Forty years ago in 1978, the world witnessed the birth of the first “Test tube baby”. Now millions of babies later, IVF is a ROUTINE medical treatment offering hope to potential parents around the globe. Whilst the basics of doing IVF have stayed the same, eggs are fertilised with sperm in the LAB and fertilised embryos are placed back in to the uterus, there have been explosive advances in Assisted Reproductive Technologies (ART) over the last four decades. Few of those are highlighted below –
Controlled Ovarian Stimulation (COS)
Although the first IVF cases were managed with natural cycles but seeing very poor pregnancy rates, soon, Controlled Ovarian Stimulation was introduced to produce multiple eggs and became a substantial part of IVF cycle.
The gonadotropin hormones (FSH & LH) used in the early years, were obtained from the urine of menopausal women, but now FSH, LH are derived from Recombinant DNA technology with extreme purity and batch to batch consistency.
Ovarian Hyperstimulation Syndrome (OHSS)
As and when the Controlled Ovarian Stimulation (COS) became uncontrolled due to patient profile/ inexperience, OHSS emerged.
It’s a real threatening complication. The issue of OHSS was thoroughly addressed over the years and has been virtually completely resolved.
‘OHSS Free Clinic’ components –
- Mild stimulation protocolsa. Individualization of doses of gonadotropins according to patient’s age, antral follicle count (AFC), AMH levelsb. Classify the patients into
Hyper responders – young age, high AFC, high AMH
- Down regulation with GnRH Antagonist
During early to mid 1980s, there was 20% to 30% incidence of ovulation occurring prior to ovum pick up procedure. To prevent this premature LH surge, GnRH Agonist down regulation was started. Unfortunately it increased the incidence of OHSS. So in 1994, GnRH antagonist was introduced in Controlled Ovarian Stimulation protocols. It is the mainstay in curbing the OHSS menace.
- Trigger oocyte maturation
Oocyte maturation is triggered by GnRH agonist bolus.
Inj HCG is avoided to prevent OHSS.
- Freeze all strategy
If OHSS is still feared, then all embryos are frozen to be transferred in the next cycle.
Ovum Pick Up
The original method was aspirating eggs through laparoscopy under general anaesthesia. Improvements in ultrasound technology has brought in Trans vaginal Sonography (TVS) guided aspiration which is used now, much as an office procedure. Special suction pumps are used to maintain suction pressure lower than 120 mmHg.
USG guided embryo transfer lowered the incidence of difficult transfers, and improved the pregnancy rates.
e SET – Elective Single Embryo Transfer
Before the embryo freezing, nearly all embryos obtained through controlled ovarian stimulation were transferred to optimize the poor pregnancy rates. It led to complications of twins or higher order pregnancy. Newer advancements helped reduce the number of embryos for transfer. Sweden, Belgium, and the UK updated their legislature to impose e SET on all women except those more than 39 yrs , or those with previous two failed IVFs.
Probably the single most significant factor in the dramatic improvement in IVF pregnancy rates over the past 10-15 yrs. At present, our IVF Laboratories appear totally different from those in 1978.
How the embryology lab has changed –
- Lab equipment and instrumentation –
- From bell jars to Time Lapse Incubators
- Disposable egg collection kits
- ET catheters
- Aspiration pump
- Heated work stations
- Bench top incubators
- Time lapse imaging
The latest in the incubator series is Embryoscope or Time Lapse Microscopy. It takes an image every 20 minutes as the embryo grows. Embryologist can inspect the embryos without the need to disturb them.
- Intra Cytoplasmic Sperm Injection (ICSI)
The ability to insert a single sperm in to ovum and achieve a live birth. ICSI made possible the biological parenthood when only a few sperms were available in the ejaculate. And ultimately ICSI could also be done on sperms retrieved from the epididymis and testis too. (PESA, TESA)
This is the technology of ultra rapid freezing. Vitrification revolutionised our ability to successfully freeze eggs and embryos. We at our hospital, began learning the vitrification technique in 2009 and have never looked back since then.
Embryo vitrification made possible
- Freezing surplus embryos
- Freeze all embryos in suspected OHSS
- Segmented IVF
- Freezing the blastocysts subjected to PGD/PGS
Egg vitrification made possible
- Fertility preservation for women who wish to delay child bearing
- Fertility preservation for oncology patients prior to receving chemo or radiation therapy
- Donor oocytes egg banks
Pre Implantation Genetic Testing – PGD and PGS
The cells are obtained from the developing embryo, and evaluated the genetic composition of this cell for specific genetic defect (PGD) or presence of embryo aneuoploidy (PGS).
Indications of PGD and PGS are
- Advanced maternal age > 37 yrs
- Recurrent miscarriages
- Recurrent IVF Failiure
- Carriers of a particular genetic disorder
- Couples with an affected child or previously affected pregnancy
Analysis of embryo’s chromosomes is done by
- FISH (Fluroscent In Situ Hybridisation
- PCR based testing for single gene disorder only
- Comparative Genomic Hybridisation (Array CGH)
- Single Nucleotide Polymorphisms (SNP Arrays)
The Big Picture: Ethical Challenges
- Possible wrong done to the embryo.
Embryo could be considered living.
Embryos that are not transferred would either be destroyed or used for research.
- Possible wrong done to the couple and the expected offspring
Success rate depends on number of embryos transferred.
Multiple pregnancy and pre term or IUGR babies.
- Possible wrong done to the offspring by the couple
Multiple pregnancies can also affect the baby negatively
- Possible wrong done to the community.
Financial resources supporting the IVF and research processes may be spent elsewhere.
The Big Picture: Psychological issues
There are many psychological issues – Birth of Louis Brown opens a new era of opportunity and hope, for the couples to achieve the dream of having a child. Oocyte donation, gestational surrogacy and fertility preservation have differentiated the three compartments of motherhood – oocyte source, gestating mom, and rearing mother.
- IVF and the ART are the routine treatment for infertile couples.
- The cost and the success rate are crucial.
- The quality of IVF Laboratory affects the results.
- OHSS must be prevented by mild stimulation, GnRH antagonist down regulation and agonist trigger.
- Single best embryo transfer must be the ultimate goal.