In-vitro fertilization (IVF)

In vitro fertilization (IVF) is a process by which egg cells are fertilized by sperm outside the body. This is also called test-tube baby. The process was first done successfully in 1978. IVF has changed since then and today, it’s a more successful and less invasive procedure than before. The first stage of IVF starts with stimulating the ovaries to produce eggs, which are collected and placed in a dish containing sperm. Once the eggs have been fertilized they can be transferred back to the woman’s uterus as embryos to implant and grow as pregnancy (this is called embryo transfer). A process known as ICSI (intra-cytoplasmic sperm injection) is often used where sperm is isolated from a male sample and injected into an egg to form an embryo in the laboratory. As before the embryo is transferred back to a woman's uterus (this process is called embryo transfer).

IVF may be recommended by your doctor either in conditions resulting in infertility that cannot be treated by other modalities or after unsuccessful attempts at other less invasive modalities such as ovulation induction-timed intercourse (OI-TI) or intrauterine insemination (IUI). Common indications for recommending IVF in couples include:

a. Fallopian tube blockage or damage

b. Ovulation disorders resulting in problems in ovulation or decrease in egg counts (low ovarian reserve)

c. Endometriosis

d. Presence of large uterine fibroids that prevent implantation of eggs

e. to prevent transmission of genetic disorders in families

f. to prevent transmission of viral infections such as HIV, hepatitis B, or hepatitis C to the mother and baby, in couples where only the male partner is positive

g. Patients who have undergone a vasectomy or tubal sterilization before

h. Patients with conditions resulting in impaired sperm production or function

i. Fertility preservation in women or couples who want to defer having a child for social, career, or health reasons

j. Patients undergoing treatment for cancer or other health conditions that may impact future reproductive outcomes

The first step of IVF today consists of stimulating the ovaries to produce oocytes (eggs). This process is called ovarian stimulation. A fertility specialist should ideally select the correct protocol for ovulation induction based on your medical condition and how your body responds to the medications. A variety of stimulation protocols are available in their arsenal today including antagonist protocol, minimal stimulation protocol, long protocol, natural cycle protocol, progesterone primed ovarian stimulation (PPOS) protocol, oocyte pooling cycles, etc.

An experienced fertility specialist can identify the right protocol for your condition rather than using a one size fits all method to ensure an optimal outcome. Key considerations for specialists to select the right protocol include:

a. your underlying medical condition

b. your response to treatments done in the past

c. your risk for side effects from treatment

d. cost of treatment

The IVF cycle can be broadly split into ovarian stimulation, oocyte retrieval (also known as the egg-pick up), the formation of embryos, and embryo transfer. The key steps in each of these processes include the following:

a. Ovarian Stimulation: The objective of ovarian stimulation is for the fertility specialist to control the process of growth and maturation of follicles in the ovaries. The fertility specialist would attempt to get a good number of oocytes during this process to maximize the chances of pregnancy in the couple. Most IVF treatments begin on the second day of the menstrual cycle with the ovarian stimulation process. The specialist would usually perform a transvaginal ultrasound scan to evaluate the number of antral follicles that may have the potential to grow into a mature follicle containing an egg (also called antral follicle count or AFC). A few blood tests can be done to evaluate adequate suppression of the ovaries so that the fertility specialist can control the growth of follicles. The fertility specialist would then start you on medications (either tablets or injections) that must be taken every day at specified times. This would continue for 7-14 days usually where the dose and duration would be determined by the response of your body towards the medications. There may be additional injections such as the antagonist injection that may be added at the right time to prevent premature rupture of the follicles. The fertility specialist monitors the growth of follicles through transvaginal ultrasound and gives the patient a trigger injection when the follicles achieve the correct size. The oocyte retrieval process must be done within 36-40 hours of the trigger to prevent spontaneous rupture and ovulation.

b. Oocyte retrieval (egg pick-up): The objective of the oocyte retrieval process is to obtain mature eggs from the ovaries after ovarian stimulation. The process of oocyte retrieval is a minor surgical procedure usually done under light anesthesia or sedation. It is important that patients need to undergo a pre-anesthetic evaluation 24-48 hours before this procedure. In the procedure, the female partner is asked to lie down and is given brief sedition. The fertility specialist then visualizes the ovaries with a transvaginal ultrasound scan and uses a fine needle to aspirate the contents within the follicles in the ovaries. The follicular fluid contains the eggs which would be used for the formation of the embryos. The overall procedure usually takes 15-20 minutes following which the patient is put into the recovery ward. The patient is discharged within 2-4 hours after the procedure after the effects of the anesthesia have worn off.

c. Formation of embryos: The next process is to form embryos in the laboratory and grow them for 3-5 days. This begins with the embryologist screening the follicular fluid under a microscope to identify the eggs. The eggs are then washed and cleaned in the laboratory. The sperm from the male partner is similarly washed and used to fertilize the eggs in a dish or by a procedure known as ICSI (intracytoplasmic semen injection) to form embryos. The embryos are then placed inside a special media containing the nutrients required for growth and development and are placed in an incubator that provides the correct temperature and environmental conditions for growth. The embryos are assessed for quality periodically and are grown for 3-5 days. On day 3 a healthy embryo is a ball of about 8 cells that grows to become a ball of more than 100 cells by day 5. Embryos on day 3 or 5 can be transferred back into the uterus or frozen for future transfers in liquid nitrogen.

d. Embryo transfer process: The objective of the embryo transfer process is to transfer healthy embryos into a uterus that is ready for the embryo to implant. The fertility specialist assesses the health of the uterus to permit implantation by evaluating the endometrial thickness on a transvaginal ultrasound scan. Healthy embryos formed in the previous step are loaded into a fine plastic tube known as an embryo transfer catheter. The embryos are placed into the uterine cavity through the vagina by the fertility specialist using this catheter under ultrasound guidance. The process may be done under mild sedation in anxious patients.

The IVF process is not painful as there are no cuts or incisions made onto the body. There is however some discomfort that may be experienced by patients during the following steps:

a. Daily injections for 7-14 days (your doctor can make you comfortable by selecting injections that cause lesser pain and discomfort or tablets for this process)

b. Heavy bloated feeling due to engorged ovaries during and immediately after ovulation induction and egg pickup

IVF cycles if done wrongly can take an emotional, financial, and psychological toll on individuals. Out of my experience in managing fertility issues across many couples, the following are a few points that all couples seeking infertility treatment must note:

a. Know that you have a right to get a second opinion. Get a second opinion if you are not sure- Look before you leap. Advanced fertility treatments such as IVF are expensive and can have serious financial implications on families. It is important that you get a second opinion if you have unanswered questions or doubts with regard to the treatment being suggested. It is important to know the available alternatives to the suggested treatment and the reasons for selecting an advanced treatment such as IVF before trying more simpler alternatives. After all, in today's world, a second opinion is but a phone call or video call away.

b. Have realistic expectations on the time to pregnancy from initiation of treatment- Infertility treatments may take up to 6-8 months to work. Do not feel disheartened to face a failure or two during a course. Also, do not expect that a doctor would help you get pregnant in a month or two. Although some people are lucky and get pregnant early on, it's important to set up realistic expectations in your mind about the time to pregnancy.

c. Know realistic measures of success rates and do not fall prey to false marketing- Success rates are often used as a measure for marketing for doctors and clinics without any way of verifying the data for correctness. Outside India, organizations such as the centers for disease control and prevention (CDC) provide success rate calculators to help patients. These numbers are obtained by looking at thousands of patients across hundreds of clinics. Be cautious if the success rates projected are not in line with established data. Please click here to go to the CDC success rate calculator.

d. Consider a specialist over a generalist- Advanced fertility treatments such as IVF is a field with rapid changes in technologies and protocols. Practices followed as early as 5 years back have changed with new evidence being generated every day. The area has also grown in depth where doctors need to know and understand aspects of andrology, endocrinology, and other aspects of medicine in addition to gynecology. A fertility specialist is one who has completed 2 years of training in the management of infertility after completing his or her post-graduation in obstetrics and gynecology. The focused training in fertility management allows a specialist to be more up to date and provide you with the right treatment rather than taking a "one size fits all" approach.

e. Select a clinic or doctor who is accessible- Fertility treatments can take up to 6-8 months before they yield results. Treatments such as IVF may also have side effects or complications that may require immediate clinical attention. The treatment is also complex in nature with several steps that need to be done in proper order and timely manner to ensure success. The process also involves several technical people in addition to the doctor such as embryologists, anthologists, radiologists, nurses, etc who are involved in various steps of the process. It is therefore important to select a doctor or a clinic to whom you have easy access on phone, video, or in-person for any questions, doubts, or complications. As each patient responds differently to IVF medications it is important for a specialist to anticipate the requirements of a patient well in advance to prevent complications and failures. It is also critical as the doctor takes complete care of your treatment and its outcomes rather than a group of people with limited accountability. Your doctor should be available and accessible to hold your hand throughout both the ups and downs of the infertility treatment journey at all times.

f. Obtain a clear diagnosis before you start treatment- A proper diagnosis before initiating treatment is critical to identify the right treatment for your condition.

g. Select a doctor who stands with you during failure as much as during success- The best fertility treatments have a success rate of 50-60% in a cycle. Therefore it is probable that you may not succeed in the first or second attempt. It is more important for a doctor to counsel a couple in dealing with a failure and than holding their hand during success. In a recent trend, many clinics push patients after cycle failures to counselors or nurses rather than the primary doctors.

h. Select a doctor who provides you with realistic reassurance- It is important for your doctor to reassure you with regard to health conditions that may exist. It is however also important that the doctor be forthright with important information in a realistic and frank manner. At the end of the day, a doctor can guide you through the best course of action but not change God's will.

i. Be careful of proprietary treatments or advanced treatments provided without evidence- There are no shortcuts in medical science! Also, there are no "proprietary treatments" that can be given without evidence as per the drugs and cosmetics act in India. Be wary of clinics projecting proprietary or advanced treatments which are not backed by adequate evidence. There is a trend to add newer treatment without adequate evidence of benefit and the possible risk of harm. The medical community follows established guidelines on acceptable treatment. Any treatment that is without adequate evidence of benefit must be informed to the patient as being experimental in nature. Many such experimental treatments may be expensive and offer little or no benefit and sometimes even be harmful to use.

j. Understand the economics involved. Be prepared for the financial commitments- Advanced fertility treatments such as IVF can be a financial burden for a couple. It is important to discuss the same with your doctor. A specialist may be able to offer you drugs at a lower cost where possible. It is also important to understand the overall costs as costs of additional procedures, embryo transfers, laboratory tests, etc may not be apparent. There are also options for availing government support or insurance facilities for fertility treatments in specific cases.

k. Select a clinic that will provide you with your treatment records in writing- Fertility treatment can be expensive and complex. It is therefore important to have clear records of the medical procedures done in the event that you would want to seek a second opinion. Its therefore important to seek and keep your records to tests, scans, and procedures done in the past so that the same is available and need not be repeated without need. Medical records are also critical in the event of any complications where your doctor may not be readily accessible. It is surprising to see that some clinics refuse to give any records of the treatment to patients. Such lack of transparency must be a clear sign to be careful in such cases.

There are many different ways in which people measure success rates. It is important to understand how each clinic measures its success rates. Different definitions of success rates may have different ways to measure outcomes such as a positive beta HCG, a pregnancy visible on ultrasound or a pregnancy resulting in a live birth delivery, and different denominators such as the number of patients treated, number of transfers done, number of embryos transferred, etc. As these measures are not standardized across clinics the term "success rate" may actually be comparing apples and oranges when used across clinics. It is also important to view success rates on the basis of the complexity of cases being handled in a clinic. In other words, a clinic that handles patients with multiple past IVF failures with a 45% success rate may be actually better than a clinic seeing young patients and recommending IVF treatment in all patients irrespective of the clinical indications. A few of the commonly used definitions are listed below:

a. Delivery rate: the number of deliveries expressed per 100 initiated cycles, aspiration cycles, or embryo transfer cycles. When delivery rates are given, the denominator (initiated, aspirated, or embryo transfer cycles) must be specified. It includes deliveries that resulted in the birth of one or more live babies and/or stillborn babies. Note: The delivery of a singleton, twin, or other multiple pregnancies is registered as one delivery.

b. Clinical pregnancy rate: The number of clinical pregnancies expressed per 100 initiated cycles, aspiration cycles, or embryo transfer cycles. Note: When clinical pregnancy rates are given, the denominator (initiated, aspirated, or embryo transfer cycles) must be specified.

c. Live birth rate: Live birth rate was defined as the number of deliveries that resulted in a live-born neonate, expressed per 100 embryo transfers (Zegers-Hochschild et al., 2009). Up to 3 cycles were included until the end of IVF ­treatment or first live birth. The WHO consensus defines the Live birth delivery rate as the number of deliveries that resulted in at least one live-born baby expressed per 100 initiated cycles, aspiration cycles, or embryo transfer cycles. When delivery rates are given, the denominator (initiated, aspirated, or embryo transfer cycles) must be specified.

Countries such as the US have a system where the data on success rates across clinics is standardized by a regulatory framework. Refer to a tutorial on using the ART report by the centers for disease control and prevention if you want to learn more about this.

Refer to definitions of common terms used in fertility treatment under the FAQ section to learn more.

A successful IVF cycle depends on healthy eggs being retrieved from a woman during the ovarian stimulation, fertilization of a healthy egg with a healthy sperm to form a good quality embryo, and the implantation of this healthy embryo in an accepting uterus. Failure during IVF treatment usually happens during three stages during the ovarian stimulation, during the development of embryos, and after the transfer of the embryos into the uterus. The reasons for the failure during these stages may be as follows:

a. Cycle cancellation, failure during ovarian stimulation- Failures during ovarian stimulation happen in about 1-4% of patients undergoing IVF. These can happen if the body does not respond adequately to the hormonal injections or if the hormonal injections are not stored and used in the proper way (wrong dose, wrong timing, injections given in an improper manner). Patients may have a follicle that may develop which is empty in a condition known as empty follicle syndrome.

b. Failure to form embryos, failure to fertilize, or arrest of embryos during development- Once oocytes are retrieved, the embryologist makes an assessment of the quality of oocytes (eggs) obtained. Poor quality of oocytes maybe because of physiological factors such as age, weight, lifestyle, or due to the dose and treatment protocol used. In my experience, some patients respond to some protocols of treatment better than others. It is important to find a protocol that works best for each individual. This is often a trial and error process guided by experience and expertise. Genetic problems due to inherited, lifestyle, or environmental causes may impact the egg or the sperm and cause a fertilization failure or prevent the embryo from growing (arrested embryo). It would be critical to treat or control the underlying causes in such cases under the care of an experienced clinician or embryologist. Embryo quality also depends on the quality processes around the embryology laboratory to ensure proper conditions such as humidity, pH, and temperature for the growth of embryos. Techniques such as freezing and thawing may impact embryo quality if not performed properly.

c. Failure to implant after transfer- The final step where failures can happen is during the embryo transfer stage. At this stage, success is dependent on a healthy embryo and a suitable uterine lining that enables the implantation of the embryo. Failures during this stage happen due to poor quality of embryos or if the uterine lining (also called the endometrium) is not prepared well for implantation of the embryo. There may also be a risk of the immune system regarding the embryo as foreign material or medical conditions that may cause implantation failure in some patients.

Don't lose hope if a transfer is unsuccessful and does not result to a pregnancy. Even when a healthy couple try naturally for pregnancy the chances of conception are 5-10% per attempt (or per month). It is important to understand and realize that none of the assisted reproduction procedures guarantee 100% success. Nonetheless, your chances to conceive will improve with the total number of embryos and the number of embryo transfers that you attempt. On an average, there is a 50-60% chance of conception on each attempt of embryo transfer. The fertility team will try to maximize this chance by selecting the healthiest looking embryos and ensuring that your uterus is ready for implantation. If the result is negative, your doctor should help you understand if there were any concerns on embryo quality (or quality of egg or sperm), preparedness of the uterus, the transfer procedure/technique or the post procedure medical care provided. Over 80% of patients trying IVF-ICSI should conceive within 3-4 attempts. If you fail to conceive repeatedly (2-3 embryo transfers) in-spite of transfer of good quality embryos and a good uterine lining during embryo transfer you may need to be further evaluated by blood tests for autoimmune disorders or other factors that may prevent implantation. Also, embryos can be checked for genetic abnormalities or aneuploidies (abnormalities in the number of chromosomes) especially in women above the age of 35 years. It is important that a couple understands how success rates work and make an informed decision on the number of attempts to try with their own gametes before opting for donor gametes or other advanced procedures.

To make a baby, things start with an embryo. To make an embryo you need an egg from the mother and a sperm from the father. If the underlying medical condition impacts the number of eggs produced by the mother or the quality of eggs, then a donor egg may be thought as an alternative. A donor egg is retrieved from a healthy unrelated, fertile, anonymous donor, in accordance with national laws and regulations to help couples conceive. If a couple opts and consents for this line of treatment, eggs from a donor with matching physical appearance and characteristics would be used along with the fathers sperm to form an embryo. This embryo would be transferred into the mother to achieve conception.

Large studies have shown that there is no additional risks in health, development or behavior of babies born through assisted reproductive procedures such as IVF as compared to those born through natural conception. This also means that risks of pre-term delivery, genetic disorders or other medical conditions may happen in babies conceived through assisted reproductive procedures in the same manner as they may happen in babies conceived through natural conception. Even when people conceive naturally, there is a minimal risk of genetic disorders, medical issues or preterm birth.

The experience of doctors with assisted reproductive procedures for over 40 years suggests that there is no additional risk of cancer in couples undergoing IVF procedures as compared to the general populations. However certain medical conditions that may cause infertility such as PCOS or endometriosis may be associated with increased risk of malignancies or cancers if not appropriately treated.

IVF success rates depend on various underlying factors such as the age of the female partner, cause of infertility, body weight of the female partner, quality of sperms and eggs, number of embryos transferred, use of self or donor gametes and so on. On an average IVF procedure has a success rate of about 50-60% per transfer. This means that over 80% of couples would conceive by 3-4 embryo transfers. There is a good chance 50-60% chance for a couple to conceive in the very first attempt in many cases with simple underlying problems.

The cost of IVF procedures can vary from clinic to clinic. The cost can also decrease or increase based on the type of medications, dose of medications and the protocol used by the doctor based on the underlying condition-

a. Cost of medicines or drugs used: The cost of drugs range from approximately 25,000 to 90,000 based on the type of drugs, brand of drug, dose and protocol used. Young women with good ovarian reserve would usually require milder stimulation with lower doses of drugs. There are protocols with relatively inexpensive drugs which can be used based on the doctors experience

b. Cost of procedure- Egg pick-up and embryo formation: This cost varies from clinic to clinic. The cost is usually between 80,000 to 1,25, 000 per episode

c. Cost of transfer- Frozen embryo transfer procedure costs about Rs. 30,000 to 45,000 based on the hospital or clinic where it is attempted.

d. Cost of additional procedures- Additional procedures such as freezing, blastocyst culture, time-lapse etc may be charged by the clinic. These costs vary between clinic to clinic. Freezing costs about Rs. 15,000-25,000. The other procedures cost between Rs. 5,000-15,000 across clinics.