The Art of IVF
Updated: Feb 17, 2018
What is ART?
Assisted Reproductive Technology (ART) is the technology employed through various procedures in order to combat infertility in the human condition. ART is comprised of a wide variety of medical methods including:
ART generally requires the bypassing of sexual intercourse, with the exception of fertility medication, with the goal to overcome the issues that many couples face with fertility.
What is IVF?
IVF stands for In Vitro Fertilisation. This translates directly to in glass fertilisation, and is the procedure involved with bringing together an egg and sperm outside the body of the animal. This fertilised egg, known scientifically as a zygote, is cultured for between 2-6 days in a growth medium before being inserted into the uterus of a female with the hope of successful implantation and ultimately establishing a successful pregnancy.
The IVF Pioneer
IVF treatment was realised by the diligent pioneer Sir Robert Geoffrey Edwards. Sir Robert Edwards work in the area of Human Embryology his pivotal friendship and collaboration with Patrick Steptoe (a gynaecologist surgeon) ultimately resulted in the first successful Test Tube Baby, Louise Brown. Mrs Brown signified the beginning of a new era in fertility treatment. It was this pioneering work that led to Sir Robert Edwards being awarded the Nobel Prize in Physiology and Medicine in 2010.
The IVF Method
IVF procedures fall under a number of different techniques, all of which are carried out so as to increase the chances of success at the end of the procedures, but the principles are all the same. Most commonly IVF is used to treat female infertility although male infertility can also be overcome using the technique.
IVF can be natural, modified natural, mild or conventional:
Natural: IVF without hyperstimulation drugs.
Modified Natural IVF: Uses hyperstimulation drugs but with a GnRH antagonist in order to suppress multiple ovulation.
Mild IVF: Involves small doses of hyperstimulation hormones and spontaneous ovulation blockers in order to harvest 2-7 eggs during the woman's natural menstrual cycle. This method is safer than conventional IVF and reduces side affects associated with the pure procedure.
Conventional IVF: This is the standard severe method of IVF. It involves shutting down the woman's natural hormones completely for a period of time and controlling the menstrual cycle/ovulation entirely using medicated hormones.
The various stages and complicated clinical and laboratory methods utilised by gynaecologists and embryologists in performing an IVF cycle are outlined below...
Controlled Ovarian Hyperstimulation
As the name suggests this procedure involves the stimulation of the ovarian follicles to induce simultaneous ovulation by several follicles. This hyerstimulation allows for many follicles to be retrieved using oocyte retrieval which will then go on to be used in IVF, or they can be left to mature and ovulate in vivo in a process known as superovulation.
The process of inducing hyperstimulation involves the use of medications that act on an endocrine level. In most patients the preferred medications are gonadtropin based that are developed after individuals undergo a personalised screening in order to determine their predicted response to the treatment. The results of screening will mean the women will either have a high, medium or low dose of Follicle Stimulating Hormone preparations. FSH preparations are either urinary preparations from menopausal woman or recombinant and doses range from up to 600 IU/day down to 75 IU/day and are administered through injections. Other preparations also exist however the evidence for there effectiveness has significantly less foundation than FSH preparations.
Final Maturation Induction
When the ovarian follicles have developed sufficiently the induction of final oocyte maturation takes place. This is done through the injection of hCG or human chorionic gonadotropin, this "trigger-shot", as it is termed, acts to simulate the surge in luteinising hormone production, by the gonadtroph cells in the anterior pituitary gland, that causes ovulation. Around 40 hours after the trigger shot ovulation would occur, therefore egg retrieval is performed between 34-36 hours after the trigger shot, just before the natural rupturing of the ovarian follicles.
In order to collect the eggs from the patient an invasive procedure performed under anaesthetic is used. The technique is known as "transvaginal ovum retrieval" or TVOR. TVOR is when a needle is used to pierce the wall of the vagina and guided up to the ovaries using ultrasound. The follicles (usually between 20-30 but sometimes more) are emptied of follicular fluid, which is then sent to an embryologist to review and select appropriate ova (eggs) that will be suitable for transferring into the laboratory phase of IVF.
Gamete Preparation and Fertilisation
The ova identified by the embryologist as suitable have any surrounding cells removed whilst the sperm undergo "sperm washing" in order to remove inactive cells and seminal fluid. These two vital ingredients are then either:
Co-Incubation: Incubated together at 75000:1 in a special culture media for upto 4 hours so that fertilisation can occur. After this time it is usual to be able to see the development of 2 pronuclei in fertilised eggs.
ICSI: Sperm is directly injected using "intracytoplasmic sperm injection" (ICSI). This is usually the case for low sperm count or motility.
Embryo Culture and Selection
Embryo culture is the period when the fertilised eggs are allowed to grow in artificial media until a set time point before being inserted into the uterus. The two time points that the embryos are allowed to grow up to are either cleavage stage (2-4 days after fertilisation/co-incubation) or blastocyst stage (5-6 days after fertilisation/co-incubation). There are benefits for each stage. Culturing until blastocyst phase is thought to confer an increased rate of live births, however there are usually fewer embryos to transfer at this stage (and/or store using cyropreservation methods), compared to culturing until cleavage only. On the flip side there are significantly larger chances of both preterm births and congenital anomalies in embryos cultured until blastocyst stage, which may be down to alterations in the epigenome (see The Epigenetic Epiphany). For this reason there is a drive to improve and optimise the procedures involved with the culture process.
Up until fairly recently the most advanced method for embryo selection was through a morphological grading scale. However since 2009 the technological advances in live imaging microscopy has led to the use of time lapse microscopy in some labs across the world. Interestingly enough, despite this it is still believed that morphological grading is the most effective judge for both oocyte and embryo quality.
This is the final stage of the IVF procedure, although regular check ups, support groups and supplementary medication follow this stage in most cases. Embryo transfer (ET) is when the embryologist has watched the development of the embryo's, selected the best, and then these are inserted into the patients uterus via a plastic catheter. The number of embryos that is legally allowed to be transferred in the UK is two so as to avoid multiple births.
IVF has a few risk factors that are thought to play either a direct or indirect baring on the result of the procedure. Some of the factors are:
Maternal Age: The optimum age for women undergoeing IVF is between 23-39 years old. Ages outside of this threshold, although can and do still work carry a greater risk of failure.
Stress: It is thought that increased stress can indirectly cause the failure of IVF through the consequence of depressive episodes in the mother during the procedure resulting in the unsuccessful completion of the complete cycle. A study investigating this possibility has suggested one method for combating this is to offer support groups and make sure the patient is involved with the entire procedure and is well informed.
Biomarkers: The presence of certain biomarkers represent either an increased or decreased success rate. For example, a high Antral follicle count confers higher success rates. While in contrast the presence of the FMR1 gene specific to their ovarias have lower chances of a successful outcome.
Environmental Factors: These include obesity, smoking, alcohol and caffeine intake. Having a healthy body mass index (BMI), being a non-smoker with a low alcohol and caffeine intake confers a better chance of pregnancy at the end of the treatment.
These factors share a large overlap with the risk factors involved with complications such as low birth weight and pre-eclampsia seen in natural pregnancies.
This article is a simple overview outlining in a basic, easy to understand way the IVF procedure and the hope it offers too couples whom are unable or struggle to conceive. It is not seeking to delve into the wider over arching issues concerning morality and the such.
IVF is a powerful and fascinating tool helping bring the gift of parenthood to couples world wide. Research into the area is exciting and cutting edge, researchers continually carry the hope to develop better more successful, safer and easier ways to bring about positive outcomes from the procedure. This attitude spans the entire reproductive technology field, which is also very active with regards to its research into the area as a whole, including placental and genetic research.