The study team, led by Mehrnaz Adib and Payman Sadeghi, enrolled 171 neonates between March 2023 and March 2024 at a single center. Crucially, they deliberately excluded babies whose mothers had active or newly diagnosed autoimmune disease, or who had experienced a disease flare during pregnancy. That design choice is what makes the study distinctive: most existing knowledge about neonatal ANA positivity comes from high-risk pregnancies where mothers have known conditions such as lupus or Sjögren’s syndrome, and where antibodies like anti-Ro/SSA can cause congenital heart block and neonatal lupus rashes. By focusing on a clinically lower-risk population, the researchers asked a more fundamental question: how often does cord blood from apparently unremarkable pregnancies test positive for antinuclear antibodies, and does that positivity translate into any detectable illness?

The technical backbone of the study was the indirect immunofluorescence assay, or ANA-IFA, performed on human epithelial type 2, or HEp-2, cells. This method remains the gold standard for ANA detection because it exposes the patient’s serum to whole cells and lets trained observers see exactly where fluorescently labeled antibodies bind within the nucleus. The assay is broad by design; it detects reactivity against many nuclear antigens at once, which makes it sensitive but not specific for any particular disease. Out of 171 cord-blood samples, 26 came back positive, a prevalence of 15.2 percent, with an exact 95 percent confidence interval ranging from 10.2 to 21.5 percent. In other words, roughly one in six newborns in this low-risk cohort carried detectable antinuclear reactivity at birth.

That number alone is striking, but the researchers went further. Each ANA-IFA-positive infant was then subjected to a multiparameter antigen-specific antibody panel, a line-immunoassay approach that probes for reactivity against individual molecular targets. Only four of the 26 positive infants, or 15.4 percent, showed reactivity on this finer-grained panel. All four carried antibodies against double-stranded DNA, a target classically associated with systemic lupus erythematosus. Two also had anti-histone antibodies, and single infants showed reactivity against anti-nucleosome, anti-Jo-1, and anti-Ro52. Notably, none of the infants had reactivity against Ro60 or La/SSB, the two antigens most tightly linked to congenital heart block and neonatal lupus when transferred across the placenta. The absence of those particular specificities is perhaps the single most clinically comforting detail in the entire dataset.

All 26 ANA-IFA-positive infants then underwent a protocol-driven evaluation that most newborn screening programs would consider exhaustive. It included hematologic assessment with complete blood counts, liver enzyme measurement, electrocardiography, echocardiography, and structured clinical examination, repeated through the first 12 months of life. The results were remarkably benign. Four infants showed transient elevations in liver enzymes, specifically alanine and aspartate aminotransferases, but these abnormalities normalized within a single month and were not accompanied by any other signs of disease. Beyond that, no clinically relevant autoimmune manifestations were detected in any of the 26 positive infants, giving a rate of zero out of 26, with an exact 95 percent confidence interval of 0.0 to 13.2 percent. Hearts were structurally normal on echocardiography, conduction was normal on electrocardiography, and blood counts stayed within expected ranges.

The 145 ANA-IFA-negative infants received routine clinical follow-up, with investigations ordered only when symptoms warranted. None was recorded as developing autoimmune manifestations during the first year, but the authors are careful to acknowledge an important asymmetry in their design: because the negative group did not undergo systematic laboratory and cardiac screening, subclinical abnormalities in that group cannot be formally excluded. This differential outcome ascertainment, where positive infants were scrutinized far more intensively than negative ones, is a standard feature of such exploratory designs but limits how confidently the two groups can be compared. It is one of several caveats the researchers list when explaining why their findings cannot yet be turned into firm risk estimates.

The maternal side of the equation adds another layer of complexity. Mothers of the 26 positive infants underwent ANA-IFA testing themselves, and three of the 26 came back positive. Intriguingly, all three of those mothers had infants with antigen-specific panel reactivity, suggesting some degree of mother-to-infant concordance in antibody profiles, exactly what one would expect if placental transfer were the source of the cord-blood signal. However, antigen-specific testing of the mothers was incomplete, which prevented the team from performing a comprehensive concordance analysis. Without paired, complete maternal and neonatal panels, it remains impossible to say definitively whether every cord-blood ANA reflects passive maternal transfer, fetal immune activity, or some mixture of both. The authors also note that limited run-level assay documentation constrains the interpretability of individual results.

What, then, should clinicians and anxious parents take away from this work? The authors are explicit: these findings do not support routine ANA-IFA testing of asymptomatic neonates, and they do not justify any change to established surveillance protocols for babies with confirmed maternal anti-Ro/SSA or anti-La/SSB exposure. The reason is straightforward. Cord-blood ANA positivity in a low-risk population turns out to be relatively frequent, roughly 15 percent, but almost entirely nonspecific, and in this cohort it carried no measurable clinical consequence within the first year. Screening every newborn would therefore generate a substantial number of positive results, trigger extensive and costly workups, and create parental anxiety, all in pursuit of a signal that, on current evidence, rarely means anything. The transient liver enzyme elevations seen in four infants resolved without intervention and did not correspond to any antigen-specific pattern of obvious concern.

The study’s limitations are candidly enumerated and worth understanding. Beyond the differential ascertainment between positive and negative infants, the sample size of 171, while respectable for an exploratory single-center cohort, is too small to detect rare outcomes such as congenital heart block, which occurs in only a small fraction of anti-Ro-exposed pregnancies even in high-risk populations. The single-center design means the findings may not generalize to populations with different genetic backgrounds, referral patterns, or assay practices. And the twelve-month follow-up window, though it covers the period when neonatal lupus manifestations typically appear, cannot speak to longer-term risks of autoimmunity that might emerge in childhood or later.

For that reason, the research team calls for larger multicenter studies with paired maternal-neonatal testing, uniform assessment protocols, documented assay runs, serial antibody measurements over time, and follow-up extending well beyond infancy. Such work would settle whether the 15 percent of newborns with cord-blood ANA reactivity represent a truly silent majority whose antibodies simply fade as maternal immunoglobulin is catabolized over the first months of life, or whether a small subset harbors a subtle signal that only longer observation can reveal. Until then, this study provides a valuable baseline: in babies born without any hint of maternal autoimmune disease, antinuclear antibodies in cord blood are common, their antigen-specific signatures are uncommon, and clinically meaningful illness in the first year of life appears to be vanishingly rare. The placenta, it seems, delivers far more reassurance than alarm.

Subject of Research: Cord-blood antinuclear antibody positivity and first-year clinical outcomes in newborns without maternal autoimmune disease

Article Title: Cord-blood ANA-IFA positivity and first-year clinical findings in a selected lower-risk population: an exploratory prospective cohort study

Article References: Adib, M., Sheykhian, T., Assari, R., Alimadad Tafreshi, A., Ashkboos, K., Raeeskarami, S. R., Ziaee, V., Habibi, A., & Sadeghi, P. (2026). Cord-blood ANA-IFA positivity and first-year clinical findings in a selected lower-risk population: an exploratory prospective cohort study. BMC Pediatrics. https://doi.org/10.1186/s12887-026-07735-0

Image Credits: AI Generated

DOI: 10.1186/s12887-026-07735-0

Keywords: antinuclear antibodies, cord blood, neonates, autoimmunity, ANA-IFA, HEp-2 cells, anti-dsDNA, neonatal lupus, anti-Ro/SSA, cohort study, pediatrics, placental antibody transfer

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