Title: Does nutrient deficiency in women with severe Hyperemesis Gravidarum contribute towards adverse outcomes in children of affected pregnancies?
Funder: Department of Health and Social Care

Abstract: Research question: Does nutrient deficiency in women with severe Hyperemesis Gravidarum (HG) contribute towards increased rates of neurodevelopmental disorders and risk factors for metabolic disease in children of affected pregnancies? Background: HG affects 0.3-3.6% of pregnant women. Maternal life-threatening complications relate to electrolyte and nutrient disturbance. Their children are at increased risk of neurodevelopmental disorders and metabolic disease. Given these associations and established relationships between maternal nutrient status and offspring neurodevelopment and metabolic disease in settings other than HG I propose the novel hypothesis that HG-associated nutrient deficiency is responsible for the increased offspring risk of neurodevelopmental and metabolic disorders. Aims/Objectives: Aim 1: Determine nutrient status in women with severe-HG and their newborns Objectives: I will prospectively measure nutrient status in women with severe-HG throughout gestation and in the neonate, and compare to matched controls without HG. Aim 2: Investigate associations between nutrient status and offspring risk of maturational differences in brain volume and susceptibility to metabolic disease in newborns of women with severe-HG Objectives: Maturational differences in brain volume will be measured in the neonate using magnetic resonance imaging (MRI) at birth Neonate metabolic outcomes will be measured using anthropometric measurements, markers of metabolic risk and lipidomic studiesMethods: In this prospective cohort study I will recruit 70 women with severe-HG and compare them to 70 matched controls. Maternal blood and urine samples for nutrient analysis will be collected at four timepoints, at each visit demographic data and clinical phenotyping will also be performed. Neonates will have anthropometric measurements at birth and a blood sample at day 5-7 of life, assayed for nutrient concentrations, metabolic markers, lipidomic studies. MRI will be performed on 18 neonates in the HG-group. Overall nutrient concentrations will be compared between the two groups. Interval regression will be used with correction for repeated measures and adjustment for confounders, with data transformation appropriate for their distribution. In the neonates nutrient concentrations will be correlated with markers of metabolic risk and anthropometry using linear and logistic regression. Random-forest-machine-learning-models will be used to study whether lipid-profile during pregnancy is related to HG and offspring metabolic outcomes. I will compare individual brain volumes of 15 HG-exposed neonates against existing normative charts of brain volumetric development. Timelines: Recruitment completed by July 2023 Completion of MRI studies by April 2024 Final data analysis completed by April 2025Impact/Dissemination: Robustly confirming nutrient deficiency as a modifiable risk factor in HG would provide a solid foundation for intervention trials in which these nutrients could be replaced, enabling recommendation of evidence-based treatments within five years, that could improve short-term outcomes for mother and fetus and long-term neurocognitive and metabolic outcomes for the children. Results will shared with the public via Pregnancy Sickness Support and other charities. In view of current public interest, the results of the study are likely to attract national media coverage. The study will be published in medical journals and presented at conferences. It will be discussed in a policy lab enabling important findings to be included in future medical guidelines.

Lay abstract: This summary was prepared with valuable support from lay members of the Research Design Service.Background:Hyperemesis gravidarum (HG) is a severe form of nausea and vomiting in pregnancy. It affects around 2 in 100 pregnancies (7,200 women per year in the UK) and is the commonest reason for hospital admission in early pregnancy. Women vomit up to 60 times per day and symptoms can last throughout the whole pregnancy. Some women become so distressed that they abort a wanted pregnancy or have suicidal thoughts.Their babies are more likely to have problems with brain development and have increased risk of heart disease, obesity and diabetes (known as 'metabolic diseases') in later life. These issues may result from low levels of nutrients during the pregnancy. Only four small studies have investigated this; one measured blood nutrient levels, the others used information from food diaries to estimate nutrient intake. These studies suggested that women with HG had very low levels of many nutrients (often lower than half the recommended amount). We know that low levels of some nutrients during pregnancy are linked to brain development problems and risk of future metabolic disease in the children of women with other medical problems, but this has not been confirmed in HG.I aim to: Establish if essential nutrient levels are low in HG-women, if so: Which nutrients are low? How much lower than normal? Whether they stay low throughout pregnancy? Whether their babies have low nutrient levels? Study brain development in the babies by using a brain scan (safe for babies) Predict the babies' risk of developing metabolic diseases in later life Follow the health of the babies into childhood (for future studies)If I find that nutrient deficiency exists in HG and/or contributes to poor brain development and increased risk of metabolic diseases, replacement nutrient treatments could be developed with potential to improve the care of women with HG and the health of their babies.Methods:I will recruit 70 women with HG and 70 women with normal pregnancies for comparison. The mothers' nutrient levels will be measured using blood and urine samples four times throughout pregnancy. If too sick to attend hospital, samples can be taken at home.A blood sample from the baby will be taken with their routine heel prick so no extra distress is caused. I will measure the babies' nutrient levels and other factors that can predict future risk of metabolic disease in a specialist laboratory in Cambridge. 18 babies born to mothers with HG will have a state-of-the-art brain scan to compare their brain development to babies whose mothers did not have HG.Patient and public involvement:When I analysed comments of 5081 women describing their HG-experience, many worried about the effects of low nutrient levels on their babies. This proposed study was designed with significant help from women who have had HG. I will soon hold a conference inviting women to learn about the study and how to get involved. I will meet regularly throughout the project with women with HG for ongoing feedback. Up-to-date study information will be available on a website.DisseminationResults will shared with pregnant women with HG and the public via Pregnancy Sickness Support and a study website/newsletters. In view of current public interest, like my previous HG-research, the results of the study are likely to attract national media coverage.The study will be published in medical journals and presented to healthcare professionals at conferences. Policy lab stakeholders will enable important findings to be included in future medical guidelines.

Research activity codes: 3.3 NUTRITION AND CHEMOPREVENTION
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH