The CAST study
Research type
Research Study
Full title
A prospective longitudinal cohort study into maternal cardiovascular changes during assisted reproductive treatment (ART): A comparison of fresh Vs. frozen cycles (The CAST study)
IRAS ID
234271
Contact name
Christoph Lees
Contact email
Sponsor organisation
Joint Research and Complaince office
Duration of Study in the UK
1 years, 0 months, 1 days
Research summary
Summary of Research
Assisted reproductive technology (ART) describes treatment given to achieve a pregnancy. We will focus on In Vitro
Fertilisation (IVF). We know that with IVF problems can occur in the mother’s heart and circulation. These can be
conditions such as blood clots and even death due to circulatory collapse (associated with excessive ovarian
stimulation).Evidence is sparse regarding the effects of IVF on the maternal heart and circulation (cardiovascular
function). Studies which do show IVF has an effect are not able to explain the cause e.g. due to increased hormones
or stimulation drugs.We aim to recruit a total of 60 patients (30 patients in each group):
1. Fresh embryo replacement involving ovarian stimulation (agonist protocol/group 1a or antagonist protocol/group1b
protocol)
2. Frozen embryo replacement cycle (HRT FERC/group 2) involving no direct ovarian stimulation. Hormone
replacement is given (oestradiol and progesterone) for thickening of the womb lining. We will carry out tests on the
mothers heart and vessel function along with blood tests at certain key points.This study is simply looking at changes
that may occur rather than interfering with usual IVF treatment. The cardiovascular tests are non-invasive but women
will be asked to provide blood samples (for hormones, biomarkers and proteomics). We will try to time this with when
they would normally have blood samples taken during a routine IVF cycle. This may not always be possible.This study will tell us if the drugs used in IVF affect the maternal circulation and therefore if she is a risk of
cardiovascular complications at the time of treatment. This may give us insight into her risk of cardiovascular
problems in later life.
This study will be conducted at the Wolfson Fertility Centre at the Hammersmith Hospital, Imperial Healthcare NHS
trust.Summary of Results
Thank you to study participants involved in the CAST study, without their trust, commitment and time this would not have been possible.
Study title:
A prospective longitudinal cohort study into maternal cardiovascular changes during assisted reproduction treatment (ART): A comparison of fresh Vs. frozen cyclesWho carried out the research? (including details of sponsor, funding and any competing interests) Study Sponsored by Imperial College London. Imperial College Healthcare Charity awarded £8000 grant which was our only funding source.
Study Chief Investigator is Professor Christoph Lees, Professor of Fetal Medicine at Imperial College London and Consultant Obstetrician at Queen Charlotte’s & Chelsea Hospital.
Research Fellow is Dr Raj Jaspal, Specialist Registrar in Obstetrics & Gynaecology and now subspecialist registrar in Reproductive Medicine.
Research Midwives: Olive Adams and Jenny Goodier.
Study Protocol was written by Professor Lees and Dr Raj Jaspal. Study recruitment and data collection was conducted by Dr Raj Jaspal, Olive Adams and Jenny Goodier.
Data analysis is being conducted by Professor Christoph Lees, Dr Raj Jaspal and the help of Statistician Lorenzo Monasto and team from the Erasmus University in the Netherlands.
What public involvement there was in the study (how many people, what their relevant lived experience was, and what they did) There was no public involvement with regard to designing, undertaking and managing the research or analysing the results. However, a short summary will be sent to all the 71 research participants after data analysis has been completed.
Patient experience:
71 patients were recruited into the study, as some patients had more than one type of In Vitro Fertilisation (IVF) cycle (i.e., a fresh followed by a frozen cycle), this meant 74 cycles were used for data collection.
Eight patients dropped out of the study, during their cycles i.e., they did not complete all four visits. The reasons given included, not enough time to attend the appointment or they were too emotionally distressed by an unsuccessful cycle to want to attend.
One patient was excluded due to undiagnosed high blood pressure being identified on her first visit, prior to her starting any treatment. She was referred to her GP to have this optimised.
Five patients had their IVF cycle cancelled prior to an embryo being replaced for reasons unrelated to the study.
Although there was no direct benefit for the patients; participation in the research study they did have an easier route of contact to the fertility clinic for any queries and a point of support for any questions during the cycle as the research fellow was also a clinical fellow in the fertility clinic. There were no complaints from any participant.
Where and when the study took place
Patients were recruited between September 2018 and April 2020 at the Wolfson Fertility Clinic at the Hammersmith Hospital, part of Imperial College Healthcare Trust.
Why was the research needed?
Infertility affects 1 in 6 couples trying to conceive in the UK, and more people than ever are seeking assisted reproductive techniques in order to have a family. According to the HFEA 53,000 patients sought treatment compared to little over 14,000 in 1992.
There is a wealth of research regarding the success rates of differing IVF protocols and with patient safety at the core there is research into some of the short and long-term complications.
We know IVF carries an acute risk of dangerous blood clots and overstimulated ovaries, known as “ovarian hyperstimulation syndrome (OHSS)”.
IVF pregnancies are also associated with a higher incidence of small for gestational age (SGA) babies and the development of blood pressure abnormalities in pregnancy (pregnancy-induced hypertension and pre-eclampsia).
However, there is conflicting evidence regarding the possible increase in cardiovascular risk and effect of IVF treatment itself.
Therefore, we sought to determine if there is a difference in the degree of change in cardiovascular function in women who undergo ovarian stimulation (fresh IVF cycles) compared to those who do not (frozen IVF cycles), during the course of In vitro fertilisation treatment and embryo replacement.What were the main questions studied?
How do changes in maternal cardiovascular function compare during fresh vs. frozen IVF cycles.
Maternal cardiovascular function was defined by: heart rate, mean arterial pressure (a marker of how well blood flows through the body, the higher the reading, the less well blood is flowing), pulse wave velocity and augmentation index (both are a measure of how ‘stiff’ the arteries are), cardiac output (what volume the heart is estimated to pump out per minute) and stroke volume ( the estimated volume of blood pumped out of the left side of the heart during each beat).
How do any changes in maternal cardiovascular function correlate with reproductive hormones, age and BMI during IVF cycles, looking at both Fresh and Frozen cycles.Who participated in the study?
Women aged 18-44years with no pre-existing high blood pressure or significant chronic illness who were about to commence In Vitro Fertilisation Treatment at the Hammersmith Hospital between September 2018- April 2020.
These women were all approached via direct contact, leaflets and posters in the Wolfson Fertility Clinic and the Hammersmith Hospital gynaecology clinic.
They were informed, consented and willing participants.What treatments or interventions did the participants take/receive?
This was an observational study meaning the study itself did not provide any intervention/ treatment. Instead, we observed what happened to our participants during their fertility treatment. Patients were divided into two groups: those who underwent a fresh IVF cycle which involves stimulating the ovaries with drugs and then collecting the eggs Vs. Frozen cycles which did not require stimulation of the ovaries as women already had embryos frozen from previous treatment or were using donor eggs with which embryos had been created.What medical problems (adverse reactions) did the participants have?
This was an observational study with no study intervention. However, one patient who had not yet commenced IVF treatment was found to have high blood pressure at her first study visit at baseline. Therefore, this patient did subsequently not take part in the study.What happened during the study?
Woment who consented to take part attended four times during the course of their IVF cycles. At baseline (prior to any medication), 3/5 days prior to embryo transfer, the day of the urinary pregnancy test ( 2 weeks after embryo transfer) and the day of the scan (which equates to 6 weeks of pregnancy). If women did not conceive, they were still asked to attend for the final study visit.
During the study visit, a conversation was had regarding their treatment, drug doses and protocols. Their weight was recorded a long with non-invasive cardiovascular measurements (heart rate, blood pressure, cardiac output, stroke volume, pulse wave velocity and augmentation index). Measurements were taken by trained personnel in the same sequence each time. Blood was also taken for measurement of hormones (oestrogen/progesterone).What were the results of the study?
Heart Rate (HR): There was a significant increase in HR from visits 2 to 3 ( i.e. during early implantation of the embryo) in those that conceived in both Fresh AND frozen cycles. However, there was a significantly greater increase in HR in those who conceived with a fresh cycle vs. conceived with a frozen cycle.
Augmentation Index (AiX): Although there were no significant changes during the course of an IVF cycle, the Aix was significantly higher in the Frozen group vs, Fresh group, regardless of whether pregnancy occurred or not.
Cardiac Output (CO): There was no significant change in maternal CO during either Fresh or Frozen cycles.
Mean arterial pressure (MAP): There was no significant change in MAP during either Fresh or Frozen cycles.How has this study helped patients and researchers?
The project itself enabled me to personally follow a patient through her journey of an IVF cycle. Many commented on the comfort they received from having a degree of continuity during their journey which cannot be generally guaranteed when in the fertility clinic. Being a fertility fellow in the Wolfson also meant I was able to answer their queries, organise appointments/ prescription’s when they could not get through to the nurses. Through the support that I offered the patients, they benefitted as did the study team from their co-operation.
The project has helped to develop the research and clinical skills of myself and my two research midwives. In addition the study also formed the basis for three Imperial College BSc students, one of who published a paper with the team (Fujitake E, Jaspal R, Monasta L, Stampalija T, Lees C. Acute cardiovascular changes in women undergoing in vitro fertilisation (IVF), a systematic review and meta-analysis. Eur J Obstet Gynecol Reprod Biol. 2020 May;248:245-251).Details of any further research planned
Not at presentWhere can I learn more about this study?
See disseminated section of this form for details re: publications and conference presentations/abstracts.REC name
East of England - Cambridge East Research Ethics Committee
REC reference
18/EE/0200
Date of REC Opinion
6 Aug 2018
REC opinion
Further Information Favourable Opinion