4.1 Principal findings

The current study showed that high maternal ferritin in early pregnancy is associated with lower child IQ in school age. This association remained when adjusting for maternal IQ, age, BMI, smoking, alcohol use, education and parity, and survived correction for multiple testing. The finding was supported by neuroimaging measures, which suggested that children whose mothers had high ferritin during pregnancy had smaller brain volume in preadolescence. High maternal ferritin was not associated with child language or motor abilities. In contrast to high maternal ferritin, low maternal ferritin was not associated with child neurodevelopmental outcomes.

4.2 Strengths of the study

The large, prospective cohort study design and population-based neuroimaging approach are strengths of the current study. Further, we had detailed, high-quality follow-up data including cognitive, motor and neuroimaging outcomes in school age and were able to control for many maternal factors that have been proposed to affect both ferritin levels and offspring development.

4.3 Limitations of the data

Ethnic homogeneity, while a strength in controlling for confounding, limits generalisability to other ethnicities. Follow-up rates were higher among more highly educated mothers, but the potential for selective attrition that could be addressed based on available data had little impact on the findings. While using pooled estimates from multiple imputation models partly addresses selective attrition and estimation uncertainty, it assumes data are missing at random given all observed values. This assumption cannot be tested, and its violation could lead to biased estimates. Maternal inflammation, metabolic diseases and substance use could elevate ferritin and influence child neurodevelopment, and we may not fully capture these phenomena by adjusting for self-reported smoking and alcohol use and BMI or excluding women with elevated CRP. While unmeasured confounders would need to have a considerable effect on both the exposure and the outcome to explain away the association between high ferritin and child IQ or brain volume—which changed only little when observed potential confounders were added as covariates—the risk of residual confounding inevitably remains, and non-observational data would be needed to overcome this limitation. Further, we had no data on iron supplements, and iron overload or its aetiology could not be confirmed with liver biopsies, genetic analyses or complimentary parameters such as fasting transferrin saturation or soluble transferrin receptor. Finally, extreme iron overload, for example due to hereditary haemochromatosis, where average serum ferritin can be >1000 µg/L, were beyond the scope of this study: studies with access to clinical rather than population-based samples may be better suited to investigate such rare disorders.3, 4, 37

4.4 Interpretation

High ferritin can indicate high storage iron levels, for example due to an iron-rich diet, and ferritin is generally considered a reliable marker of iron status during pregnancy.3, 4, 37 However, as an active phase protein, ferritin can also increase through inflammation, thus measurements of inflammatory markers including CRP can be used in combination with ferritin when assessing iron status.4 In the current study, findings remained similar after excluding mothers with elevated CRP, which makes it less likely that inflammation-related increase in ferritin explained the findings. Further, factors such as overweight and alcohol are associated with higher ferritin.4, 30 In our study, associations between maternal ferritin and child neurodevelopment remained similar after adding maternal BMI, IQ, age, smoking, alcohol use, education and parity as covariates. Taken together, these results offer some support that maternal iron status is associated with child neurodevelopment; however, we advise caution in drawing causal conclusions based on observational data.

Excess iron exposure could lead to oxidative stress, interact with other nutrients and decrease key neurotransmitter levels in the developing brain.7 However, prior evidence mostly comes from animal models and postnatal iron overload among preterm infants.7 Some studies suggest that low maternal iron intake/anaemia during pregnancy is associated with neonatal alterations in hippocampal morphogenesis,38 serum brain-derived neurotrophic factor levels,38 and white matter maturation.39 In our sample, high maternal ferritin during pregnancy was associated with smaller child brain volume, which is in line with our finding that high maternal ferritin during pregnancy is associated with lower IQ. This is in accordance with the consistent finding in the neuroscience of intelligence that larger brain volume is associated with better cognitive abilities; however, the basis of this correlation is not fully understood.27 We found no evidence of structural specificity (differences specific to cortical or subcortical grey matter, white matter or cerebellar volume), after taking into account an overall reduction in brain volume, which is plausible considering the early timing of the exposure. Taken together, our neuroimaging and IQ findings are consistent and support the hypothesis that maternal iron status is associated with offspring brain development.

High maternal ferritin during pregnancy was associated with poorer child cognitive abilities in the current study, while some previous studies have suggested that low maternal ferritin during pregnancy predicts poorer child cognitive abilities.5, 6 This may seem like a discrepancy; however, some differences in study populations may help elucidate how our findings add to the existing literature, rather than contradict it. The current study was carried out in a population that was well-suited to detect associations with high ferritin: a relatively high proportion of mothers (~9%) had ferritin concentrations >150 µg/L.4 Conversely, severe iron deficiency was rare, thus we may be unable to detect adverse effects driven by severe iron-deficiency, which may be a true concern in more iron-deficient populations.40 Further, our population had access to routine haemoglobin controls during pregnancy and, if anaemic, to iron supplementation through the Dutch antenatal care system.41 This may have mitigated potentially adverse effects of iron deficiency on offspring neurodevelopment.

This study does not offer proof of underlying causal mechanisms, nor should its results be directly translated into clinical recommendations. Importantly, our results are not evidence that iron supplementation during pregnancy is unnecessary or harmful. It remains important to identify and treat iron-deficiency anaemia.42 For non-targeted antenatal iron supplementation, the long-term effects remain unclear and most likely vary by population: in low-income settings with high rates of iron-deficiency, routine antenatal iron supplementation may be associated with some benefits.40, 43 We encourage future studies to analyse data on maternal iron intake, particularly from randomised controlled trials, to see if there is an optimal level of intake—not too low and not too high—that we should target, to optimise maternal and child health.

We are not aware of prior studies showing an association between high ferritin during pregnancy and child cognitive abilities or brain morphology and encourage replication of our findings. Prenatal MRI studies could elucidate the underlying mechanisms further: we refrained from testing mediation of ferritin on IQ through morphology, as children underwent MRI after cognitive tests. Repeated maternal measures and measuring maternal and child ferritin could elucidate timing-specificity and mediation through child iron stores.

In our study, higher ferritin was associated with lower IQ and smaller brain volume, while associations with language abilities were less clear, and motor skills seemed unrelated to maternal ferritin. This could suggest outcome-specificity; however, IQ and language abilities were assessed earlier in life, and the sensitivity of tests aimed at measuring different phenotypes may vary. Nonetheless, we encourage research into possible outcome-specificity, and note that offspring mental health outcomes could also be of interest.44, 45

Finally, in the current study, we focussed on maternal ferritin; however, we also tested if haemoglobin was associated with child neurodevelopmental outcomes. While iron deficiency ultimately leads to low haemoglobin, haemoglobin is a less specific marker of iron status, compared to ferritin. In the current study, we observed an association between low maternal haemoglobin and child language abilities. This association, while in line with some studies linking maternal anaemia with offspring neurodevelopment,46, 47 seemed not to be driven by iron status. Thus, to understand the associations between maternal haemoglobin or anaemia and child neurodevelopment, we encourage research into the many genetic and environmental factors that can affect haemoglobin, beyond just iron-deficiency.42