Ironing out placental adaptations of fetal growth restriction

Experts have long felt that the placenta may be the most underappreciated organ in human development. For decades, it was simply viewed as a passive conduit that facilitated the delivery of oxygen and nutrients from maternal to fetal circulation. However, research has reshaped this dated opinion, demonstrating that the placenta is a highly adaptive organ capable of sensing and responding to intrauterine stressors through tightly regulated molecular and physiological processes. Fetal growth restriction (FGR), affecting ∼10% of pregnancies worldwide, has been a condition of particular focus and importance within the field for studying these placental adaptations. Characterised by the inability of the fetus to achieve its genetically predetermined growth potential, FGR has long been associated with altered placental nutrient transport, oxidative stress and vascular remodelling. These perturbations to placental function can impair fetal oxygenation and energy supply, which are known drivers for later life disease risk. This emphasises a need for greater understanding of – and appreciation for – this remarkable organ. Experimental animal studies show that under hypoxic or nutrient‑restricted conditions the placenta alters its structure, transporter expression and metabolic pathways (Zhang et al. , 2015). These responses may be an attempt to prioritise resource allocation to the fetus, which highlights dynamic, stressor-dependent adaptations rather than passive function. Indeed, there are many essential nutrients required for placental function. Of particular interest is iron. Placental mitochondria require iron for haem and iron-sulfur (Fe-S) cluster synthesis, supporting cellular energy, and antioxidant capacity, all of which are critical for ensuring fetal growth and development, and thus later life health, is maintained. Therefore, disruptions to iron availability, or changes to how iron is utilised within the placenta, may have consequences for intergenerational health. The recent study by Botha et al. (2026) shows that the FGR human placenta upregulates iron importers, a response similar to that observed in pregnancies impacted by maternal iron deficiency (Sangkhae et al. , 2020), despite the present study finding no clinically significant change in maternal iron status. At the mitochondrial level, mitoferrin-1 is preserved to support haem synthesis, whereas mitoferrin-2, which delivers iron for iron-sulfur (Fe-S) cluster assembly, is reduced. Early-stage Fe-S cluster assembly is maintained, but late-stage is impaired; the authors propose this as a mechanism by which placental haem production and utilisation is prioritised over complete Fe-S cluster synthesis. This ‘bottleneck’ in late-stage Fe-S cluster assembly may contribute to the mitochondrial dysfunction – and associated oxidative stress – often observed in FGR placentae. The study also reports a lower abundance of haemoglobin proteins and altered erythrocyte structural proteins, indicating that placental erythropoiesis is remodelled. Together, the study demonstrates that FGR placental adaptations dictate how iron is utilised, indicating that iron-dependent oxygen delivery may be preferentially favoured over other iron-dependent pathways. It is not uncommon for a study to finish with more questions than were originally asked: the work by Botha et al. (2026) is no different. While the present study provides a comprehensive snapshot of iron utilisation in the FGR human placenta, there remain several unanswered questions. The iron-dependent programming of cell death, ferroptosis, has been implicated in placentae of complicated pregnancies (Park et al. , 2025) and thus its induction may be expected in the cohort utilised in the present study, particularly when considering the observed changes in iron uptake and utilisation. No doubt there is always opportunity for another research question to be answered using valuable biospecimens such as those acquired in the present study. As a bona fide sex differences enthusiast, another question that remains to be answered is whether the reported adaptations vary between male and female placentae. It is well established in the field that sex-specific placental adaptations to normal and pathophysiological pregnancies occur (Meakin et al. , 2021). Males ‘grow dangerously in the womb’, particularly under stressful intrauterine environments. These sexually dimorphic responses may be driven by inadequate placental adaptations and, indeed, this may extend to iron uptake and utilisation. It would certainly be interesting for future studies to expand on the work of Botha et al. (2026) to identify whether iron (mis) handling is impacted by placental sex. Ultimately, the work by Botha et al. (2026) adds to an ever-growing body of evidence that describes the placenta as an active and adaptive organ, not simply a passive conduit, and highlights its central role in orchestrating fetal growth and development and thus later life health, albeit via countless interconnected and complex signalling pathways. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article. No competing interests declared. Sole author. National Heart Foundation of Australia (Heart Foundation): Ashley Meakin, 108 157- 2024PDF. Open access publishing facilitated by Adelaide University, as part of the Wiley - Adelaide University agreement via the Council of Australasian University Librarians