Antibody Sugar Coatings Shift Within Weeks of Conception, Pregnancy Study Finds

Pregnancy demands one of the most remarkable immunological balancing acts in human biology. The developing fetus carries genetic material from both parents, making it, from the immune system’s perspective, a partially foreign entity that must be tolerated rather than attacked. A new longitudinal study from the Rotterdam Periconception Cohort, published in Reproductive Sciences, has now mapped in unprecedented detail how the molecular decorations on maternal antibodies change throughout gestation, revealing that the immune system begins recalibrating toward an anti-inflammatory state remarkably early, within the first trimester, and that a woman’s body mass index, parity, and mode of conception leave detectable signatures on these antibody modifications from the very start.

The research, led by Lotte W. Voskamp of Erasmus University Medical Center in Rotterdam together with colleagues at Leiden University Medical Center, focused on glycosylation, the enzymatic attachment of carbohydrate chains to proteins. Immunoglobulin G, the only antibody class capable of crossing the placenta to provide the fetus with passive immunity, and immunoglobulin A, the second most abundant antibody in serum, both carry glycans at defined sites that profoundly alter their function. Adding galactose and sialic acid to these glycans generally pushes antibodies toward anti-inflammatory, tolerogenic behavior, whereas a bisecting N-acetylglucosamine residue is associated with more pro-inflammatory effector activity. Fucosylation, the attachment of a fucose sugar, modulates how antibodies engage Fc receptors and the complement system.

To track these molecular shifts, the team analyzed serum samples from 202 women with singleton pregnancies, collected at approximately 9, 11, 13, 22, and 32 weeks of gestation, with umbilical cord blood obtained at delivery for a subset of 78 neonates. Using a validated liquid chromatography-mass spectrometry workflow, the researchers affinity-captured IgG and IgA, digested the antibodies with trypsin, and quantified site-specific glycopeptides with the LaCyTools software package. Laboratory personnel were blinded to clinical characteristics, and longitudinal changes were modeled with linear mixed-effects models that accounted for repeated measurements in each participant, with false discovery rate correction applied to control for multiple comparisons.

The central finding is striking in its timing. As early as week 9 of gestation, galactosylation and sialylation of both IgG and IgA were already increasing, while bisection declined, indicating that the shift toward an immunological tolerance profile begins well before previous studies had captured it. For IgG, this anti-inflammatory trajectory continued throughout pregnancy, with sialylation rising even more prominently than galactosylation, particularly in the IgG2 subclass. Bisection on IgG1 fell significantly between weeks 9 and 13, from a mean of 15.88 to 14.79, before reversing course and climbing toward the third trimester, a pattern the authors interpret as possible immune recalibration that prepares the maternal body for labor, itself a coordinated inflammatory process.

IgA told a more complicated story. At several N-glycosylation sites, including those designated LSL, TPL, LAGC, and LAGY, the early first-trimester increase in galactosylation and sialylation reversed after week 13, with bisection rising and the anti-inflammatory traits declining through the second and third trimesters. Meanwhile, at the O-glycosylated hinge region of IgA1, the study documented a shift from immature toward more mature, galactosylated structures, with Tn antigens, markers of incomplete glycan processing, declining over gestation. Because IgA glycosylation in pregnancy has been examined in only a handful of prior studies, these data fill a substantial gap and suggest that IgA follows its own dynamic program rather than simply mirroring IgG.

The study’s second major contribution is the demonstration that maternal characteristics imprint themselves on antibody glycosylation from early pregnancy onward. Women with a higher body mass index displayed a more pro-inflammatory profile, with significantly lower galactosylation and sialylation in the IgG4 subclass and increased core fucosylation of IgG1 and of IgA at the TPL and joining-chain sites. This aligns with evidence outside of pregnancy linking obesity to reduced IgG galactosylation and elevated inflammatory tone, and it raises the possibility that antibody glycosylation represents one biological pathway connecting elevated BMI to adverse pregnancy outcomes such as gestational diabetes and hypertensive disorders.

Parity and conception mode also mattered. Nulliparous women, who face a higher risk of immune-mediated complications such as pre-eclampsia, showed lower galactosylation in the O-glycosylated hinge region of IgA1 alongside elevated Tn antigens, but paradoxically a trend toward higher, more anti-inflammatory galactosylation and sialylation at N-glycosylation sites. Pregnancies conceived through in vitro fertilization or intracytoplasmic sperm injection exhibited broadly elevated galactosylation, sialylation, and fucosylation across multiple IgG and IgA sites, a more complex and anti-inflammatory glycan landscape. The authors caution that these associations may be confounded by the underlying causes of subfertility or by the exogenous estrogen and progesterone used in fertility treatment, noting that estradiol has been shown in prior work to promote anti-inflammatory IgG glycosylation patterns.

Because nulliparity was considerably more common in the ART group than among spontaneous conceptions, the team performed a sensitivity analysis to disentangle the two effects. The direction of the observed associations remained consistent after stratification, although some findings lost statistical significance, likely reflecting reduced power in the smaller subgroups. The LAGY-site differences in nulliparous women were replicated only within the IVF/ICSI subgroup, while in spontaneously conceived first pregnancies, bisection and sialylation per galactose at the LAGC and TPL sites were significantly higher. These nuances underscore both the promise and the statistical challenges of glycomics research, where dozens of traits are tracked simultaneously across many clinical variables.

The cord blood analysis added a neonatal dimension to the story. Consistent with the hypothesis that the placenta preferentially transports certain glycoforms, IgG galactosylation and sialylation in cord blood exceeded even the elevated levels found in maternal third-trimester serum, likely reflecting selective binding to the neonatal Fc receptor during transplacental transfer. IgA, which does not cross the placenta, was detectable in cord blood only at the SES region, and its galactosylation, sialylation, bisection, and fucosylation were all lower than in maternal blood, consistent with endogenous fetal production late in gestation. Gestational age at birth correlated positively with SES-region sialylation and galactosylation, and exploratory correlations emerged between glycosylation traits and fetal sex and birthweight percentile, findings the authors emphasize require confirmation in larger cohorts.

The broader significance of this work lies in its biomarker potential. In rheumatoid arthritis, reduced IgG galactosylation and sialylation precede disease onset and track with disease activity and treatment response, while in metabolic and cardiovascular disease, lower IgG galactosylation has been linked to insulin resistance and heightened cardiovascular risk. If first-trimester glycosylation signatures prove predictive of pre-eclampsia, fetal growth restriction, or preterm birth, a simple blood draw in early pregnancy could eventually help identify women who need intensified surveillance during the critical periconceptional window, when implantation, embryogenesis, and placentation are initiated. The authors call for future studies linking early glycosylation changes directly to adverse outcomes and to measures of first-trimester placentation, and for mechanistic work that accounts for hormonal regulation, conception mode, parity, and BMI. For now, the study establishes that the maternal immune system’s sweet transformation begins almost immediately after conception, and that the shape of that transformation is written, in part, by the biology a woman brings to pregnancy.

Subject of Research: Longitudinal changes in IgG and IgA antibody glycosylation during pregnancy and their associations with maternal BMI, parity, and conception mode

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

Article References: Voskamp, L. W., Daniels, A., Rousian, M., van Hoek, M., Wuhrer, M., Steegers-Theunissen, R. P. M., Danser, A. H. J., & Verdonk, K. (2026). Longitudinal Profiling of IgG and IgA Glycosylation in Pregnancy Reveals Early Associations with BMI, Nulliparity and Conception Mode: The Rotterdam Periconception Cohort. Reproductive Sciences. https://doi.org/10.1007/s43032-026-02190-9

Image Credits: AI Generated

DOI: 10.1007/s43032-026-02190-9

Keywords: pregnancy, glycosylation, IgG, IgA, immune tolerance, first trimester, BMI, nulliparity, assisted reproduction, mass spectrometry, Rotterdam Periconception Cohort, biomarkers