IVF

What is IVF?

In vitro fertilization (IVF), also sometimes known as “test tube baby” basically refers to a process in which fertilization of egg with sperms happen outside of human body. IVF literally means “in glass” as in IVF the eggs and sperms are removed, placed in a petri dish and allowed to interact in a more conducive environment of a specialised incubator which gives them a chance to fertilize and develop into an embryo. The embryo is transferred back in the mother’s womb and if implantation is successful, the embryo develops into a foetus and eventually into a baby.

Who are the appropriate candidates for IVF?

In Vitro Fertilization (IVF) was originally used to overcome obstruction in the fallopian tubes, a condition in which sperms cannot travel through the fallopian tubes to fertilize the egg even in presence of a healthy uterus, eggs and sperms. But, over the years, the indications of this technique have expanded and IVF is now used to treat infertility arising from a variety of causes and this technique has helped millions of childless couples conceive their babies. Some of the most common conditions, in which the infertile couples can benefit from IVF are:

  1. Fallopian tubal blockage
  2. Ovulatory disorders
  3. Endometriosis
  4. Unexplained infertility
  5. Age related infertility
  6. Mild male factor infertility

What are the steps for doing IVF?

The process of IVF involves the following steps:

1. Pre IVF Investigations and medications– We ensure that all the patients undergo a detailed work up so that the finer details are not missed and treatment can be individualised. The pre- IVF tests, which a patient may need include:

  • Blood Investigations- Blood level of Anti-Mullerian hormone (AMH), Day-2 FSH (Follicle Stimulating Hormone), LH (Luteinising Hormone) and E2 (Estradiol) is tested in the female partner. We also routinely test the female partner for blood levels of thyroid (TSH, T3 & T4) and prolactin hormones, complete blood count and status of Rubella infection. Thalassemia screening and a complete check for infectious diseases including HIV, Hepatitis B, Hepatitis C and Syphilis is also sometimes required.
  • Transvaginal ultrasound- It is done to assess the anatomy of ovaries and uterus. An ultrasound scan done at the beginning of menstruation also helps in assessing the antral follicular count (AFC), which is a very good marker for ovarian reserve and a mid-cycle scan helps in assessing the  endometrial status.
  • Hysteroscopy- The best evaluation of uterine cavity is done by directly seeing it from inside. Several defects in the uterine cavity like polyps, adhesions, septum and fibroids can prevent the embryo from attaching in the uterine cavity. Hysteroscope is a very thin telescope which can be passed into the uterus through vagina and helps us study the structure of uterus from its inside. Hysteroscopy also allows surgical correction of many of the structural abnormalities in the same sitting. Hysteroscopy is performed under brief general anaesthesia and can be completed as a day care procedure.
  • Sonosalpingography (SSG)- SSG is a simple diagnostic procedure primarily used for evaluating inside of uterine cavity for presence of submucous fibroids, polyps or other lesions inside uterus and check for patency of fallopian tubes. SSG is a very safe procedure and is generally conducted as an OPD procedure without need for any anaesthesia. In SSG, a physiological liquid is pushed into the uterus under pressure using a catheter and the outlet of vagina is blocked using inflated balloon of the catheter. The liquid passes through the patent tubes under pressure and the flow of liquid through the patent tubes is detected using ultrasound scan.

2. Pre-stimulation treatment- The patients about to start the IVF should take special health precautions, avoid smoking and drinking and should maintain good healthy diet and hygiene. The patients should try and avoid any stress and anxiety.

A very important medication that is often started in the pre-stimulation phase is GnRH agonist- given either as injection or as nasal spray. The primary role of GnRH agonist is to prevent premature LH surge, which could result in premature ovulation before eggs are ready to be retrieved. There are many different protocols in which GnRH agonist play an important role. In the down regulation protocol, GnRH agonist is generally started from day 21 of the previous cycle on a daily basis and continued till the day of HCG trigger. It suppresses the pituitary so that there is no endogenous FSH and LH and the body is solely dependent of exogenous FSH and LH for egg growth and ovulation.

Some women planning for an IVF may also need pre-treatment with a birth control pill in the preceding cycle. This ensures that GnRH agonist therapy can be started on time in women who have irregular cycles. Another benefit of these pills is that they prevent the formation of ovarian cysts, which may develop with GnRH agonist or as a residual of previous ovulatory cycle.

 3. Hormonal stimulation- Hormonal stimulation of the ovaries is the process of using hormone injections to help ovaries produce multiple eggs in one cycle. While only one egg is required for successful pregnancy, all eggs produced by the ovaries are not suitable to yield a pregnancy. Therefore gonadotropins injections are given to the patient so that her ovaries produce many eggs in a cycle. This improves the chances of getting enough good quality eggs for fertilisation, and therefore, of achieving a pregnancy. This is a very controlled process where injections are given not only to stimulate growth of eggs, but also to control the process of ovulation. Just like Gonadotropins are given to develop many follicles, injections are also needed to prevent LH surge in the body which may lead to premature ovulation before the eggs can be extracted. This is achieved either by GnRH Agonist which is started as discussed above or by giving GnRH antagonist injections daily once  dominant follicle reaches 13-14mm in size. For a vast majority of patients the average duration of Gonadotropin stimulation is 10-12 days, where the aim is to produce 10-12 eggs and the patient is under regular monitoring to ensure good growth of follicles and also to time ovulation.

4. Follicular monitoring- It is essential to regularly monitor the cycle using serial ultrasounds and periodic assessment of blood estrogen level in order to optimize the outcome of ovarian stimulation. This assessment helps in tracking growth of the follicles and deciding when the eggs have become sufficiently big and mature. Once the majority of egg follicles are between 16 and 20 mm on average diameter, a final injection of Human Chorionic Gonadotropins (HCG) is given which prompts the eggs to mature and ovulate.

5. Egg retrieval- The eggs are likely to ovulate from the follicles 36 hours after the HCG injection. Therefore, we plan the egg retrieval 36 hrs from the time of HCG injection. This procedure is timed exactly according to the timing of the HCG injection, as we need the eggs to be mature but the follicle should not rupture.

Egg retrieval is the only time in the full IVF cycle, when we expect the patient to be admitted on day care basis. The patient is asked not to not eat or drink 6 to 8 hrs prior to the egg retrieval. During the egg retrieval procedure, short general anesthesia is administered to make the process comfortable and pain free for the lady. The vagina is then washed with a sterile water solution. A needle is placed under ultrasound guidance through the vagina into the ovary and fluid, and eggs from the follicles in the ovaries are collected into a test tube and sent to the IVF lab. The whole procedure takes about 30 minutes, and discomfort is generally very minimal.

2PN6. Fertilization- A good IVF lab with trained personnel is the heart of a successful IVF program. In the IVF lab the eggs that have been retrieved from ovaries are kept in a culture medium in an incubator for some time and then every egg is overlaid with 50,000 to 10000 sperms from the partner. The sperm sample is also first prepared and washed to remove all the dead sperms, debris and liquid from the semen and then good quality sperms selected for fertilizing the eggs. Following this process of inseminating the egg petridish is paced in the incubator again, for the sperms to enter and fertilize the egg.

The fertilized eggs called the embryos start dividing and become 4 celled by 2nd day, progressing to 8 cells by 3rd day and up to 100 cells by 5th day. The embryologist and the clinician keep a check on the growth and quality of the embryos. The final decision of embryo transfer and timing of the same is based on the embryo status & quality and the clinical details of the patient.

7. Embryo Transfer- The embryo transfer can be done either on Day 2, Day 3 or Day 5 following the egg retrieval. We discuss with our patient to finalize the number of embryos to be transferred into the uterus of the recipient. The decision is generally based on the number and quality of embryos formed, patient’s age and clinical indication of IVF. The number of embryos to be transferred per cycle can range from a single embryo to up to 3 embryos. Any additional embryos are generally frozen and can be used in future, if required.

  •  Post transfer care- After completing the transfer the patient rests in a relaxed position for 20 minutes and then can go home. The patients are given the following instructions to facilitate a better recovery:
  • Embryo Transfer Procedure- The procedure of transfer is a gentle and simple procedure though needs a lot of precision by the doctor to be able to transfer at the correct spot in the uterus. After appropriate patient and embryo verification, the correct no of embryos are loaded in a thin catheter which is passed into the uterus through the cervix, simultaneously the passage of the catheter is checked by abdominal ultrasound and then embryos softly ejected from the catheter into the uterine cavity. The procedure is almost painless and takes less than 10 minutes time and is generally performed as an OPD procedure without requirement of any kind of anesthesia.
  • Preparing for Embryo Transfer- The day of embryo transfer is one of the most crucial days in the whole cycle. We expect the patient to relax and come to the centre with the urinary bladder at least half full in order to allow us to visualize the uterus using an abdominal ultrasound.
    • Avoid any vigorous activity like aerobics or running. After 8 hours, they may gently increase their activity. The ovaries will still be full of fluid from the effects of the stimulation and one may feel some bloating or pelvic discomfort at this time. It is okay to take stairs slowly, and walk short distances.
    • Avoid vaginal creams, lubricants, or spermicides.
    • Avoid vaginal intercourse or orgasm for about a week after the transfer.
    • If the patient has to travel, allow twice as much time as usual and minimize stress.
    • Drink plenty of clear fluids to stay well-hydrated.

It is helpful to understand that at this point, successful embryo implantation and pregnancy will depend primarily on the health of the embryo rather than on patient’s activities.

8. Pregnancy test-

A pregnancy test is performed around 12- 14 days after the embryo transfer. This test confirms the success of the IVF treatment, if positive. The patient is generally instructed to repeat the test after 2 days to be doubly sure of the outcome of the procedure. The doctor may instruct to stop the medications if the pregnancy test is negative.

Four weeks after the first positive blood pregnancy test, an ultrasound scan is performed to confirm a clinical pregnancy, which is the presence of a gestational sac in the uterine cavity (the gestational sac can be seen before the embryo is visible).

What are various stimulation protocols for doing IVF?

One of the more common questions we get asked by patients who are preparing to undergo IVF concerns which stimulation protocol is best for them. Before we answer this specific question, it is important to understand that the ultimate outcome is based on a number of factors including the patient’s age, her ovarian reserve status, and the associated hormonal parameters. In general older women and women with associated diseases like endometriosis or history of ovarian surgery produce lesser eggs than women without these factors.

Our approach at Blessings fertility is to individualize and tailor the stimulation protocol as per the needs of that specific patient in order to optimize the outcome of treatment.

Some of the most commonly used stimulation protocols are:

1. Long Down regulation / Agonist Protocol- The principle behind this protocol is to artificially suppress the pituitary gland by giving exogenous GnRH agonist (Inj Lupron) and then stimulate the ovaries with FSH/ HMG injections for a proper controlled ovarian stimulation. This protocol can be applied in the following steps-

  • The patient starts taking a daily dose of Inj Lupron from the 21st day of the previous cycle. Alternatively, the patient takes a birth control pill for 3-4 weeks and then Inj Lupron is started 3-4 days before stopping the pill. Inj Lupron acts on the pituitary gland and stimulates it continuously, which desensitizes/ suppresses the pituitary gland.
  • Once the patient gets her period, she starts taking gonadotropin (FSH/ HMG) injections and undergoes regular ultrasound and Estradiol monitoring to assess the response to stimulation. It takes around 10-12 days of injections to produce mature follicles. Inj Lupron is also simultaneously continued till the day of HCG administration.
  • Inj HCG is given when the dominant follicle is 18 mm in size, in order to get the oocytes matured. Once HCG is given the follicle are likely to ovulate 36 hrs later.
  • Patient undergoes egg retrieval around 35-36 hrs after HCG administration.
  • Progesterone  in the form of either vaginal pessaries or injection is started after egg retrieval to prepare the uterine lining for embryo transfer.

2. Antagonist Protocol- Antagonist protocol has become very popular these days because the number of days for which the patient has to take the injections, and also the dose of stimulation, is less as compared to the long down regulation/ agonist protocol.this protocol also offers greater flexibility in starting the IVF cycle. Another big advantage of this protocol is that the risk of hyper stimulation with antagonist protocol is also lower than the down regulation protocol. Numerous studies have found the results in this protocol to be as good as long protocol.

This protocol is applied in the following steps-

  •  The patient starts taking Gonadotropin (FSH/ HMG) injections from the day of menstruation and undergoes regular ultrasound and estradiol monitoring to assess the response to stimulation.
  • The antagonist injections (Ex Inj Cetrorelix) are started from Day 6 of stimulation or when the dominant follicle reaches 13-14 mm and given till the day of HCG administration. GnRH antagonist acts immediately and rapidly, thus preventing any premature LH surge within a matter of hours.
  • Inj HCG is given when the dominant follicle is 18 mm in size, in order to get the oocytes matured. Once HCG is given the follicle are likely to ovulate 36 hrs later.
  • Patient undergoes egg retrieval around 35-36 hrs after HCG administration.
  • Progesterone is started after egg retrieval to prepare the uterine lining for embryo transfer.

3. Short Flare Protocol- The real challenge in ovarian stimulation is to get the optimum number of eggs from all women. However, a subgroup of women will not respond to stimulation as we wish because their inherent ovarian reserve is low. “Flare Protocol” is used to maximally stimulate the ovaries of such low reserve/ poor responder patients.

In this regimen, Inj Lupron is started twice a day in a very small dosage and for a short duration. Inj Lupron, combined with high dose gonadotropin stimulates the pituitary gland to releases a lot of follicle stimulating hormone (FSH). This endogenous FSH, supplemented with exogenous FSH injections helps in recruiting a large no of follicles in the ovary.

Poor responder is one of the more challenging clinical issues faced by the reproductive endocrinologists, and therefore, many alternatives to the flare protocol have been proposed.  Some of these involve the use of oral medications such as Clomiphene in addition to gonadotropin injections or Growth hormone injections. Supplements like DHEA have also been tried to enhance outcome in poor responders with poor ovarian reserve.

What is Natural Cycle IVF?

Of late, there has been renewed interest in natural cycle IVF. In a natural cycle IVF the routine fertility medications are not used. Instead, the follicle is allowed to grow normally in a natural cycle. The patients are monitored using ultrasound and blood tests to assess the development of the follicle and then the egg retrieval in performed after an appropriate time of detecting the LH surge. If an egg is found in the follicle it is fertilized with sperms and if fertilization is successful and embryo is formed, the fertilized embryo is transferred back in the uterus.

Advantages:

  1. No use of fertility medications
  2. No risk of complications like hyper stimulation syndrome
  3. Less cost

Disadvantages: Despite appearing as a very attractive treatment modality, Natural Cycle IVF has not become very popular. The disadvantages include-

  1. Poor success rate- In approximately 20% of “natural” cycles, no egg is retrieved at the time of egg retrieval and in another 20% of cycles there is no fertilization and so no embryo is formed. So only about half the patient who start their natural cycle with an intention to do IVF, actually get formed embryos. Furthermore, the pregnancy rate in the patients who undergo transfer is only close to 10 %. This pregnancy rate is very much comparable to their chances of conceiving naturally or with IUI.
  2. Poor success rates mean that the patients need to undergo monitoring , egg retrieval and  IVF repeatedly.
  3. May ultimately lead to increased cost as compared to conventional IVF (which has success rates of up to 40-50% in good settings).

Due to the above mentioned disadvantages/ shortcomings, a few modifications of natural cycle IVF protocol have been suggested. A variant of natural cycle IVF, popular by the name of “modified natural IVF”, includes adding the antagonist to the otherwise natural cycle in order to prevent premature ovulation. When a mild stimulation is added to help grow 2-5 follicles in an otherwise natural cycle, it is called as “minimal stimulation IVF”. These modifications may improve the success rates of IVF a little bit, but the overall success rate of such variants still remain much lower than with conventional IVF procedure.

What are various risks associated with IVF?

IVF is a fairly safe procedure with rather few side effects. The commonly seen side effects include:

1. Side effects Due to medications-

  • Nausea and occasionally vomiting
  • Breast tenderness
  • Mood swings and fatigue
  • Mild bruising, soreness and allergic reactions at the injection site due to repeated daily injections.
  • Ovarian Hyper Stimulation Syndrome (OHSS)- Use of stimulating hormones and HCG leads to development of many follicles in the ovary. The symptoms of OHSS appear when the ovaries become too enlarged. In mild cases, the symptoms of OHSS include nausea, vomiting and bloating. However, in severe cases there is accumulation of fluid in the abdomen and lungs, which can cause great respiratory distress, breathlessness, dehydration, raised blood coagulability and in rare cases, may also lead to kidney failure and death.

2. Risks associated with Egg retrieval-

  • Injury to organs near the ovaries, such as the bladder, bowel, or blood vessels and bleeding
  • Pelvic infection (mild to severe). Pelvic infections following egg retrieval or embryo transfer are not common. Severe infection may require hospitalization and/or treatment with intravenous antibiotics. These are more commonly seen in women with endometriosis or frozen pelvis.

3. Risks associated with Embryo transfer-

There is a theoretical possibility of pelvic infections, but with proper precautions its seen very rarely.

What are the risks associated with IVF pregnancy?

1. Multiple pregnancies: In order to enhance the chances of conception with IVF, the physicians often transfer more than one embryo. This can often results in multiple pregnancies- most often twin pregnancy, but can rarely cause more than twin pregnancies also. Multiple pregnancy can pose significant risks including:

  • Preterm labour and premature babies- Babies born before term are at risk for health complication such as lung development problems, intestinal infections, and cerebral palsy. This may necessitate admission of these babies to neonatal intensive care unit.
  • Maternal hemorrhage
  • Delivery by caesarean section (C-section)
  • Pregnancy-related high blood pressure
  • Gestational diabetes
  • Fetal reduction- In cases of high order conception like triplets and more, the patient may have to undergo fetal reduction to prevent complications in the fetuses, but which by itself also increase the chances of miscarriage.

2. Ectopic Pregnancy: It is a rare complication of IVF. Sometimes the transferred embryos may get pushed into the fallopian tubes due to the uterine contractions. If the embryo gets lodged in the tubes it leads to tubal pregnancy. Other abnormal sites where a pregnancy may lodge is cervix, ovary or abdomen.

3. Birth Defects: The incidence of birth defects with assisted reproduction is higher than with naturally conceived pregnancies. However, the role of infertility treatments in higher incidence of birth defects is not clearly understood and it is still not known if these defects are caused by IVF or are due to the actual cause of infertility itself.

Advertisements

Leave a Reply

Fill in your details below or click an icon to log in:

WordPress.com Logo

You are commenting using your WordPress.com account. Log Out / Change )

Twitter picture

You are commenting using your Twitter account. Log Out / Change )

Facebook photo

You are commenting using your Facebook account. Log Out / Change )

Google+ photo

You are commenting using your Google+ account. Log Out / Change )

Connecting to %s