Pathophysiology of prothrombotic state in overweight pregnant women v1
Research type
Research Study
Full title
An investigation of the pathophysiology underlying the increased risk of venous thrombosis in overweight and obese pregnant women.
IRAS ID
253577
Contact name
Catherine Bagot
Contact email
Sponsor organisation
NHS Greater Glasgow and Clyde
Duration of Study in the UK
1 years, 11 months, 25 days
Research summary
Summary of Research
Blood clots in veins are the commonest cause of death in pregnant women. Overweight and obese pregnant women have a greater chance of developing and dying from blood clots than normal weight pregnant women. National guidelines recommend an increased dose of heparin in overweight and obese pregnant women to try and reduce this increased risk. However, this has not been proven to be effective and it may increase the risk of bleeding, a known side effect of heparin.
Our study will investigate why overweight and obese pregnant women have a higher risk of blood clots. It may be due to an abnormality in the function and location of fat cells in the body. We will take blood from normal weight and overweight pregnant women and test the blood to see how easily it clots and how fat cells work. We will measure the amount of fat cells under the skin and around the abdominal organs using ultrasound, a test safe in pregnancy.
The study will be open to all pregnant women attending the Princess Royal Maternity Hospital, Glasgow. We will recruit women of all body sizes and compare the results between normal weight, overweight and obese pregnant women.
Our study aim is to explain why overweight and obese pregnant women are at increased risk of blood clots. This information should allow further studies to be performed to determine what heparin dose should be used to reduce the risk of blood clots in overweight and obese pregnant women.Summary of Results
The IPOP (An Investigation of the Prothrombotic effect of Obesity during Pregnancy) study was an observational study looking at changes in blood clotting during pregnancy.
Pregnancy is known to be a period of increased risk for developing venous thromboembolism (blood clots), either in the legs (deep vein thrombosis) or lungs (pulmonary embolism). During pregnancy, it is normal for there to be changes in the blood that make it more likely to clot, and this is thought to be nature’s way of reducing how much blood women lose at delivery.
However, blood clots are a leading cause of death for women during and shortly after pregnancy, and women who are obese appear to be at greater risk. Obese women may be at increased risk of blood clots due to different levels of fat hormones (adipokines) produced by their fat tissue, or where they carry the additional fat, whether under the skin (subcutaneous), around the organs (visceral), or on the waist or hips.
The purpose of this study was to look at the changes in blood clotting which occur during pregnancy, comparing women of normal weight to women who are overweight and obese. We hoped to identify why obese women are at increased risk of blood clots during pregnancy by comparing measurements of the blood clotting system with measurements of body fat location and fat hormone levels.
267 pregnant women agreed to participate in the study and were recruited when attending for their first antenatal appointment (around 10 weeks pregnant) at the Princess Royal Maternity Hospital, Glasgow, between April 2019 and March 2020.
The study participants told the researchers their medical history and had their height, weight, and waist and hip circumference measured. Blood samples were taken at the same time as routine blood tests for pregnancy. The women were then asked to attend for an ultrasound scan to look at abdominal fat and how much fat was carried under the skin (subcutaneous fat) and how much around the organs (visceral fat). Blood samples were taken again for the study at 28 weeks pregnant. Information about the rest of the pregnancy and delivery of the baby were collected from the electronic case notes.
Unfortunately, due to the COVID-19 pandemic, we were unable to follow-up 61 women at the 28 week appointment, however a total of 173 women attended both study visits, providing a large amount of data for review
Blood samples were processed and then frozen in the Glasgow Royal Infirmary Haemostasis laboratory to allow testing in batches at a later date. Blood clotting was measured using a test called thrombin generation which measures the ability of the blood to clot. Other parts of the blood clotting system were also measured, including clotting factors which promote blood clotting (Factor VIII and fibrinogen) and other proteins which reduce blood clotting (protein S, TFPI and PAI-1). Fat hormones leptin and adiponectin were measured along with hormones linked to inflammation (IL-6, TNF-α and IL-1β).
Main findings:
1. Obese women have a more prolonged period of increased blood clotting, compared to normal weight women, during pregnancy. Women who were obese had levels of clotting factors (increased fibrinogen and thrombin generation; decreased PAI-1, TFPI), indicating increased blood clotting, at 12 weeks of pregnancy compared to normal weight women. In addition, for all women, markers of blood clotting increased between 12 weeks and 28 weeks pregnant. These findings suggest that obese women are exposed to an increased risk of blood clots for longer than normal weight women during pregnancy.
2. Carrying more fat under the skin is linked to higher levels of the fat hormone, leptin, and the inflammatory protein, IL-6. Previous research has shown that where fat is found in the body influences how it works and which types of hormones it produces. In this study, women carrying the most fat under the skin had significantly higher levels of the fat hormone leptin, and the inflammatory protein, IL-6.
3. Higher levels of the fat hormone, leptin, and the inflammatory protein, IL-6, could be linked to the increased blood clotting in obese pregnant women. Obese pregnant women were found to have higher levels of the fat hormone leptin and the inflammatory protein, IL-6, compared to normal weight pregnant women. We know that high levels of leptin can cause inflammation and inflammation can cause increased blood clotting. In this study we found high levels of leptin and IL-6 to be linked with increased levels of the clotting protein fibrinogen and thrombin generation. High levels of Leptin and IL6 may therefore explain why there is increased blood clotting in obese pregnant women.We believe our study has shown that the increased risk of blood clots in obese women during pregnancy may be due to exposure to increased levels of blood clotting for longer than normal weight women. This increased blood clotting may be linked to high levels of leptin and IL-6, which are produced in greater quantities by women who carry more fat under the skin.
This study has been very helpful in improving our understanding of blood clotting in obese women during pregnancy, and suggests some possible reasons why obese women have a higher risk of blood clots during pregnancy. By furthering our understanding of the mechanisms involved in increased blood clotting in obese pregnant women, we now plan to investigate ways to reduce the risk of blood clots in this patient group.
Our next study will aim to confirm these findings in a larger patient group, and also look at the effect of anticoagulation (blood thinning medicines) on markers of blood clotting in obese women.
We would like to thank all of the women who kindly agreed to take part in this study. By giving up their time and donating blood samples to research, they have allowed us to take a step forward in reducing the risk of blood clots during pregnancy, a complication which can have devastating consequences.
The principal investigators for the study were Dr Catherine Bagot (Consultant Haematologist) and Dr Dilys Freeman (University of Glasgow). Participant recruitment and data collection were carried out by Dr Susan McNeill (Haematology Clinical Research Fellow) with support from Glasgow Clinical Research Facility midwives and Glasgow Royal Infirmary Haemostasis laboratory. Laboratory analyses were performed by Dr Susan McNeill and Mrs Fiona Jordan (research technician, University of Glasgow). The study was funded by the British Heart Foundation and ethical approval was given by the West of Scotland Research Ethics Committee.
REC name
West of Scotland REC 4
REC reference
19/WS/0022
Date of REC Opinion
6 Feb 2019
REC opinion
Favourable Opinion