Iron Regulation at the Fetomaternal Interface

Not having enough iron in the fetus causes irreversible brain defects leading to impaired language and motor skills in later life. Therefore, it is important that the fetus has enough iron reserves to support its growth not only before birth, but also in the early months of life. All the iron in the fetus is obtained through the placenta from its mother, often leading to the mother's reserves being completely used up. Therefore, the World Health Organisation recommends that all pregnant women are given iron supplements to ensure that they have enough iron to support the growth of their babies. While not having enough iron is bad, having too much iron can also have negative effects on the health of the mother and her baby, e.g. giving iron to malaria-infected mothers helps the growth of the malaria parasite, and can increase the risk of death from malaria. Also, accumulation of iron in the organs causes cellular stress, and sometime diabetes in the mother, which is why the UK's medicine governing body NICE does not recommend iron supplementation for all pregnant women. Scientists and doctors have now realised that we need a "targeted" iron supplementation approach to ensure that iron given to the mother benefits her baby and does not endanger her or the baby's health. But in order to achieve this, we need to understand better how the fetus obtains iron from its mother. The aim of our project is to achieve a better understanding of how the fetus obtains iron from its mother.

Ferroportin is an important protein that exports iron from tissues into the blood. In the adult, it is necessary for obtaining iron from the gut (where iron is absorbed from the diet), and from the liver and the spleen (where iron is stored). The action of ferroportin is blocked by a hormone called hepcidin which causes iron to be trapped in the gut, the spleen or the liver. Interestingly, ferroportin is also present in the placenta, and previous animal studies hinted at the possibility that it may export maternal iron from the placenta to the blood of the fetus. Also, it has been suggested that hepcidin coming from the fetus itself or the placenta may be able to block ferroportin in the placenta in order to stop iron export to the fetus. So far, it has not been possible to test these hypotheses, because there were no suitable animal models for this purpose. We have now addressed this problem by producing three new genetically-modified mouse models to help us manipulate hepcidin and ferroportin in the fetus and the placenta, and to study how iron supply to the fetus is affected by those manipulations.

By understanding the functions of hepcidin and ferroportin in regulating iron supply to the fetus, we will be able to help clinicians set up human studies in order to develop better ways of targeting iron supplementation for pregnant women. Ultimately, this should result in a better quality of life for mothers and their babies.

Limited iron supply in utero causes lifelong cognitive deficits that are not reversed by later iron supplementation. It is therefore critical that fetal iron stores are sufficient to support its development. Approximately 300mg of iron are deposited in the human fetus, all of which are acquired from the mother, through placental flow. This, together with the high prevalence of iron deficiency in women of reproductive age, has lead to the WHO's recommendation for universal iron supplementation. In the UK however, this was not advocated in the most recent NICE guidelines because of potential drawbacks for the mother and fetus. In addition, iron supplementation increases mortality rates in malaria-endemic regions. Therefore, to avoid unnecessary supplementaion, there is a need for it to be tailored to fetal iron demand, necessitating better mechanistic understanding of iron regulation at the fetomaternal interface.
Ferroportin releases iron into the circulation from the sites of absorption (duodenum), recycling (splenic macrophages) and storage (hepatocytes). It is inhibited by the liver-derived hormone HAMP. Interestingly, FPN is also expressed in the basolateral side of the placenta. Animal studies have hinted at a role for FPN in delivery of fetal iron, its regulation by fetal HAMP, and the influence of fetal iron status on maternal iron homeostasis. However, due to the lack of appropriate tissue-specific models, it has not been possible to examine formally these hypotheses. We have generated novel conditional mouse models to enable deletion of placental FPN and HAMP and fetal liver HAMP, and expression of placental HAMP-resistant FPN. We will use these models to obtain a mechanistic understanding of iron regulation at the fetomaternal interface. Such undesrtanding will form part of the evidence necessary to help clinicians devise a targeted iron supplementation that is tailored to fetal needs and to avoid the harmful effects of unnecessary supplementaion.

By communicating the results of our research, highlighting their implications and applications, making available the resources and expertise acquired from the project, we will be able to benefit a number research users.

Short term impact:
1. Basic scientists in the iron and developmental fields: Our studies will inform the design and interpretation of studies of genetic models of iron metabolism and also mechanistic studies into the links between iron and metabolic diseases in the mother and in the newborn. In addition, our animal models will be made available through collaborations, which is likely to expand their applications, and attract further funding to the field. (timescale-within the timeframe of our studies)
2. Clinical scientists: The new mechanistic understanding of iron homeostasis at the fetomaternal interface will form a platform for a new set of clinical trials into iron intervention (both through supplements and diet) in pregnancy. Our findings will also inform the design of these clinical studies, including new screening parameters for detecting fetal iron deficiency and the form in which iron is given (heme vs non-heme) (timescale-2-3 years from end the end of our studies to the start of clinical trials).
Long term impact:
3. Policy makers: The WHO and NICE have different guidelines (universal vs targetted) on iron supplementation for pregnant women. In addition, the WHO has introduced special guidelines on iron supplementation in malaria-endemic regions. Ultimately, the outcome of clinical trials that are informed by our studies will prompt an evidence-based review of these guidelines, and help implement a new set of policies to combat the detrimental effects of iron deficiency in pregnancy worldwide. (timescale-3-5 years depending on the length of clinical trials)
4. Commercial sector: As well as informing the design of commercially-led clinical trials, our findings will help identify candidate biological markers of fetal iron deficiency, which should help the development of the relavant diagnostic tools in humans. (timescale 5-7 years).
5. Public sector: The outcome of the clinical trials described in 2 will help the NHS to reform its practice on iron supplementation in pregnancy according to the new policies described in 3 and using the new diagnostic tools described in 4. (timescale 7-10 years).
6. Wider public: Ultimately, changes implemented by the health sector (as described in 5) should translate into a better quality of life for mothers and their babies, both in the short term (e.g. reducing malaria-related deaths in iron-supplemented individuals, prevention of gestational diabetes in the mother) and in the long term (prevention of cognitive defects and metabolic disorders associated with iron deficiency in utero). In addition, better assessment and management of maternal iron stores should extend these benefits to subsequent pregnancies. (timescale 10-15 years)
7. Developing countries: Discovery of the link between iron overload and malarial parasitic burden and mortality has highlighted the dangers of prophylactic iron supplementation. Development of a targeted iron supplementation approach in humans, which will be helped by the mechanistic understanding from our studies, will ensure that future iron supplementation programmes do not increase the risk of mortality from malaria and other infectious diseases (timescale 10-15 years).