Iron Deficiency in Pregnancy May Disrupt Infant Microbiome Inheritance, Review Proposes

Maternal iron deficiency, the most prevalent micronutrient deficiency worldwide and one that disproportionately affects pregnant women, may interfere with the microbial inheritance that mothers pass to their infants, according to a narrative review published in Frontiers in Cellular and Infection Microbiology. The review, which surveyed peer-reviewed literature from January 2000 to June 2026 across PubMed, Embase, and Web of Science, proposes what its authors call a double-hit hypothesis: a first hit in which iron deficiency potentially alters the maternal microbial and immunologic inputs delivered through the vaginal, gut, and breast milk ecosystems, and a second hit in which preterm birth and neonatal intensive care disrupt the early succession of microbes colonizing the infant gut. Crucially, the authors frame this as a hypothesis-generating framework rather than an established causal pathway, and they are explicit that no study has ever evaluated the complete integrated pathway.

The concept of microbial inheritance sits at the center of the argument. Maternal microbial communities constitute major sources of the infant’s early microbiota, transferred mainly through the maternal gut, vaginal delivery, breast milk, and skin-to-skin contact during the first thousand days of life, a critical window for microbiome-mediated immune and metabolic programming. Large-scale studies have shown substantial contributions of maternal source communities to early infant microbiota composition across six maternal body sites, including vaginal, fecal, skin, nasal, oral, and breast milk niches. A large Dutch birth cohort estimated that 58.5 percent of infant microbiota composition across sampled niches was attributable to maternal source communities, though the authors caution that this figure applies across sampled infant niches and should not be read as the infant gut alone.

The durability of these contributions differs sharply by source. Strain-level metagenomic profiling has revealed that maternal skin and vaginal strains colonize the infant only transiently, whereas maternal gut strains prove more persistent and ecologically better adapted in the infant gut. A study of maternal gut microbiota at 32 weeks of gestation found it to be the primary source of meconium microbiota in vaginally delivered infants, while maternal vaginal microbiota contributed minimally. By 28 days of life, amplicon sequence variants shared with the maternal rectal microbiota constituted a substantially higher proportion of the neonatal gut than those shared with the vaginal microbiota. The Maternal Microbiome Legacy Project, spanning 585 Canadian mother-infant dyads, detected near-identical vaginal-stool strain sharing in 38.9 percent of dyads, but this sharing occurred irrespective of delivery mode, suggesting that shared strains likely originate from the maternal gut or breast milk rather than from vaginal transmission. This distinction between transient exposure and persistent colonization is critical to how the framework should be interpreted.

The vaginal route is where the evidence is thinnest and most provocative. The only direct human epidemiological link between maternal iron status and vaginal dysbiosis comes from a single nested case-control study from 2005, in which subclinical iron deficiency at a mean gestational age of 9.2 weeks was an independent predictor of bacterial vaginosis-like microflora, with an adjusted odds ratio of 4.5 and a 95 percent confidence interval of 1.4 to 14.2. The authors emphasize the preliminary nature of this finding: it is a single, unreplicated study with a small case group, no sequencing, no longitudinal community state type assessment, and no infant outcomes. Vaginal microbial communities are classified into community state types, from Lactobacillus crispatus-dominant CST I to diverse low-Lactobacillus CST IV, and CST III and CST IV communities have been associated with bacterial vaginosis, preterm birth, and adverse neonatal outcomes in observational research.

An apparent biological paradox shapes the proposed mechanism. Lactobacilli, the predominant bacteria in a healthy vaginal microbiome, use manganese-dependent metabolic pathways that substitute for iron-requiring enzymes, making them uniquely resistant to iron-restricted environments. If Lactobacillus requires little or no iron, how could maternal iron deficiency promote its displacement? The review’s answer is that iron deficiency would not affect the vaginal microbiome by starving lactobacilli, but rather by undermining the host defenses that maintain their dominance. Iron is an essential cofactor for the NADPH oxidase enzyme complex responsible for the neutrophil oxidative burst, the principal mechanism by which neutrophils kill invading bacteria. Iron deficiency may therefore impair cervicovaginal mucosal defenses, allowing iron-dependent pathobionts such as Gardnerella and Prevotella to expand. Local iron handling adds further complexity: hepcidin-driven ferroportin downregulation can sequester iron within genital-tract cells independently of circulating stores, and whether systemic iron deficiency alters cervicovaginal iron availability during pregnancy remains unknown.

The gut-vaginal route is presented as an indirect and testable component rather than an established mechanism. Experimental iron-depletion studies in rats have reported enrichment of Clostridium and Enterobacteriaceae and depletion of butyrate-producing commensals such as Roseburia, with some alterations persisting after iron repletion, but these findings cannot be directly extrapolated to pregnant women. Limited human evidence includes a longitudinal Pune cohort of 218 pregnant women in which maternal anemia, defined by hemoglobin rather than iron biomarkers, was associated with distinct maternal gut microbiota profiles at six months postpartum and distinct infant gut microbiota profiles at six months of age. Culture-based studies of paired vaginal and rectal samples from pregnant women support the rectum as a possible reservoir for vaginal colonization, with approximately 36 percent of participants in one study carrying at least one of the same species at both sites, but the direction and dynamics of microbial exchange remain unresolved.

The breast milk route is even more speculative. Breast milk lactoferrin plays a dual role through direct antimicrobial activity and prebiotic promotion of Bifidobacterium and Lactobacillus colonization, and one observational cohort found that milk lactoferrin concentration was associated with neonatal fecal lactoferrin and early fecal Bifidobacterium and Lactobacillus abundance. However, evidence relating maternal iron status to milk lactoferrin is inconsistent. A prospective study of 200 mothers, 100 anemic and 100 nonanemic, found no correlation between maternal hemoglobin, serum iron, ferritin, or transferrin saturation and breast milk lactoferrin, and a study in northern Kenya found no evidence that maternal iron-deficiency anemia reduced lactoferrin delivery through milk. In contrast, a recent prospective Chinese cohort of 160 mothers reported an association between prenatal mean corpuscular volume and longitudinal lactoferrin trajectories, but mean corpuscular volume is a nonspecific marker requiring replication with specific iron biomarkers. No study links maternal iron status to human milk oligosaccharide composition, and the direct effect of maternal iron deficiency on the breast milk microbiome has never been examined.

The second hit rests on firmer epidemiological ground but still on association, not causation. Meta-analytic evidence indicates that maternal iron-deficiency anemia is associated with approximately a 1.5-fold increase in the odds of preterm birth, with an odds ratio of 1.54 and a 95 percent confidence interval of 1.36 to 1.76. Evidence for iron deficiency without anemia is sparse and non-significant, with an adjusted odds ratio of 0.9 from only two studies, a gap the authors flag as warranting dedicated investigation. Preterm infants develop a particularly vulnerable intestinal ecosystem characterized by low microbial diversity, depletion of Bifidobacterium, and expansion of Enterobacteriaceae and hospital-associated opportunistic taxa, reflecting intestinal and immune immaturity combined with frequent antibiotic exposure, altered feeding, and the neonatal intensive care environment. Prospective neonatal cohorts have shown that altered gut profiles preceded late-onset sepsis and that a subset of bloodstream pathogens was strain-matched to earlier gut isolates, though preceding dysbiosis does not alone prove causation, and gestational age, delivery mode, antibiotics, feeding, and illness severity are difficult to disentangle.

The authors stress that the framework’s translational implications are deliberately restrained. Screening and treatment of maternal iron deficiency or anemia, human milk support, and neonatal antibiotic stewardship have clinical rationales independent of this hypothesis, but their ability to prevent or mitigate the proposed microbiome-related hits remains untested. Candidate microbiome-directed strategies, including defined vaginal live biotherapeutics, neonatal probiotics, enteral lactoferrin supplementation, and vaginal seeding after cesarean delivery, differ substantially in evidence base and safety and should not be treated as equivalent. Professional bodies do not recommend vaginal seeding outside approved research protocols. The review’s central proposal is methodological: a single prospective study integrating biomarker-confirmed maternal iron status, serial vaginal community state type sampling across gestation, breast milk composition, maternal gut microbiome assessment, and longitudinal infant stool sampling through the first year could directly test whether maternal iron deficiency and preterm birth independently or jointly influence infant microbial succession. Until such studies are conducted, every connection in the double-hit model remains a testable hypothesis rather than a demonstrated pathway.

Subject of Research: A proposed double-hit hypothesis linking maternal iron deficiency, preterm birth, and disrupted maternal-to-infant microbial transmission

Article Title: Maternal iron deficiency, preterm birth, and disrupted microbial inheritance: a proposed double-hit hypothesis

Article References: Khan, F. Z. A., & Ali, S. A. (2026). Maternal iron deficiency, preterm birth, and disrupted microbial inheritance: a proposed double-hit hypothesis. Frontiers in Cellular and Infection Microbiology, 16, Article 1953925. https://doi.org/10.3389/fcimb.2026.1953925

Image Credits: AI Generated

DOI: 10.3389/fcimb.2026.1953925

Keywords: maternal iron deficiency, infant microbiome, preterm birth, vaginal microbiome, breast milk lactoferrin, microbial transmission, neonatal intensive care, community state types, bacterial vaginosis, gut-vaginal axis, narrative review, maternal anemia