God, infertility and IVF

I was introduced to God by my parents at a very young age; perhaps during the time when I started to imitate my elders. They took me to temples , asked me to keep my palms together and said, “Ask God that He should take care of you and protect you”. I repeated what they said without even understanding the meaning of what I am repeating “God please protect me !”. My parents were very happy and so were my near and dear ones . They enjoyed the childishness in the words I uttered. They were pleased that I would grow into a “God-fearing” child. But I had no idea who God is. I felt happy to be in a temple because I could see so many different people there; I was excited to repeat what I was told to - because everyone’s attention was on me and I got lots of appreciation for what I did. This is how God came into my life. I never knew at that point of time that this invisible person, whom I will never meet, will shape my life; will have a strong control over me and will provide me with emotional protection. I also never knew that He can make me feel guilty and fill me with irrational fears !

When I grew a bit older, my parents used God as a tool to control my pranks. They used to say “Manju, if you tell lies God will pierce your eyes; so do not lie.” I used to get terrible dreams of losing my eye sight every time I lied. However, the lie saved me from my elder’s anger more effectively than God would. But the fear that God will punish me remained etched in my mind.

I was educated in schools run by Christian organizations. I learned a lot about God there. We had a church within the school; there were regular prayer meetings and bible studies. In such an environment, I got to hear the message - “God loves you” , and this was a very new message for me. I was taught until then that God will protect me from harm and He will punish me when I do something wrong; but no one told me that God loves me and I had no insightful thinking to assume that the “super power”loves me. Those were the times I started to feel closer to God ; I started to treat Him as my friend. I shared with Him my fears and wants; when I was worried, and when I could not talk to anyone about what bothered me, I knew where to go. I went to church, kneeled in front of Him, told Him my worries and asked for help. When I reached out to Him, my fears appeared less bothersome and I strongly believed that I would get help. I asked Him help for everything –for getting good marks, so that my dad wouldn’t get upset; for protecting me from my teachers’ wrath whenever I failed to do my homework; for giving me the things I desired; for protecting my mom, dad and sister; for curing my dear ones - and for many more things ! God became my confidant – He knew everything about me – each of my secrets. I struggled hard to keep my thinking good – I was scared that bad thinking would bring forth God’s anger and He would punish me ! I also learned to seek His forgiveness whenever I did something wrong; whenever I went against my conscience. I got a lot of relief when I could repent and get His forgiveness. The bonding I had with Him increased day by day , and I am sure He loved me unconditionally!

I was taught this prayer during school days – and I can recite it even now :

Our Father, who art in heaven, hallowed be Thy name, Thy kingdom come, Thy will be done on earth as it is in heaven. Give us this day our daily bread; and forgive us our trespasses as we forgive those who trespass against us; and lead us not into temptation, but deliver us from evil. For thine is the kingdom and the power and the glory forever and ever. Amen.

Then came my teen age years – I was physically and mentally metamorphosing into a new person. Raging hormones; physical changes; and lots of new, exciting thoughts and feelings set in. With that came in a lot more guilt ! I became uncomfortable about the fact that God knew “all”my thoughts. I struggled between keeping myself pure so that God remains pleased with me , but my “Mills and Boon”desires seem to pull me away from God many a time ! That was the most beautiful and highly confused period of my life. I tried hard to keep my thoughts “blemish free” and concentrated on my studies.

As I grew, I learned to bargain with God too. I would tell Him “God I will not eat non-vegetarian food on particular days; I will control my desire to eat it– can you please make my wish about coming first in this test come true ? “I used to panic a lot when my mom fell ill; and I always ended up feeling guilty because I believed that God was punishing me by making my mom suffer because of my evil thoughts and deeds ! In short, when my thought processes were not fully mature , I viewed God as a powerful person , who knew everything, including my innermost thoughts and desires . I believed that if I was good , I would be spared of His anger and He would bless me by granting me all my desires. This fear of God acted as a protective shield from many unwanted distractions I encountered in life. But it also curtailed my rational analyzing power many a time , and left me with irrational feelings of guilt !

Then came my college days and a much more mature me. I went to temples whenever I could and felt very peaceful when I stood in front of Him with my hands folded. I no longer kept my eyes closed when I prayed to Him. I found happiness looking at Him; talking to Him just like I talk to a friend - and I started to love Him too. I felt immense strength when I had Him near me. I prayed to Him frequently to give me a good future – a good job, a good life-partner and I constantly pestered Him to make my wishes come true !

Soon I entered into a period of life where I was well-settled; I found a wonderful life-partner and was ready to have lots of babies. Life was happy - but I found to my dismay that I could not get pregnant. I saw that something which was very natural and easy for others was denied to me. During this time I got a lot of advises on - which God to pray; what to offer Him; what kind of fasting and prayers I could do in order to please Him so that I could get my child! I prayed to God faithfully; swallowed the “prasadams” which was offered to Him - and fasted as instructed. I got pregnant – but went through a traumatic miscarriage!

This was when I was exposed to “life”. My pain made me receptive to other’s pain. I started to look around and realized that there are many others who suffer more than me. Suffering leads to “enlightenment”;suffering and pain opens up our mind; it makes us to search for “truth”. We only learn from adversity in our life – and what we choose to learn is upto us ! I am sure the “Bodhi tree” stands as an euphemism for “suffering” - and everyone becomes a little Buddha during some point in their life when they are faced with grief and agony !

The pain of infertility was so intense that I did my best to escape from it. The only reasonable way out, which is within my reach, is to acquire knowledge. When I say knowledge , it doesn’t mean scientific knowledge alone , but an attempt to get some rational answers to philosophical questions. Why did this happen to me ? Why did God forsake me ? Why is He making me suffer ? What did I do wrong ? Why do I have to endure this pain ? Is infertility a punishment ? Why can’t God help me out ? Why does God bless someone with a baby when they don’t want one - and when I need one so badly, why is He denying me that happiness ? Why are unwanted babies created and thrown in dustbins when there are so many people struggling to have one ? Why are so many children born to people who cannot even feed them properly ? When many drug addicts and pedophiles can have a baby without trouble, why can’t I? Why do bad things happen to good people ? I needed answers; answers which could ease my pain. Whom should I turn to? Where will I get the answers so that I will find peace of mind ?

When I carefully analyzed all the questions which arose in my mind, I understood that God is the anchor and all the questions are connected to Him in one way or another. I realized that, I will get the needed answers only if I could understand who God is ! Do I really know the person whom I am depending on all my life ? Where is He, what does He look like ? Does He really have anything to do with suffering ? Does He punish us when we do wrong ? Will He wipe my tears ? Does He posses the magical wand to make our reasonable desires (my baby wish !) come true ? WHO IS HE ?!

Below is my humble attempt to understand who God is ! I am no expert in religious literature, although I do try to grasp the crux of what is said in them. This article is like a baby’s first step , and I hope it doesn’t hurt anyone’s ideology. I hope I will not get a mail saying I am a blasphemer! The following definition I developed in my mind about God helped to me to be at peace with myself - and I hope it helps some of you too.

God is a form of energy. There is a powerful energy which is operating in this world. We can understand it when we think about this world’s architecture. In fact, why consider such complex things –just think about our body and how reproduction happens. Two minute cells unite to give birth to the most complex living organism. Being a biologist, I am always bewildered by all the minute yet complex processes that work in unison to keep us alive- and to create a new life form ! For such a complex process to work perfectly, there should be a designer. Doesn’t the accuracy by which this world functions and by which our body functions demand the existence of an omnipotent designer ? I believe there is a “super brain” at work behind the complexities and perfectness of life. There is an unimaginable and unfathomable force that operates in this world and we call that energy God. Imagine neglecting your home for a few months – the orderliness of your home will be gone ! Your home needs “you” to keep it in order ! Likewise , this world needs a “super power” to maintain its orderliness!

However, that energy (God) has nothing to do with making us cry or wiping your tears; it has nothing to do with the sufferings that happen in this world; it has nothing to do with giving me a baby or not giving me a baby; it is not responsible for our happiness or sadness. In short, it is an energy which doesn’t operate keeping an individual’s goodness in mind. It doesn’t even have a mind (thoughts like humans !), it is just an energy which is dissipated evenly throughout this world!

Such magnificent energy cannot be seen but it can be felt. You can feel it when you immerse yourself in the beauty and magnificence of nature. You can feel it in the kindness which people show you and in the love you give others. You can feel it when you help others - and when they help you. You can feel it , if you keep your heart open, in the work you do; in the warmth and compassion in this world; in a baby (any baby - not only in a human baby!); in suffering and pain; in happiness and joy; in a beautiful smile; in the perfect functioning of our body ..........in everything, everything ! You can also feel that energy when it takes a destructive form - in a storm, in a tsunami, in an earthquake. The same energy which protects this world can destroy it too !

Why is it so; why do bad things happen ? Why there are natural disasters ? Why there are diseases, hatred, war, crime ? Why do humans inflict suffering on fellow humans ? Again , it has nothing to do with that energy’s intent. You can use that energy to help you; to make you a better person; to live in absolute love and peace; to increase your happiness; and to make this world a better place to live in. You can also use that energy to destroy your happiness; to destroy peace and love; to make yourself miserable; and to bring darkness into this world. That energy which pervades everything actually takes the form of the mind which uses it. The negative form of that energy is very powerful and dangerous too. But without its negative form , we will never be able to appreciate its positivity.

This is why it is said that God is everywhere, in all life forms. I don’t believe in a God who is ready to wipe my tears; I don't believe in a God who is waiting to punish when I do something wrong or reward me when I do something good; I don’t believe in a God who gives me what I desire; I don’t believe in a God who will come to help me when I am in pain ! All this cannot be performed by God (by that energy)– but humans can do it , with the help of that omnipotent, omnipresent energy. Every human takes the role of God many a time. I see God in the love I get, in the help I receive, in the warmth and compassion of many fellow beings, I see God in a beautiful smile, in a child’s happiness and I see God in myself too , many a time.

A Chinese student works with me; I help him in his work. Few days before he asked me when I am going to India; and I told him about IVF treatment and so on. I told him when everything goes OK , I will go very soon for having a FET. Few days later he came to me and said, “Manju, I want to tell you something”. I thought he wants to talk about his work. But he said “ Manju my mom and dad got married very late. I was born to my mom at 35 and my little brother was born when my mom was 40; so Manju, please do not worry, everything will happen in good time for you as well “. I saw that positive energy in him; the energy which wanted me to give me some courage and comfort. I had tears in my eye - and even now they roll down my cheeks when I write about his kindness. There is God in the feeling I am having now - absolute gratefulness !

Please do not think that sufferings are a punishment from God. God doesn’t punish or reward anyone. When we are happy and content we never think “Why me ?”. We accept it so naturally. Just like happiness and joy, pain and suffering are an essential part of life; and we need to accept them too. Every adverse moment helps us to grow spiritually; it teaches us to use the omnipotent energy in the proper way. When there is no pain there is no gain ! We should learn to use the positive form of God (love, empathy, compassion, contentment, gratitude , knowledge, wisdom etc) to keep us strong during difficult times. After all, the aim of life is to find its purpose and such an“enlightenment” comes only during arduous times ! Remember, only the people who go through tough times make this world a better place to live in, with their contributions to mankind ! Gandhi was determined to fight for freedom only after he was thrown out of the railway compartment by an arrogant Britisher ! He transmuted his anger into a positive desire to help his suffering countrymen ! God comes wherever there is pain and suffering. You get to know God better when you suffer.

Always keep in mind that our thinking has enormous power. That is why we unknowingly attract people whom we love and repel people whom we hate. We are what we think ! Prayer is nothing but concentrated thinking. Praying to God may not get you what you want , but it will help you to accept what you get . Thinking and praying is also an expression of that omnipotent energy – good thinking bring forth good deeds and hence a better life ! A better life doesn’t just mean physical comforts; a better life doesn’t always mean a baby; a better life doesn’t mean good health – a better life means a heart ready to accept things as they are, and a mind which is prepared to face the struggle and come out of it successfully !

So, instead of searching for God somewhere else; instead of believing that God will help us ; instead of believing that God will make this world a better place; if we try to use the energy which is within us; which is around us; which is everywhere–we can make this world a better and beautiful place to live in. God is the energy that keeps the world going. It is the energy that keeps us going too. Perhaps that’s the energy which gives me the courage and strength to fight infertility! There is no guarantee that I will end up with a baby in hand with the help of God; but I am sure I will be a better person at the end of this journey - and that is what matters the most !

I believe in God, but not as one thing, not as an old man in the sky. I believe that what people call God is something in all of us. I believe that what Jesus and Mohammed and Buddha and all the rest said was right. It's just that the translations have gone wrong.

-          John Lennon

The smoke and mirrors behind HLA matching and NK cells activity assay – the “reason” and “cure” for unexplained implantation failure!

I was recently reading a blog post from Dr.Sher.  He discusses immunological implantation dysfunction and claims that it is a common cause of repeated, “unexplained” implantation failure. He says that due to immunological dysfunction the embryo will be destroyed by “malfunctional” NK cells and hence implantation failure ensues. He assures patients that such ruthless “killing” of your precious embryos by “crazy” NK cells can be prevented by some specific therapies.  I was startled to see the way that article is written without any sound scientific basis – a nicely concocted story without any evidence!

The link for that article is here: http://haveababy.com/fertility-information/ivf-authority/unexplained-infertility-and-ivf-failure

Before reading it, you must understand the meaning of two different words which are used frequently in that article – HLA and NK cells. HLA stands for Human Leucocyte Antigen. These are molecules which are present on the surface of almost all the cells of our body and help to protect us against infections.  They are also known as the major histocompatibility complex (MHC) . When our cells are infected by harmful microorganisms, their antigens are loaded on to the cell’s HLA molecules. These HLA molecules then carry the viral or bacterial fragments to the cell’s surface. Once they come to the surface of the cell, they present the microbial fragments to our body’s immune cells called cytotoxic T cells.  Cytotoxic T cells constantly scrutinize our body for foreign antigens (microbial fragments or any other protein which are not normally present in our body). They can recognize these foreign microbial fragments only when they are presented to them by the body’s own  HLA molecules. Once the cytotoxic T cells recognize that a particular cell is infected by a microorganism , it kills the cell , thus protecting our body from harmful microbes. Consider this analogy :  a thief (microbe) enters your home (cell). You need to tell the policemen (cytotocxic T cells) who are on surveillance duty that a thief is in your home. When the thief is not watching, you send one of your servants ( the HLA molecule) with information on a piece of paper (microbial fragment) outside your home , so that the police men gets notified about the thief and can protect you. This is the exact scenario but with a minute difference-our body’s policemen (cytotoxic T cells) destroy (sacrifice) the infected cell to save the nearby healthy cells – they burn the house down to kill the thief !

In order to evade our intelligent immune system some microbes prevent the HLA molecules from carrying the microbial fragments to the surface of the cell. This is analogous to the thief who prevents the servant from going out of the house with the piece of information about the thief. In such circumstances , Natural Killer (NK) cells come to the rescue. When an NK cell recognizes that a particular cell doesn’t express enough MHC molecules on its surface as it should, it just destroys the cell by suspecting a possible invasion. Amazing , right ?

In short,  HLA molecules and NK cells are components of our immune system which help to protect us against microbial invasion and other insults.  If this is so, how they are connected to implantation failure?

Our immune cells attack not only cells that express microbial antigens but all cells that express non-self antigens (proteins that are not normally present in our body). This is why transplanted organs from a non-compatible donor are attacked by our immune system , and this is why they are rejected. A donor is said to be compatible if he/she carries identical HLA molecules as that of the recipient. If the donor’s organ express non-identical HLA molecules , then cytotoxic T cells recognize these foreign HLA molecules and destroy the cells of the donated organ.  This is why HLA is also called Major Histocompatibility (Histo =tissue) Complex (MHC).  It is only after checking the HLA compatibility between the donor and the recipient that organ donations are performed.

If this is the case, how does a fetus which carries half of its genes from its father (and hence different HLA molecules on its cells’ surface) survive the maternal immune system attack? In order to explain this , a hypothesis was proposed: that the uterus is an immunologically privileged site, and for a fetus to be not rejected by the maternal immune system , it has to carry different HLA antigens on its surface , and this helps the maternal immune system to develop tolerance to the fetus. This is exactly the opposite of the organ transplantations scenario , where the donor and recipient’s HLAs should match. As a result , when husband and wife have excessive similarity in their HLA molecules ( a high degree of HLA matching) and suffer from infertility , they are treated with a variety of immune therapies , to try to stop the maternal immune system from rejecting the fetus!

In his post , Dr. Sher writes:

“We diagnose alloimmune ID ( immunological dysfunction) by testing the male and female partners for the degree of sharing of genetic markers , known as of as DQa and HLA. A sufficient degree of matching clinches the diagnosis. We also test the embryo recipient for Nka in an attempt to measure the relative severity of the problem. This is because once the NK cells in the uterine lining are activated and the cytokine balance is disrupted, the situation is grave and will remain so (or worsen) unless the NKa cells are medically deactivated (down-regulated) at least 1 week in advance of the embryo(s) reaching the uterus”.

He obviously loves medical jargon , and talks about DQa and HLA, in order to impress patients ( and doctors !) as to how well-informed and erudite he is . DQa is just one sub-class of HLA. HLA is divided into class I and class II. Class I consists of HLA A, B, C and also HLA E, F, G. Class II consists of HLA DQ, DR and DB. Now what is the connection between HLA and NK ( natural killer) cells? How does HLA compatibility between the partners triggers NK cell activity which kills the embryo ?

 I have no clue – and neither does he, but he cloaks his ignorance in a lot of medical gobbledygook.

I need to explain here some scientifically proven facts about HLA expression in the human embryo,  and human NK cells:

Ø  The part of the human embryo which comes in contact with the maternal immune system is its trophoblast cells - more specifically , the external villus trophoblast (EVT).

Ø  These EVTs do not express class II HLA molecules (DR, DQ, DB) at all. They do not express highly antigenic class I HLA molecules (HLA A, HLA B). The EVT cells only express HLA G, E and C.

Ø  You must note that most of the HLA matching between you and your partner is done for HLA A, HLA B, HLA DQ.  Even if there is a high degree of matching between you and your partner for these molecules , this does not have any significance as regards your fertility, because of the simple fact that these molecules are not expressed at all in the cells of your embryos which come in contact with the maternal immune system!

Ø  It was believed (but never proved!) that if partners carry similar HLA molecules, the maternal immune system develop toxic T cells that might destroy the embryo . However, there is no proof that T cells attack human embryo.

The NK cell is another tall tale. I will enlist some facts about human NK cells below:

Ø  There are two types of NK cells: CD56 ^bright+ CD ¹⁶⁺ and CD56 ^dim+ CD¹⁶⁺. CD56 ^bright+ CD ¹⁶⁺ is the cell type predominantly present in the uterus.  This does not have significant cytotoxic activity.CD56 ^dim+ CD¹⁶⁺ is the NK cell type present in peripheral blood and has extensive cytotoxic activity.

Ø  The NK cell activity assay is mostly performed with the NK cells collected from the peripheral blood of infertile women . The NK cells present in peripheral blood do not reflect anything about the NK cell activity in the uterus. In other words, tests performed on peripheral blood NK cells cannot be used to draw conclusions about the uterus NK cells ! This testing is completely flawed.

Ø  NK cells activity assay is performed by measuring its ability to kill K562 cells. K562 cells are cancer cells , and they do not express the HLA molecules (HLA G, E and C.) that are expressed on the human embryo’s extravillous trophoblast. When K562 cells are scientifically manipulated to express HLA E or G, the  NK cells failed to kill the K562 cells!

Ø  When human trophoblast cells are grown in vitro (in laboratory environment) they do not express the same HLA molecules which they express in vivo (in the uterus). Also, even NK cells in vitro do not kill trophoblast cells!

The above scientifically proven facts I have painstakingly collected from the scientific literature emphasize only one thing – HLA compatibility between you and your partner and/or NK cell “malfunction” cannot kill your embryos It is wise to avoid tests used to “diagnose” them and therapies intended to “treat” and “cure” them. I sincerely wish that infertility specialists don’t make the vulnerable and desperate infertile patients’ condition even worse by making a mountain out of a mole hill. When a doctor meets a patient who suffers from unexplained infertility or repeated implantation failure, it is much more honest and humane to say ‘I do not know’ than to sell them false hope. 

Please read these articles for detailed info on this subject: 

http://myselfishgenes.blogspot.de/2013/03/does-hla-sharing-cause-miscarriage.html

http://myselfishgenes.blogspot.de/2014/07/tests-for-nk-cells-and-cures-for.html

‘Tests’ for NK cells and ‘cures’ for infertility and miscarriage – yet another way to exploit the desperate, vulnerable patient!

 

I get mails from patients saying that their NK cell number or NK cell activity is high and hence their doctor has asked  them to undergo  immunotherapy , using either IVIG infusion ; or intralipid therapy; Lymphocyte Immunotherapy (LIT) ; or tumour necrosis factor alpha blocking agents and steroids , or a combination of these, in order to 'treat' this abnormality.  They are advised that, by doing this, they can improve their chance of having a baby. Is this claim justified ? What are NK cells ? What are their functions in human body ? How are they connected to fertility ?  Do women who undergo this therapy improve their odds of having a baby  ? Does your doctor who asked you to undergo this test and therapy have  proof for its efficacy ? Is it wise to invest so much emotional, physical and financial energy in it ? There are so many unanswered questions and this article might help in answering them.

What are NK cells ?

Our body is attacked by bacteria and viruses constantly. Some cells in our body can become cancerous if errors occur in their DNA during cell division. In order to protect our body from microbes and from tumour causing cells, our body has developed a surveillance mechanism called the immune system  which consists of cells called white blood cells. These cells constantly scrutinize our body and remove the infected or abnormal cells.  Natural Killer (abbreviated as NK cells) cells are part of our immune system and are involved in early defense.  As the name suggests, their main function is to
kill ! They have the ability to remove the microbe infected cells and genetically abnormal cells which might cause cancer. They do this by secreting a protein called perforin which makes hole in the infected cells. Then a lethal dose of enzymes are used to destroy the deleterious cells. In short, these NK cells function to protect our body against infections and cancer.  The name natural 'killer' cells comes from the invitro assay used to identify them (identifying NK cells by its ability to kill target cells). Please do not imagine NK cells as something which is waiting in the uterus to devour your much loved embryos !

Where are natural killer cells present in our body ?

NK cells are mainly found in the blood stream.  They are also found in liver, skin, lungs, thymus and uterus. They are the predominant type of maternal immune cells found in the uterine mucosa during the formation of placenta. They are also present in the endometrium of non-pregnant woman and accumulate at large numbers in the implantation site. Uterine natural killer cells are present in high numbers in early gestation.

Are peripheral NK cells and uterine NK cells similar ?

No they are not ! Both these cells are functionally as well as phenotypically different. NK cells are identified by the receptor they are carrying. The receptor used to identify NK cells are called as CD 56. NK cells which express less CD 56 are called CD 56 dim cells. These kind of NK cells are predominant in peripheral blood and show extensive cytolytic (killing deleterious cells) activity. The NK cells present in uterine mucosa carry more CD 56 receptors on them and are called CD 56 bright cells. Their cytolytic potential is comparatively less than the CD 56 dim cells.

If so, is studying peripheral blood cells in order to assess the number and activity of uterine NK cells justified ?

 

Definitely not !  It is analogous to counting  the number of people and studying their behavior in Africa in an attempt to study the same in Asia. Both are humans but neither the place they inhabit nor their behaviour is similar !

What functions do NK cells have in uterus ?

The truth is, the function of NK cells in uterus is not yet clearly defined. The NK cells in the uterus are thought to produce several angiogenic factors and thereby help in regulating the menstraul cycle. There is evidence that they play a beneficial role by helping the proper invasion of placental trophoblast cells into uterine decidua by secreting essential cytokines and thus helping to establish a normal blood supply to the fetus and placenta throughout pregnancy. NK cells do not kill trophoplast cells !

How are natural killer cells linked to infertility and why it is not a scientifically valid observation ?

It was shown that women with recurrent miscarriage had increased amount of NK cells in their peripheral blood circulation or in their endometrium and/or their NK cells showed increased cytotoxic property . It was hypothesized that, in infertile women, overactive (malfunctional) uterine NK cells destroyed the trophoblast of the developing embryo preventing implantation or leading to miscarriage.  But this observation had many flaws to it :

1. The method used to measure the number of NK cells varied in different studies. The results can vary a lot , depending on the technique used to measure NK cells.

2. NK cells in the blood of normal healthy individual can vary from 5% to 29% depending on the sex of the individual, ethnicity, stress and age. Inspite of this, infertile women who had more than 12% NK cells in their circulation are defined as having “ abnormally elevated “ NK cells and are ‘treated’ in the studies conducted. Moreover peripheral blood NK cells are different from uterine NK cells. Studying peripheral blood NK cells cannot throw light on the number and function of uterine NK cells.

3. When NK cells are collected from the uterus, they must be isolated from the same depth in all women because their density varies widely along the uterine mucosa. If not, the results can vary widely.

4. Well designed, sufficiently powered clinical trials with appropriate population selection and using the same NK cell testing methodology are lacking.

5. The cytolytic potential of NK cells are tested using cancer cells (K562 cells). It was shown that NK cells can kill cancer cells and not normal human trophoblastic cells invitro.

So there is no scientific rationale for these tests !

Why is it unlikely that uterine NK cells will attack the embryo ?

Progesterone is considered as one of nature's best immunosuppresant. It was shown that progesterone at the concentration present at the materno-fetal interface inhibits NK cell activity. The placenta also secretes several factors which act as immunosuppressants. Even the human embryo has been shown to produce certain chemicals which stimulate the maternal system to produce Early Pregnancy Factor ( EPF) which acts as an immunosuppressant too. Trophoblast cells also express certain receptors which prevent NK cells from attacking them. Hence it is highly unlikely that uterine NK cells attack your embryo in vivo.

What is the NK cell activity assay and how useful is this assay ?

In order to find out whether NK cells show abnormal cytotoxic activity, the NK cells (mostly from peripheral blood) are removed from our body's natural environment where progesterone, placental factors and other natural immunosuppressants are present in plenty. Then an in vitro assay is carried out using k562 cells as a target . k562 is a myelogenous leukemia cell line. The percentage of k562 cells lysed or killed by NK cells gives an idea about how active your NK cells are. Using the result of this NK cell cytotoxicity assay , some doctors decide whether a particular woman should undergo immune therapy or not.

There are certain important points to be noted here: K562 are cancerous cells and such cancerous cells are readily recognized by healthy NK cells. It is the normal function of NK cells to kill cancer causing cells. The use of the K562 lysis assay to determine whether your NK cells have the capability to attack your embryo is a very crude, vague and controversial method. Even if a particular woman’s NK cells are active against cancer cells (K562) , this doesn’t necessarily mean that her cells will behave the same way against her embryo's trophoblast cells. So why don’t labs test NK cells activity against trophoblast cells in vitro ? This is because NK cells in such invitro assays do not kill human trophoblast cells !

It must be kept in mind that the in vitro environment is extremely different from in vivo conditions. Uterus environment (in vivo environment) is extremely rich in natural immunosuppressant (like progesterone) and when a competent embryo enters the uterus , it signals the maternal system to secrete immunosuppressants. How can an assay conducted without simulating a natural in vivo environment be used to predict NK cell cytotoxicity against human embryos ? How could one correlate activity against a cancer cell line with activity against human trophoblast cells? How many studies were done to determine the cut-off value for determining NK cell cytotoxicity?  Very few studies have been done , and most of them were published in low-ranking journals , which means they lack enough power !

What are the ‘therapies’ available to ‘treat’ malfunctional NK cells and how useful they are?

It is believed that by using intravenous immunoglobulins , intralipids, lymphocyte immunotherapy or by using tumour necrosis factor - alpha blocking agents and steroids the ‘raised’ or ‘malfunctional’ NK cells can be ‘ treated’ by dampening the immune response. Such therapies have no scientific validity and can pose significant health risks to the patients. Intravenous immunoglobulin is a pooled blood product and can result in anaphylactic response, fever, flushing, nausea, and headache and pose an increased risk for the transmission of infectious diseases. Intralipid therapy and IVIG, can dampen the immune response and make one prone to infectious diseases.

If this is true; why do many REs offer NK cell testing and therapy?

There are many reasons for this :

1.            Money – many doctors are not ashamed to make money out of your desperation and vulnerability.

2.            Doctors are humans too and are prone to cognitive biases. They conveniently forget the 9 patients who failed IVF after undergoing such scientifically invalid therapy , but they remember that one patient who had 8 failed IVFs and who achieved success after being treated for malfunctional NK cells! They remember their sensational success stories and crave credit for it. As a result many become vocal advocates for pseudo science!  Many REs do not maintain proper records of the treatment they offer and hence have no chance to make a valid statistical analysis of the treatment they offer. They value their personal experience much more than the knowledge accumulated by several scientists after careful research over a period of time.  As a result they forget that evidence based medicine is the golden standard of good medical practice.

3.            Patients, out of desperation, believe all the sensational media news which is based on anecdotal evidence (for example read this: http://www.dailymail.co.uk/femail/article-2361112/Mayonnaise-miracle-babies-150-IVF-attempts-controversial-egg-yolk-oil-jabs-theyre-mums-last.html - very impressive, beautiful pictures, right). Extensive coverage of anecdotal success stories by the media creates a bandwagon effect. Because of their lack of scientific knowledge , patients are unable separate the wheat from the chaff.  As a result, they believe that by using the therapy they read about on a website or in an article in the newspaper ( which may actually just be a press release) they can get their much desired baby. This kind of blind expectation of patients in the efficacy of new, unproven treatments pushes many REs to offer them these treatment, irrespective of their scientific validity. Patient pressure forces doctors to do stuff they may not believe I because they are scared they might lose their patient to some other doctor who offers them !

5.            Many doctors find it difficult to understand the rationale behind these tests. They get duped by the diagnostic and pharmaceutical companies who promote these tests and therapies.

How do you explain all the success stories of women who have failed 5 IVF cycles and then got pregnant after treating their high NK cell activity?

Let me ask you another question: how will you explain all the failure stories , even after the high NK cell activity was “treated” ? Just because your friend or a blogger says that they achieved success after taking treatment for their high NK cell activity  doesn’t mean that the observation is scientifically valid . Anecdotes are not proof of efficacy! We humans are social storytelling animals and we learn by the experience of others  -  this is how we are hardwired. That is why our mind gives undue importance to such stories , instead of looking for valid scientific proof. Another important thing we must realize is that patients who benefit from a particular treatment are more likely to boast about it than the patients who didn’t get success, who are resigned to their fate. So for every five women who succeed, there might be another fifty who failed , but you do not get a chance to know about them. This is why anecdotal evidence is not reliable. In order to test the effectiveness of a particular treatment, a randomized clinical trial with sufficient power must be conducted. At present , there are not enough RCTs to prove that NK cell testing and therapy really benefits infertile patients.

My RE says experience is as important as knowledge and assures that he has seen it work in his practice!

Just because your RE has seen it work in his practice doesn’t mean it really works ! Again your RE is telling you a story , and this can only be considered as his individual view about the treatment – just more anecdotal “ evidence” . As I have already mentioned, your RE is a human too with cognitive biases , and hence his judgments can be flawed too.

I read a RE’s blog where he defends his approach of providing treatment based on anecdotal evidence , by giving an elephant trail adage. He quotes this:

Elephants in Africa migrate hundreds of miles each year to reach their ancestral feeding grounds. The journey requires that they cross mountains, ravines, jungles, turbulent rivers and unforgiving desert terrains. They always follow the same path, one that over time has proven to be the least challenging and the most productive.  Indeed, in the beginning they must have made many costly directional and topographic errors, but over time they eventually defined the best way to reach their destination safely. This is how I learn too – from my experience, over years of trial and error.

Humans are rational animals! They need not have to subject themselves to risks which animals have to go through. As humans , we can form a hypothesis and test its validity by conducting proper research - we don’t have to believe anecdotal evidence alone.  The  RE equates his patients to experimental rats , and claims that everyone learns by mistakes , and that errors do happen. If someone wants to experiment on their patients, it has to be done with informed consent , and not by exploiting their vulnerability. If an experimental procedure is tried on you, why should you pay them a huge fee for the treatment? Is it even ethical? He claims that he has no scientific evidence to prove intralipid therapy is effective but he knows that it works by his experience! If doctors can judge correctly by their experience alone, then there is no need for pharmaceutical companies to spend millions on performing  RCTs and extensive research !

What should I do now ? Why shouldn’t I take a chance and try the therapy (I am desperate to have a baby!) Who know, it might work for me!

After hearing all the rational arguments , if your heart still says that you must give it a try, then you can go ahead.  But please understand the following :

Try to see whether you can enroll yourself in clinical trials which are conducted to assess the therapy’s validity. If not , ask your RE whether he could provide the treatment free of charge, since it is not a proven treatment and is based on anecdotal evidence. This way, you get the treatment and he gains knowledge – a ‘win-win situation’ (I bet no RE will agree to this unless and until they themselves are involved in conducting a clinical trial for the same)

Please educate yourself about the risks involved in such treatments and be aware of the emotional risks such treatments carry! There is also the opportunity cost to consider.   By barking up the wrong tree ,you may waste a lot of time and tons of money.

If you are a woman of advanced maternal age , please understand that it is your oocyte competence which is the most important factor in influencing implantation – not your NK cell activity ! Please do not subject yourself to such unproven therapies – they are very unlikely to help !

Take home messages

1.            NK cells are not proven to kill your embryo by attacking the trophoblast. They do not kill trophoblast even in the invitro assay used to assess its activity !

2.            The tests available for measuring NK cell number and assaying its activity are highly variable and do not yield consistent results.

3.            Your NK cell number in peripheral blood can vary a lot,  depending on stress, age, ethnicity etc

4.            Peripheral blood NK cells are very different than that of uterine ( uNK) NK  cells; studying them will not shed light on uNK cells.

5.            The therapies offered for NK cell malfunction have many side-effects, please be well-informed about these.

6.            Your RE’s personal experience and observation (plural of anecdote is not data !) cannot replace good clinical research data.

7.            In your quest for a baby , do not get desperate and allow the idiosyncratic personal practices of some physicians to exploit you !

What to do if you and your spouse disagree about treatment options !

When tackling infertility, you will be flooded with a variety of treatment options. The field of ART is vast, and depending on the nature of your problem , the treatment choices can vary all the way from from simple ovulation induction with clomiphene to IVF and surrogacy. 

With the advances in the field of ART, there is a solution for almost any kind of infertility problem you face, but being open to different treatment options is not easy for everybody.  Not everyone is comfortable in subjecting themselves or their spouse to treatments which are not agreeable to them physically or mentally. Financial conditions, social, cultural and religious limitations and fear of medical procedures all play a major role in deciding whether to pursue a particular infertility treatment or not.

Infertility is more of an emotional ailment than a physical one ! The unquenchable desire for a baby combined with social and peer pressure are the most important driving forces which compel couples to undergo different infertility treatments.  As long as both partners are on the same page regarding pursuing a particular fertility treatment option, everything is well and fine. But what happens when they do not see eye to eye about their options ? What happens when one of the partner wants to put an end to the infertility treatment and move on with life, while the other person could not imagine a life without a baby ?

Infertility becomes easier to handle when there is understanding between the partners. When one of the partners is ready to move heaven and earth in order to realize their dream of having a baby, and the other cannot understand this overwhelming craving to procreate, then the relationship gets strained. The stress of infertility combined with a strained relationship can play havoc !  There are couples who decide to end their marital relationship because unable to bear the brunt of the assisted baby-making journey !

When you and your spouse do not agree about treatment options what can be done ? How can you find a balance so that your relationship goes on smoothly ? Should one person sacrifice their desire for the sake of the other ?

But before going into what can be done, let us see where the problem arises. Below are the some of the common reasons why a spouse might not be ready to undergo fertility treatment or might be uncomfortable pursuing a particular treatment option :

Denial 

This happens during the initial stage of infertility diagnosis. The natural reaction from many would be “ I am healthy and normal, I will not undergo any treatment – we will have our baby without any treatment !” Many will want to bury their head in sand and try to pretend that everything is well and good.  A man normally equates his fertility to virility. He panics that because of the diagnosis of infertility, his manliness is being questioned ! Likewise, a woman also thinks that her feminity is in suspect if she cannot conceive ! This mental make-up makes the diagnosis of infertility impossible to accept , and as a result some people might vehemently refuse to go through any kind of infertility treatment.

Fear of invasive procedures and injections

Infertility treatments demand a lot of blood tests, use of injectable medicines and sometimes invasive procedures for diagnosis and treatment. As a result people who are phobic about injections and surgeries become jittery to carry on with infertility treatment.

Concern about the effect of infertility treatment on prospective children

There are lots of misconception surrounding infertility treatment and its effect on children born out of such treatments. This might create fear in the mind of your partner and he or she might consider such fear as a valid reason for avoiding infertility treatments.

Worry about the enormous cost associated with infertility treatment

In most parts of the world , infertility treatments are very costly , and can be a very big economic burden for the family. It can lead to emptying of your bank balance and can leave you financially insecure. This can create enormous mental pressure for the bread-winner of the family who would naturally want refuse to undergo costly treatments where the outcome is always uncertain.

Social, cultural and religious limitations

Third party reproductive assistance such as using donor sperms, donor eggs, donor embryos and surrogacy is banned in certain religious groups. Social and cultural restrictions will also play a major role in deciding whether a couple is willing to undergo a particular fertility treatment or not.

Fed up of infertility treatments

Fertility treatments consume lots of time as well as physical and emotional energy.  There is also a lot of uncertainty inherent in such treatments – there is no guarantee that you will end up pregnant after spending so much of your time, money and energy. The stress of infertility treatment can make life lacklustre. This can create an aversion towards infertility treatments !

So when a situation arises where you and your spouse do not agree about infertility treatment options, how can you deal with it ? How to constructively resolve your disagreement ?

When disagreement arises in a marital relationship there are four possible ways to solve it :

1. End the disagreement by agreeing with the other person’s choice
2. Coming to a mutually acceptable solution
3. Living with the difference
4. Separating and ending the relationship

When one of the partners does not want to pursue IVF and the other wants to leave no stone unturned in order to have a baby, but decides to end the conflict by agreeing to the option of not undergoing IVF (either out of love or out of coercion !) , it appears that the disagreement is solved and all is well. But, this kind of conflict solving usually causes lots of bitterness and may ultimately lead to the loss of intimacy ! Even if a partner sacrifices his/her wish out of love, it will never be a creative experience because “baby lust” is much stronger than anyone could imagine. The urge to have a baby is very hard to sacrifice and the partner who decided to “sacrifice” will always regret his/her decision , whenever they see a “cute little family”! These kind of “solutions” can lead to your marital relationship breaking at some point or the other !

So, how can you come to a mutually acceptable solution ?

 

Have an open mind

Most problems in life become difficult to tackle if we close our mind to new information and ideas. Having a closed mind also makes it impossible for you to understand and appreciate the goodness in your partner’s point of view. It also becomes tiresome and frustrating for your partner to have a rational argument with you , because you are incapable of seeing things from their perspective .  When you adamantly hold on to your views , there will be no possibility of a fair argument which involves give and take. For example, if you believe that taking infertility treatment increases your risk of having children with mental and physical disabilities, this is a very valid concern. But, having an open mind will help you to judge the validity of your belief with the help of scientific information , and by talking to people who are better informed than you are ! Closed-mindedness when facing infertility may curtail your treatment options and hence your opportunity to have a baby.  It might also leave your partner wounded forever !

“Your assumptions are your windows on the world. Scrub them off every once in a while, or the light won't come in.”  - Issac Asimov

Have a heart to heart talk!

Try to be expressive and talk openly about what is in your mind. It is very difficult for your partner to read your mind if you are not ready for healthy communication. The worst enemy to a good communication is emotional outbursts (crying, name-calling, slamming doors, threatening) ! Disagreement regarding infertility treatment is a highly emotional topic, so make sure you find a good time to talk about it. Do not raise the issue when your partner is tired, upset or irritated. Explain clearly - why you are not ready to agree about a particular treatment option ;  what your fears and concerns are ; how avoiding or pursuing a particular treatment option will be beneficial for you both (not only for you !). Try to analyse the pros and cons of your decision rationally. Remember, communication is a two way street. It is very important to allow your partner to talk and try to be heedful ! Listen to  your partner’s concern and respect their fears and insecurity. Do not interfere when your partner is talking ; do not discourage them when they express their point of view and never be sarcastic ! Never think that the problem is with the other person and you are always right !  I would like my partner to sit close to me, hold my hand, give me a few hugs so that I feel the warmth and kindness. Such intimate, non-sexual contact can make the communication much easier by adding lubrication and hence can make it very honest too ! Mutually acceptable solutions can never be reached without proper communication and deep understanding of the conflict.  Once you understand where the conflict lies , it is easier to reach a solution.

“Seek first to understand, then to be understood.”   -        Stephen R. Covey

Respect each other’s differences !

If you allow yourself to see other person’s point of view, you will naturally respect their fears and concerns.  Their concern may appear very silly and insignificant for you, but you have to understand that it really bothers your partner ! For example, the fear of injection or surgery can be a powerful deterring force for undergoing particular treatments. Instead of laughing at it and ignoring it, try to ease their fears by showing them how little the injection needles are ! You can also show them educational videos, where your partner could watch how the injections are administered or how a particular surgery is performed. This will help in reducing their fears and concerns about the treatment ! When your partner is worried about the financial aspect of a particular treatment, please respect this -remember, that your financial security is as important as having a baby ! Do not get emotional and blame that your partner for being money-minded ! Respecting each other’s concern and giving proper importance to their thought process plays a very important role in amicably solving the disagreement.

To be one, to be united is a great thing. But to respect the right to be different is maybe even greater. - Author Unknown

Be well informed !

It is very important to be well-informed about your treatment options. Learn all you can ! This will help in thinking clearly and agree or disagree with your partner in a rational manner. Knowing the pros and cons of different treatment options will also aid in solving the disagreement that arise between you and your partner in a wise manner, so that you can reach a consensus which benefits both !

Find a good counsellor

If all your attempts in arriving at a mutually acceptable solution fail, it is wise to turn to a counsellor who is knowledgeable about infertility and the treatment options that are available.  A counsellor can give a rational and impartial view of the situation which can help both of you to see the truth and resolve the conflict amicably.

Going through infertility is an excellent time to understand your partner and build a strong, everlasting relationship. Relationships actually get stronger during a time of crisis provided you have the maturity to make use of your difficult marital times constructively ! Disagreements between couples are very common when grappling with infertility, but make sure you disagree in an agreeable way. It is important to “fight fairly” and find a way which will lead to your most important goal – a baby ! Please do not  “sacrifice” your desires for each other’s sake – not all sacrifices create a happy ending. Make sure that the decision you take about the treatment options will not leave your partner hurt and wounded for life ! In your pursuit for having a baby do not lose the essential ingredients in your relationship  - Mutual LOVE, RESPECT AND ADMIRATION !