IVF Protocols

The Long Protocol  

This is the commonest protocol that is used in IVF. The suppressive effects of the initial injections(buserelin) seem to be beneficial for women with endometriosis which sometimes can be undiagnosed. Studies have shown that success rates with Long protocol are marginally better than the short protocol.

The first visit to the clinic is roughly about a week before the onset of the woman’s menses, which is usually Day 21 of her menstrual cycle. During this visit, she will undergo a scan to confirm that she has ovulated. Sometimes, the doctor may give her some oral contraceptive pills (OCPs) from the beginning of her menstrual cycle (usually Day 2 or Day 3) and she will commence injections on her own a few days before the last pill. Yes, if you didn’t know, IVF involves A LOT of injections. Self-administered injections.

The first type of injection is called buserelin (Suprefact) and is given as a daily dose in the morning before she goes about her usual daily activities. These injections are well tolerated though sometimes she may have hot flushes. She will still have a menstrual period though it may be lighter or prolonged.

After about 2 weeks of injections, she will be seen in the clinic for a repeat scan to confirm down regulation (ovaries that are quiet). The dose of busereline is subsequently reduced and approximately a week later, she will commence on stimulation of the ovaries. This involves the use of a daily hormonal injection called FSH (Gonal F or Puregon) for about 10 to 12 days. More injections, yeay!

In total, the Long protocol takes about 4 weeks plus involving around 50 self-administered injections. It is not for the faint-hearted. 

 Are you strong enough to give yourself shots?

 

 Buserelin (Suprefact)
 

 

 The needle

 

 Lots and lots of needles!
 



Gonal-F

The Short Protocol

This protocol is gaining prominence due to its shorter duration and less amount of injections. It is particularly useful in women with polycystic ovaries, as there is a lower risk of ovarian hyperstimulation syndrome.

The doctor may sometimes give several days (up to 3 weeks) of OCPs from the onset of the woman’s menses. Then on the second or third day of her withdrawal menses after the pill, she commences the daily FSH injections immediately. A scan would be repeated on Day 5 of injections after which another injection called GnRH antagonist (Cetrotide or Orgalutran) is commenced. This injection which is also done daily prevents premature release of the eggs. In total she will do about 10 to 12 days of injections. Much kinder to the body compared to 50 injections for the Long protocol.

 Gonal-F needle pen 

 



In-Vitro Fertilization (IVF)

It is now more than 34 years since the world’s first birth from IVF, a technique that mimics the process of human fertilization in the laboratory. Over this period of time, countless couples all over the world have benefited from IVF, the majority of whom would never have been able to have a child without it. While it is now readily and widely available, a high degree of knowledge, skill and attention to detail by the doctor and the laboratory is required before consistently high pregnancy rates can be achieved.

Couples are recommended to undergo IVF if they face one of the following problems:

·         tubal factors (tubal blockage or dysfunction)

·         endometriosis

·         male factor infertility

·         immunological infertility (anti-sperm antibodies)

·         repeated unsuccessful IUI

·         unexplained infertility

The wife undergoes controlled ovarian hyperstimulation (COH), either with long protocol or short protocol, depending on her condition. A hCG injection is given to mature the eggs when the leading follicles have reached 18mm. 34 hours later, oocyte pick up (OPU) or egg collection, will be done. OPU is the process of aspirating the eggs through the vagina.

 

The OPU is a minor procedure performed under sedation or general anaesthesia as a daycase. The OPU is performed in a specialized IVF Operating Theatre (OT). A very fine needle is inserted through the vagina under transvaginal ultrasound guidance. The needle punctures through the vaginal wall and into the ovaries to harvest the eggs. The eggs which are now in a test tube are handed over to the embryologist for processing. The laboratory is located next to the IVF OT to ensure minimal exposure to the external environment. The entire procedure takes only about 15 minutes and she will wake up immediately after that. She will be allowed to go home after 2 hours.

After the semen is produced by the husband, the laboratory technician or embryologist will process the semen by removing the seminal plasma, debris, residual cells, dead and sluggish sperm. This is done by a series of steps including adding sperm wash media and centrifuging. The final solution with live and motile sperm will be inseminated to the culture media containing eggs to allow fertilisation to occur. The mixture will be cultured in the Carbon Dioxide incubator.

The eggs are fertilized and are now called embryos. The embryos are cultured for between 2 to 5 days, depending on the number of fertilized eggs available. Embryo transfer (ET) is a minor procedure where the fertilized eggs are transferred into the womb through a very fine flexible catheter. the number of embryos to be transferred depends on several factors such as the age of the woman, the quality of the embryos and the wishes of the couple. Doctors will usually transfer the optimum number of embryos to achieve the best results with the least risk of multiple pregnancies. Good embryos that are not transferred will be frozen for use in the future.

3 day old embryos

 

Embryo transfer (ET) requires no sedation or anaesthesia and it is similar to that of IUI. However, ET requires ultrasound guidance. A speculum is inserted into vagina to hold it open. Ultrasound guidance enables the doctor to visualise the insertion of ET catheter into the uterus so that can ensure that the embryos will be place near the fundus and minimise the trauma to the endometrium. The whole procedure takes only 5 minutes to complete.

After ET, the wife will require some luteal support such as vaginal pessary or injection. She has to take extra care such as:

·         rest more and avoid excessive physical activities. Bed rest is not necessary.

·         remember to take progesterone medication daily

·         drink plenty of water

·         not take any medication without doctor consultation

·         avoid sexual intercourse for at least three months

A blood pregnancy test will be carried out approximately 2 weeks after the transfer. If she is pregnant, she will be required to continue the progesterone support for another month or so. If unfortunately she is not pregnant, the doctor will review the entire treatment with her and discuss her options if she would like to try again. If she has excess embryos frozen, she may undergo a Frozen Embryo Transfer (FET) about 2 months later.

Since the first IVF-ET carried out in 1978, over four million babies have been born using this method. It is an effective treatment for almost all causes of infertility. There is no increase in the risk of abnormality of the baby compared to a natural conception. 

6 week old twin IVF pregnancy

9 week old IVF pregnancy

12 week old IVF foetus

32 week old IVF baby

VF costs between RM 12,000 to RM20,000 per cycle in Malaysia and there is no 100% guarantee you will succeed on your first try. Due to the high cost, it is imperative for couples to do a thorough research in finding the right fertility specialist with vast experience and high success rates.

 

Intra-Uterine Insemination (IUI)

A simple fertility treatment, IUI is commonly the first line of treatment especially when no fertility problem is identified. It is meant to be easy and inexpensive but may need to be repeated multiple times as pregnancy rates are only 15-20% each time it is performed.

This is the simplest form of assisted conception treatment. It involves inserting the husband's sperm into the wife’s uterus at the time of ovulation. The sperm sample is first prepared to remove dead and weak sperm and the best sperm are then strengthened even further to improve their ability to make a baby. On the day of IUI, the husband has to produce his semen by masturbation. He is advised to comply with the following instructions: ·         3 to 5 days of abstinence prior to semen collection ·         inform the nurse if he was sick or on any medication for the past 2 months ·         collection by masturbation is preferred ·         wash hands with soap and clean with water before semen collection ·         do not use lubricant, soap or perfume during semen collection ·         avoid spillage when semen is collected

After the semen is produced, the laboratory technician or embryologist will process the semen by removing the seminal plasma, debris, residual cells, dead and sluggish sperm. This is done by a series of steps including adding sperm wash media and centrifuging. The final solution with live and motile sperm will be used for insemination.

The wife too is usually given hormonal medications (tablets and occasionally hormonal injections) so that she will produce more eggs from her ovaries. When the ovarian follicles reach 18mm in diameter, a human chorionic gonadotropin (hCG) injection is given to mature the eggs and trigger ovulation. The hCG injection is usually given 36 hours before IUI is performed.

The process of IUI requires no sedation or anaesthesia and it is similar to that of pap smear. A speculum is inserted into vagina to hold it open. Then the washed sperm is inserted into the wife's uterus using a long and thin catheter through the cervical canal. The whole procedure takes just 5 minutes to complete.

 

After IUI, the wife may require some luteal support to strengthen the uterus such as vaginal pessary or injection. She has to take extra care such as:

·         rest more and avoid excessive physical activities. Bed rest is not necessary.   ·         drink plenty of water ·         do not take any medication without doctor consultation

Urine or blood pregnancy test will be done two weeks after the procedure to confirm pregnancy.

This combination of good sperm, extra eggs and timing during ovulation is the key to success. IUI is useful for couples with unexplained infertility and where the husband’s sperm quality or quantity is slightly below normal. It cannot be used where the fallopian tubes are damaged or where the sperm is very poor.

Acronyms / Jargons

For a newbie in the world of TTC (Trying to Conceive), there are many acronyms or jargons you should familiarize yourself with. Especially if you’ve decided to join any of the online support groups and forums as these jargons are used extensively within the support groups or forums. Here are some of the acronyms/jargons most commonly used:

2WW - 2 week wait

AF - Aunt Flo = Period (menses)
BBT - Body Basal Temperature = to detect ovulation
BCP - Birth Control Pills
Beta - Blood test used to detect pregnancy
BFP - Big Fat Positive = Pregnant
BFN - Big Fat Negative = Not pregnant
BW - Blood work
CD - Cycle Day
CM - Cervical Mucus
DE - Donor Eggs
DH - Darling Husband
DPO - DaysPost Ovulation
DPR - Days Post Retrieval
DPT - Days Post Transfer
DS - Donor Sperm
DX - Diagnosis
ED - Egg Donor
ER - Egg Retrieval
ET - Embryo transfer
FET - Frozen Embryo Transfer
FSH - Follicle Stimulating Hormone
GS - Gestational Surrogate
HCG - Human Chorionic Gonadotropin
HPT - Home Pregnancy Test
ICSI - Intracytoplasmic Sperm Injection
IUI - Intra-uterine Insemination
IVF - In-vitro Fertilization
LH - Luteinizing Hormone
LP - Luteal Phase
MC - Miscarriage
MF - Male Factor
OHSS - Ovarian Hyperstimulation Syndrome
OPK - Ovulation Prediction Kit
OPU - Oocyte (egg) Pick Up
PCOS - Polycystic Ovarian Syndrome
POAS - Peeing on a Stick = Pregnancy test
POF - Premature Ovarian Failure
PGD- Pre-implantation Genetic Diagnosis
Prog or P4 - Progesterone
PUPO - Pregnant Until Proven Otherwise
RE - Reproductive Endocrinologist
SA - Semen Analysis
UPT - Urine Pregnancy Test
TTC - Trying to Conceive
US - Ultrasound
UTI - Urinary Tract Infection
TVS - Transvaginal Scan

 

Infertility Treatments

Now that the cause of your childlessness has been established, it is time to discuss what are the treatments available. Depending on the results of the tests, you may be directed towards one particular treatment or may be offered a range of appropriate options. Unfortunately, in human fertility, no one treatment is guaranteed to succeed and each one is associated with a particular chance of pregnancy. Many other factors also may play a part in the success rates such as lifestyle, the woman’s age, smoking etc. and these will all be addressed. The most important thing to remember is that with persistence, the majority of couples will be rewarded with a child, or more! :)

 

There are multiple treatments available to help a couple become pregnant. It all depends on the cause, and most times, the test results will indicate the problem that needs treatment.

The simplest treatments relate to couples who have difficulty deciding when the most fertile time of the month is. This is especially true for women who have irregular menstrual cycles due to either early or late ovulation. Ovulation problems account for about a quarter of the problems in childless couples and these are often the easiest to resolve without needing expensive treatments. There are medications which can regulate the ovulation, for example Clomiphene. This type of treatment is called Ovarian Induction.

If ovarian induction doesn’t work after a couple of months, or if there are other problems such as weak sperm, it may be wise to move on to intrauterine insemination (IUI) as the next step. If all else fails, or if it a severe problem such as blocked or damaged fallopian tubes or an extremely low sperm count, In-vitro Fertilization (IVF) or Intracytoplasmic Sperm Injection (ICSI) may be necessary. These last two treatments have very high success rates.

All of these treatments will be discussed further in upcoming posts.

The Causes of Infertility

Let's find out what are the things that's keeping you from being pregnant.

Causes of Female Infertility

1.       Hormonal Imbalance

The right hormonal balance is very important for conception. Hormonal imbalance can lead to the disturbance of the ripening process of the egg, a lack of ovulation or poor luteinisation (the process by which the ruptured follicle transforms into the corpus luteum). Somewhat suprisingly, women produce small amount of male hormones, androgens, in their bodies and sometimes increased amounts of this hormone can disturb the hormonal balance, often in combination with ovarian cyst (follicle like-structure).

Hormonal balance can also be disturbed by being very underweight or overweight, large weight changes in a short period of time, extreme physical exertion, disturbance in the working of thyroid gland or in the secretion of the hormone prolactin, certain types of medication and stress.

2. Tube-related Problems

In some childless women, the fallopian tubes are found to be partly or completely blocked. Most frequently, the fallopian tubes are damaged by infection which might have happened many years before. Other possible causes are an earlier pregnancy in which the embryo implanted in the fallopian tube instead of the uterus (ectopic pregnancy) or adhesions (scar tissues) following an operation or endometriosis.

3. Endometriosis

Endometriosis is the growth of endometrium (the lining of the uterus) outside the uterus itself. It is not known exactly how this occurs. It is probably due to very small amounts of the endometrium passing through the fallopian tubes to the abdominal cavity during menstruation. Here it may settle, causing adhesions between the abdominal organs and painful menstruation.

4. Antibodies Against Egg-cells.

This is an uncommon cause of infertility. In rare cases, the body does not recognize its own egg cells and the immune system forms antibodies against them. Antibodies against the man’s sperm in the cervical secretions are quite common. As a result, sperm cannot enter the womb and fertilization does not take place.

5.Uterus Abnormalities.

A bicornuate uterus (a womb with two 'horns') is the most common. Instead of the womb being pear-shaped, it is shaped like a heart, with a deep indentation at the top. This means that the baby has less space to grow than in a normally shaped womb.

A uterine fibroid is a non-cancerous tumour that originates from the smooth muscle layer and the accompanying connective tissue of the uterus. Fibroids are the most common benign tumours in females and typically found during the middle and later reproductive years. They can grow and cause heavy and painful menstruation.

Causes of Male Infertility

1.       Disturbance of Sperm Maturation.

The most frequent problem affecting the male fertility is insufficient production of normal, freely mobile sperm. Male semen (a mixture of sperms and nutrient fluids) is considered to be of normal quality if there are more than 20 million sperms per millilitre (ml), about half a teaspoon, of semen. Even in fertile men, most sperm are imperfect and many cannot swim properly, but at least 30% of them should be normally formed and 50% freely mobile. If these values are not reached, the man’s procreative capability can be reduced. However, even with normal sperm a functional problem may prevent sperm from penetrating the egg. The ability to produce healthy sperm may be reduced as are result of a mumps infection in childhood. Varicose veins in the testicles (varicocele) may also lead to poor sperm quality. Other causes are hormonal disturbances, stress, environmental factors such as smoking, undescended testes or hereditary factors such as genetic damage. Infections such as flu may reduce sperm quality, but this is usually temporary. Semen analysis is conducted to assess the condition of the sperm.

2.       Disturbance in Sperm Transportation.

In 4% of cases, sufficient semen is formed but cannot enter the woman’s body on ejaculation because the seminal duct is blocked. This situation is comparable with blockage of the fallopian tube in women. Possible causes are previous sterilization or sperm ducts which are underdeveloped or blocked by adhesions, usually as a result of a previous infection of the reproductive organs.

3. Other Causes

Other factors could be sexual difficulties such as erectile dysfunction or the inability to ejaculate.

So, has the cause of your or your husband's infertility been determined? What will you do next?

Ovulation, Fertilization and Implantation

Ovulation

 

For those who are still unsure of the process, here is a scientific explanation of how a baby is made. In a woman’s body, each month about 30 immature eggs will develop in small follicles. At about the 9th day of the menstrual cycle, one of the follicles will become the dominant follicle and it will suppress the growth of other follicles. The dominant follicle will mature on the 14th day, rupture and release the egg from the ovary. This process is called ovulation. The egg that is released is swept into the fallopian tube, where fertilisation will take place. The egg can be fertilised for 24 hours after ovulation. So sexual intercourse should be done with 24 hours after ovulation in order for the fertilisation to take place.

These are the signs and symptoms that may suggest ovulation is occuring:

·         Increase in cervical mucus which is thin and stretchable.

·         Pain due to rupturing of the mature follicle.

·         Rise and fall of oestrogen levels.

·         Breast tenderness due to progesterone stimulation.

·         Increase in basal body temperature due to rise of progesterone levels

 

 

Fertilization

 

The sperm will travel from the vagina through the cervical canal, up to the uterus and into the fallopian tubes. Fertilization usually occurs in the ampula (the swelling end) of the tubes. The egg is covered by zona pellucida (egg-shell) and on it are receptors for the sperm to attach and fertilise it. The sperm will penetrate the zona pellucida through these receptors , fertilise the egg and together form the zygote. After one sperm has entered the egg, the zona pellucida will be depolarized (the shell will harden) to prevent other sperm from entering. So, only 1 sperm can fertilize an egg. After fertilization, the zygote (fertilised egg) will travel along the tube towards the uterus, due to the wave movements of the fimbriae and cilia. During its travel to the uterus, zygote will undergo cell divisions and differentiation.

 

 

Implantation and Pregnancy

 

After 24-hours of fertilization, the zygote will divide into two cells, then four cells, then eight cells. On the fifth day, the embryo will become a blastocyst (70-100 cells) and reach the uterine cavity. Just before implantation the cells of the blastocyst have to hatch out of the zona pellucida (a hole in the zona pellucida for the cells to come out). The blastocyst will usually implant on the posterior uterine wall. There may be a spot of bleeding when the blastocyst penetrates then endometrium. The cells in the blastocyst will continue to divide and differentiate to form inner cell mass (future foetus), trophoblast (future placenta) and amnotic sac. The trophoblast will produce progesterone which is essential for the embryo to grow and develop at the implantational site. It also produces hCG which can be detected in the woman’s blood after 10 days of fertilisation or in the urine after 14 days of fertilsation. 3 weeks after fertilisation, the amniotic sac can be detected using ultrasound scan. So there it is, the precious baby you've sooo been longing for!

Here's a video of the ovulation-fertilization-implantation-menstruation process, except that we don't want the menstruation part. We want the embryo to stay embedded in the uterine lining and grow into a healthy foetus and come into the world some 9 months later :)