Objective: Placenta-related complications are major contributors to maternal and neonatal morbidity. While most research has focused on vascular dysfunction, growing evidence shows that inadequate maternal immune adaptation, marked by increased inflammation and reduced tolerance, also plays a key role in their pathogenesis. Immunoglobulin (Ig) glycosylation, the enzymatic attachment of glycans, modulates immune function by altering molecular structure and receptor affinity (Figure 1). During pregnancy, IgG and IgA glycosylation normally shift toward a more anti-inflammatory profile. We hypothesize that this adaptation is attenuated in complicated pregnancies, reflecting impaired immune adaptation. Therefore, our aim was to investigate whether longitudinal IgG and IgA glycosylation trajectories differ between pregnancies with and without placenta-related complications. Design and method: This study used data from women with singleton pregnancies enrolled in a prospective periconceptional cohort at a large academic medical center in the Netherlands between 2017 and 2018. Serum samples were collected at 9, 11, 13, 22, and 32 weeks gestational age (GA). IgG and IgA glycosylation was measured using LC-MS, 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 one placenta-related complication. In these pregnancies, galactosylation and sialylation were consistently lower, whereas fucosylation and bisection were higher. From 9 weeks GA 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 maternal pro-inflammatory glycosylation profiles. These findings suggest a role of immunoglobulin glycosylation in placental dysfunction, with specific glycoforms as possible biomarkers or novel targets for prevention and therapy in hypertensive disorders of pregnancy.
Voskamp et al. (Fri,) studied this question.
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