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Optimal Nutrition for Prevention of Hypertension in Pregnancy (OptiPREG)

Primary Purpose

Blood Pressure, Pregnancy

Status
Recruiting
Phase
Not Applicable
Locations
International
Study Type
Interventional
Intervention
Riboflavin (5mg)
5-methyltetrahydrofolate (400µg)
Placebo
Sponsored by
University of Ulster
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional prevention trial for Blood Pressure focused on measuring Pregnancy, Maternal blood pressure, MTHFR 677TT genotype, Riboflavin, 5-methyltetrahydrofolate, Offspring blood pressure

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)FemaleAccepts Healthy Volunteers

Inclusion Criteria:

• Women with a singleton pregnancy who are in their first trimester of pregnancy

Exclusion Criteria:

  • Patients who have a high risk pregnancy, a previous pregnancy with a neural tube defect (NTD) or are the first degree relative of a woman who had a pregnancy affected by NTD or are themselves a sufferer of an NTD
  • Women who are taking medication known to interfere with B-vitamin metabolism

Sites / Locations

  • Letterkenny University HospitalRecruiting
  • Northern Health and Social Care TrustRecruiting
  • Western Health and Social Care TrustRecruiting

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm 5

Arm 6

Arm Type

Active Comparator

Experimental

Placebo Comparator

Active Comparator

Experimental

Placebo Comparator

Arm Label

TT genotype active comparator group

TT genotype experimental group

TT genotype placebo group

CT genotype active comparator group

CT genotype experimental group

CT genotype placebo group

Arm Description

5mg riboflavin per day from 16th gestational week

5mg riboflavin + 400µg 5-methyltetrahydrofolate per day from 16th gestational week

Placebo supplement from 16th gestational week

5mg riboflavin per day from 16th gestational week

5mg riboflavin + 400µg 5-methyltetrahydrofolate per day from 16th gestational week

Placebo supplement from 16th gestational week

Outcomes

Primary Outcome Measures

Maternal Blood Pressure
Taken according to the clinical guidelines in pregnancy from the UK National Institute for Health and Care Excellence (NICE)

Secondary Outcome Measures

Vitamin B12 status
Measured by a microbiological L. Leichmannii assay; serum methylmalonic acid concentrations by Gas Chromatography-Mass Spectrometry
Plasma homocysteine
Measured using a fluorescence polarization immunoassay
Riboflavin status
Measured using the erythrocyte glutathione reductase activation coefficient
Vitamin B6 status
Plasma pyridoxal phosphate concentrations measured by High Performance Liquid Chromatography
Folate status
Measured by a microbiological L.casei assay
MTHFR C677T polymorphism (rs1801133)
Determined by restriction enzyme typing Hinf1 digestion in DNA extracted from buccal swabs
Maternal blood pressure
Taken according to the clinical guidelines in pregnancy from the UK National Institute for Health and Care Excellence (NICE)
Offspring blood pressure
Offspring anthropometry
Length (cm)
Offspring anthropometry
Weight (kg)
Maternal anthropometry
Weight (kg) and height (m) will be combined to report BMI in kg/m^2
Placenta size
Placenta weight (g)
Placenta size
Dimensions (cm)
Placenta and umbilical cord histology
Samples will be examined for villous changes (i.e. presence of infarcts, increased syncytial knots and fibrin deposition, hyalinized avascular villi) and vascular lesions (i.e. decidual vascular thrombosis, spiral artery fibrinoid necrosis, mural hypertrophy of decidual arterioles, thrombi in large fetal vessels, fibromuscular sclerosis in intermediate-sized fetal vessels)

Full Information

First Posted
January 12, 2021
Last Updated
January 20, 2021
Sponsor
University of Ulster
Collaborators
DSM Ltd, Public Health Agency (Northern Ireland)
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1. Study Identification

Unique Protocol Identification Number
NCT04723836
Brief Title
Optimal Nutrition for Prevention of Hypertension in Pregnancy
Acronym
OptiPREG
Official Title
Optimal Nutrition for Prevention of Hypertension in Pregnancy Using a Personalised Approach
Study Type
Interventional

2. Study Status

Record Verification Date
January 2021
Overall Recruitment Status
Recruiting
Study Start Date
March 1, 2017 (Actual)
Primary Completion Date
April 12, 2024 (Anticipated)
Study Completion Date
April 12, 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
University of Ulster
Collaborators
DSM Ltd, Public Health Agency (Northern Ireland)

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No

5. Study Description

Brief Summary
The aim of this study is to investigate the role of the 677C→T polymorphism in the methylenetetrahydrofolate reductase (MTHFR) gene on blood pressure (BP) during pregnancy, and to examine the effect of intervention with riboflavin, alone or in combination with 5-methyltetrahydrofolate (5-MTHF), as a non-drug approach for managing BP in pregnancy in women with the variant TT genotype. In addition, we aim to examine the effect of maternal supplementation with riboflavin, alone or combined with 5-MTHF, on BP in the offspring in early infancy. Study design: A double-blind randomized controlled trial in pregnant women will be conducted. Women with a singleton pregnancy who are in their first trimester will be recruited from antenatal clinics in Northern Ireland and the Republic of Ireland. Women interested in the study will provide informed consent, complete a screening questionnaire and will provide a buccal swab to collect DNA to screen for the MTHFR 677C→T polymorphism. Women with multiple pregnancies, a previous NTD-affected pregnancy and those who are taking medication interfering with B-vitamin metabolism will be excluded from participation in the study. At approximately the 16th gestational week (GW), those with the variant TT genotype and age-matched heterozygous women (CT genotype) will be randomised to receive riboflavin (5 mg/day) alone, or in combination with 5-MTHF (400µg/day), or placebo, until the end of pregnancy. A non-fasting blood sample will be collected for biomarker assessment of B-vitamin status and other relevant variables from each participant before intervention and at the 36th GW. At the same time points, anthropometric and BP measurements will be taken. Women will also complete a health and lifestyle questionnaire and a 4-day dietary record. Samples of cord blood, umbilical cord and placenta will be collected after delivery and anthropometric parameters of the newborns will be retrieved postpartum. Maternal and infant BP will be measured 2-4 months after birth. In parallel with the intervention trial, age-matched pregnant women who do not carry the variant gene (CC genotype) and have not been randomized to treatment, will be monitored in order to control for any changes associated with normal pregnancy in the study outcome measurements. In the pilot phase, the feasibility and acceptability of the study procedures and treatment will be evaluated for clarification of the sample size and refinement of the study protocol.
Detailed Description
The overall aim of this study is to investigate the role of a common genetic polymorphism in folate metabolism, MTHFR 677C→T, on blood pressure (BP) during pregnancy and the impact of B-vitamin supplementation as a non-drug approach for the management of BP in pregnancy in women with variant TT genotype. To investigate BP in relation to MTHFR 677C→T polymorphism in pregnancy; To investigate the response of BP during pregnancy to supplementation with riboflavin (5mg/d) alone, or in combination with 5-MTHF (400μg/d), targeted at women with the TT genotype; To examine the effect of maternal supplementation with riboflavin (5mg/d) alone, or in combination with 5-MTHF (400μg/d), on BP of the offspring at 2-4 months after birth in relation to this polymorphism; To evaluate the feasibility and acceptability of the study procedures to inform for the required sample size and refinements of the study protocol (pilot phase). We hypothesise that: BP will be higher in women with the TT genotype compared to those with CT and CC genotype; Targeted supplementation with riboflavin during pregnancy will prevent the greater increase in BP observed in TT women compared to women with CC or CT genotypes; Supplementation with riboflavin in combination with 5-MTHF maybe more effective in preventing the greater increase in BP observed in TT women compared to women with CC or CT genotypes; Maternal supplementation with riboflavin, alone or riboflavin in combination with 5-MTHF, will influence the BP of newborns with TT genotype. In non-supplemented mothers, newborns with the TT genotype will have higher BP compared to newborns with CC and CT genotype. In supplemented mothers no genotype differences in newborns will be observed. In advance of their first antenatal appointment, participants will receive a participant information sheet from their obstetrician and those who are interested in the study will be referred by the staff at antenatal clinics to the OptiPREG research team. At baseline, pregnant women will provide a signed informed consent. Women with a singleton pregnancy who are in their first trimester of pregnancy will be eligible to take part in the study. Exclusion criteria will be: a high-risk pregnancy; a previous neural tube defect (NTD)-affected pregnancy or being the first degree relative of a woman who had a pregnancy affected with an NTD, or are themselves a sufferer of an NTD; use of medication known to interfere with B vitamin metabolism (Chloramphenicol, Methotrexate, Metformin, Sulfasalazine, Phenobarbital, Phenytoin, Primidone, Triamterene, Barbiturates). Those women who are eligible to take part in the study will provide at baseline a buccal swab to collect DNA for MTHFR genotyping, a non-fasting blood sample, and will have BP measured, along with weight and height measurements and will complete a health and lifestyle questionnaire and a 4-day food diary. At 16th gestational week (GW), women with the TT genotype will be matched for age and systolic BP to women with the CT and CC genotypes. Although the primary purpose of the OptiPREG trial is to examine the effect of riboflavin intervention on BP in women with the TT genotype, those with the CT genotype will be also randomised to intervention (in a parallel trial). The purpose of this arm of the trial (in the CT genotype group) will be to identify any potential foetuses with the TT genotype so that their BP, and the impact of maternal B vitamin intervention, can be investigated. Within each genotype group (TT and CT), women will be stratified by systolic BP and age and will be randomized to receive 5 mg/day riboflavin, alone or in combination with 5-MTHF at 400µg/day, or placebo, until the end of pregnancy. In order to encourage maximal compliance, participants will be contacted regularly and provided with supplements in blister packs every 6 weeks during the intervention, and will be asked to return the blister packs; the number of unused capsules will be recorded to monitor compliance. A second appointment will be organised at approximately the 36th GW when participants will provide a second non-fasting blood sample, will have BP and weight measurements taken and will provide information regarding any changes in health status, lifestyle and medication usage. Following delivery, cord blood sample will be collected; dimensions and the weight of placenta will be measured, and placenta samples will be collected, together with a small section of the umbilical cord. The weight and length of the newborn, as well as the type of delivery and any complications in late pregnancy and birth will be retrieved from the mothers records postpartum. In parallel with the TT and CT women on intervention, age-matched pregnant women with the CC genotype (not on intervention) will be monitored at the same time points (8-15 GW; 36 GW) in order to control for any changes in BP and other study outcome measurements associated with normal pregnancy. Mother-child pairs will be visited at home when the baby is 2-4 months old. Weight, length and BP of the infant will be measured, and a buccal swab will be taken for MTHFR genotyping. Maternal BP and weight will be measured and mothers will be asked to provide information on health and lifestyle, infant feeding practice and health status.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Blood Pressure, Pregnancy
Keywords
Pregnancy, Maternal blood pressure, MTHFR 677TT genotype, Riboflavin, 5-methyltetrahydrofolate, Offspring blood pressure

7. Study Design

Primary Purpose
Prevention
Study Phase
Not Applicable
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
2250 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
TT genotype active comparator group
Arm Type
Active Comparator
Arm Description
5mg riboflavin per day from 16th gestational week
Arm Title
TT genotype experimental group
Arm Type
Experimental
Arm Description
5mg riboflavin + 400µg 5-methyltetrahydrofolate per day from 16th gestational week
Arm Title
TT genotype placebo group
Arm Type
Placebo Comparator
Arm Description
Placebo supplement from 16th gestational week
Arm Title
CT genotype active comparator group
Arm Type
Active Comparator
Arm Description
5mg riboflavin per day from 16th gestational week
Arm Title
CT genotype experimental group
Arm Type
Experimental
Arm Description
5mg riboflavin + 400µg 5-methyltetrahydrofolate per day from 16th gestational week
Arm Title
CT genotype placebo group
Arm Type
Placebo Comparator
Arm Description
Placebo supplement from 16th gestational week
Intervention Type
Dietary Supplement
Intervention Name(s)
Riboflavin (5mg)
Other Intervention Name(s)
Vitamin B2
Intervention Description
From 16th week gestation until end of pregnancy
Intervention Type
Dietary Supplement
Intervention Name(s)
5-methyltetrahydrofolate (400µg)
Intervention Description
From 16th week gestation until end of pregnancy
Intervention Type
Dietary Supplement
Intervention Name(s)
Placebo
Intervention Description
From 16th week gestation until end of pregnancy
Primary Outcome Measure Information:
Title
Maternal Blood Pressure
Description
Taken according to the clinical guidelines in pregnancy from the UK National Institute for Health and Care Excellence (NICE)
Time Frame
Change between baseline (16-week gestation) and end of intervention (36-week gestation)
Secondary Outcome Measure Information:
Title
Vitamin B12 status
Description
Measured by a microbiological L. Leichmannii assay; serum methylmalonic acid concentrations by Gas Chromatography-Mass Spectrometry
Time Frame
Change between baseline (16-week gestation) and end of intervention (36-week gestation)
Title
Plasma homocysteine
Description
Measured using a fluorescence polarization immunoassay
Time Frame
Change between baseline (16-week gestation) and end of intervention (36-week gestation)
Title
Riboflavin status
Description
Measured using the erythrocyte glutathione reductase activation coefficient
Time Frame
Change between baseline (16-week gestation) and end of intervention (36-week gestation)
Title
Vitamin B6 status
Description
Plasma pyridoxal phosphate concentrations measured by High Performance Liquid Chromatography
Time Frame
Change between baseline (16-week gestation) and end of intervention (36-week gestation)
Title
Folate status
Description
Measured by a microbiological L.casei assay
Time Frame
Change between baseline (16-week gestation) and end of intervention (36-week gestation)
Title
MTHFR C677T polymorphism (rs1801133)
Description
Determined by restriction enzyme typing Hinf1 digestion in DNA extracted from buccal swabs
Time Frame
Change between baseline (16-week gestation) and end of intervention (36-week gestation)
Title
Maternal blood pressure
Description
Taken according to the clinical guidelines in pregnancy from the UK National Institute for Health and Care Excellence (NICE)
Time Frame
2-4 months postpartum
Title
Offspring blood pressure
Time Frame
2-4 months after birth
Title
Offspring anthropometry
Description
Length (cm)
Time Frame
2-4 months after birth
Title
Offspring anthropometry
Description
Weight (kg)
Time Frame
2-4 months after birth
Title
Maternal anthropometry
Description
Weight (kg) and height (m) will be combined to report BMI in kg/m^2
Time Frame
At baseline, 36 gestational week (weight only), 2-4 months postpartum (weight only)
Title
Placenta size
Description
Placenta weight (g)
Time Frame
At birth
Title
Placenta size
Description
Dimensions (cm)
Time Frame
At birth
Title
Placenta and umbilical cord histology
Description
Samples will be examined for villous changes (i.e. presence of infarcts, increased syncytial knots and fibrin deposition, hyalinized avascular villi) and vascular lesions (i.e. decidual vascular thrombosis, spiral artery fibrinoid necrosis, mural hypertrophy of decidual arterioles, thrombi in large fetal vessels, fibromuscular sclerosis in intermediate-sized fetal vessels)
Time Frame
At birth

10. Eligibility

Sex
Female
Gender Based
Yes
Gender Eligibility Description
Women only
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility Criteria
Inclusion Criteria: • Women with a singleton pregnancy who are in their first trimester of pregnancy Exclusion Criteria: Patients who have a high risk pregnancy, a previous pregnancy with a neural tube defect (NTD) or are the first degree relative of a woman who had a pregnancy affected by NTD or are themselves a sufferer of an NTD Women who are taking medication known to interfere with B-vitamin metabolism
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Kristina Pentieva
Phone
+44 28 70124675
Ext
24675
Email
k.pentieva@ulster.ac.uk
First Name & Middle Initial & Last Name or Official Title & Degree
Helene McNulty
Phone
+44 28 70123076
Ext
23076
Email
h.mcnulty@ulster.ac.uk
Facility Information:
Facility Name
Letterkenny University Hospital
City
Letterkenny
Country
Ireland
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Evelyn Smith
Phone
+35374 9123501
Facility Name
Northern Health and Social Care Trust
City
Coleraine
State/Province
N.Ireland
ZIP/Postal Code
BT52 1HS
Country
United Kingdom
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Laura Doherty
Phone
+4428 7034 6061
Email
Laura.Doherty@northerntrust.hscni.net
Facility Name
Western Health and Social Care Trust
City
Londonderry
State/Province
N.Ireland
ZIP/Postal Code
BT47 6SB
Country
United Kingdom
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Kevin Glackin
Email
kevin.glackin@westerntrust.hscni.net

12. IPD Sharing Statement

Plan to Share IPD
Undecided

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Optimal Nutrition for Prevention of Hypertension in Pregnancy

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