Investigating a placental origin for pregnancy and postpartum mood disorders:

Puerperal psychosis is a very rare but severe psychiatric illness and the leading indirect cause of maternal death in the UK. While this disorder is relatively rare, affecting approximately 800 women per annum in the UK, 10-20% of all women will experience significant mood changes during pregnancy, such as anxiety and depression. While in most cases normal mood is restored, chronic depression and anxiety during pregnancy is associated with low birth weight while both pre and postnatal mood disorders are independently associated with poorer mental health outcomes for children. The biological relevance of these associations is unclear. Do maternal mood disorders contribute to low birth weight and poorer outcomes because these mothers adopt less optimal lifestyles? Are the unfavorable behavioural, emotional and cognitive outcomes for children a result of the programming of these disorders in utero or poor post natal care early in life? Or are these disorders all manifestations of one underlying biological problem?

A key change that occurs during pregnancy is exposure to placental hormones. The placenta is a powerful endocrine organ pumping out vast quantities of hormones acting on the mother to induce changes in maternal physiology required to ensure a safe and successful pregnancy. In addition to securing nutrient transport to the fetus, these changes include the induction of mothering behaviours. Thus a placental defect involving aberrant hormonal signaling could result in both a low birth weight baby and abnormal maternal mood.

Recent studies suggest a role for imprinted genes in maternal mood disorders. Imprinted genes regulate placental development and fetal growth. Our studies from experimental models suggest that imprinted genes may influence maternal behaviour by regulating the endocrine compartment of the placenta. Endocrine lineages manufacture placental lactogens which have been shown to induce mothering behaviours in rodents. We have pilot data to show that female mice carrying mutant placenta with a disrupted endocrine compartment, induced by genetic modification of an imprinted gene, show altered behaviour. In another pilot study, we found an association between prenatal depression and placental expression of an imprinted gene and human placental lactogen. This provides preliminary data to support the hypothesis that the epigenetic misprogramming of placental signals contributes to maternal mood disorders in human pregnancies.

In the proposed study we will obtain further evidence that the placenta can program maternal behaviour using our existing animal model. We will concurrently identify gene changes in the placenta from human pregnancies blighted by depression and anxiety. We will then bring these two elements together to ask whether the changes we observe in human placenta can drive altered behaviour in an animal model. Mice are not able to model all aspect of human disease, particularly with respect to complex cognitive behaviours, but we can determine causal relationships which will provide greater biological insight into the origins of abnormal maternal behaviour and may support the development of diagnostic tools predicting postnatal mood disorders for early intervention.

Four investigators will bring together their skills in placental epigenetics, behavioural and molecular neuroscience, obstetrics and perinatal psychiatry to tackle one of the greatest challenges of perinatal medicine - understanding why pregnancy provokes maternal mood disorders in some women. Mothers are exposed to very high levels of placental hormones during pregnancy. Data from animal models suggest that these hormones are important for maternal behaviour. Several imprinted genes regulate the endocrine compartment of the placenta suggesting a role for placental epigenetics in maternal behaviour. We will examine maternal behaviour in an animal model in which the endocrine compartment of the placenta is compromised by genetically altered expression of an imprinted gene. In preliminary work, we find that wild type females change their behaviour towards their pups and show altered brain gene expression in response to our placental mutation. Concurrently, we will undertake a study examining the expression of imprinted genes and hormones in term placenta from women assessed for symptoms of depression (Edinburgh Depression Scale) and anxiety (Spielberger State/Trait Index) before and immediately after delivery. We will initially apply targeted RNAseq and pyrosequencing to a set of discovery placental samples representing extreme moods to obtain further evidence that imprinted genes and placental hormones are aberrantly expressed. Our pilot data identified significantly altered placental expression of an imprinted gene and placental lactogen associated with prenatal depression. Finally, we will bring these two projects together to test the function of the most promising candidate gene identified in our human study in the experimental protocol established using our current animal model. At the end of this study we will have a list of gene changes associated with maternal mood disorders and experimental evidence that these play a causal role.

Clinicians - our work will impact clinicians managing pregnant women and also our perinatal psychiatrist colleagues by providing a new understanding to maternal mood disorders which will help support their clinical management of affected women. Moreover, it is possible that our work will lead to the development of new diagnostic and predictive tools based on simple biomarkers to support the identification and management of at risk women and their children.

Mothers and their children - Maternal mood disorders affect nearly 30% of all pregnancies impacting quality of life, increasing absenteeism from work and healthcare ultilisation. While symptoms can generally be managed through no pharmacological treatment, depression during pregnancy is associated with poor health behaviour, risk-taking behavior, preterm delivery and low infant birth weight all of which increase infant mortality. Prenatal depression is highly predictive of postnatal depression which can result in suboptimal cognitive and emotional development of the child. And both pre and post natal depression are associated with poorer long term outcomes for children including increased risk of schizophrenia, autism and attention deficit/hyperactivity disorder. These have variously been ascribed to fetal programming in utero and poor mother-baby interactions. Our work may lead to improved diagnosis and support for these women and their children. Importantly, a biologically informed understanding of factors promoting altered gene expression in the placenta and the placentas role in inducing mood disorders may lead to more effective treatments.

This work may also be pertinent in the disorder Puerperal Psychosis, a life threatening disorder affecting 1 women in every 500 which can result in them committing suicide or killing their baby. Women with a diagnosis of bipolar disorder are at 50% risk of Puerperal Psychosis but the majority of cases have no family history. A new diagnostic tool could benefit this group of women in particular.

Commercial private sector - with any potential diagnostic tool, there is the potential for commercial exploitation. This project may result in patentable outcomes (biomarkers and diagnostic tools). Cardiff University actively encourages the initiation of commercial relationships with local firms and major multinational companies. Such activities are supported by the Research and Commercial Division and the Innovation Network.

Policy-makers - there is increasing knowledge that in utero exposures such as poor diet, smoking, alcohol and stress can program disease in children. Our work suggests that mothers may similarly be programmed to develop mood disorders. Increasing knowledge in this area would inform policy makers which may lead to changes in advice to pregnant women and those planning pregnancy.

Beneficiaries within the wider public - This work will benefit the wider community by providing a better understanding of pre and post natal mood disorders so that those whose partners, siblings or friends who are effected will receive greater support and understanding.

Economy
The health care costs of managing all maternal mood disorders have not been estimated but data from a 2002 study suggests that more than 100,000 women in the UK will experience postnatal depression every year at an estimated cost to the NHS of 40 million pounds. Even a moderate reduction in occurrence or severity would have a major impact.