Reproductive and Cardio-metabolic health: Debbie Lawlor
In the next 5-yearsthis programme will provide the evidence base that will improve treatment success with IVF and enable stratified and effective antenatal care in IVF and spontaneous conceptions (SC), such that adverse perinatal and pregnancy outcomes will be reduced, and offspring cardio-metabolic health improved. Our overarching aim is split into four areas of research (A1 to A4): A1. IVF – pregnancy, perinatal, and offspring cardio-metabolic outcomes. A2. SC – pregnancy and perinatal outcomes. A3. SC – offspring cardio-metabolic outcomes. A4. Developing novel causal methods.
Aims & Objectives
The overarching aim is to accurately predict and identify causal paths for: (i) response to IVF; (ii) healthy pregnancy and perinatal outcomes in IVF and SC; and (iii) offspring cardio-metabolic health. Our focus is primarily on maternal smoking, physical activity, adiposity, pregnancy metabolic profiles and fetal (cord-blood) DNA methylation as potential predictors or causal risk factors. We will also contribute to the development of novel causal methods, for example in how we can determine effects of risk factors measured in pregnant women on health outcomes in their child some years later.
Two highlights of the last 3 years that are illustrative of our research and its impact. Predicting and optimising outcomes with IVF We have developed a tool that accurately predicts live-birth in women receiving IVF, demonstrated the optimal number of embryos to transfer in IVF by strata of women’s prognosis and shown that with repeat cycles of IVF women can achieve live-birth rates similar to those with spontaneous conception. This work has influenced clinical practice through national and international guidelines. Key Reference: Smith ADAC, Tilling K, Nelson S, Lawlor DA. Live-birth rate associated with repeat in vitro fertilization treatment cycles. JAMA 2015; 314: 2654-2662
Pregnancy, maternal adiposity and offspring cardio-metabolic health. We have shown that there is widespread metabolic disruption on becoming pregnant, which then returns to normal. This disruption is more extreme in obese women and having higher body mass index (BMI) and fasting glucose in pregnancy causes larger babies at birth. Key Reference: Tyrrell J, [61 additional authors], Lawlor DA*, Freathy RM*, for the Early Growth Genetics (EGG) Consortium [*Joint senior & corresponding authors]. Genetic evidence for causal relationships between maternal obesity-related traits and birth weight. JAMA 2016; 315: 1129-1240.
Predicting outcomes and optimising outcomes with IVF
We have developed a tool that accurately predicts live-birth in women receiving IVF, demonstrated the optimal number of embryos to transfer in IVF by strata of women’s age (a key prognostic indicator) and shown that with repeat cycles of IVF women can achieve live-birth rates similar to those with SC. #
Pregnancy, maternal adiposity and offspring cardio-metabolic health
We have shown that there is widespread metabolic disruption on becoming pregnant, which is more extreme in obese women. Having higher BMI and fasting glucose in pregnancy causes larger babies at birth, but does not appear to have sustained impact on future offspring adiposity and adverse cardio-metabolic health. By contrast we find evidence for a causal effect of gestational diabetes on future offspring adiposity. https://jamanetwork.com/journals/jama/fullarticle/2503173
Development of novel causal methods
We have developed criteria for using triangulation to improve causal inference and developed methods that address specific issues that might bias MR when it is used to test causal effects of risk factors in pregnant women on outcomes in their offspring.
Is adiponectin a causal risk factor for Coronary Heart Disease?
Using two-sample Mendelian Randomization we have shown that higher circulating adiponectin levels do not protect against CHD risk, suggesting that previous observations of a protective association were confounded. We have also shown that circulating adiponectin does not causally affect circulating lipids, lipoproteins, fatty acids or a range of small molecules.
GWAS for Chronotype
We completed the first large scale Genome Wide Association Study (GWAS) of chronotype (morning vs evening person), sleep quality and insomnia, and have shown, using Mendelian randomization, that insomnia is potentially causally related to increased risk of CHD, depressive symptoms and subjective wellbeing.