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Thursday, 13 November 2014

Fertility in women over 40

Decline in fertility has become a real problem in today's world. Gender differences in terms of ambitions and aspirations are blurring. Nature has been a little unfair with the fairer sex in the department of fertility. The eggs that a woman is born with slowly deplete with age, the better quality eggs first. So as the age advances, the egg reserve gets lower and the quality of eggs that are present in the reserve declines too. Whats worse is that sometimes the so called biological clock may be faster than usual!

Many women are aware of the vagaries of the biological clock, but there is still a large section of women who remain blissfully ignorant. When they do find out, they are left with limited options, many times with no acceptable options! 

In a lady in her forties, Intrauterine Insemination (IUI) should be used only if the ovarian reserve (assessed using Antral follicle count and AMH) is reasonable, there is no associated male factor infertility and the duration of infertility is short. The IUI trial should be short and should be upgraded to IVF if unsuccessful. In case the duration of infertility is longer and/or there is an associated male factor infertility, the couple should be counselled to opt for IVF immediately. If the ovarian reserve is low or if the lady is >43yrs old, the recommended option would be IVF using donor eggs. 

There is always a way......

Tuesday, 4 November 2014

When to call it quits with IUI?

Intrauterine Insemination or IUI in short is often the first line of treatment for infertility. The main advantages when compared to IVF, are that it is cheaper, doesn't involve daily injections and lesser stress levels. It is possible to get this treatment at your routine gynaecologist whereas IVF may only be done at an infertility specialist's clinic. Changing the treating doctor is usually disconcerting to most couples as it involves risks and having to build up rapport with a hitherto unknown person and talking about something so sensitive as fertility.

In my opinion, at least in India, too many people are reluctant to call it quits with IUI. As per studies done, the pregnancy chances with IUI plateau within 3-6 cycles. As such the recommendation is to restrict the number of cycles to 6 in couples with unexplained infertility. IUI works best in unexplained infertility, couples with psycho-sexual problems and when the cause of infertility is PCOS. Couples where there are other contributing factors to infertility especially if the woman is older than 35 years, should be reviewed after three cycles of IUI. Further IUI cycles should ideally be under the supervision of infertility specialist and that too after a thorough counselling.

Tuesday, 14 October 2014

All izz well!

As a fertility specialist, I meet many people, singles and couples anxious to conceive. As is well known but barely acknowledged is the fact that the success rates of fertility treatments in most cases are less than 50%! That means, as one of my mentor used to tell all patients, you are more likely to not conceive than to succeed from fertility treatments. Yet hope and faith are the two big must-haves for all patients. Indeed I have realised time and again that it is those who have an overdose of hope and faith that do actually get pregnant against all odds!

When I consult, I make every effort to build up a rapport with my patients, I am brutally honest but stop short of breaking that very fragile hope that is their only lifeline. Even after the best efforts, when patients don't conceive, it is upsetting to all involved. More upsetting than I would like to acknowledge.

But equally rewarding is the report of pregnancy which wipes away the negative thoughts but strengthens the resolve to do better and more for the others who seek my advice. I cherish the photos of all the babies that are born and the thought that comes is : "All is well.....keep going...."

Sunday, 12 October 2014

Intrauterine Insemination with Donor Sperm

Intrauterine Insemination or simply IUI has already been described in an earlier post. There are many situations where IUI with donated sperms may be indicated. The reason may be a complete lack of sperms in the husband's semen. Sometimes the semen quality is poor and pregnancy may only be possible with advanced technique of ICSI. This may be unacceptable due to cost implications or due to personal beliefs. Occasionally, donor sperm may also be required to prevent a serious genetic disorder from being transmitted to the offspring. Last but certainly not the least are the single women who do not want to lose out on the chance of having a baby simply because they have not met Mr. Right yet!

The procedure of IUI remains the same except that the sperms belong to a donor. The donor is selected after a rigorous screening process and continue to be tested for any transmissible infections while they are in the process of donation. The semen is processed and motile sperms are frozen. After a period of at least 6 months quarantine, they are released for use. The non-identifying characteristics of the donor are made available to the recipient for selection. This generally includes height, weight, build, complexion, colour of eyes and colour of hair and Blood group. 

In India, as per ICMR guidelines, the donation is anonymous. However the details of the donor may be revealed on request to the offspring born once he/she is 18 years of age. Experts recommend disclosure to the children about the donor although the onus is on the parents. 

In the Indian context, my experience is that the parents rarely even acknowledge to the family and have no intention of disclosing to the children. Before accepting this treatment modality, the most important concern is for confidentiality. The other concern is that the baby may not resemble them and so their secret may get out this way. Reassurance goes a long way in allaying both fears. 

Tuesday, 7 October 2014

Tuboplasty: assumptions versus reality

 When there is a block in the tubes, tubal surgery is offered as an alternative to patients for treatment of infertility. The usual assumption is that tuboplasty should be the first option as it "corrects" what is wrong. Unfortunately it is not as simple as this. I have described the sophistication which is integral to function of the tubes in my earlier post.  

The efficacy with which tubal surgery would work really depends on the extent of damage that has already occurred. If the cells lining the tubes are extensively damaged and the cilia (the hair like structures that assist in moving the egg/embryo towards the uterus) are non-functional or absent the woman would be at a risk of a pregnancy settling in the tube. This condition is called Ectopic Pregnancy and it is potentially life-threatening. Similarly, if the cells that are responsible for secretions that nurture the egg/sperms/embryo and create an environment that allows an embryo to develop are spoiled, the chances of embryo formation fall. How then would tubal surgery done by the best surgeon in the world help?

With the advances in IVF, the chances of pregnancy now are superior to those after tuboplasty. Without a doubt there is a place for tubal surgery and indeed, there have been women who have conceived after a surgery to repair the tubes. Tuboplasty has a role in cases where the damage is minimal to mild and impact on fertility is essentially due to obstruction and so by removing the obstruction, the woman chances of natural conception are restored. The best advantage of surgery is that the effect usually lasts longer term unlike an IVF cycle which is only offering a chance of conception in the treatment cycle. It may be the only option available to couples who have religious or ethical objections to IVF. The major drawback is the uncertainty pertaining the fertility renewal and the very real risk of ectopic pregnancy as a result of tuboplasty. Women who fail to conceive should move on to IVF if no pregnancy occurs within 6-12 months. There is also clear evidence that women with severely damaged tubes that are swollen (called Hydrosalpinx) would benefit from removal or delinking of the tubes prior to IVF. 

Friday, 12 September 2014

Surgical sperm collection

Surgical removal of sperms is done in men with no sperms in the semen (azoospermia). The reasons for azoospermia may be due to a blockage in the tubes that carry the sperms from the testes (Vas Deferens) or due to a vasectomy. Some men may also have a congenital absence of the Vas Deferens. Lack of sperms may also result from a slowing or stopping of sperm production in the testes. 

Men who are unable to ejaculate may also require to undergo this procedure. In this scenario PESA is not done to avoid injury to the otherwise normal anatomy.

These procedures are generally done under local anaesthesia either on the same day as the egg collection of the wife or as an stand-alone technique. In the latter case, sperms may be frozen for later use. The disadvantage of freezing is that a significant proportion of sperms are lost in the freeze-thaw process. 

The surgical retrieval sperms is done from either the testes or the epididymis. The procedures that are commonly done are

PESA - Percutaneous Epididymal Sperm Aspiration is commonly used where there is either a blockage or an absent Vas Deferens. By aspirating fluid from the Epididymis, sperms that have been produced by the testes but are unable to go forward can be retrieved and used for fertility treatments and surplus sperms can even be frozen for future use.

TESA - Testicular Sperm Aspiration is employed where there is a slow production of sperms. A needle is used to aspirate fluid from the testes and this fluid is scanned under the microscope for presence of sperms. 

TESE - Testicular Sperm Extraction involves removal of  one or more tubules in which sperm production normally occurs. Sperms are then extracted from these tubules.

Friday, 5 September 2014

Donor egg IVF

Donor egg IVF is the modality of fertility treatment where eggs are taken from a donor (through ovarian stimulation and egg collection); these are fertilised using the husband's sperms and transferred into the uterus of a recipient after 2-5 days of culture. 

Donor egg IVF can be opted for in a number of situations. The women in whom ovarian reserve is either very low or who have entered menopause can opt for a donor egg. This may be either because of prior surgeries, chemotherapy or radiotherapy (for cancer treatment). In situations where the embryos formed are poor quality or there is a persistent failure of fertilisation, donor egg can be used to achieve a pregnancy. Successful outcome from IVF declines with age, so this option can be taken by women who are older than 40-42 who are keen to increase their chances of conception. Last but not the least, if the women is the carrier of inheritable disease that can be passed on to the child, donor eggs can be used to prevent the disease transmission to the child. In the last scenario where facilities are available and where the gene defect can be tested, PGD can be used to screen embryos before transferring.

The cycles of the donor and the recipient are synchronised either with hormone pills. The donor undergoes ovarian stimulation while the recipient has estrogen tablets to help prepare the lining of the uterus. In addition, the recipient may also be given an an injection to prevent any ovarian activity as this could interfere with the cycle. Once the donor is ready for egg collection, the couple are informed. On the day of egg collection, the donor's eggs and the sperms from the male partner are used to form embryos. The recipient now starts taking progesterone hormone (most commonly in the form of pessaries) to enable the best chances of conception. Embryo transfer is done as usual after selection of embryos. Surplus embryos may be frozen for later use.

Donor egg opens the door to the possibility of conception in many couples and can be a very precious gift for the couple trying to conceive.

Sunday, 24 August 2014

Assisted Hatching

Human eggs have a shell all around. This shell is called Zona Pellucida or just Zona in short. The function of the zona is to protect the embryo and to maintain its integrity (by keeping all cells of the embryo together). The function of zona ends when it is time for implantation. An embryo has to hatch out this very shell at the blastocyst stage, otherwise pregnancy will not occur.

Assisted Hatching is a technique which is used to either make a hole in the zona. The thought is to 'assist' an embryo which may either have a thicker zona or lesser ability to make a hole in the zona. 

There are three methods of Assisted hatching: 

  • Mechanical (in which the zona is tangentially pierced with a special needle)
  • Chemical (in which a chemical is delivered to a limited area of the zona to make a hole, the extra chemical is then removed to prevent the chemical from damaging the cells of the embryo)
  • Lasers (where energy from laser is used to make a very controlled breach in the zona)

Assisted hatching is generally applied to Day 3 embryos but can also be applied to Blastocysts to increase implantation rates. 
The current opinion with regard to the use of Assisted Hatching is that this technique can be offered to couples with previous implantation failures, and may improve the pregnancy rates in patients undergoing thawed embryo transfer. It is not clear whether it is beneficial for patients of advanced age. It is not without risks and therefore not recommended for routine use.

Sunday, 3 August 2014

Blastocyst or Freezing?

The ultimate aim of assisted reproductive techniques is not a positive pregnancy test, but a healthy fully grown baby. Advances in the stimulation protocols and embryo culture media have led to an improved ability to grow and select embryos. Despite this, only about 30% of the transferred embryos reach their full developmental potential.

To overcome the low implantation rates, the initial strategy that was employed was to increase the number of embryos. However, this led to an unacceptable incidence of higher order multiple pregnancy with associated complications both to the pregnant mother and to the babies. In a conscious effort to reduce multiple pregnancy, the embryo numbers are therefore restricted. To enable this without affecting the chances of success, there are broadly two options.

The first option is that of embryo freezing. Once a select number of embryos is transferred, the supernumerary embryos are frozen for later use. The newer more efficient technique of Vitrification has further improved cumulative pregnancy rates with frozen embryos. Using this you can actually try transferring all the good embryos a few at a time without the risk of higher order multiple pregnancy. This can also allow the conception of siblings if the initial transfer is successful. 

The second option is to grow the embryos to the blastocyst stage. By extended culture and selecting the best one or at the most two blastocysts, better pregnancy rates can be achieved without increasing the number of embryos that are transferred. The drawback with this option is that only 40-50% of embryos reach blastocyst stage. The biggest advantage is that multiple embryo transfers can be avoided. Most women I know find the two-week wait the most trying period in any treatment cycle. Occasionally, you may be lucky to get supernumerary good quality blastocysts that can be frozen for later use. 

In short both options are good options and decision should be taken collectively keeping in mind the embryo parameters as well as the couple's preference. 

Sunday, 20 July 2014

Embryo transfer: How many embryos is too many?

Once embryos are in culture, one or more of these need to be transferred into the uterus with the hope that nature will nurture the embryo and a pregnancy would result. Embryo transfer is a simple procedure much like an Intrauterine Insemination in which embryos are simply deposited in the womb cavity. Most often it is done under ultrasound guidance. Since the ultrasound is done on the abdomen, it is imperative that the bladder is full. 

The question is how many embryos should be transferred to achieve the optimal pregnancy chances? Logic dictates the insertion of as many embryos as are available! But does this really improve the pregnancy and what are the implications? The answer is that with the increase in the number of embryos that are inserted, the pregnancy after a certain point plateaus. In addition, there are higher chances of multiple pregnancies too. We have all heard of twins but triplets, quadruplets, and higher order pregnancies are also not uncommon!
There are practical problems of having to deal with a multiple pregnancy, but there are also serious risks (to both mother and the babies) associated with a multiple pregnancy. These risks exponentially rise with the number of embryos that are growing. As such Fetal reduction is usually recommended whenever the pregnancy is of higher order than twins. This option is unthinkable and unacceptable for many and therefore best prevented. 

The easy solution is to put in less number of embryos! Of course this has to be done cleverly so as to not let the success rate take a hit. This decision is best taken in consultation with the fertility specialist and embryologist, taking into account, the age and medical history of the woman, the number and quality of embryos and the budget of the couple. Where the couple are adamant in avoiding even twins, they can opt for the transfer of a single embryo at blastocyst stage. Any surplus embryos can be frozen for later transfer.

Sunday, 6 July 2014

Grading of embryos

The embryos are graded morphologically - the way they look under the microscope. The grading of embryos is done in order to identify the embryos with the best potential to implant and lead to a pregnancy. But please remember, it is only an indication, we all see embryos of the best grade failing to lead to a pregnancy while lower quality embryos can also grow into a pregnancy.

The ideal embryo at the Day 2-3 stage should have blastomeres  (cells of embryos) that are uniform in size and should have no fragments or leaked out contents of the cell during the division process. The ideal cell number on the second day of embryo's life (two days after the egg collection) is 4-cells while the cell number should be as close to 8 cells on the day 3 stage. Embryos that are slower or faster are marked down as are embryos that have unequal blastomeres or fragmentation.

It is also important to realise that the grade has no bearing on the normality of the embryo formed. In other words, the best grade embryo may be chromosomally abnormal and a poor grade embryo may be normal. Different labs use different grading systems and so please ask your lab to explain what their grading system is.

Tuesday, 1 July 2014

Embryo culture

Embryo culture involves incubating embryos till the time of their transfer into the uterus. After the appropriate method of fertilisation (IVF or ICSI) the eggs are left undisturbed in the incubator to allow the process of fertilisation to occur. There are accepted norms in identifying the days around embryo culture. The day of the pickup is called Day 0. The next day (when fertilisation is checked) is the first day of an embryo's life and this is called Day1. From here the days are counted serially.
Once fertilisation occurs, the genetic material carried by the egg and the sperm align together (the structure is called Pronucleus) and then fuse. In case the number of pronuclei is 3, these are abnormal in the amount of genetic material present in them and so these are discarded. The single cell of the embryo now starts dividing and the cell number (the cells of an embryo are called Blastomeres) starts increasing.
The ideal number of blastomeres is four on day 2 and eight on day 3. On the day 4 the embryo looks like a tight ball of cells. This day is a very dynamic stage and a lot of changes occur in the embryo. By the day 5, the cells have split into two groups, several of the cells align themselves on the periphery of the sphere that is covered by the egg shell - these ultimately play a role in implantation and form placenta. The others continue to stay in the form of a tight ball of cells at one pole of the embryo. These will ultimately form the baby. This stage of embryo on the day 5 of its life is called Blastocyst. Embryo transfer is typically done on the days 2, day 3 or day 5.

Sunday, 22 June 2014

ICSI: Intracytoplasmic sperm injection

Conventional IVF involves placement of motile sperms in close proximity of the eggs (oocytes). The sperms release enzymes that disperse the cumulus cells around the eggs and one of the sperms then penetrates the shell of the egg and the combination of egg and sperm leads to the formation of an embryo. When the motility of sperms is less or the number is insufficient, fertilisation may fail to occur. Intracytoplasmic Sperm Injection is the technique used to overcome this situation. ICSI is also required in cycles where PGD or PGS is employed as otherwise erroneous results may occur. 

The procedure is carried out in the embryology laboratory. Oocytes are normally surrounded by a thick fluffy cluster of cells (cumulus cells). In order to perform ICSI, the oocytes need to be denuded which means the cumulus cells need to be removed from around the oocytes by chemical or mechanical means. Denudation is essential for smooth and correct ICSI technique. Only mature eggs can be used for ICSI. The immature eggs cannot be used as these will form abnormal embryos.

The pregnancy rates and outcomes of cycles do not vary with the technique used for fertilisation (i.e., IVF versus ICSI). Embryo created are not superior to those produced after IVF and hence the decision to perform ICSI is based on the assessment of the couple and the embryologist's assessment of the semen parameters on the day of the egg collection. 

Sunday, 8 June 2014

Alternative trigger shot

Trigger shot is essentially to facilitate retrieval of eggs which up until the final maturation are attached with a stalk to the wall of the follicle. After trigger injection, the final maturation starts and the eggs complete their maturation division. Also the egg is released into the follicle fluid. Unless this happens, all the efforts of stimulation would be futile as lesser number or no eggs will be obtained at egg collection procedure. The traditional shot consists of hCG (or pregnancy hormone). The way it works has been explained in my previous post: IVF trigger shot.

What is the need for an alternative? It is the very real and very serious risk of OHSS (also discussed in a previous post: Is too much stimulation good?). In order to negate the risk of OHSS, an alternative trigger shot can be used. This is in the form of GnRH agonist. I have explained how agonists and antagonists work in my post: How is ovulation prevented in IVF?

The alternative trigger shot can only be used in antagonist cycles, in those women who are at risk of OHSS or those who are going through a egg donation cycle. Agonists 'trigger' a response from the pituitary in the form of release of a large amount of LH. This causes the final maturation in the follicles. As the life of LH is much shorter than hCG molecules, the risk of OHSS is very limited and short lasting with this protocol.

Women who have agonist as a trigger, should have a modified luteal phase support as otherwise the pregnancy rates are lower and miscarriage rates are higher. In my opinion, in the strife to eliminate OHSS, patients should be adequately counselled with respect to freezing of all embryos. My reason is that even if pregnancy occurs in these women, they are still at a risk of secondary OHSS which occurs from the pregnancy hormone released from the new pregnancy that has implanted. These symptoms will take much longer to abate in the background of an ongoing pregnancy!

Sunday, 1 June 2014

In vitro fertilisation

Once the eggs are collected, there are two methods of making embryos. The most common method is IVF. In vitro literally means in glass. So fertilisation that happens in petri dishes that were originally made of glass was termed in vitro fertilisation or IVF. The other method is called ICSI or Intra Cytoplasmic Sperm Injection which I will cover in the next post.

The eggs that are retrieved through aspiration of the follicle fluid are surrounded by a fluffy coat of small cells that surround and nourish the egg. These cells are called cumulus cells. These cells are also crucial for the maturation of the egg. In the natural cycles, the released egg is  surrounded by the cumulus cells. These cells are dispersed by the enzymes released from the head of the sperms (acrosome). This dispersal allows the sperms to reach the egg and one of the sperms is selected by nature to fertilise it.

The procedure is carried out on the same day as the egg collection and solution with specific concentration of motile sperms is added to the culture drops on the petri dish that contain the eggs. This mirrors what happens in nature. We rely on nature to certain extent to allow the best sperm to fertilize each of the eggs retrieved. It is generally recommended to fertilize eggs using this technique whenever possible. Next post on ICSI.....

Thursday, 29 May 2014

IVF trigger shot

IVF trigger shot is the last injection that is given approximately 36 hours before the egg collection. This is one of the most crucial steps of IVF and if done incorrectly or missed will prevent retrieval of eggs.

"Why trigger?" and "Trigger what?" are the most natural questions that would come to mind. The eggs that are developing in the growing follicles during ovarian stimulation are not fit to form an embryo. They have not yet completed their maturation division that leads to halving of the number of chromosomes. This has been discussed already in my earliest posts. In addition, the egg encased in the clump of cumulus cells (called COC or cumulus oocyte complex) is still attached by a stalk to the wall of the follicle. Till such time that this stalk is intact, aspiration of follicle fluid will not yield the egg that is present in the follicle.

In the natural cycle, these final events and the ovulation are triggered by the release of a large amount of LH hormone (called LH surge) from pituitary gland. In IVF cycles the natural release of hormones from pituitary gland are restricted due to the IVF medicines (as explained in my previous post on agonists and antagonists). Hence there is a need to artificially facilitate these important steps.

The trigger injections are in the form of Human Chorionic Gonadotrophin (hCG) which is the same as pregnancy hormone. This hormone is very similar to LH in structure and so can carry out the functions of an LH surge. Based of the source, hCG comes is of two types: urinary and recombinant. Both are equally effective. Recombinant hCG however is a little more expensive than urinary for obvious reasons.

Alternative trigger injection in the next post....

Sunday, 25 May 2014

Ectopic pregnancy

Ectopic pregnancy refers to those pregnancies that settle in a site other than the normal - the uterine cavity. The commonest is the fallopian tube. Other sites are cervix, ovary and the abdominal cavity. An ectopic is a potentially dangerous situation because unlike the uterus (which the nature has built to allow expansion so as to accomodate a growing pregnancy), the expansion afforded at these abnormal sites is limited and at some point the tearing/bursting of the organ can lead to life-threatening haemorrhage. This necessitates immediate surgery to deal with the bleeding and save the life of the woman. Where the ectopic pregnancy is diagnosed early it can also be managed using an injection of an anti-cancer drug (methotrexate) to kill the growing cells of the pregnancy. 

Why does an ectopic pregnancy occur? For simplicity, I am restricting myself to those that occur in the fallopian tubes. Tubes are delicate structures and any infection or inflammation can cause injury leading to partial or complete block of the tube.  The mucosa or the inside skin of the tube may become damaged leading to the dysfunctional movement of a newly formed embryo towards the uterus. The embryo therefore may get stuck and start growing in the tube itself. In many women, it may be impossible to identify the episode/cause of the damage.

For someone who has had an ectopic pregnancy in the past, what are the implications? Women who have an ectopic pregnancy are at risk of another ectopic pregnancy. This happens because, the event/agent that caused injury or damage to one tube may well have affected the other tube. It is not uncommon to conceive spontaneously and have uneventful normal pregnancy (and delivery) after an ectopic pregnancy. However, a delay in conceiving should be managed appropriately. Depending on the clinical circumstances, IVF may be recommended. Even if Intrauterine insemination is attempted, the trial of this treatment should be short with the escalation to IVF. This will avoid the additional implications of declining egg quality with age. A short-sighted approach of low-cost treatments for too long may otherwise be a disservice to the couple involved.

Sunday, 18 May 2014

Is too much stimulation in IVF good?

In the context of ovarian stimulation, caution should be exercised with respect to the follicles that grow as a result. What is the ideal number? The answer to this question varies with the treatment, with the physician treating and with the patient as well. You could wonder why too little or too much is a problem.

Whereas 2-3 follicles are acceptable in an IUI cycle, the same cannot be said for IVF cycle. In the context of IVF cycle too little understandably would not lead to a good pregnancy rate - the aim of fertility treatment. 

The fact that too much can also be a problem is less commonly realized by patients. When the ovarian stimulation is being done in conjunction with IUI, a higher number of follicles that start growing could ultimately lead to a higher order multiple pregnancy with the set of complications that come with it. In IVF, if we think logically, more follicles should mean more eggs, more embryos and more success rate. However, where there are more than 15-20 eggs, a disproportionate number of eggs are immature and these do not contribute to the formation of embryos. More eggs does not therefore mean more good eggs and more good embryos. 

To make matters worse is a complication called OHSS - Ovarian Hyper Stimulation Syndrome. OHSS happens as a result of a cascade of chemical reactions in the blood stream that results in leaky blood vessels. As a result fluid accumulates in the tummy cavity and sometimes in the chest around lungs and heart. This can be quite uncomfortable or even intensely painful to the woman. The leaking of fluid leads to the blood becoming thicker. Affected women are therefore at a risk of developing blood clots in the major veins. Deep vein thrombosis (as this condition is called), can occasionally cause death. Understandably, every IVF clinician strives to avoid this complication.

Sunday, 11 May 2014

Immature eggs?

Anyone who has gone through IVF is likely to have come across this term: Immature eggs. When I say this to my patients during the course of IVF, many roll their eyes! It  is really not that complicated. As I had mentioned in my post on egg quality, eggs need to go through a reduction division of its genetic material in order to maintain normality. The big question is how do we know whether the egg has undergone this process?

The reduction division takes place in two stages. While the first stage is complete before fertilization, the second division only occurs after the sperm has entered the egg. 

At the end of the first stage, the egg splits into two cells each with one set of the two sets of chromosomes that are present to begin with. Normally, the division of the genetic material is equal but the cytoplasm (the cell fluid that surrounds the nucleus or genetic material) is divided disproportionately. The egg keeps almost all of the cytoplasm while the other cell - now called polar body has only a small amount.

A mature egg therefore looks like the picture given below. The small polar body is clearly visible. The absence of polar body means the first stage of reduction division is not complete and this egg cannot be used to make embryos for the fear of forming embryos with more than normal amount of genetic material.  

Thursday, 8 May 2014

Egg collection

After a bit of a hiatus (for which I apologise), this post will explain the process of egg collection or oocyte retrieval. It may sound scary but it isn't, really! The time of the egg collection is dictated by that of the trigger injection (hCG or GnRH analog). The time interval is slightly shorter if analog trigger is given. The procedure can be done either under sedation or short general anaesthesia. Commonly it is a short procedure and takes 15- 20 minutes. It may take longer or shorter time depending on the number of follicles that have developed as well as the type of anaesthesia.

Egg collection is almost always done through the vaginal approach. The ultrasound probe (that is used for the internal scan) has an attachment which enables the surgeon to guide the needle into each of the follicles, one at a time and take the fluid out. The eggs come along with the fluid. The fluid from the follicles is collected in test tubes and taken to the laboratory where the eggs are separated and kept in culture medium at optimal conditions in the incubator till the next step of fertilization.

Occasionally massive enlargement of uterus (from fibroids), prior surgery or rarely congenital anomalies may lead to displacement of the ovaries and may require egg collection to be done from the abdominal route. This can either be done through the abdomen using the ultrasound guidance or through keyhole surgery.

Depending on the anesthesia given for the procedure the recovery time may vary from 1-3 hours. Common symptoms to expect are nausea or vomiting (especially after general anesthesia), mild/minimal vaginal bleeding, and abdominal pain/tenderness. Heavy bleeding, severe pain, fever, smelly vaginal discharge, persistent vomiting should be reported to the doctor. If you have any other symptoms, please also consult/inform your specialist.

Sunday, 20 April 2014

IVF regimes explained

There are many protocols that are used in IVF. The commonest ones are
  • Long protocol: In this regime, GnRH analogs are started on the 18th to 21st day of the cycle (contraceptive pills are taken daily from the 2nd day of the period). Once downregulation is confirmed on scan/blood tests, ovarian stimulation is started with daily  injections of FSH or hMG alongside the analog injections. This continues till the leading follicles are 18mm or so. At this point, the last analog injection is given and a trigger injection is given to enable eggs in the follicles to complete their maturation and be ready for "pick-up".  The egg collection is scheduled approximately 36 hours later.
  • Short or Flare protocol: GnRH analog is started on the second day of the cycle and the ovarian stimulation the next day (i.e., 3rd day). The rest of the regime is the same as long protocol. This is particularly used for women with lower ovarian reserve.
  • Antagonist protocol: This is the latest kid on the block. Ovarian stimulation is commenced on the day 2 of the cycle and the daily GnRH antagonist injections are added on the day 6 of stimulation or once the leading follicles are >13mm. Both injections continue till the leading follicles are 17mm or so. On this day, the last antagonist is given followed by the trigger injection. The egg collection is scheduled approximately 36 hours later.
I hope this has clarified the readers' understanding of the different types of protocols that are used in IVF. There are of course subtle variations that exist but this post was to give a broad understanding of the process.

Friday, 18 April 2014

How is ovulation prevented in IVF?

The drama that is enacted in the ovary every month is directed by pituitary (an organ in brain) through messengers FSH and LH (together called Gonadotrophins). The "Director" Pituitary in turn has to act as per the orders of "Grandmaster" Hypothalamus (also a part of brain). Hypothalamus sends its signals to pituitary via messengers called gonadotropin releasing hormones (GnRH). The two medicines used to prevent ovulation during IVF are GnRH analogs and GnRH antagonists.

GnRH analogs (such as Lupride, Buserelin etc.) are substances which have a structure similar to GnRH and cause some response from the pituitary (called flare response) in the form of release of FSH and LH. On being given daily, the flare stops and the pituitary becomes unresponsive and hereafter no release of FSH and LH occurs. This is called down regulation and take about 5 days of injections.

GnRH antagonists (such as Cetrotide and Ganirelix) resemble GnRH molecule but unlike analogs, these elicit no flare response from the pituitary. They are effective immediately in stopping the pituitary from releasing any gonadotropins. 

In IVF, either agonists or antagonists are used alongside ovarian stimulation to prevent premature ovulation from occurring. I will discuss the different protocols used in IVF in my next post....

Sunday, 13 April 2014

Ovarian stimulation in IVF: principles

The concepts of ovarian stimulation are not too complicated. First, let us understand what happens in the when no medications are taken.

In the natural cycle, antral follicles start growing (at the behest of FSH from brain) in the initial part of the menstrual cycle. One of these establishes dominance and only this dominant follicle continues to grow. Reason is when follicles start growing, they release estrogen hormone, levels of which starts increasing due to the contribution from the several follicles. As a reaction to the rising estrogen, brain (in particular pituitary) starts decreasing the amount of FSH that is released. With the decreasing levels of FSH, the smaller follicles' growth slows down and eventually stops. Only the dominant follicle has the ability to survive and grow to eventually ovulate and release the egg.

When we stimulate the ovaries, we do not let the FSH levels drop - by giving the same amount of hormone artificially. This allows even the smaller antral follicles to continue their growth. Stimulation is continued till the biggest two-three follicles are ready for ovulation (size ~18mm). 

The other principle that needs to be taken care of is ovulation. In the natural cycle, ovulation is triggered when estrogen hormone rises to a particular level. Ovulation is caused by way of release of a huge amount of hormone LH - this mechanism is called LH surge. As there is only one follicle that is "allowed" to grow, the threshold level of estrogen that triggers LH surge is not very high. 

In the context of ovarian stimulation, multiple follicles are growing and releasing estrogen, as such the level of estrogen required to "trigger" the response is reached quickly. In order to prevent LH surge interfering with the ovarian stimulation, we have to use one of two medications - GnRH analogues (such as Buserelin, Lupride, etc.,) and GnRH antagonists (such as Cetrotide and Ganirelix). These medications are quite different in the way they can be used and I will discuss these in the next post.

Thursday, 10 April 2014

What is IVF?

In vitro fertilisation or IVF is increasingly being used to help people who face difficulty in conceiving. IVF also called test-tube baby treatment is the treatment in which embryos are created in petri dishes (originally made of glass hence the name in vitro) outside of the human body and these embryos are then transferred in the uterus after growing them for a few days.

IVF when it started in 1978 was done without any stimulation and had a low success rate. The advent of injectable medicines (such as hMG and FSH) enabled retrieval of more eggs from which more embryos can be created and good quality embryos can be selected. The process is intensive and the fertility specialist will need to monitor the patient very closely throughout the treatment. It is extremely important for patients to understand what is happening and to follow instructions very carefully as this can affect the end result.

The process of IVF is a complicated one and I will talk about it over the next few posts. There are essentially the following steps:
  • Ovarian stimulation (in some protocols down-regulation step precedes this)
  • Egg collection
  • IVF
  • Embryo transfer

Sunday, 6 April 2014

IUI: What is it?

In the simplest terms, Intrauterine insemination (IUI) consists of inserting sperms into the uterus at or around the time of ovulation. IUI is often offered to infertile couples as a first option as it is less expensive and less stressful.

Why IUI?
The logic of IUI is to ensure that the sperms are present in the reproductive tract during the first 24 hours after ovulation. This is because the egg stays alive and can fertilise only during this 24 hour time period. In order to make the process more efficient fertility specialists often advise ovarian stimulation in conjunction with IUI. If ovarian stimulation is done with daily injections of FSH or hMG, it is recommended that the lady takes progesterone in the form of pessaries for at least 14 days for hormonal support of the impending pregnancy.

What happens naturally?
Sperms make up less than 5% of the volume of the semen that is produced. These sperms are a mix of motile and immotile (but live) as well as dead sperms. These sperms are suspended in a fluid along with substances that are nutritive and protective. The function of the fluid is to transport the sperms to the vagina. From there only the sperms can swim up, these are filtered by the cervix (the neck of the womb) while the rest of the fluid comes out. 

What happens in IUI?
Processing of the semen is done to isolate motile sperms, these moving sperms are then suspended in fresh medium and released into the uterus. The procedure is NOT painful but the insertion of fluid into the uterus may cause muscles of the uterus to contract. This will cause cramping pain similar to that experienced during periods.

How many times?
IUI can be done once or on two consecutive days by different fertility specialists. This is usually decided by the specialist and so far studies have not been able to show which is better.

Friday, 4 April 2014

Ovulation induction in special circumstances

In the introductory post on Ovulation induction, I had mentioned that there are some special circumstances where ovulation does not occur due to a problem in the hypothalamus. In the normal individuals, the hormones FSH and LH (the common term for these two together is Gonadotrophins) are released from the pituitary gland in brain and their role is to enable the growth of follicles in the ovary culminating in ovulation. This action of pituitary gland is controlled by another organ in the brain called hypothalamus with the help of hormones called Gonadotrophin releasing hormones. 

When the "circuitry" in the hypothalamus is faulty, the ovaries fail to work. There is no hormone producing activity in the ovary and so the cyclical growing and shedding of womb lining (menstrual cycle) does not occur. This condition is called Hypothalamic Hypomenorrhoea or Hypogonadotrophic hypogonadism (hypo hypo in short). Ovulation induction in such women can only be done by giving FSH and LH injections to artificially stimulate the ovaries. The crucial point to remember is that the ovulation induction in these ladies must be done by the 'old-fashioned' stimulating injections called HMG (Human menopausal gonadotrophins) which contains both FSH and LH. Recombinant FSH in such women will not be helpful. 

Thursday, 27 March 2014

Demystifying ovarian stimulation

While undergoing treatment of infertility, you are 'bombarded' with a lot of complicated information. It is of course difficult to understand and assimilate the information that is relevant so that informed decisions can be taken. I will therefore attempt to present before you the different aspects in a simplified manner. Let me begin with ovarian stimulation drugs.

The two hormones which 'drive' the growth of the follicles in ovary are Follicle Stimulating Hormone (or FSH) and Luteinising Hormone (or LH). Both these hormones work in tandem leading to the follicle growth that culminates in the release of egg (ovulation) from the ovary. 

In order to induce ovulation artificially, there are two ways: tablets and injections. The tablets (commonest being Clomiphene) do not directly stimulate the ovary, these cause the brain to release FSH and LH at exaggerated levels. The injections on the other hand directly stimulate the ovaries. In the vast majority of women, FSH injections suffice for stimulation. 

Injections that are given for ovarian stimulation are of two types:

  • human Menopausal Gonadotrophins (hMG)purified from natural sources (urine of menopausal women
  • Recombinant FSH (r-FSH): synthesized using technology (Recombinant DNA technology)

rFSH can be given subcutaneously (like insulin injections) and are very expensive. hMG is much cheaper but as effective as r-FSH. However hMG injections can only be given into muscle. Highly purified versions of hMG are also available that are a little more expensive (but not as much as r-FSH) and can be given subcutaneously.

Sunday, 23 March 2014

Ovulation Induction in PCOD

Women with PCOD are a diverse group and therefore the management has to be done by a fertility specialist.  In case you do not have regular periods, the doctor will need to give you medications to bring on a period. In women with PCOD, there are many antral follicles in the ovaries that are in a suspended state and these can respond to hormones. The biggest challenge therefore is that any hormonal treatment intended to cause ovulation causes many or all of these to start growing leading to multiple ovulations and multiple pregnancy. A complication known as ovarian hyperstimulation syndrome (OHSS) can also result.

The process of ovulation induction is most often done with the help of tablets called Clomiphene citrate. These are typically taken in the dose of either 50mg or 100mg (occasionally higher) for five days from the second or third day of a spontaneous or induced period. This is ideally followed by serial ultrasound scans to track the follicle/s that start to grow and eventually ovulate from one or both ovaries. When ovulation is confirmed, the couple are advised to have relations.

Many women with PCOD do not respond to the tablets in which case, they are advised to start daily hormone injections to induce ovulation. The aim is to give the smallest effective dose that would allow ideally a single follicle (but no more than 6 follicles) to grow and release an egg. This is extremely challenging in PCOD and therefore requires a lot of skill and patience. The doctor may have to cancel the treatment and start again at a lower dose of injections in case too many follicles start growing to prevent OHSS and high order multiple pregnancy. It is however not always possible to prevent multiple ovulations as the ovarian response in women with polycystic ovaries can be either too much or too less!

Friday, 21 March 2014

Polycystic ovarian disease: What next?

The most common condition which causes a disturbance in ovulation is Polycystic ovary disease. If your periods are absent or occur more than 35 days apart please consult a fertility specialist rather than wasting time trying to conceive naturally in the absence of ovulation.

When you go to see a fertility specialist, you and your husband/partner will be advised to undergo some basic tests to ensure that there are no other contributory causes to delay in conception. The tests would include hormone tests to confirm that the cause of irregular cycles is PCOD, tests for checking thyroid hormones and prolactin and may include patency test for tubes. You will also be advised to have tests to confirm that you are otherwise healthy and free of infections that can be transmitted to the baby. Once this is done, the doctor will start the process of ovulation induction. 

Weight loss in women who are overweight/obese is highly recommended. When age permits, it is well worth taking the effort to normalize the BMI as the response to treatment is better after weight loss along with a lower risk of miscarriage. Some women who have high levels of insulin will also benefit from taking Metformin tablets. I have had many patients who have conceived at this initial stage of treatment

Ovulation induction in PCOD in the next post....

Monday, 17 March 2014

Ovulation Induction: when?

When ovulation occurs regularly, the menstrual cycles are regular. As a corollary, if the periods are irregular or absent, it can be inferred that ovulation is irregular. There can be three situations where this can happen:
  1. Where the ovary is normal but the stimulating hormones from the brain are absent. This is usually an inborn problem with hypothalamus, a part of the brain that makes pituitary release FSH and LH hormones to stimulate ovary. (Please refer to my earlier post Role of ovary in conception). This condition is often but not always associated with decreased sense of smell.
  2. Where ovulation does not occur despite a normal egg reserve and a normal function of pituitary (Polycystic ovary disease)
  3. Where the egg reserve is so low that ovulation has become irregular. This usually precedes menopause.

Whereas the ideal treatment for situation 3 is to use donated eggs, for the situations 1 and 2 the appropriate treatment would be ovulation induction. Ovulation induction is the process of stimulating the ovary to release one or more eggs. 

PCOD and ovulation induction in my next post....

Thursday, 13 March 2014

Preconception check-up

It is a good idea for a couple who have started trying to conceive to see a doctor to ensure that the pre-existing diseases are controlled as well as possible with medicines that affect the growing baby as little as possible. This will also enable as yet undiagnosed medical conditions to be identified and treated. 

There are a lot of women with undiagnosed Diabetes who conceive. Women with PCOD, family history of Diabetes or with an increased body mass index should ideally get themselves checked. High blood sugars can cause structural abnormalities in the unborn child, miscarriage, growth problems etc. "Glycosylated Haemoglobin" or HbA1c will indicate the average blood sugars in the three months preceding the test. Dietary changes and/or medicines can then enable normalisation of blood sugars. If blood sugars are normal (HbA1c < 5.6%) at the time of conception and during pregnancy, there is little impact of diabetes on pregnancy.

Last but not the least, all women who are trying to conceive must take Folic acid tablets in the dose of 5mg daily as soon as they decide to start trying. This will prevent  some of the congenital abnormalities related to brain and spinal cord (such as anencephaly and spina bifida). In case you prefer taking prenatal multivitamins, take folic acid tablet in addition. 

Sunday, 9 March 2014

Unexplained Infertility

I have at long last come to the very last in the series of my posts on causes of infertility. Fertility specialists have a set of tests that includes checking at least the semen analysis, tests to confirm ovulation and tests to confirm tubal patency. In 15-30% of infertile couples no cause can be found on investigations.  In these couples the delay in conception may either be a chance delay or there may be a subtle or as yet undetected cause. It is a little disconcerting to get this diagnosis of course. But there is a silver lining here. The couples in this category have the best chances of conceiving!

On an average only about 20% of women get pregnant in a monthly cycle. At the end of one year of regular relations, approximately 85% of couples achieve pregnancy. The 15% that remain are advised to seek advice. These are not necessarily infertile though they may have some degree of subfertility or it may be a chance event. In the latter case trying for a little while longer will enable the couple to conceive. Of note is the fact that 60% of couples will achieve a pregnancy in the second year of trying, but if you have been trying for three years or more, the chances of a conception are very low at 1-2%.

The message that I am trying to convey is that the course of action that you take is up to you. If you are anxious you can seek help at the end of a year of trying. It may be better if you at least get investigated to ensure that there is no obvious cause for the delay and then continue to try on your own for the next year. However, if you have already been trying for several years, it would be highly recommended to seek help with a fertility specialist immediately. Many infertility units would recommend IVF if you have failed to achieve pregnancy after cohabiting for more than 3 years! 

Do not despair, there is hope!

Thursday, 6 March 2014


When a man goes for a semen test, the one thing that he dreads the most either consciously or subconsciously is an abnormal result. It is impossible to fathom the blow to a man whose sperm test shows no sperms. The immediate reaction is that of despair and disbelief, of denial and anger.

The process starts in the millions of sperm producing tubules in the testes where special cells called Spermatogonia multiply and after a maturation process (that takes nearly 72 days) form sperms. The newly formed sperms are stored in a structure called Epididymis. During ejaculation the sperms are brought up and mixed with fluids secreted by the prostate and the seminal vesicles. This final fluid is semen. 

The condition where there is a total absence of sperms in the semen sample (checked on two occasions) is called Azoospermia. This condition is present in approximately 1% of all men and 10-15% of infertile men. This condition can either happen because there has been a damage or insult to the sperm production mechanism or because the sperms are being produced but unable to come out through the ducts and into the ejaculate (due to an obstruction or an anomaly in the ducts). 

Sperm production is under hormonal control and some endocrine conditions may impair sperm production. These are potentially correctable with medicines. In case of an obstruction, technology is available that involves retrieval of sperms from the testes and the couple can undergo IVF using these sperms. Where the sperm production machinery has started failing due to a disease or an insult (such as chemotherapy or radiation therapy), it may still be possible to use the few sperms that are present in the testes. In those men where there is no sperm production whatsoever, using donated sperms is the only option. This can be decided by an andrologist after appropriate hormone tests and a testicular biopsy to assess the situation.

Monday, 3 March 2014

Smoking and Fertility

The effect of smoking on health is common knowledge. However most people do not know the degree of damage smoking can do to the fertility in both men and women. 

In the men, many studies have documented the effects of smoking on the number, motility and the shape of sperms. Many men who smoke can have normal sperm parameters on testing. Do not think that no harm has been done in these. The genetic material (DNA) in the sperm cells is packaged and stabilized by proteins (called protamines). In smokers, the ratio of the two types of protamines is altered and this leads to the sperm DNA being vulnerable to damage. Studies have also shown that the fertilizing capacity of sperms can be affected and the embryos can stop growing after a few days. The chances of pregnancy are therefore lower.  

In women, the effects of smoking are stark. The quality as well as the quantity of eggs is affected. This leads to a delay in conception and increase in miscarriages. ICSI, a technique in which sperm is injected to achieve fertilisation, cannot overcome the damage caused and the chances of pregnancy after IVF/ICSI are almost half as that of non-smokers. Women who smoke also have an earlier menopause because of the effect of smoking on the ovaries.

Smoking is therefore discouraged in men and women who are yet to complete their family.

Friday, 28 February 2014

Male infertility

Many people still believe that infertility is primarily a problem in the woman. This is not true and 50% of the time a problem can be identified in the male partner either in isolation or along with a female contributory cause. Therefore the couple should always be investigated simultaneously. I have had couples who insist on having the woman investigated first, to the extent of having even painful surgeries to ensure that everything is "normal" before the husband relents to having a semen analysis. This is most unfortunate and apart from ignorance there is a morbid psychological fear (that there may indeed be a problem with their semen) in some men that may be responsible for this behaviour.

A fact that is not well known is that we do not have an adequate test that REALLY tests fertility of the man. Yes, we do have semen analysis and we can check how many sperms are present, how many of these are motile and what percent of the sperms have a normal shape. There is a wide overlap in the findings of semen analysis between fertile and infertile men. And the fact remains that just by looking at a semen analysis report no one can say with certainty whether that man is fertile or nor. Of course the exception to this is when there are no sperms at all!

Sperm parameters (i.e., count, motility and morphology) also fluctuate widely and therefore if there are any concerns, the doctor will ask you to repeat the test. It is extremely important that the entire ejaculate is collected. It is the first part which is sperm-rich and in the event where the first few drops are lost, the analysis may be abnormal.

Monday, 24 February 2014

Prolactin and Thyroid Hormones

In my last several posts, I have been relating the various causes of subfertility in the female and with this I am coming to the end of the common causes. In this post, I am going to talk about abnormal Prolactin and Thyroid hormone levels causing subfertility. 

Prolactin is a hormone with a number of functions, the most important is the growth of milk glands in the breast and milk production after giving birth. Prolactin excess can lead to menstrual irregularities, secretion of milk (not associated with childbirth) or just infertility even in the absence of any symptoms. Pregnancy, breastfeeding and even the stress of blood test can increase Prolactin levels. Women with Polycystic ovary disease often have raised levels. Other causes are medications, tumours in pituitary, some brain diseases, chest wall injuries and decreased thyroid gland function. The good news is that most of the time the levels are only raised mildly and these can be easily reversed using medicines. In case of high levels of course, further tests and treatment may be required.

An overactive and underactive thyroid gland can also interfere with fertility and as such levels of TSH are usually checked in women trying to conceive. Underactive thyroid is quite common and often undiagnosed. It is extremely essential to achieve and manage  normal levels of thyroid hormones not just when trying to conceive but also during pregnancy with the help of an endocrine doctor in conjunction with your fertility doctor/gynaecologist. This is because thyroid hormone requirements increase during pregnancy and the unborn baby can be affected in case these requirements are not met.

Suggestions/Comments/Questions are welcome. 

Unexplained infertility in the next post.....

Saturday, 22 February 2014

Uterine malformations: Does it matter?

Like all our body parts the way our reproductive organs form while still in the mother's womb can sometimes go a little awry. The reason why this happens is usually impossible to decipher though. But the big question is what can go wrong and does it matter?

What all can go wrong is too complicated for this forum but the range is complete lack of development of vagina and/or uterus to very mild changes in the shape.  For obvious reasons severe malformations preclude fertility and will require the assistance of fertility specialists. For example, if there is a block or curtain (called septum by doctors) in vagina but the upper structures are normal, then the surgical removal of the septum would suffice but if the uterus is absent or too underdeveloped then surrogacy is the only option.

It is important to keep in mind that a girl who has entered puberty and is having abdominal pain some days of the month but not having periods may have a problem like hymen without perforation or a vaginal septum. This required immediate treatment through a gynaecologist.  

The presence of uterine malformations has been linked with infertility, miscarriage, preterm labour and pregnancy complications such as placental abruption, growth problems in the baby, prematurity and death of the baby. The correlation between uterine malformations and these complications is hard to prove and surgical correction of all malformations may not be beneficial. The decision has to be individualized by the treating doctor. In patients with infertility or with recurrent miscarriages, removal of uterine septum is generally recommended. Other more complicated surgeries to unite two uterine cavities into one are generally not recommended nowadays.