PreeclampsiaEpigenetics
Research type
Research Study
Full title
Infants of mothers with preeclampsia: Epigenetic changes and relation to infant outcomes.
IRAS ID
285608
Contact name
Ajay Sinha
Contact email
Sponsor organisation
Barts Health NHS Trust
Duration of Study in the UK
1 years, 11 months, 30 days
Research summary
Summary of Research
Preeclampsia is a serious disease during pregnancy resulting in increase in the blood pressure. It affects 2-8 % of all pregnancies worldwide affecting the outcomes of pregnant women and their babies. These infants not only have increased risk of neonatal complications including preterm birth (birth before 37 weeks of pregnancy), intrauterine growth restriction (babies who have not grown in womb as expected), necrotising enterocolitis (serious bowel disease, causing it to die), and bronchopulmonary dysplasia (lung disease resulting in oxygen need or breathing support) but also have increased risk of abnormal neurodevelopmental outcomes, heart disease and stroke during childhood and adulthood. Preeclampsia affect haematopoiesis (production of blood cells) leading to low platelets and neutrophils levels and reduced immune function (ability to fight infections) in neonates.Our aim of this observational study is to investigate the effect of preeclampsia on infant genome through detecting the changes in DNA in response to this disease and investigate the relationship between these epigenetic changes, immune response and neonatal outcomes.
The recruitment of the 3 groups of participants and their babies will be from the Barts Health NHS Trust.
1. Preeclamptic patients (20 patients)
2. Pregnancy induced hypertension (20 patients)
3. Healthy pregnant women (20 patients)Patients with preeclampsia will be consented prior to delivery. Healthy pregnant women as controls and women with pregnancy induced hypertension will be recruited at matched gestations.
Participants will be asked to give consent for collection of placental tissue and cord blood samples and would be tested for epigenetics changes and immune cells function. They would also be requested to consent for an echocardiography examination of their babies and collection of routine clinical data.This observational study will give new insight into how the preeclamptic pregnancies affect the epigenetics changes, immune function and neonatal outcomes.
Summary of Results
: Fifty nine patients were recruited in this study. The placenta of mothers with preeclampsia shows changes in the genes which is important for regulating other gene function with a role in development of preeclampsia and its complication. The cardiovascular assessment of newborn infants showed that these infants have similar level of blood flow to brain from carotid artery and similar volume of blood flowing from heart.
Dissemination plan: These preliminary findings have been presented in national and international meeting and preprint of article is available and has been submitted for publication in a peer reviewed journal Informing participants: Participants would be provided with study findings after final analysis of data.
Sharing of data and tissueWe began recruiting participants for the study in March 2021 after receiving ethics committee approval (HRA 21/55/0010) to assess the effect of preeclampsia on the cardiovascular status, immunological cells, and epigenetic changes on infants.
A total of fiftynine patient were enrolled from March 2021 to March 2022 after informed written consent from parents. We evaluated the infants of cardiac output and cerebral blood flow by using ultrasound machine. In cord blood samples, we compared the T helper cells function (CD4CD25FoxP3) by using the flow cytometry in infants from preeclampsia mother with those from normotensive mothers. In placental tissue, we examined the epigenetic markers H3K27ac and H4K16ac on the whole genome and isolated the RNA to evaluate the genes’ function.
We performed cardiovascular evaluation on 42 infants (25 babies from mothers with preeclampsia – 10 babies from mothers with pregnancy induced hypertension – 7 babies form mother with normal pregnancy). We measured cardiac output to determine cardiac function and assessed the cerebral blood flow by measuring the blood flow via right common carotid artery (RCCA) by using doppler ultrasound. We showed that preeclampsia, Pregnancy-induced hypertension, and antihypertensive medication did not affect RCCA flow, a marker of cerebral blood flow or cardiac output in new-born infants. RCCA flow was associated with gestational age, birth weight and cardiac output; however, birth weight was the only significant predictor of RCCA blood flow. Our conclusion is the cardiovascular and neurodevelopmental effects seen in infants of mothers with preeclampsia are unlikely to be blood flow mediated. We presented an abstract of our research on the European congress of perinatal meeting 2022. We are currently finishing up a comprehensive paper based on these findings with the intention of publishing it in a peer reviewed journal.
We sequenced the epigenetic (H3K27ac - acetylation level at histone H3 lysine 27 and H4K16ac - acetylation level at histone H4 lysine 16) marks on the whole genome and performed RNA isolation on the placental samples of different study groups. We did it on four samples form mother with severe preeclampsia, five samples from mothers with mild preeclampsia, and six sample from normotensive mothers.
The key findings were:
Transposable elements are upregulated in preeclamptic placentas. We found a specific increase in acetylation level at histone H4 lysine 16 (H4K16ac) across transposable elements (TEs) in preeclamptic placenta compared to control. H4K16ac hyperacetylation in pre-eclampsia is associated with increased transcript levels of endogenous retrovirus (ERV) and long interspersed nuclear element 1 (L1, LINE1) subfamilies of TEs in PE placenta from independent pregnancy cohorts.
Placenta of mothers with PE+IUGR foetus have lower level of methylation across LINE1. Lower DNA methylation level in the PE+IUGR placentas together with higher H4K16ac and higher transcription of these TEs in PE placenta confirms the role of altered epigenetic and chromatin structure in contributing to TE deregulation in PE.
Preeclampsia placentas have higher level of type1 interferon response PE is associated with inflammation, our data and analysis of multiple PE placental cohorts suggests that higher level of L1 and HERV LTRs in the PE placenta leads to elevated level of antiviral type I IFN pathway due to sensing of these TE derived nucleic acids IFN1 receptors.
We presented our finding on the UK neonatal society meeting in June 2022 as an abstract and oral presentation. The manuscript has been deposited in an online repository and been submitted for publication in a peer reviewed journal.
We assessed the T helper cells function on the cord blood sample of 11 infants from preeclampsia mother, 11 infants from normotensive control, and 7 infants from pregnancy induced hypertension mothers. We used the flowcytometry (NovoCyte machine) to assess the CD4, CD25, FoxP3, CD45RO, CD45RA, and CD69 markers. We found that the CD4CD25 and CD4CD25FoxP3 are lower in the cord blood samples from preeclampsia mothers, which could explain some of the complication which occur in these babies.Preprint available on: https://eur03.safelinks.protection.outlook.com/?url=https%3A%2F%2Fclick.pstmrk.it%2F3ts%2Fwww.biorxiv.org%252Fcontent%252F10.1101%252F2024.11.08.622691v1.full%2FNBTI%2Fk_25AQ%2FAQ%2F47be5b3e-794e-4396-a272-944d32a6c4cc%2F1%2FJjSq8BqhhH&data=05%7C02%7Capprovals%40hra.nhs.uk%7C978a72cf8a644ae107a008dd192d6686%7C8e1f0acad87d4f20939e36243d574267%7C0%7C0%7C638694404976193452%7CUnknown%7CTWFpbGZsb3d8eyJFbXB0eU1hcGkiOnRydWUsIlYiOiIwLjAuMDAwMCIsIlAiOiJXaW4zMiIsIkFOIjoiTWFpbCIsIldUIjoyfQ%3D%3D%7C0%7C%7C%7C&sdata=C8uIoswr%2F6MECWJfVXJUOZKhmr%2BhExdJHgk%2FYcIZgEQ%3D&reserved=0
REC name
South East Scotland REC 02
REC reference
21/SS/0010
Date of REC Opinion
4 Mar 2021
REC opinion
Further Information Favourable Opinion