Placental inflammation in high risk pregnancies: a novel therapeutic target to prevent stillbirth?

Stillbirth describes the death of a baby before birth after 24 weeks of pregnancy. This occurs in approximately 1 in 220 pregnancies in the UK; in 2012 there were 3,696 stillborn babies in the UK. The rate of stillbirth has decreased much more slowly than deaths of babies after birth. The UK has a higher stillbirth rate than neighbouring countries in Europe. Experts have called upon countries such as ours to halve the number of stillbirths by 2020.

In the UK, the most common condition associated with stillbirth is fetal growth restriction (FGR); this describes a baby that does not reach their expected size. Over 40% of stillbirths are associated with FGR, and FGR babies are 17 times more likely to be stillborn. To prevent stillbirths, babies with FGR may be delivered prematurely, placing them at an increased risk of disability due to brain damage sustained before and after birth. They also have a higher likelihood of becoming obese, diabetic and having higher blood pressure in later life than babies of a healthy birthweight. This project therefore focuses on clinical conditions that need to be addressed.

The placenta (afterbirth) is essential for a healthy pregnancy. Over 65% of stillbirths are associated with abnormalities of the placenta. Abnormalities in the placenta include reduction in blood flow from the mother and damage from inflammation or infection. Although inflammation during pregnancy is a major cause of pregnancy complications and lifelong problems for surviving babies, we do not understood how inflammation leads to these poor outcomes. As a result, we cannot identify inflammation during pregnancy and do not have any treatments to prevent poor outcomes.

We have shown in humans and animals that the placenta is damaged by inflammation making it unable to function normally. We found higher levels of inflammatory factors in the placenta and mothers' blood in pregnancies at high risk of stillbirth. Importantly, in an animal model of inflammation during pregnancy, treatment with a new anti-inflammatory drug prevented placental damage and the adverse effects on growth and survival of the offspring. This provides hope that anti-inflammatory treatment targeting the placenta could prevent FGR and stillbirth in human pregnancies.

It is currently too early to give these anti-inflammatory treatments to pregnant women; however, the current study will provide further evidence of the role of inflammation in placental damage and FGR/stillbirth. We will perform detailed studies of human high risk pregnancies and test whether addition of a blood test for placental inflammation can improve current methods to detect babies at greatest risk of stillbirth. To do thus, we will use human placental and maternal blood samples from healthy pregnancies and those with FGR and stillbirth to understand the link between inflammation and adverse pregnancy outcomes. We have already collected over 1,000 blood samples from mothers with high risk pregnancies, with detailed clinical information on mothers and babies. We will study how inflammatory factors cause placental damage and test anti-inflammatory treatments in human and animal pregnancies. These experiments will provide further evidence that treating inflammation can protect the placenta from damage and reduce the incidence of FGR and stillbirth. These studies are essential first steps in our goal to develop new treatments to prevent babies from dying or being born with serious disabilities and will facilitate human clinical trials.

Stillbirth is a devastating pregnancy outcome, affecting 1:220 pregnancies in UK. Although stillbirth is strongly associated with fetal growth restriction (FGR) and placental dysfunction, the underlying mechanisms are poorly understood and no diagnostic or treatment options are currently available to address placental dysfunction. Animal models have demonstrated that excessive inflammation at the maternal-fetal interface adversely affects placental function, resulting in FGR and fetal death. Combating inflammation in a rat model with targeted anti-inflammatory therapy protects the placenta, preventing adverse fetal outcomes. We recently identified a distinct placental pro-inflammatory cytokine profile in pregnancies at high risk of stillbirth, which was also evident in the maternal circulation. These women did not exhibit clinical signs of infection, but had elevated circulating levels of endogenous mediators of inflammation - the alarmins (uric acid, high-mobility group box 1 (HMGB1) and cell-free fetal DNA (cffDNA)) - suggesting these danger signals could trigger inflammation. Our preliminary data demonstrates alarmins induce placental dysfunction in vitro and in animal models, and have defined a central role for placental interleukin(IL)-1 as a downstream mediator. We propose that alarmins released following an early pregnancy insult, such as hypoxia, oxidative stress or subclinical infection, induce placental inflammation, thus exacerbating placental dysfunction and leading to FGR and stillbirth. We aim to improve understanding of the link between alarmin-induced inflammation, placental dysfunction and adverse fetal outcome and investigate whether inflammatory biomarkers can identify pregnancies at greatest risk of stillbirth. We will determine whether inflammation exacerbates existing placental dysfunction and test the therapeutic potential of anti-inflammatory therapy to protect against placental dysfunction and stillbirth using in vitro and in vivo models.

Placental dysfunction, which is clinically manifest as fetal growth restriction (FGR), increases the risk of death and disability for the baby and can also have life-long health consequences, leading to a considerable social and financial burden for society as well as affected families.

Currently, few tests are able to predict adverse pregnancy outcome with sufficient efficacy for use in clinical practice and there are currently no treatments available for FGR except for the obstetrician delivering the baby prematurely, which has its own set of associated risks. Our research aims to better identify placental dysfunction in vivo and develop interventions that directly address it, promoting improved fetal growth and infant outcome. This topic was identified as a research priority by parents and professionals participating in the Stillbirth Priority Setting Partnership (headed by Heazell). If successful the findings from the current study will be translated to clinical trials in the medium term (5 years), as we have previously done (e.g. Reduced Movements Intervention Trial - Heazell et al 2013).

Consequently, our work will have impact by:
1. reducing fetal and neonatal mortality and morbidity;
2. reducing costs associated with caring for sick babies, offering novel and affordable treatments - benefits for clinicians, managers and commissioners in the NHS;
3. furthering understanding of the role of inflammation in human pathologies (in and outside reproductive biology).

This will be of immediate benefit to the following groups:
1. Women, unborn children and infants will benefit because FGR complicates up to 10% of human pregnancies. In the UK, 1 in 220 pregnancies ends in stillbirth; 40% of which are associated with FGR.

2. Obstetricians, NHS managers and commissioners will benefit as FGR pregnancies that have to be delivered prematurely currently account for ~10% of the occupancy of neonatal intensive care cots. Stillbirth places a direct economic burden estimated to be £20M per annum. In combination with the enhanced neonatal requirements of FGR infants, the NHS spends in excess of £250M annually on the conditions we are focused on. The indirect and intangible costs of stillbirth and FGR are likely to be much greater. There is a need to reduce the burden of stillbirth and FGR. The new treatments we develop will reduce these costs, and enable obstetricians, and NHS managers and commissioners to more effectively focus increasingly scarce resources.

3. Researchers into the role of inflammation in human diseases from clinical and basic science background. Our work on placental inflammation has already led to collaboration with a colleague who is investigating the role of macrophages in autoimmune eye disease. The University of Manchester hosts the Institute of Inflammation and Repair, allowing development of links with high-quality researchers from other disciplines. The models developed by this project will also be of interest to researchers investigating the role of inflammation in neonatal brain injury, which is related to cerebral palsy and neurodevelopmental delay.

Our ability to benefit these groups is enhanced by the strong tradition of the University of Manchester in using its research to make positive impacts on real world challenges, from informing health policy through to the commercialisation of intellectual property.