Longitudinal Maternal IgG and IgA Glycosylation Profiles in Pregnancy Reveal Early Immune Alterations in Placenta-Related Complications: The Rotterdam Periconception Cohort

BACKGROUND: Placenta-related complications are major contributors to maternal and neonatal morbidity. Glycosylation modulates immunoglobulin function by altering molecular structure and receptor affinity. During pregnancy, IgG (immunoglobulin G) and IgA (immunoglobulin A) glycosylation normally shift toward a more anti-inflammatory profile. We hypothesized that this adaptation is attenuated in complicated pregnancies, resulting in altered glycosylation trajectories. METHODS: Women with singleton pregnancies were enrolled in the prospective Rotterdam Periconception Cohort (2017–2018). Serum samples were collected at 9, 11, 13, 22, and 32 weeks of gestational age. IgG and IgA glycosylation was measured using liquid chromatography-mass spectrometry, and summarized into glycosylation traits (galactosylation, sialylation, fucosylation, bisection). Placenta-related complications (preeclampsia, pregnancy-induced hypertension, preterm birth, or small-for-gestational-age) were identified from medical records. Longitudinal changes and group differences in Ig glycosylation were analyzed using linear mixed-effects models with false discovery rate correction. RESULTS: Among the included 193 pregnancies, 54 were complicated by at least 1 placenta-related disorder. In complicated pregnancies, galactosylation and sialylation were consistently lower, whereas fucosylation and bisection were higher. From 9 weeks of gestational age onwards, fucosylation was significantly elevated at IgA Asn327/Asn340 and Asn205 ( Z -score difference: 0.45–0.52; q =0.002–0.004 and 0.33–0.37; q =0.038). Bisection increased more steeply at IgG1, IgA Asn144/Asn131, and IgA Asn327/Asn340 ( q =0.021–0.027). IgG galactosylation rose less across gestation ( q =0.021–0.024), and IgA galactosylation and sialylation declined more sharply at Asn144/Asn131, Asn205, and Asn327/Asn340 (q=0.000–0.026). CONCLUSIONS: Pregnancies with placenta-related complications exhibit more proinflammatory glycosylation profiles. These findings suggest a potential mechanistic link between immunoglobulin glycosylation and placental dysfunction, with specific glycopeptides as possible biomarkers. REGISTRATION: URL: https://onderzoekmetmensen.nl/en/trial/57880 ; Unique identifier: NL-OMON57880.