Longitudinal Profiling of IgG and IgA Glycosylation in Pregnancy Reveals Early Associations with BMI, Nulliparity and Conception Mode: The Rotterdam Periconception Cohort

During early pregnancy, the maternal immune system recalibrates to tolerate the semi-allogeneic fetus. Immunoglobulin (Ig) function is modulated by glycosylation. Prior studies showed increases in anti-inflammatory glycosylation traits (galactosylation and sialylation) in IgG and to a lesser extent in IgA towards the third trimester. This study aimed to characterize IgG and IgA glycosylation patterns throughout pregnancy and assess associations with maternal age, gravidity, body mass index (BMI) and conception mode. In the Rotterdam Periconception Cohort, serum samples from 202 women with singleton pregnancies were collected at 9, 11, 13, 22, and 32 weeks'' gestation. IgG and IgA glycopeptides were analyzed using validated liquid chromatography-mass spectrometry and summarized into galactosylation, sialylation, fucosylation, and bisection traits. Longitudinal changes were assessed with linear mixed-effects models and FDR correction and associations with maternal factors were derived from model estimates. Already in the first trimester, galactosylation and sialylation increased and bisection decreased for both IgG and IgA. IgG galactosylation and sialylation continued rising throughout pregnancy, whereas most IgA traits reversed after the first trimester. Higher BMI was associated with a pro-inflammatory profile (lower IgG galactosylation; higher IgG and IgA fucosylation). Assisted reproduction and nulliparity were associated with anti-inflammatory changes, including higher galactosylation and sialylation. In conclusion, IgG and IgA glycosylation shifts towards an anti-inflammatory profile as early as the first trimester, potentially promoting immune tolerance. Pro-inflammatory changes with higher BMI, and distinct profiles in nulliparous and ART pregnancies, may represent biological pathways linking maternal factors to pregnancy outcomes, supporting glycosylation as a candidate biomarker.Trial registration number: This study is registered at the Dutch Trial Register (NTR6854).