A randomised controlled trial of a preconceptional dietary intervention in women undergoing ivf treatment (prepare trial)
Kermack et al. BMC Women's Health 2014, 14:130http://www.biomedcentral.com/1472-6874/14/130
A randomised controlled trial of apreconceptional dietary intervention in womenundergoing IVF treatment (PREPARE trial)
Alexandra J Kermack1,2,3*, Philip C Calder1,3, Franchesca D Houghton1, Keith M Godfrey1,3,4and Nicholas S Macklon1,2,3
Background: In vitro fertilisation (IVF) treatment provides an opportunity to study early developmental responsesto periconceptional dietary interventions. Retrospective studies have suggested links between preconception dietand fertility, and more recently, a "Mediterranean" diet has been reported to increase pregnancy rates by up to40%. In addition, a prospective study examining increased intake of omega-3 polyunsaturated fats demonstrated aquickened rate of embryo development after IVF. However, up to now, few prospective randomised controlled trialshave investigated the impact of periconceptional dietary interventions on fertility outcomes.
Methods and design: The study is a randomised controlled trial of a dietary intervention consisting of olive oil forcooking, an olive oil based spread, and a daily supplement drink enriched with Vitamin D (10 microgram daily) andmarine omega-3 fatty acids (2 g daily) for 6 weeks preconception versus a control diet of sunflower seed oil forcooking, a sunflower oil based spread, and a daily supplement drink without added Vitamin D or marine omega-3fatty acids. Couples undergoing IVF will be randomised to either the intervention or control group (55 in each arm).
The primary endpoint is embryo developmental competency in vitro, measured by validated morphokineticmarkers. Secondary outcomes will include the effect of the dietary intervention on the nutritional content of theintrauterine environment.
Discussion: This approach will enable rigorous examination of the impact of the dietary intervention on earlyembryo development, together with the influence of the peri-implantation intra-uterine nutritional environment.
a 40% increase in the probability of pregnancy The
Large prospective cohort studies have demonstrated the
findings of a subsequent case control study by another
impact of female and male preconceptional nutritional
research group also suggested that fertility outcomes
status on fertility, perinatal and long term health of the
were improved in couples with a Mediterranean diet
offspring More recently, research has shown that
In a further prospective study of the association between
variations in preconceptional diet may impact IVF out-
dietary intake of polyunsaturated fatty acids, significant
comes. A ‘Mediterranean' diet high in vegetable oils, fish,
correlations were observed between the reported dietary
vegetables and legumes and low in carbohydrate-rich
intake of the omega-3 fatty acids (FAs) alpha-linolenic acid
snacks was positively associated with red blood cell fol-
and docosahexaenoic acid (DHA) and embryo morph-
ate and vitamin B6 in blood and follicular fluid and with
ology after IVF . Despite this, no large prospective ran-domised intervention studies have investigated the impactof optimising the periconceptional diet on fertility out-
* Correspondence: 1Human Development and Health Academic Unit, Faculty of Medicine,
comes, perinatal or child health outcomes . Moreover,
University of Southampton, Southampton SO16 6YD, UK
it remains unclear by which mechanisms nutritional modi-
2Department of Obstetrics & Gynaecology, Princess Anne Hospital, Room
fications act to impact embryo quality, implantation and
F86, Level F, Coxford Road, Southampton SO16 5YA, UKFull list of author information is available at the end of the article
subsequent periconceptional and perinatal development.
2014 Kermack et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the CreativeCommons Attribution License which permits unrestricted use, distribution, andreproduction in any medium, provided the original work is properly credited. The Creative Commons Public DomainDedication waiver applies to the data made available in this article,unless otherwise stated.
Kermack et al. BMC Women's Health 2014, 14:130
One reason for the lack of data from intervention stud-
At the time of oocyte retrieval in IVF, follicular fluid and
ies derives from the challenges involved in encouraging
blood can be sampled and analysed for nutritional bio-
and monitoring compliance to specific dietary regimens,
markers. Since the fate of the oocyte can be followed in
particularly when the intervention is rigorous and/or of
terms of morphology, fertilisation and embryo develop-
long duration. However, recent data, primarily from ro-
ment, direct correlations between the nutritional environ-
dent studies demonstrate that dietary manipulations
ment of the developing oocyte and spermatozoa and IVF
within a very short window around the time of implant-
outcomes can be ascertained, as our group and others
ation can have profound effects on early development .
have shown previously At the oocyte level, high fat
Administration of a maternal low protein diet during the
diets in rodents have been shown to lead to lipid accumu-
4 days of mouse pre-implantation development, followed
lation and endoplasmic reticulum (ER) stress , while
by a control diet thereafter resulted in clear adaptive re-
follicular fluid folate levels have been shown to correlate
sponses such as altered blastocyst numbers, upregulation
to embryo quality .
of endocytosis into the yolksac, and an increase in the rate
Embryo quality can be assessed in terms of implant-
of trophoblast invasion. While these adaptive responses
ation potential on the basis of morphological and devel-
were observed to protect growth, they appeared to
opmental criteria. The recent availability of incubators
come at the cost of hypertension and abnormal behav-
fitted with time lapse video monitoring technologies rep-
iour patterns in adulthood Another group has
resents a step change in the ability to time precisely
shown that administering a high fat diet in this short
when key milestones of development are reached (‘mor-
period results in altered zygote viability , while treating
phokinetics'). This non-invasive means of interrogating
with an insulin sensitizer during this period normalises
early human development is enhanced by the generation
the effects of obesity on oocyte quality and developmental
of a video of each embryo allowing detailed analysis of
development markers at a later date In addition,
While extrapolation from rodents to humans brings
analysis of embryo conditioned medium provides further
uncertainties, this work suggests that a relatively brief
non-invasive means of assessing the impact of pericon-
dietary intervention in the 6 weeks prior to conception
ceptional diet on embryo metabolism
could have measureable effects on biomarkers of gamete
Recent techniques developed by our group also allow
and embryo health, the intra-uterine nutritional environ-
us to analyse the impact of preconceptional diet on the
ment, and subsequent fetal and placental development,
intra-uterine environment. We have previously demon-
with implications for the long-term health of the offspring.
strated the utility and practicality of aspirating endomet-
Such a short period is likely to increase willingness to take
rial secretions at the time of embryo transfer, which
part in a dietary intervention study and improve compli-
allows the study of the immediate intrauterine environ-
ance during the intervention period. In addition, some
ment encountered by the embryo It is now clear
lipid pools will have achieved maximal, or near-maximal,
that uterine secretions have a key role in providing nu-
changes in eicosapentaenoic acid (EPA) and docosahexae-
tritional support for the pre-implantation embryo and
noic acid (DHA) content within 6 weeks .
recently the role of female reproductive tract fluid com-
Studying the impact of short-term interventions in
position on developmental origins of later health has
the general population is complicated by the difficulty
been highlighted Current work is investigating the
of accessing couples in this preconceptional phase, and
amino acid and glucose content of human endometrial
the relatively low probability of subsequent conception
fluid. Moreover, we have developed in-vitro models of
within one or two months of completing the intervention.
embryo-endometrial interaction which provide the
These challenges are markedly alleviated in a population
means to study the impact of nutritional interventions
attempting to conceive by means of assisted conception
on embryo-endometrial signalling using donated cryo-
techniques. Couples reporting for fertility treatment are
preserved embryos ].
readily accessed in the periconceptional phase, and have
These approaches will enable rigorous examination of the
on average a 30% chance of conceiving in their first cycle
impact of the dietary intervention on early embryo develop-
of treatment. It is therefore feasible to study the impact of
ment, and the peri-implantation intra-uterine nutritional
a relatively short dietary intervention, which by virtue of
environment. Should a significant positive impact of a diet-
its limited duration is more likely to be adhered to for the
ary intervention on early development be demonstrated,
this would have major implications for health policy and
A further advantage of this model is the unique access
strengthen arguments for the provision of preconceptional
IVF treatment gives to human gametes, embryos and the
nutritional advice to the general population. The data gen-
peri-implantation uterine environment. IVF offers a win-
erated will inform new approaches to improving precon-
dow on how the complex biological processes in early
ceptional nutrition, and provide the basis for a major
human development are affected by nutritional status.
prospective community based intervention study aimed at
Kermack et al. BMC Women's Health 2014, 14:130
determining the effectiveness of relatively short, low cost
basic characteristics will be obtained to identify any selec-
and feasible dietary intervention on pregnancy outcomes
tion bias (Figure
and child health.
This study will be conducted in compliance with the
protocol, GCP and the applicable regulatory requirements.
The PREPARE trial is a single centre, randomised con-trolled trial, powered to demonstrate a difference in mean
Methods and design
duration of the second cell cycle (CC2) of embryos gener-
ated by IVF after exposure of the couple to the interven-
Although retrospective studies have suggested a link be-
tion versus control. Both the male and female in the
tween preconception diet and human fecundity, several
intervention group will receive a six week diet of olive oil
questions still remain for example which nutrients are
for cooking, an olive oil based spread, and a daily supple-
beneficial and how long they need to be taken prior to
ment drink enriched with Vitamin D (10 micrograms) and
conception. This prospective, randomised, controlled trial
the marine omega-3 FAs EPA (1 g) and DHA (1 g daily)
(the PREPARE trial (PREconception dietary suPplements
versus the control diet of sunflower seed oil for cooking, a
in Assisted REproduction)) aims to address the questions
sunflower oil based spread, and a daily supplement drink
of the effect of a diet rich in marine omega-3 FAs and
without vitamin D, EPA or DHA.
Vitamin D on a developing embryo and the intrauterine
Following inclusion into the study but prior to ran-
domisation, consenting participants will be invited tocomplete a preconception questionnaire and the short
Southampton Food Frequency Questionnaire (FFQ) in
Our hypothesis is that a diet rich in marine omega-3
order to characterise their lifestyle and diet prior to
FAs and Vitamin D will be beneficial to a developing
entry into the study At this time, samples of blood,
embryo and thus improve morphokinetic markers used
uterine fluid and endometrium will be obtained from the
to predict embryo viability and implantation. Further to
women in order to provide baseline data of the nutri-
this, it is thought that this diet will affect the nutritional
tional and immune cell content prior to the intervention.
content of the intrauterine environment and alter the
The male participants will be asked to provide a semen
endometrial tissue immune cell populations.
sample which will be analysed for concentration, motilityand morphology according to the WHO criteria .
Study population and recruitment
The women embarking on the study will undergo ovar-
Women participating in the PREPARE trial will be be-
ian stimulation according to our standard protocol, pro-
tween the ages of 18 and 41 years, with a body mass index
vided no abnormality is seen on their baseline scan on day
(BMI) between 20 and 32 kg/m2, and undergoing their first
2 of their cycle. Oocyte retrieval will be performed 36 hours
or second cycle of IVF or in vitro fertilisation – intracyto-
following the single dose of human chorionic gonado-
plasmic sperm injection (IVF-ICSI). Their partners must be
trophin (hCG), which promotes oocyte maturation. At the
using their own sperm and be prepared to provide a fresh
point of oocyte retrieval, further blood will be taken from
sample prior to the dietary intervention and on the day of
the female participants and the follicular fluid and cumulus
oocyte retrieval (they should not be using frozen sperm or
cells that are routinely removed, during IVF-ICSI, from the
sperm obtained by surgical retrieval). Additional inclusion
oocyte prior to insemination will be snap frozen. A further
criteria include an anti-műllerian hormone (AMH) of
semen sample from the males will be analysed according
greater than 7 pmol/l or an antral follicle count (AFC) of
to the WHO criteria prior to insemination.
more than 10. Participants must be willing to provide writ-
The embryos will be cultured in Vitrolife IVF media in a
ten informed consent to participate in the study.
validated time lapse incubator (Embryoscope, Unisense,
Exclusion criteria are: any medical contraindication to
FertiliTech, Denmark) in 5% CO2, 5%O2 and at 37°C.
IVF or IVF-ICSI treatment or to a specific dietary inter-
During the incubation, twenty one plane focal images will
vention, previously diagnosed diabetes, taking prescribed
be generated every hour and analysed according to mor-
medication or herbal remedies apart from simple pain-
phological and morphokinetic markers ]. For women
killers, and eating oily fish (as defined by the UK Food
in whom embryo transfer is possible, uterine fluid aspir-
Standards Agency) more than once a week.
ation will be carried out prior to the procedure. In those
Eligible patients will be informed about the PREPARE
not undergoing embryo transfers, an endometrial biopsy
study during information evenings or their initial con-
will also be performed.
sultation with the medical team. A minimum reflection
Compliance with the diet will be monitored by a daily
period of 3 days will be offered. Eligible patients who
diary completed at home by the couple and by counting
wish to participate will be randomised after providing writ-
the empty cartons when they are returned to the Fertility
ten consent. If an eligible patient declines participation,
Kermack et al. BMC Women's Health 2014, 14:130
Figure 1 Flowchart of eligible patients.
A recent systematic review of current literature and
the appearance and disappearance of the pronuclei
trial registers identified no other randomised controlled
Nutritional markers, including the concentration of fatty
trials (RCTs) addressing this subject.
acids, Vitamins D, B12, and B6, folate, prostaglandin E2(PGE2) and prostaglandin F2α (PGF2α) will be measured
Primary and secondary endpoints
in blood, endometrial fluid and follicular fluid pre and
The primary endpoint is the mean period in hours for
post intervention. Changes in endometrial tissue im-
the cleaved embryos from participants in each arm of
mune cell populations will also be examined. In male
the study to develop from the 2 cell to the 3 cell stage
participants, changes in semen quality pre and post diet-
(CC2). Secondary endpoints include using the Embryo-
ary intervention will be recorded according to standard
scope to examine embryo quality, including S2 (syn-
chrony during second set of cleavage divisions), T5 (time
Implantation rates and pregnancy outcomes will be re-
between fertilisation and the five cell embryo formation)
corded and analysed. These include antenatal ultrasound
CC3 (duration of the third cell cycle) and
markers; such as crown-rump length at 7 weeks and
Figure 2 Flow chart of study design.
Kermack et al. BMC Women's Health 2014, 14:130
12 weeks and fetal head and abdominal circumference,
2.25 hours, but not normally distributed) have been re-
femur length and cross sectional metaphyseal area and pla-
ported to have an implantation rate of 35% compared to
cental volume at 20 weeks gestation. Perinatal measure-
28% when this key developmental step took longer than
ments including birthweight and length and placenta
11.9 hours. Moreover, in a study correlating morphoki-
dimensions and weight will also be recorded. Participants
netic parameters with static morphology scoring, a CC2
will be invited to bring their neonate to undergo a Dual en-
less than 11.9 hours was shown to correlate with an over-
ergy X-ray Absorptiometry (DXA) to measure bone min-
all increase in embryo score of 0.5 points on a 5 point
eral content and density soon after birth.
scale ]. This is similar in magnitude to the impact onembryo morphology reported to be achieved by exposure
to a high omega 3 FA diet as described above [.
This is a single centre study that will be conducted at the
The primary end point of this study is therefore the
Complete Fertility Centre, a tertiary unit within the Uni-
difference in mean CC2 score of embryos generated by
versity Hospital Southampton NHS Foundation Trust.
IVF after exposure of the couple to the intervention ver-sus control diet. In order to detect a minimum absolute
difference of 12% (1.4 hours) in mean CC2, or effect size
After collection of baseline data in the cycle prior to the
of 0.670, with power ≥80% at p <0.05 a non-parametric
intervention commencing, participating couples will be
comparison (Wilcoxon test) indicates a requirement of
randomised to one or other of the study arms. The re-
46 couples per group in the analysis.
search team will be blinded to the randomisation. Strati-
To allow for drop outs and failure to produce suffi-
fication will be performed at randomisation for planned
cient viable embryos, a further 20% will be recruited.
mode of fertilisation: in vitro fertilisation or intra-
This requires the randomisation of a minimum of 55
cytoplasmic sperm injection.
couples per group (110 in total).
Data collection will be performed using a case report
In order to adjust for pre-defined confounders such as
form (CRF). Data relating to clinical treatment out-
age, AMH level, ovarian stimulation method, fertilisation
comes, including embryo quality measurements will be
method and the number of oocytes obtained, univariate
acquired from the Fertility Unit's electronic data collec-
and multivariate analyses will be performed. This will en-
tion system. Questionnaire responses will be inputted
able the independent contribution of the dietary factor to
electronically into the CRF. Additional data relating to
the primary and secondary outcome measures to be
laboratory assays will be obtained directly from the
laboratory's database or the respective external labora-
Differences in embryo quality parameters will be tested
tories and entered into the CRF. This minimises the risk
by Wilcoxon testing, and differences in blood and endo-
of transcription errors; however, all data will be verified
metrial fluid levels of the stated secondary outcome pa-
and cleansed prior to analysis.
rameters will be tested by the Mann Whitney U test.
Sample size and power considerations
This study is designed using the guidelines for good clinical
In a previous retrospective study from our group, a diet
practice (GCP) as well as the Declaration of Helsinki 1964
rich in the omega-3 FAs was shown to be associated
as revised and recognised by governing laws and EU Direc-
with improved embryo morphology when assessed on
tives. Full ethical approval (13/SC/0544) was granted from
day 3 post fertilisation. Using a published scoring system
South Central (Oxford A) Research Ethics Committee
between 1 (highest quality) and 5 (lowest quality), em-
(NRES) via the Integrated Research Application System
bryos generated in women with a daily mean total intake
(IRAS). In accordance with the GCP guidelines, written in-
of omega-3 FAs in the 4 weeks prior to IVF greater than
formed consent prior to randomisation will be mandatory.
1.7 g scored a mean of 0.6 (SE 0.26) points higher thanthose embryos derived from a woman reporting an in-
take of <1 g per day. Recently, morphokinetic analysis of
With this study we aim to clarify whether a diet rich in
human embryos has shown the duration of key develop-
Vitamin D and marine omega-3 FAs significantly im-
ment phases to be correlated to standard conventional
proves embryo development by improving morphoki-
morphological criteria, but more highly predictive of im-
netic markers of embryo quality. Moreover, we will
plantation potential One of the most sensitive
identify how a change in diet for six weeks alters the nu-
predictors of implantation has been shown to be CC2.
tritional and immune environment of the developing oo-
Embryos with a CC2 shorter than 11.9 hours (pooled SD
cyte, sperm and implanting embryo.
Kermack et al. BMC Women's Health 2014, 14:130
The decision to use morphokinetic markers of embryo
Southampton NHS Foundation Trust and University of Southampton,
quality as the primary endpoint rather than number of
Southampton SO16 6YD, UK. 4MRC Lifecourse Epidemiology Unit, Universityof Southampton, Southampton University Hospitals NHS Trust, Southampton,
live births was taken for a number of reasons. Primarily,
clinical pregnancy rate reflects the success of IVF treat-ment in subfertility and while dietary intervention may
Received: 24 February 2014 Accepted: 7 October 2014Published: 18 November 2014
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The Embryoscope has been supplied by Unisense, FertiliTech, Denmark and
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Steegers-Theunissen RP: Preconception folic acid treatment affects the
approved the final manuscript.
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Biomedical Research Centre and the Complete Fertility Centre, Southampton.
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doi:10.1186/1472-6874-14-130Cite this article as: Kermack et al.: A randomised controlled trial of apreconceptional dietary intervention in women undergoing IVFtreatment (PREPARE trial). BMC Women's Health 2014 14:130.
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British Journal of Nutrition (2007), 98, Suppl. 1, S46–S53 q The Authors 2007 Polyunsaturated fatty acids in the pathogenesis and treatment ofmultiple sclerosis Laurence S. Harbige1,2* and Mohammad K. Sharief 31Centre for Bioscience Research, School of Science, University of Greenwich at Medway, United Kingdom2Medway School of Pharmacy,University of Kent and University of Greenwich, United Kingdom3Department of Neurology, King's, Guy's and St Thomas' Hospital, London, United Kingdom
A Study of Online SocialNetworks in Mauritius: Impact on Secondary Education Assoc. Prof. Kavi Khedo Mr. S.M.R.A. ElaheebocusMr. R. Suntoo Ms. A. Mocktoolah February 2015 Funded by the Mauritius Research Council Under the Unsolicited Research Grant Scheme Agenda} Online Social Networks } Aim of the Project