COGI 2018: 5 key messages

COGI is over for another year. Now we can take time to digest the information from the inspiring and thought-provoking sessions and ask ourselves: ‘what have we learnt?’

In this special edition blog we look back at five key messages and highlights from the three days.

 

1.       Time to consider HRT for primary CHD?

Research suggests that estrogen has a clear biological effect on the cardiovascular system, demonstrating beneficial effects on some of the key risk factors of Cardiovascular Heart Disease (CHD). While there is a lack of definitive evidence supporting HRT as a prevention for postmenopausal CHD, there are a growing number of epidemiological and observational studies supporting its use. In these studies, timing was shown to be a key factor with HRT demonstrating no benefit in older women. However, although there was no benefit there was also no evidence of harm.

 

2.       The role of epigenetics in long term health

Specific epigenetic input during development can produce a lasting difference in phenotype, meaning fetal programming, metabolic endocrine disruption and structural change in organs can all significantly affect the birth of a child.

For example, Caesarean Sections are linked to increases in neonatal morbidity, auto-immune diseases and metabolic disease in the offspring. Maternal obesity and smoking are also shown to be associated with long term negative outcomes for the child. In fact, research suggests that these negative effects may even cross generations.

 

3.       Fertility may be able to be preserved in women with POI

Primary ovarian insufficiency (POI) affects 1 in 100 women at the age of 40. In order to plan the most effective fertility preservation treatment, it is crucial to predict as much as possible whether POI may be imminent. While this is not simple, the condition is hereditary therefore assessing family history may help to provide important insight. Additionally, more research is taking place into the genetic basis of POI, with some evidence suggesting that reproductive health and success may be a marker for identifying POI and health outcomes later in life.  

There are many more options available for treating imminent POI than confirmed POI, including vitrification of oocytes or embryos following ovarian stimulation, freezing of ovarian tissue or a combination of the two. When treating confirmed POI, the options are more complex. While a small number of sufferers may go on to experience a spontaneous pregnancy, researchers are now considering a new technique: in vitro follicle activation (IVA). However, refinement and improvement of the technique is needed for it to lead to an effective strategy for these patients.

  

4.       The freezing debate is definitely not over!

The debate on whether freezing oocytes for non-medicinal reasons is truly beneficial contined at COGI. Speakers argued that social freezing could be seen as a purely commercial enterprise with advertising often aggressive and marred with misinformation. In fact, only 12% women actually return to the clinic and there is a far from certain chance of success.

However, freezing was shown to provide effective results in younger women seeing fertility preservation. In addition, some studies have demonstrated that freezing may be able to reduce risk of OHSS and be beneficial for groups of high responders.

 

5.       ART may be driving rates of pre-term birth

ART is associated with increased incidence of multiple pregnancy. Multiple pregnancy in turn is related with higher risk of pre-term birth and Cerebral Palsy. Using real world data we were shown that incidence of twins born at <32 weeks increased 27-fold from 1987 to 2010, with ART suggested as a main driver.

ART and preterm birth - What is the link?

Preterm birth is associated with a number of adverse health conditions contributing to increased rates of infant mortality, morbidity and long-term disability.[1] For example, 3-4% of very preterm and very low birth weight babies have Cerebral Palsy. [2]

Speaking at COGI 2018, Prof. Andrew Shennan explained that the issue is considerable, costing the NHS around £1 billion a year.  To be able to effectively tackle the problem, we must understand the key causal factors along with developing and improving management and prevention techniques.

 

Is ART driving premature pregnancy?

The link between ART and increased incidence of multiple pregnancy is well established.[3] In 2014, data from the Centers for Disease Control and Prevention (CDC) indicated that over 20% of all births following ART were multiple births.

Also established is the understanding that multiple pregnancy can result in higher rates of mortality and morbidity both for the mother and child.[2] One of the key complications resulting from multiple pregnancy is pre-term birth. In a thought-provoking session, Prof. Isaac Blickstein discussed why we therefore must consider the major impact that ART could be having on rates of premature pregnancy.

Using mathematical analysis of current preterm and Cerebral Palsy population statistics, Prof. Blickstein demonstrated that out of 100,000 spontaneous births, 2000 twins would be expected, of which 1685 would be very premature and 59 would have Cerebral Palsy.  In contrast, just 10,000 births by ART would be expected to produce 7400 twins, 740 very premature births and 26 cases of Cerebral Palsy.

But how about using real world data? Well, sharing data from a recent population trial, Prof. Blickstein indicated that the incidence of twins after ART born at <32 weeks increased 27-fold from 1987 to 2010 and has not reduced from the peak incidence in the last decade. He suggested that this high level of multiple pregnancy is a key driver of the issue of pre-term birth that we see today.  

 

Managing preterm birth

The speakers agreed that unfortunately there is no clear and definitive strategy to manage pre-term birth, especially in regards to multiple pregnancy. It was discussed that short cervical length is clearly associated with preterm labour and can be used in predicting and preparing for prophylactic intervention. These include:

-          Progesterone

o   While progesterone has been shown to be effective in singleton birth, it has not in multiple pregnancy, even if the delivery is high risk.[4]

-          Cervical Pessary

o   There is no clear evidence to the benefit of the cervical pessary, with some supporting studies and some suggesting no benefit at all.

o   However, Prof. Ben Mol discussed that the treatment could be effective for patients that have a short cervix (25-30mm). He recommended that it may especially be useful for women with multiple pregnancy, as progesterone is not shown to be effective.

-          Cerclage

o   Cerclage needs to be further researched in modern randomised controlled trials. However, Prof. Shennan explained that it could be beneficial in high risk cases.

o   Abdominal cerclage was not recommended as a first line treatment however could be effective for women who had a failed vaginal cerclage.

-          Lifestyle factors

o   Smoking and obesity were outlined as factors increasing risk of complication.

In the UK, Public Health England have announced they will aim to reduce preterm birth to 6% by 2025. While this may not necessarily be reached, it hopefully means that there will be budget available to help future research.


Sources:

[1] Keelan JA, Newnham JP. Recent advances in the prevention of preterm birth. F1000Res. 2017;6:F1000 Faculty Rev-1139. Published 2017 Jul 18. doi:10.12688/f1000research.11385.1

 [2] Kim Van Naarden Braun, Nancy Doernberg, Laura Schieve, et al. Birth Prevalence of Cerebral Palsy: A Population-Based Study. Pediatrics. Jan 2016, 137 (1) e20152872; DOI: 10.1542/peds.2015-2872

 [3] Multiple pregnancies following assisted reproductive technologies – A happy consequence or double trouble? Seminars in Fetal and Neonatal Medicine, 19(4), 222-227, 2014 doi: https://doi.org/10.1016/j.siny.2014.03.001

 [4] Klein, K. , Rode, L. , Nicolaides, K. H., Krampl‐Bettelheim, E. , Tabor, A. and , (2011), Vaginal micronized progesterone and risk of preterm delivery in high‐risk twin pregnancies: secondary analysis of a placebo‐controlled randomized trial and meta‐analysis. Ultrasound Obstet Gynecol, 38: 281-287. doi:10.1002/uog.9092

Time to give IVM a second chance?

The area of assisted reproduction has seen development of a great number of technologies. Some have come and gone, while others have established their importance and have been further developed over the years. And, while it is clear that great steps have been made in the effectiveness of assisted reproductive technology (ART), there are still some key improvements to be made. These include:

-          Reducing incidence of OHSS

-          Reducing psychological pressure

-          Reducing financial pressure

-          Increasing access to treatment

When considering how to make these improvements, we must consider the value of the procedures being offered in clinics today. Are there some that may be being overused? And are some not being used enough? At COGI 2018, we listened as a panel of expert speakers discussed these key questions.

 

Reconsidering IVM

In vitro maturation (IVM) involves the procedure of retrieving early follicles, followed by their maturation in the laboratory. The process was initially developed by Pincus and Enzmann in 1935, with Cha et al the first to successfully deliver a human live birth in 1991. However, in recent years the procedure has been relatively side-lined in clinics.  

Dr. Johan Smitz discussed why this may be. He explained there were two key reasons why IVM remains under-utilized:

-          Follicle heterogeneity - injecting hCG on the small 6-12 mm follicles can cause asynchronous maturation of the oocyte

-          Inappropriate signalling -  IVM can result in spontaneous re-initiation of meiosis

In addition, further issues are associated with IVM. There is a steep learning curve for those undertaking the procedure and a current lack of clear standard operating procedures means that there is a risk that success would not be easily standardised between centres. Also, Dr. Smitz explained that there are certain prejudices related to IVM, with many women believing that the treatment is more painful than IVF. However, this may not necessarily be the truth.

Despite these issues, IVM has a number of significant advantages. When compared with IVF, IVM requires less consultations, monitoring and injections. Dr. Smitz also explained the treatment can be more cost effective and more comfortable.

IVM is also the only ART with zero risk of OHSS. This means that the procedure could be especially suitable for women suffering from Polycystic Ovary Syndrome (PCOS).

 

How can we improve IVM?

Dr. Smitz outlined five key steps to improve the IVM procedure.

Abandon the hCG injection to avoid the issues associated with asynchronous maturation

-          Apply a positive in-vitro maturation stimulus to help to avoid the issues related with inappropriate signalling

-          Give FSH or HO-hMG Priming at 2-3 days

-          Use defining culture media

-          Use a pre-maturation culture

 

Is Capacitation – IVM a step to the future?

Adopting capacitation culture (CAPA) conditions was shown to improve success of IVM. Dr. Smitz shared data from five pilot studies demonstrating that CAPA-IVM can result in high implantation rates and increased number of embryos per oocyte-pickup. The results of these studies remain unpublished at this time however we cannot wait to read the full reports! Further study, improvement and adoption of this procedure can clearly benefit the field and we are excited to see what comes next.

Social freezing - A debate

 Traditionally oocytes were only frozen for the purpose of fertility preservation, including for women who may be undergoing chemotherapy.

However, in recent years the concept of social freezing has flourished, where oocytes are frozen for non-medical reasons. This decision to delay conception and pregnancy may be taken for a number of different reasons. Indeed overall, research suggests that both age of marriage and pregnancy are generally rising in high economic countries.

At COGI we were treated to an engaging debate on the key discussions surrounding social freezing, considering whether it truly is a benefit or whether it should be seen as a purely commercial function.

Dr. Ana Cobo opened the discussion, explaining that social freezing can provide effective results in younger women. Oocyte quality is affected by age, therefore the younger the age when the oocyte frozen, the better the chance of a positive clinical outcome later on. However, Dr. Cobo discussed that the majority of patients desiring social freezing were over 35 years old. 16% were 40 years or older. She explained that the outcomes in older women were significantly reduced and that the quality of the oocytes would be severely impacted.

Even in younger healthy women, there is not a complete success rate, with survival failure still a risk. Dr. Cobo shared data from a cohort of younger women which also demonstrated that after a single cycle failure, risk of a second cycle failure was 4x greater. It is therefore important to manage expectations and provide clear information to all women desiring to undertake social freezing.

 

Is social  freezing a purely commercial product?

In his presentation, Dr. Norbert Gleicher reiterated the importance of providing women with accurate and evidence based information in order for them to make an informed decision before undertaking social freezing.

He argued that social freezing can be seen as a purely commercial product. In the US, misinformation and aggressive advertising results in misunderstanding that oocytes can be frozen at any age and will be able to be used to deliver a healthy child when desired. Dr. Gleicher explained that social freezing is often advertised as an insurance, when in fact the success of the process is much less certain.

We must also consider the low number of returning women to actually use the frozen oocytes. In one framework, Dr. Gliecher discussed that only 12% women actually returned. With the high upfront costs associated with freezing oocytes, the low level of returning women and the uncertain level of success, we can see why it is so important to understand why ensuring a high level of informed consent and transparency is so important.

 

Is social freezing cost effective?

Dr. Zion Ben Rafael closed the debate by arguing that social freezing is not cost effective. He explained that the cost is an estimated $1million per birth and that the process is only cost effective after the age of 37. However, with live birth rates known to be lower in women over 35, while the process may be cost effective there is no guarantee of success. While success rates are higher in younger women, Dr. Rafael explained that the younger a woman is, the less likely it is that they will use their frozen oocytes as it more likely that they will have a natural birth.

Why we should consider epigenetic factors for IVF

 Research has demonstrated that children born through assisted reproductive technology (ART) are at a higher risk of preterm birth and associated morbidity.[1] So, why is? Well, the cause is likely to be multifactorial. There is the potential that IVF techniques could result in obstetric complications that negatively impact the child, or that ovarian stimulation may negatively impact placental development.[1] However, growing evidence suggests that parental characteristics play a crucial role.  

The opening night of the 26th Annual COGI Conference kicked off with a thought provoking exploration of this fascinating area of epigenetics, considering how parental factors can affect the health of an IVF child.  Epigenetics, the speakers explained, is inherently linked to the concept of developmental plasticity. Specific input during development can produce a lasting difference in phenotype.[2] As such, factors including fetal programming, metabolic endocrine disruption and structural change in organs can all significantly affect the birth of the child.

Effectively understanding how parental factors may affect future health outcomes could help us in the drive for increased precision medicine, where we can adapt specific treatments based on individual factors.

 

Caesarean Sections

 

Prof. Giancarlo Di Rienzo explained that IVF is associated with an increased use of Caesarean Section (CS) during birth. He showed that CS is in turn linked to increases in risk of:

-          Neonatal morbidity

-          Auto-immune diseases in the offspring

-          Metabolic disease in the offspring

 

Maternal Obesity and Smoking

 

Maternal obesity was highlighted as an important factor leading to higher risk of pre-term birth. Similarly, maternal smoking was shown to cause significant epigenetic changes. Interestingly, not only does smoking negatively affect the mother and the unborn child, but if the child is a female the smoke could also affect her reproductive cells. Therefore, these epigenetic changes could result in transgenerational negative effects. Indeed, Prof. Rienzo explained how increased risk of both pre-term birth and small for gestational age (SGA) infants has been shown to span multiple generations.

In his presentation, Prof. Nick Macklon also reiterated the role that diet and nutrition has in affecting epigenetic change.  

 

Could a Mediterranean Diet help?

 

Prof. Macklon explained that a Mediterranean diet is often recommended to women preparing for IVF. But is there really a benefit? To answer this question, he shared data assessing whether the diet has any significant positive impact on embryo quality and overall IVF success rate.

While there was some cohort evidence that the Mediterranean diet positively related to clinical pregnancy, Prof. Macklon explained that we must consider the important confounding factors including microbiome and genetics. He demonstrated that the positive impact of the diet, along with other advertised nutritionals on IVF outcomes is very slight, however this may have a greater cumulative effect over time.


Sources:

[1] A. Pinborg, U.B. Wennerholm, L.B. Romundstad, et al; Why do singletons conceived after assisted reproduction technology have adverse perinatal outcome? Systematic review and meta-analysis, Human Reproduction Update, Volume 19, Issue 2, 1 March 2013, Pages 87–104, https://doi.org/10.1093/humupd/dms044

[2] Nettle D, Bateson M. Adaptive developmental plasticity: what is it, how can we recognize it and when can it evolve?. Proc Biol Sci. 2015;282(1812):20151005.

The freeze all debate: an introduction

Despite IVF technology evolving significantly over the last 40 years, the process is far from perfect. Current research is still incredibly important to study how we can improve live birth rates, patient safety and reduce the time to live birth. [1]

One area of particular debate is whether a freeze all or fresh transfer approach is preferable when transferring embryos. But what is a freeze all approach and why is this discussion important?

What is a freeze all approach?

Following oocyte stimulation, retrieval and oocyte fertilisation, two options for embryo transfer are available. During a fresh embryo transfer a selected embryo can be transferred back to the mother soon after oocyte retrieval. Alternatively, the embryos can be vitrified and stored for transfer later. This is also called the “freeze all” approach, where embryos are then thawed before transfer.[1] 

The freeze all method was initially developed for the purpose of fertility preservation, such as for patients due to undergo chemotherapy. However, there is evidence that it may be a preferred option for all fertility patients. This is in light of data suggesting that staggering oocyte stimulation and embryo transfer allows the endometrium to be better primed for receipt of an oocyte.[2] There is also evidence that it can lessen the risk of ovarian hyperstimulation syndrome (OHSS).[1]

 

Effect of the freeze all method on outcomes in pregnancy, birth and neonate health

A 2014 retrospective cohort study, the largest of its kind, concluded that the use of vitrified thawed embryos did not worsen the outcomes in respect to pregnancy, birth and neonate health in comparison to the use of fresh embryos. The only notable differences were a greater number of interventions and a lower number of urinary tract infections reported with the vitrified oocyte group compared to the fresh oocyte group.[3]

 Further data from the Society for Assisted Reproductive Technology in 2011, found that gestational carriers receiving frozen-thawed embryos had 7-8% higher age-adjusted success rates than non-gestational carrier comparators receiving fresh embryos.[2]

 

The programmed endometrium 

There is evidence to suggest that ovarian stimulation can cause irregular endocrine milieu which could hinder embryo implantation during a fresh IVF cycle. Whereas, the freeze all method allows thawed embryos to be transferred at later cycles when the endometrium is programmed to be more receptive to freeze-thawed embryos.[1]

 

Risk of OHSS

There is evidence that the risk of developing OHSS is greater during fresh IVF cycles as oocyte development, retrieval and embryo transfer occur around the same time. It has been suggested that staggering oocyte stimulation by using the freeze all method could reduce this risk. Robust randomised controlled trials are underway to determine if the freeze-all method could lessen the risk of OHSS without reducing successful treatment outcomes.[1]

 

The debate continues at COGI

The World Congress on Controversies in Obstetrics, Gynecology & Infertility (COGI) congress will be held in London on 23rd-25th November, with key discussions including a debate on social freezing and a presentation titled ‘the end of freeze all?’. We will be attending to provide you with the latest updates from the conference, including research highlights and key messages.

Sources:

1.       Niederberger, C., Pellicer, A. and Cohen, J. et al. Forty years of IVF. Fertil Steril. 2018; 110 (2), 185-324.

2.       Society for Assisted Reproductive Technology. 2010 and 2011 SART fertility success rate report. Available at: http://www.sart.org/SART_Success_Rates.

3.       Cabo, A., Serra, V., Garrido, N. et al., Obstetric and perinatal outcome of babies born from vitrified oocytes. Fertil Steril. 2014; 102 (4), 1006-1015.

40 years of IVF – key breakthroughs

2018 marks the 40th year since the birth of the first IVF baby. This remarkable technological advance changed the world and millions of children are alive today that could not have been born before the development of IVF.

Here we will discuss some of the key breakthroughs in the history of IVF and what advances we may be able to look forward to in the future.

 

1.       The evolution of gonadotropins

The evolution of gonadotropins has been instrumental in improving IVF live birth outcomes.  Early attempts to extract preparations from animals, human cadavers and human urine encountered issues with purity and risk of disease. However, over the decades dedicated research striving for purer, safer and more efficacious gonadotropins have led us to where we are today. Now, availability of recombinant hFSH, recombinant hLH and recombinant hCG allow clinicians to develop individualised protocols for each patient. Coupled with personalised and precise dosing, we can now see both improved patient safety and increased live birth rates. And with more research currently taking place into developing oral active FSH antagonists and agonists we hope to see this evolution continue.

 

2.       Advanced embryo culture systems

Culture media has come a long way since the simple salt solutions developed nearly 150 years ago. IVF laboratories are now using complex optimised media, standardised and regulated to promote consistency and a high level of quality. And as we know, a high quality media is just one factor to consider when culturing embryos. The development of closed culture systems has provided embryologists with a stable environment helping to shield the embryo from outside stresses and increase both efficiency and efficacy.

 

3.       Cryopreservation

In 1971 the field of embryology changed as the first cleavage-stage mouse embryos were frozen. This led the way for cryopreservation of human embryos at all embryonic stages. Improvements in cryopreservation technologies mean that embryo survival rates are now nearly 100% and provided women with the choice to freeze eggs for fertility preservation as well as for medical reasons. Research continues into this area, and the debate on whether a ‘freeze all’ approach should be applied is still being hotly debated.

 

4.       ICSI

Early pioneers in IVF encountered a frustrating issue. Often couples could not partake in IVF programmes due to a low number of mobile sperm and there were no techniques to effectively address this problem. A breakthrough came with the development of intracytoplasmic sperm injection (ICSI) which allows individual sperm cells to be carefully selected and injected into the embryo. ICSI can almost be considered as much of a breakthrough as IVF itself, greatly extending the success of infertility treatments. ICSI technology is here to stay and is expected to play a pivotal role in the future treatments of male infertility including stem cell therapy and extended germ culture.

 

5.       Time-lapse technology

Equipment in the IVF laboratory has dramatically evolved over the decades. Advances in engineering have provided ever more effective options for creating stable and controlled culture environments for embryos. A recent breakthrough has been the availability of time-lapse technology which allows embryologists to follow development of the embryo frame by frame, allowing for an even better understanding of developmental timing and morphology.

 

These are just a few of the many key developments in the history of IVF. And the future is even brighter with key research and advancements still being made in the field of reproductive medicine. At this year’s COGI conference on November 26-28, experts will be discussing some of the key controversies and sharing their latest research. We will be attending to provide you with the highlights so stay tuned for the most up to date insights in this remarkable area.

 

Sources:

Niderberger C, Pellicer A, Cohen J, et al. Forty years of IVF. Fertil and Steril. 2018; 110(2):185-324.e5