PhD Study : Nutrition intervention for healthy blood pressure in pregnancy: impact on placenta development and neonatal wellbeing

Summary

Pregnancy induced hypertension (PIH) affects an estimated 10-15% of all pregnancies and is considered one of the major causes of maternal and prenatal morbidity and mortality (1). Along with established nutrition and lifestyle determinants, genetic factors also contribute to development of high blood pressure (BP), with evidence from Genome-Wide Association Studies implicating the MTHFR gene (encoding the folate-metabolising enzyme methylenetetrahydrofolate reductase). Meta-analyses of prospective observational studies have confirmed the link of MTHFR 677C→T polymorphism with PIH (2) and preeclampsia (3). In recent years, researchers at Ulster made the novel discovery that riboflavin, the MTHFR co-factor, plays a key role in driving the BP phenotype and risk of hypertension associated with this folate polymorphism. In three randomised controlled trials (RCTs) published to date, we showed that riboflavin supplementation targeted at homozygous individuals (MTHFR 677TT genotype) lowers systolic blood pressure by 6-13 mmHg, independently of the effect of antihypertensive drugs (4-6). The TT genotype affects an estimated 10% of populations worldwide, and 12% of Irish adults. For people with this genotype riboflavin may offer an effective treatment or preventative strategy for hypertension, but to date this has not been investigated in the context of pregnancy.  The placenta is a transient structure where the maternal and fetal vasculatures intersect in order to allow transfer of nutrients and other substances. It is a highly specialised and tightly regulated organ whose functioning has an impact on health and wellbeing of the fetus and neonate, as well as influencing the risk of high BP in childhood and in later life (7, 8). Perturbed growth and development of placental villi occurs in pregnancies complicated by fetal growth restriction (9), PIH and/or preeclampsia (10); however, it is unknown if the MTHFR 677TT genotype can independently affect the development and function of placenta.

The overall aim of this PhD project is to test the use of riboflavin as a non-drug, personalised approach for managing BP in pregnancy in women who are genetically at-risk of higher BP. In addition, the project will investigate the role of MTHFR 677TT genotype on placental development at term, by quantifying morphological, cellular and molecular markers and particularly whether the treatment with riboflavin has a modifying impact on these measures. A double-blinded RCT will be conducted on pregnant women recruited in the first trimester of pregnancy. Women will be genotyped for MTHFR 677C→T polymorphism and will be randomised to receive either 5 mg/day riboflavin or placebo from 16 GW until the end of pregnancy. Blood samples and BP measurements will be taken before and at the end of the intervention. Placenta and cord blood samples will be collected at delivery. Blood samples will be analysed for riboflavin and B-vitamin biomarkers whereas placenta samples will be subjected to histological, stereological, immunohistochemical and ultrastructural assessment. The student will receive full training (human studies and laboratory methods), but previous experience in subject recruitment and/or relevant laboratory techniques would be an advantage.

This project will be based in Ulster's Nutrition Innovation Centre for Food and Health (NICHE).

References:

1.Macdonald-Wallis C, Silverwood RJ, de Stavola BL, Inskip H, Cooper C, Godfrey KM, Crozier S, Fraser A, Nelson SM, Lawlor DA & Tilling K. Antenatal blood pressure for prediction of pre-eclampsia, preterm birth, and small for gestational age babies: development and validation in two general population cohorts. BMJ. 2015;351:h5948

2.Yang B, Fan S, Zhi x, Li Y, Liu Y, Wang D, He M, Hou Y, Zheng Q & Sun G. Associations of MTHFR gene polymorphism and hypertension and hypertension in pregnancy: a meta-analysis from 114 studies. PLoS ONE. 2014.9, e87497

3.Xia X., Chang W, Cao Y, 2012. Meta-analysis of the methylenetetrahydrofolate reductase C677T polymorphism and susceptibility to pre-eclampsia. Hypertens Res. 2012;35(12):1129-34.

4.Horigan G, McNulty H, Ward M, Strain J, Purvis J & Scott JM. Riboflavin lowers blood pressure in cardiovascular disease patients homozygous for the 677C-->T polymorphism in MTHFR. J Hypertens. 2010.28:478-86

5.Wilson CP, McNulty H Ward M et al. (2012). Riboflavin offers a targeted strategy for managing hypertension in patients with the MTHFR C77TT genotype: a 4y follow up. Am J. 95,766-772

6.Wilson CP, McNulty H, Scott JM, Strain JJ, Ward M. The MTHFR C677T polymorphism, B-vitamins and blood pressure. Proc Nutr Soc, 2010. 69 156-165.

7.Barker DJ, Thornburg KL, Osmond C, Kajantie E, Eriksson JG. The surface area of the placenta and hypertension in the offspring in later life. Int J Dev Biol. 2010;54(2-3):525-30.

8.Barker D, Osmond C, Grant S, Thornburg KL, Cooper C, Ring S, Davey-Smith G. Maternal cotyledons at birth predict blood pressure in childhood. Placenta. 2013 Aug;34(8):672-5.

9.T.M. Mayhew, C. Ohadike, P.N. Baker, I.P. Crocker, C. Mitchell and S.S. Ong (2003) Stereological investigation of placental morphology in pregnancies complicated by pre-eclampsia with and without intrauterine growth restriction. Placenta 24: 219 – 226

10.Jones CP & Fox H. An ultrastructural and ultrahistochemical study of the human placenta in maternal pre-eclampsia. Placenta 1980; 1: 61-76.

Essential criteria

Applicants should hold, or expect to obtain, a First or Upper Second Class Honours Degree in a subject relevant to the proposed area of study.

We may also consider applications from those who hold equivalent qualifications, for example, a Lower Second Class Honours Degree plus a Master’s Degree with Distinction.

In exceptional circumstances, the University may consider a portfolio of evidence from applicants who have appropriate professional experience which is equivalent to the learning outcomes of an Honours degree in lieu of academic qualifications.

• Sound understanding of subject area as evidenced by a comprehensive research proposal
• A comprehensive and articulate personal statement

Desirable Criteria

If the University receives a large number of applicants for the project, the following desirable criteria may be applied to shortlist applicants for interview.

• First Class Honours (1st) Degree
• Completion of Masters at a level equivalent to commendation or distinction at Ulster
• Research project completion within taught Masters degree or MRES
• Experience using research methods or other approaches relevant to the subject domain
• Work experience relevant to the proposed project
• Publications - peer-reviewed
• Experience of presentation of research findings

Funding and eligibility

The University offers the following levels of support:

Vice Chancellors Research Studentship (VCRS)

The following scholarship options are available to applicants worldwide:

• Full Award: (full-time tuition fees + £19,000 (tbc))
• Part Award: (full-time tuition fees + £9,500)
• Fees Only Award: (full-time tuition fees)

These scholarships will cover full-time PhD tuition fees for three years (subject to satisfactory academic performance) and will provide a £900 per annum research training support grant (RTSG) to help support the PhD researcher.

Applicants who already hold a doctoral degree or who have been registered on a programme of research leading to the award of a doctoral degree on a full-time basis for more than one year (or part-time equivalent) are NOT eligible to apply for an award.

Please note: you will automatically be entered into the competition for the Full Award, unless you state otherwise in your application.

Department for the Economy (DFE)

The scholarship will cover tuition fees at the Home rate and a maintenance allowance of £19,000 (tbc) per annum for three years (subject to satisfactory academic performance).

This scholarship also comes with £900 per annum for three years as a research training support grant (RTSG) allocation to help support the PhD researcher.

• Candidates with pre-settled or settled status under the EU Settlement Scheme, who also satisfy a three year residency requirement in the UK prior to the start of the course for which a Studentship is held MAY receive a Studentship covering fees and maintenance.
• Republic of Ireland (ROI) nationals who satisfy three years’ residency in the UK prior to the start of the course MAY receive a Studentship covering fees and maintenance (ROI nationals don’t need to have pre-settled or settled status under the EU Settlement Scheme to qualify).
• Other non-ROI EU applicants are ‘International’ are not eligible for this source of funding.
• Applicants who already hold a doctoral degree or who have been registered on a programme of research leading to the award of a doctoral degree on a full-time basis for more than one year (or part-time equivalent) are NOT eligible to apply for an award.

Due consideration should be given to financing your studies. Further information on cost of living