Investigating a novel molecular diagnostic tool for identification and stratification of pregnancy complications

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Babies who grow poorly in the womb, called small for gestational age (SGA), are at increased risk of health problems for both mother and baby. For example, full-term infants who are SGA have up to 30 times higher risk of neonatal death compared to term infants born at average weight. Screening pregnant women in an attempt to detect SGA babies has the potential to reduce the number of these adverse outcomes -the combined deaths from stillbirth and neonatal problems exceed 5000 babies every year in the UK. Currently it is difficult to monitor growth of the baby in the womb, and even harder to predict if there will be health problems associated with this. While there are a number of scan and blood markers for SGA babies, none of these is good enough on its own to predict them. We have recently found that by measuring a protein called DLK1 in the mother's blood we can improve the prediction of whether the baby will be small. In this first study we examined only a small selection of pregnant women, but the data suggested that abnormal DLK1 levels were associated with failure to make an efficient placenta. The placenta is a temporary organ that is necessary for providing nutrition and oxygen to the baby from the mother's blood, and for removing waste. Many of the complications of pregnancy are thought to occur because the placenta does not develop properly. However, we still have much to discover about which genes are needed to make a healthy placenta, and how this goes wrong if the genes are mutated. Interestingly, DLK1 is made in the placenta. When we studied mice with a mutated DLK1 gene we found that they had smaller placentas and a reduced area for nutrient and oxygen exchange between the maternal and fetal blood. However, we currently don't understand why DLK1 is required to make a healthy placenta. The aim of this project is firstly to see how measuring DLK1 in the blood of a large number of pregnant women can help us improve prediction of small babies. We have access to scan information, blood samples and placental samples from a large scale study of unselected women in their first pregnancy (~3000 women). The overarching aim of the present application is to see if we can find better markers in the mother's blood of poorly grown babies, and further link the levels of DLK1 to problems with the placenta. Secondly, because we have mice without a working DLK1 gene, we can study them to understand the processes necessary to make a healthy placenta. We will use the new ideas generated by studying the mice to design experiments using the human placental samples to test if our findings can help to understand why placentation goes wrong in humans.