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.