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

The study, conducted by a team led by Dong Keon Yon of Kyung Hee University College of Medicine and published in the World Journal of Pediatrics, capitalized on a uniquely powerful data resource: the National Health Insurance Service of Korea, which covers virtually the entire population. The researchers identified 3,012,992 mother-child pairs between January 1, 2009, and December 31, 2023, and after applying inclusion criteria, followed 2,777,119 children for a mean of 9.6 years. Of these, 507,845 had been exposed in utero to acid-suppressive medications, making this by far the largest dataset ever assembled to address the question of whether these common drugs leave a lasting imprint on the developing immune system.

Acid-suppressive medications are among the most frequently prescribed drugs in pregnancy. Proton pump inhibitors, or PPIs, block the hydrogen-potassium ATPase enzyme in gastric parietal cells, dramatically reducing stomach acid secretion, while histamine-2 receptor antagonists, or H2RAs, achieve a similar effect by blocking histamine signaling at the H2 receptor. Pregnant women take them for gastroesophageal reflux disease, dyspepsia, and related conditions, and their use has been considered relatively safe based on decades of pharmacovigilance. Yet the biological rationale for concern is real. Gastric acid serves as a chemical barrier shaping the gut microbiome, and animal and human studies have shown that acid suppression can alter microbial composition, promote oral-to-gut bacterial transmission, and influence immune programming. Because the fetal immune system undergoes critical developmental windows in utero—including thymic selection of the T cell repertoire—researchers have long wondered whether perturbing the maternal and fetal microbial environment could tilt immune development toward autoreactivity.

To answer that question rigorously, the team classified outcomes using International Classification of Diseases, 10th Revision codes, capturing systemic autoimmune diseases, autoimmune endocrine diseases, autoimmune thyroid diseases, autoimmune hepatitis, and other autoimmune conditions such as lupus erythematosus, psoriasis, and rheumatoid arthritis. To reduce the bias that plagues observational studies of medication use, the researchers employed propensity score-based overlap weighting, a technique that reweights exposed and unexposed children so that their measured baseline characteristics—maternal age, comorbidities, co-medications, and other confounders—become statistically balanced. After weighting, the analytic cohort comprised 404,550 exposed and 404,551 unexposed pairs, and Cox proportional hazards models were used to estimate adjusted hazard ratios with 95 percent confidence intervals.

The headline findings were statistically significant but numerically small. Prenatal exposure to acid-suppressive medications was associated with an 11 percent increase in the risk of systemic autoimmune diseases (adjusted hazard ratio 1.11, 95 percent confidence interval 1.01 to 1.21) and a 9 percent increase in other autoimmune diseases (adjusted hazard ratio 1.09, 95 percent confidence interval 1.05 to 1.12). Translated into absolute terms, however, the excess risk was vanishingly small: the numbers needed to harm were 37,716 per year for systemic autoimmune diseases and 6,102 per year for other autoimmune conditions. In other words, for every several thousand exposed pregnancies followed for a year, at most one additional case of autoimmune disease would be expected beyond what would occur anyway—a magnitude of risk that is difficult to detect at the individual patient level and of questionable clinical consequence.

The most informative analysis came from the sibling comparison. By treating each mother as a separate stratum and comparing exposed children with their unexposed siblings, the researchers effectively controlled not only for measured confounders but also for the stable, unmeasured factors that siblings share: genetics, household environment, socioeconomic background, and maternal health tendencies. In this within-family analysis, the associations vanished entirely. The adjusted hazard ratio for systemic autoimmune diseases fell to 0.89 (95 percent confidence interval 0.77 to 1.03) and for other autoimmune diseases to 0.97 (95 percent confidence interval 0.92 to 1.02)—both statistically indistinguishable from no effect. Because familial confounding is the dominant alternative explanation in pharmacoepidemiology, the null sibling findings weigh heavily against a causal interpretation of the modest between-family associations.

Timing mattered in one respect. When the researchers examined exposure by trimester, first-trimester exposure was associated with a slightly elevated risk of any autoimmune disease (adjusted hazard ratio 1.09, 95 percent confidence interval 1.06 to 1.13). The first trimester coincides with the earliest phases of immune system organogenesis, including the initial establishment of hematopoietic and lymphoid lineages, and it is also the window in which maternal physiological changes make reflux symptoms particularly common—raising the possibility that the underlying indication for treatment, rather than the medication, contributes to the observed signal. The authors note that exposure during this period may warrant careful clinical consideration, even as they emphasize that the overall evidence points to limited clinical concern.

The study’s sensitivity analyses strengthened its robustness. The team examined risks separately by medication type, distinguishing PPIs from H2RAs, and by trimester of exposure, and they modeled risk as a function of time since exposure. They also conducted stratified analyses across numerous subgroups. This methodological architecture matters because prior research on acid suppression in pregnancy and early life has produced a patchwork of associations with allergic diseases, asthma, celiac disease autoimmunity, and even neuropsychiatric disorders, and much of that literature has struggled to separate drug effects from confounding by indication. The present study’s scale—nearly 2.8 million children followed for close to a decade—gives it statistical power that smaller cohorts cannot match, while the sibling design addresses the confounding problem that has undermined earlier work.

The biological plausibility of a link between acid suppression and autoimmunity rests on several converging lines of evidence. Randomized trials have shown that PPIs induce stronger oral-to-gut microbial transmission and greater gut microbiome alterations than H2RAs, and the gut microbiome is increasingly recognized as a modulator of systemic immune tolerance. H2 receptor blockade has been shown to selectively affect B and T cell function in healthy subjects, and cimetidine in particular possesses immunomodulatory properties. Meanwhile, large-scale single-cell atlases of the human thymus have illuminated how precisely T cell self-tolerance is calibrated during development, and epidemiological studies have linked gut microbiota composition to genetic risk for rheumatoid arthritis. Against this backdrop, a true drug effect on fetal immune programming was biologically conceivable—which is precisely why a study of this scale was needed to test it.

For clinicians and expectant mothers, the practical takeaway is one of measured reassurance. Untreated severe gastroesophageal reflux in pregnancy carries its own burdens, from pain and sleep disruption to impaired nutrition, and the new findings provide no compelling basis to withhold acid-suppressive therapy when it is indicated. The authors conclude that the low absolute excess risks and the null sibling-comparison findings indicate limited clinical concern, while flagging first-trimester exposure as the one scenario deserving of thoughtful prescribing decisions. As with all observational research, residual confounding cannot be excluded entirely, and the study population was confined to South Korea, which may limit generalizability to other genetic and dietary environments. But in the hierarchy of evidence on prenatal medication safety, a nationwide cohort of 2.7 million children with sibling-based negative controls represents about as close to a definitive answer as the field can currently achieve—and that answer is, on balance, a comforting one.

Subject of Research: Prenatal exposure to acid-suppressive medications and the risk of autoimmune diseases in offspring

Article Title: Association between prenatal exposure to acid-suppressive medications and subsequent risk of autoimmune diseases in offspring: a nationwide birth cohort study in South Korea

Article References: Lee, Y., Lee, K., Jo, Y., Hong, S., Lee, S., Jo, H., Woo, S., Hwang, Y., Kim, S., Hwang, H. S., Lee, J., Park, J., Lee, H., & Yon, D. K. (2026). Association between prenatal exposure to acid-suppressive medications and subsequent risk of autoimmune diseases in offspring: a nationwide birth cohort study in South Korea. World Journal of Pediatrics. https://doi.org/10.1007/s12519-026-01077-8

Image Credits: AI Generated

DOI: 10.1007/s12519-026-01077-8

Keywords: acid-suppressive medications, proton pump inhibitors, histamine-2 receptor antagonists, autoimmune diseases, prenatal exposure, birth cohort, pediatrics, South Korea, National Health Insurance Service, gut microbiome, pregnancy, first trimester