA exposure were associated with an increased risk for antibodies (aOR 2.39; 95% CI 1.12- 5.13 and aOR 3.34; 95% CI 1.55-7.24, respectively). Again, the interaction term showed a decreased risk for antibodies against NIMA after at least two months BF (aOR 0.12; 95% CI 0.03-0.42). These associations remained when comparing at least three months BF to a shorter period. Continuation of BF beyond three months did not seem to provide additional protection against the formation of NIMA antibodies (Table 3).
For all analyses, antigen immunogenicity and number of IUTs were associated with an increased risk for antibod- ies, while IUT-year and the interaction term NIMA by antigen immunogenicity were not associated with anti- body risk.
Discussion
The role of exposure to RBC-NIMAs during fetal or neonatal life on later development of (non-D) RBC anti- bodies after re-exposure to the antigens during pregnancy
as IPAs or by transfusions was investigated in 125 three- generation families with a (grand)child with HDFN treat- ed with IUT. In contrast to women who were breastfed for less than two months, BF for at least two months was associated with a significantly lower incidence of alloanti- bodies to NIMAs compared to the same antigens not pre- viously encountered as NIMA.
The relevance of BF in the induction of tolerance against NIMA has mainly been studied in the context of the major histocompatibility complex (MHC) antigens in mice mod- els.12,26,27 These studies clearly showed that a maximal immunoregulatory effect to NIMA is obtained after expo- sure both in utero and by BF.12,13 However, the underlying mechanism(s) remain elusive, and several immunological consequences of fetal/maternal interactions have been proposed both in mice and humans. BF in mice induced Foxp3+CD25+ T regulator cells potentially capable of regu- lating anti-maternal MHC immune responses.13,28 BF
Table 1. Characteristics of the 125 mothers. Characteristics
Age at follow up, median (range), years
BF duration in months, median (range)
No breastfeeding One month
Two months
Three months
Four to six months More than six months
N (%)*
40 (24–52)
2 (0-12)
45 (36) 17 (14) 15 (12) 17 (14) 18 (14) 13 (10)
Birth order of first IUT treated child, median (range) 3 (1–7) Number of IUTs, median (range) 3 (1–10) Maternal-fetal major ABO compatibility – N/N tested (%)101/112 (90)
HLA-DRB1*15 positive Antibody causing HDFN:
Anti-D
Anti-K
Anti-c
Anti-Kpa and -Cw
38 (30)
93 (74) 19 (15) 11 (9) 2 (2)
Table 2. Variables associated with RBC antibody formation after mismatched antigen exposures, univariate analysis.
BF: breastfeeding; IUT: intra-uterine transfusion; HDFN: hemolytic disease of the fetus and newborn. *: Data presented as number (%) of women unless stated otherwise.
Variables
RBC antigen immunogenicity (low** [non Rh, K] vs. high [Rh, K]) Number of IUTs (1, 2, 3, 4 and >4)
IUT year (5-year blocks)
ABO compatibility** versus incompatibility
HLA-DRB1*15 genotype absent** versus present Number of pregnancies (≤2, 3 and >3) Exposure not as a NIMA** vs. NIMA re-exposure Breastfeeding months (0, 1, 2, 3, 4-6 and >6)
Antibodies after NIMA-mismatched exposures
Antibodies after NIMA-matched exposures
OR 95% CI
17.3 10.0-29.9
1.22 1.04-1.43
0.85 0.68-1.06
1.26 0.62-2.57
1.10 0.69-1.75
0.98 0.75-1.27
0.78 0.50-1.21
0.98 0.87-1.10
1.08 0.93-1.25
0.82 0.67-1.01
P
<0.001
0.014
0.148
0.531
0.689
0.877
0.265
0.721
0.320
0.062
RBC:red blood cell;OR:odds ratio;CI:confidence interval;IUT:intra-uterine transfusion;NIMA:non-inherited maternal antigen;[non Rh,K]:Fya,Fyb,Jka,Jkb,M,S and s antigens; [Rh, K]: C, c, E, e and K antigens; **: reference.
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