Research into miscarriage

A miscarriage is the loss of a baby before 24 weeks of gestation. It is a sad fact that one in four women will experience a miscarriage and Tommy’s is dedicated to improving this.

Our Manchester centre is studying the role of the placenta in early pregnancy. We have found that a major cause of pregnancy problems such as miscarriage is when the blood vessels in the uterus fail to widen properly, restricting blood flow to the baby. We’ve identified that the placenta controls this process and we’re working to find treatments to improve blood vessel widening in pregnancies where it’s impaired. Another area of focus for our research is the process of nutrient and oxygen transfer from the mother to the baby via the placenta, as problems with this can lead to fetal growth restriction.

Although there is still a long way to go, our research is already starting to make a real difference. At our centre in London, Tommy’s Professor Andy Shennan sees about 30 women every week who have had multiple pregnancy losses. However, using the research we’re conducting into the function of the placenta and uterus, 90% of those women go on to have a healthy baby.

Individual research projects

Investigating the effectiveness of a cervical or abdominal stitch (the MAVRIC trial)
Investigators: Professor Andrew Shennan, Annette Briley, Dr Manju Chandiramani, Dr Anna Kenyon
Funding: Tommy’s funds several of the doctors working on this project.
Timescale: 2007-¬2010
Summary: A ‘weak’ cervix can gradually open as pregnancy progresses and the fetus is no longer held within the uterus, resulting in miscarriage or early delivery. One of the interventions for a weak cervix is the insertion of a ‘stitch’, known as a cervical cerclage, which can be inserted either via the abdomen or through the vagina. The vaginal route is preferred as it is less invasive and results in fewer complications. However, some women still miscarry or have early deliveries regardless of the presence of the vaginal stitch. We do not understand why this method works for some women and not for others. In women who have had a failed vaginal stitch, a reasonable option is to insert a stitch via the abdominal route for future pregnancies, or a vaginal stitch that is placed higher. This randomised clinical trial, known as the MAVRIC trial, will compare the outcome of women who have cervical stitches put in via the abdominal route versus the vaginal route.
Progress report: We are well on our way to reaching our recruitment target of 129 women for this study, which will be large enough to determine whether abdominal sutures reduce preterm birth before 32 weeks, and reduce neonatal deaths.

Finding ways to help the placenta grow normally
Investigators: Dr Karen Forbes, Dr Melissa Westwood, Professor John Aplin
Funding: Study taking place in a Tommy’s funded centre
Timescale: 2006 onwards
Summary: Development of the placenta very early in pregnancy is a prerequisite for normal fetal growth. If the placenta doesn't develop properly then the nutrient and oxygen supply to the fetus is compromised, resulting in impaired growth. We know that a family of hormones called the insulin-like growth factors (IGFs) are required to help the placenta grow. In this project we have demonstrated that IGF delivered from the maternal side stimulates placental growth. This means that it might be possible to enhance placental and subsequent fetal growth by increasing this effect of IGFs. Before this can happen, we need to understand how IGFs work in the placenta.

Progress report: In the course of this project, we have made an important discovery. We have shown that cholesterol-lowering drugs called statins, which are often prescribed to diabetic or obese women, stop IGFs from working properly in the placenta and so great care needs to be taken when prescribing these drugs to pregnant women. We have also developed new methods to eliminate proteins that prevent normal placental development and have identified proteins that act in tandem with IGFs to help the placenta grow.

Investigating placental development
Investigators: Sylvia Liu, Dr Clare Tower, Professor John Aplin
Funding: Study taking place in a Tommy’s funded centre
Timescale: 2006 onwards
Summary: Problems arising during placental development can result in miscarriage, pre-eclampsia and fetal growth restriction. This project is investigating two factors known to be important in its development: angiotensin II and transforming growth factor beta 1.

Investigating placental development and function
Investigators: Dr Jo Glazier, Dr Sue Kimber, Chloe Duval
Funding: Study taking place in a Tommy’s funded centre
Timescale: 2010–2013
Summary: Our previous studies have suggested that parathyroid hormone related peptide (PTHrP) can influence placental function. In this study we are examining the role of PTHrP in regulating optimal placental development, growth and function. PTHrP is produced by cells within the placenta (fetal-derived) and is also produced by the uterus (maternal-derived). We are particularly interested in this aspect and whether PTHrP derived from maternal or fetal tissues contributes to regulation of placental development. The possibility exists that both sources are important in regulating both embryonic and placental development.

The role of sphingosine-1-phosphate in placental development
Investigators: Dr Daman Adlam, Khiria Alsaghir, Dr Melissa Westwood, Dr Ed Johnstone
Funding: Study taking place in a Tommy’s funded centre
Timescale: 2009–2013
Summary: A well-recognised feature of pre-eclampsia is deficient invasion of the placental cells into the lining of the womb. The human body has many systems to control the migration and invasion of cells to prevent diseases such as cancer developing while at the same time allowing normal processes such as tissue repair to occur. One of the most recently recognised systems controlling cell migration is sphingolipid signalling. Sphingolipids are lipids (or fats) that tell cells whether to advance or retreat when interactions occur with cell surface receptors. We are investigating the role of sphingosine-1-phosphate (S1P) in placental development.

Protecting the fetus from harmful toxins
Investigators: Dr Diane Atkinson, Bernadette Baker, Professor Colin Sibley
Funding: Study taking place in a Tommy’s funded centre
Timescale: 2007–2010
Summary: The human placenta acts to protect the baby from drugs and toxic substances present in the mother's blood. Multi drug resistance proteins (MDRPs) are a family of compounds known as transporters which do this job. Anything that reduces MDRP activity in the placenta may increase the exposure of the baby to such harmful compounds. This study is investigating whether mutations in the MDRP genes make them less effective and thus less able to protect the baby, and the effects of these mutations on fetal development.

Looking at the effects of drug abuse on pregnancy
Investigators: Deirdre Thajam, Dr Diane Atkinson, Professor Colin Sibley, Dr Sue Greenwood
Funding: Study taking place in a Tommy’s funded centre
Timescale: 2008–2011
Summary: Drug abuse during pregnancy increases the risk of miscarriage and preterm birth. It also increases the chances of the baby being born small, having congenital defects or dying just after birth. We are investigating the possibility that the severity of effects on the fetus depends on the ability of the placenta to prevent drug transfer to the fetus. A group of proteins responsible for preventing transfer of a whole range of drugs and toxic substances across the placenta, the multi drug resistance proteins (MDRPs), are being studied. We are also looking at the genes for these proteins, as being able to predict which babies are at particular risk of poor outcomes following maternal drug abuse would be of major benefit to the clinical management of these patients, both in terms of counselling and in planning treatment of the baby once delivered.

Investigating the blood vessel system linking the uterus and placenta
Investigators: Samantha Smith, Dr Lynda Harris, Professor John Aplin, Dr Caroline Dunk (University of Toronto), Dr Rebecca Jones
Funding: Study taking place in a Tommy’s funded centre
Timescale: 2006–2009
Summary: During the first 12 weeks of pregnancy, it is essential that the placenta combines well with the uterus so that there is maximum delivery of nutrients and oxygen from mother to baby. A system of blood vessels develops to achieve this, but sometimes it doesn’t develop properly and this is a major cause of pre-eclampsia, fetal growth restriction and miscarriage. This project is trying to work out the chemical processes that cause this blood vessel system to develop so we can discover why they sometimes malfunction.
Progress report: We have found that white blood cells, or leukocytes, are involved and that they produce enzymes that help to destroy the wall of the uterus, allowing the web of blood vessels to form between womb and placenta. Further work will investigate how these processes are impaired in pregnancies where the development of these blood vessels is abnormal. For this work, Samantha Smith won a President’s Presenter Award at the annual conference of the Society for Gynecologic Investigation in March 2009.

Problems with placental blood flow
Investigators: Jayne Fitzsimmons, Dr Melissa Westwood, Professor John Aplin
Funding: Study taking place in a Tommy’s funded centre
Timescale: 2006–2009
Summary: The development of blood vessels in the placenta is essential to the health of the growing baby, since they receive the oxygen and nutrients transferred from maternal blood across the placenta. In cases where these vessels develop poorly, babies are underweight, and this can also lead to pre-eclampsia and miscarriage.
Progress report: The blood vessels connecting the placenta and uterus are believed to form from stem cells in placental tissue. We are working to identify and isolate this process, which will allow us to investigate the factors that stimulate the growth of these vessels, and thus improve the placental blood supply to an undergrown baby.

The role of estrogen and IGF in placental blood flow
Investigators: Jemma Corcoran, Professor Michael Taggart (University of Newcastle), Dr Melissa Westwood
Funding: Study taking place in a Tommy’s funded centre
Timescale: 2006–2010
Summary: This project examines the mechanisms for regulating blood flow to and within the placenta, focusing particularly on the role of estrogen and insulin-like growth factor (IGF-1). It is hoped that this research will lead to an innovative approach for targeting abnormal blood flow during pregnancy.
Progress report: We have shown that the blood vessels in the placenta and womb relax in response to estrogen, allowing improved blood flow. With further research, estrogen may become a possible treatment for pregnancies where the baby isn't growing properly. IGF-1 does not influence relaxation of placental blood vessels but we have shown that this factor causes less constriction in the vessels from the womb. We are now working towards understanding how IGF-1 causes this reaction.

Investigating the role of 2-ME2 in pre-eclampsia
Investigators: Dr Yu Zhang, Dr Jo Stanley, Prof Philip Baker, Dr Ian Crocker.
Funding: Study taking place in a Tommy’s funded centre
Timescale: 2008–2010
Summary: It has recently been suggested that pre-eclampsia can be linked to reduced levels of a metabolite of estradiol called 2-methoxyestradiol (2-ME2). Through animal models of pregnancy it has been proposed that a lack of this enzyme in the placenta can predispose the organ to inadvertently react to restricted oxygen, thus releasing damaging factors into the maternal circulation which cause the blood vessel complications of pre-eclampsia.
Progress report: While we have been unable to confirm this hypothesis, we were able to establish a more direct effect of 2-ME2 on preparing the mother’s blood vessels for pregnancy and preventing pre-eclampsia. The manipulation and mode of action of 2ME-2 is therefore under further investigation.

Investigating the process of baby and placenta acceptance
Investigators: Beth Holder, Professor John Aplin, Dr Clare Tower, Dr Vikki Abrahams (Yale University)
Funding: Study taking place in a Tommy’s funded centre
Timescale: 2007–2010
Summary: Half of the genes in the baby come from the father and a remarkable feature of a successful pregnancy is that the mother’s body does not recognise the baby and placenta as foreign. Normally cells from another individual would be destroyed by the maternal immune system. There is evidence that pre-eclampsia is caused by an abnormal immune response to pregnancy, and this project is investigating the process by which the mother’s body learns to accept the baby and placenta as non-foreign. We are interested in a family of proteins found in the placenta that are produced from human endogenous retroviruses (HERVs). HERV genes originally came from viruses whose DNA became integrated into our genetic material during evolution. This project is investigating whether these genes have a similar function in pregnancy and allow an apparently foreign body to be accepted.

Developing a treatment to enhance placental cell survival
Investigators: Dr Lynda Harris, Dr Ian Crocker, Professor Philip Baker, Professor John Aplin, Dr Melissa Westwood
Funding: Study taking place in a Tommy’s funded centre
Timescale: 2006 onwards
Summary: Abnormal placental function and excessive placental cell death may lead to pre-eclampsia, fetal growth restriction and miscarriage. Treatments that improve the efficiency or survival of placental cells may prolong pregnancy and improve the outcomes for both mother and baby. This project investigates a substance called insulin-like growth factor (IGF-2) that has been shown to enhance growth and survival of placental cells.
Progress report: We are currently developing a treatment that will increase the amount of IGF-2 available to the placenta, thus improving its function by promoting cell survival and cell growth.

Looking at amino acid transfer from mother to baby
Investigators: Dr Michelle Desforges, Professor Colin Sibley, Dr Jo Glazier, Dr Susan Greenwood, Dr Melissa Westwood, Dr Kurt Mynett
Funding: Study taking place in a Tommy’s funded centre
Timescale: 2006–2009
Summary: The placenta connects the mother to her baby and a failure to correctly transport vital amino acids can lead to fetal growth restriction. This project is investigating the mechanisms by which these amino acids are transported to see whether it will be possible to modulate this process and thus improve or restore amino acid transfer.
Progress report: There are three types of transporter for amino acids, known as SNAT1, SNAT2 and SNAT4. We have discovered that SNAT4’s contribution to placental amino acid transport is higher in early pregnancy and that SNAT1 is significant in late pregnancy. We are now investigating how the different SNATs are controlled. A better understanding of placental amino acid transport will help in developing strategies for treating fetal growth restriction.

Understanding how nutrient transfer and fetal blood flow in the placenta is regulated
Investigators: Dr Paul Brownbill, Professor Colin Sibley
Funding: Study taking place in a Tommy’s funded centre
Timescale: 2008 onwards
Summary: The placenta is a vital organ to fetal growth and survival, where the mother’s and baby’s blood flow closely but are kept separate, and where nutrients and oxygen cross into the baby’s blood. The placenta needs to cope with increased demand as the baby grows faster throughout pregnancy. Placental blood vessels sense the blood flow and respond to a cocktail of chemical signals in the fetal blood, and the vessels’ muscles will either relax or tighten. Disruption of these processes in the placenta is likely to compromise fetal growth and development, and severe disruption may threaten the pregnancy itself or force a clinical decision for preterm delivery. Our work aims to understand how nutrient transfer and fetal blood flow is controlled, with the hope of finding ways of rebalancing these important placental events in pregnancy.