We signed the surrogacy contract and our time in MADURAI

I am a South Indian, Tamilian and my native is Madurai.  I am sure you would have captured my haughtiness in the previous line. Who wouldn’t be proud of their roots? The day we left for Madurai from Rajender’s place I was so happy. I was going to see my mom - is there anything else needed to be happy ? My mom was eagerly waiting for me too. She was heartbroken about whatever happened.  She went from temple to temple all those 5 months of my pregnancy. She lived with the thought of her grandchildren whom she never saw. I know she carried them in her heart and to let go of such a beautiful dream at the age of 60 is painful, very painful. 

Madurai is a very small, beautiful city. It is famous for the temples situated there (every street has a small temple!). The most famous temple is called Madurai Meenakshi Amman temple and the above picture shows one of the temple’s towers, magnificent isn’t it? Every time I go there the temple’s architecture never ceases to amaze me. I love roaming around the streets situated close to the temple rather than going inside. Oh, I simply love Madurai for its liveliness. 

We reached Madurai at early morning 4:30. We took an auto from the railway station to our home. The auto driver was a young lad and was chatting happily. The moment we were to enter our village border, the auto driver turned to me and asked, are you wearing slippers. I was not sure whether I heard it right, his question didn’t make any sense to me. So I asked him to repeat his question. He again asked, do you have slippers in your feet? I was so confused; what kind of question is this! I reluctantly said yes and he replied, I will tell you the reason for this question later. When we were nearing our home he said, sister, there is a graveyard at that turning. If you do not wear something in your feet, the spirits (ghosts) which live there will catch hold of you and come along with you. I always make sure I wear something on my feet when I cross that area. A big smile appeared on my face and I knew at that moment that I was In Madurai, a city with gullible, friendly people. I looked at Rajender and he was smiling at me, no actually grinning at me and I know the meaning of it! He just said with his eyes, is there a bigger ghost than you, will anything even dare to come near you!

My mom was waiting for us. At 5’o clock in the morning she has made hot, hot idlies, chutney and sambhar. Another name for mother is love; no one can take her place. In my in-law’s place I have nothing to complain but I was never as happy and comfortable as I am with my mom. In my place I am the queen, I can get up whenever I want, I can eat whatever I like, I can sleep whenever I want and I can be myself. In my in-law’s place I have to behave well and it is very, very hard to be someone else all the time. At 5 AM, I ate the breakfast which I love most and slept happily until 10 only to wake up and ask, ‘what’s for lunch amma!’ 

When I said to my mom that we are going to take the surrogacy route she was very happy. She said, ‘Manju how long will you suffer like this. How many injections, how many injuries to your body and mind! I think surrogacy is a better option’.  She wanted her daughter not to suffer anymore. My sister is a gynecologist, when I asked her opinion, she said, do whatever appears right for you. With such a fear about carrying a pregnancy, it is not wise to try to get pregnant again. I support you both completely regarding your decision to opt for surrogacy. 

My dad is no more, but if he is alive he would have guided me in a very wise manner. When I have to take important decisions in life I miss him dearly.  He was a Judge, a very honest Judge. In every nook and corner of my home I feel my dad’s presence.  If someone says that I am courageous or appreciate my perseverance, I owe all such praises to my dad. He is the one who brought me up with all these qualities. I take after my dad not physically but mentally. I strongly believe that the good life me and my sister live now is just because of my dad, because of his honesty and good deeds. 

I mailed Dr. Malpani regarding our decision to opt for surrogacy.  Between the times I lost my twins and the decision regarding surrogacy, I might have asked innumerous questions to my Dr! He was very, very patient with me. He understood my fears and insecurities. He did his best to help me. He would say,’ Manju, we will do our best to help you have a baby’, and those words mean a lot to me. He never, ever said an uncompassionate word, nothing which would hurt me even unintentionally. He took the role of my counselor too! I owe my ability to live normally and happily even after whatever I went through to him, perhaps only to him!

I was not patient; I wanted everything to happen quickly. Dr.Malpani told me that they have to search for a surrogate first and then have to prepare the agreement. I was wondering how long it might take. But I received the surrogacy contract in my hand within a few weeks. I was reading it page by page and for the first time I got to see Rita, my surrogate! There was a passport size photo of her and her husband. I kept on looking at the photo. She appeared shy, calm and humble. I knew that she has two children and she is a first time surrogate.  I had so many questions in my mind : Why she opted to be a surrogate? What is her husband doing? How old are her children? Does her husband treat her well? Where does she live, in a slum? Will she take care of my baby well? I am going to take a great leap of faith and trust her, am I doing everything right?  In my quest for a baby, am I putting my baby itself at risk? So many questions haunted me and I asked Dr. Malpani everything. All he said was, Manju you must come and visit Rita, and then many of your fears will vanish. 

I didn’t sign the contract at that time. The reason is, my name is misspelled in the document. So I sent it back to the lawyer. In between the time I sent the contract back and received a new contract, we went for a pilgrimage, yes a pilgrimage in search of baby luck!

Did I meet Rita in person?  Where was the pilgrimage to? A lot more to share! :)

A big YES to surrogacy!

In Rajender’s village time just rolls on lazily. His parents are farmers. All the necessary produce comes from his farm. There won’t be any need to buy things from outside. If someone sacrifices goat or hen to the nearby Goddess, there will be meat for lunch. If someone catches fish in nearby pond they send us fish too. There won’t be electricity for 12h. You might wonder how it is possible to live there. It is not only possible but the atmosphere is very relaxing too. When all the ladies finish cooking, they meet in someone’s home. There will be lots of chatter, laughter and gossiping going on. They speak in a typical dialect which is very difficult for me to understand (Rajender’s mother tongue and mine are different yet we speak each other’s language). When they need to gossip their voice gets even milder and how hard I try, I wouldn’t understand a thing, which is of course very frustrating for me! If I am there they would love to ask about Germany, our lifestyle there and they will also have umpteen reasons to make fun of me. In short, there will be no source of tension. If I lie down in the afternoon after eating the very tasty, sumptuous lunch prepared by my mother-in-law I get such a sound sleep, a sleep which I could never have in the most comfortable Germany!

Ok, let me come to the main story! I was wondering how to start the topic about surrogacy to my in-laws. Although I am happy there, my mind was restless most of the time. I am a kind of person who wants to decide ‘what’s next’ as quick as possible. But Rajender seemed to be cool and relaxed. I am so happy to see him like that after months of struggle. But when I felt so helpless, all my anger was directed towards him.  One day I, Rajender and my mother-in-law were at home. I started to pester Rajender to talk about surrogacy to his mom. An argument broke out and I was visibly restless. My mother-in-law saw this, couldn’t understand what is going on and asked Rajender what the problem is.  I burst into tears. She was very afraid to see the way I was crying. She asked me what happened. Rajender understanding his mom’s fear and in order to calm her down told her that, Manju no more wants to carry a baby. My mother-in-law said nothing and looked at Rajender for further words. Rajender slowly said, she wants the baby to be carried by another woman. My mother-in-law’s face had a very confused look. I was wondering what she was thinking within herself, is she thinking of a “natural surrogacy”- OMG :) ! I was much angrier on Rajender for breaking the news without proper explanation. My mother-in-law’s face became normal after some time, she just said that we will think of all that later, you are here to take rest. Why do you want to spoil this time, be calm and happy. This is what all she said and the situation became normal again. This is how Rajender and his parents are. Nobody gets tensed, restless or excited for anything. There is a kind of understanding between them. There won’t be unnecessary talks or arguments and most importantly I have never seen Rajender raise his voice for anything against his parents and it is the same with his parents too! His parents wisdom about life is unbelievable and there is always a decency which I have never seen in much educated households !

Evening came. My father-in-law came from the farm. Everyone was sitting in the hall. I was looking at Rajender pathetically. My eyes were pleading him to tell the matter to my father-in-law. Rajender slowly started the topic. He said that Manju is very afraid to carry another pregnancy. She says that if another miscarriage happens, she won’t survive that. Her uterus was weak too. So we decided that we will have our baby grow in another woman’s womb. I was so afraid what my father-in-law would say. Does he really understand what it means and how it is done? I respect my father-in-law so much. He is such a calm and composed person, who is very good at soul. His words do mean a lot to me. When I lost my twins and was having unnatural fears, he calmed them by saying, ‘never worry about how people will treat you when you come here. No one will hurt you in any way. You are like our daughter; please remember that all the time’. I am forever grateful for all those kind words. Rajender, started to explain what surrogacy is. He is struggling for words; I could understand that he was a bit uncomfortable and shy too. My father-in-law talked for the first time. He said, I know about it, they will keep the embryo in another woman’s uterus, am I right? I have read it in newspapers all the time. Recently an actor (Mr.Sharukh Khan) had his son using surrogacy, right? I can’t explain the relief I felt in words! I thanked all the Khans and actors who had their baby through surrogacy. I thanked all the media coverage on it. Then the talk immediately moved to how they will select my surrogate, who will take care of her during the entire pregnancy etc (all the scans, medical tests, delivery ). My father-in-law was at ease but my mother-in-law was worried about who will take care of our baby ( fetus! ). My father-in-law said, their doctor will take care of all that, why do you worry unnecessarily? Rajender’s face showed a great relief, afterall he escaped from my constant pestering, wrath and crying spells. He smiled at me with a warm look. And that is how we stepped into the world of surrogacy! Surrogacy with whom - ofcourse with Dr. Malpani!

There are two things which put me at ease about surrogacy with Dr. Malpani:

The trust I have on my Dr!

In his surrogacy program, surrogates are allowed to live their normal life without being housed in special places like cattles and treated as just baby-making machines!

More to come! :)

India and the decision regarding surrogacy!

We landed in India on December 31^st, 2013. We slept so well that night in the comfort of our homeland and relatives. We have accumulated a huge sleep debt. We lost our little ones on November 5^th, 2013 or I would rather prefer to say, our twins were born on November 5^th, 2013. From that day on wards our life changed completely.  We rarely had a good sleep after that. The last few days in Germany were too hectic too - getting relieved from work; vacating our home; selling our car; saying bye to friends…there was so much to do! I was so proud of Rajender. He stood strong the entire time. After so many years of hesitation and planning (it is hard to find money amidst infertility treatment expenses!) he brought his car. He enjoyed driving it so much. He took care of his car like a child. On the day when he sold it and returned home, I asked him whether it hurts. He replied, ‘nothing is more painful than losing my children’. I wanted to tell you all this because I realized a very naked truth – life can change upside down in a moment. Nothing is permanent, nothing! Life is too unpredictable. I think, if we realize this, we will learn to live a better life, enjoying every moment. Until 2013 we both were working, we had not one but two children (a boy and a girl) who were the result of many years of emotionally, financially and physically draining infertility treatment; we were planning to move into a bigger home, even gave advance for it and suddenly we were ripped-off everything.  You can call it 'bad karma' or simply 'bad luck' but I would prefer to call it 'LIFE' - there is nothing good or bad in it. I believe that life has a beginning and an end and everything in between is just a continuum. There are no happy endings or sad endings; good or bad in whatever happens - there is only 'LIFE'!

We woke up in India on January 1^st, 2014. The first thought I had when I opened my eyes was: we no more have a nest of our own! To be very honest, it was very scary, but only for a moment. When I came out and stood in the balcony, bright,warm sun light hit my face (nothing is as healing as SUN). The smell of Indian breakfast hit my nostrils. I could see my sister-in-law with a warm smile. All my insecurity vanished immediately. I happily got ready to enjoy my time in India.

We went to Rajender’s place first. His native is a village, a very remote village in India. People who live there are so innocent, warm and friendly. Everyday so many women came to visit us. They cried hearing what happened, said so many comforting words, they told me stories of  many women who had children after going through many miscarriages. I no more felt alone. Everyone told us how our mother and father in-law suffered during the time when we lost our twins. They said, your mother-in-law cried for days together, almost all the time. I looked at my mother-in-law; she looked at me with utmost warmth and I thanked God for keeping me amongst such affectionate people. One of Rajender’s relative, a very old woman, came to see us. She didn’t have children. She lost her eyesight recently too. She sat near me with tears in her eyes. Her hands were trying to feel mine. She pulled me close to her and gave a warm kiss. I felt safe, very safe after many months! I felt appreciated for the suffering I underwent.

I waited patiently for a week, yes one long week for Rajender’s words regarding surrogacy. Then I asked him, when we can start the process. He said, first we have to tell my parents. I was angry, felt somehow humiliated. Why would you want to tell them? Until now we never explained them anything and why now! My most important fear was, why to make them go through the roller coaster which we are going through, aren’t they too naive to understand all that? My in-laws would never interfere in our life; eventhough they are not so educated and live in a remote village they clearly know their limits. Rajender looked at me angrily and asked, are you out of your senses, will you just bring a baby out of nowhere and tell them that it is ours! True, I didn’t even think about it. He said, look at them: there were lots of village women, his relatives, who were sitting and chatting with my mother-in-law. Rajender said, only when we entered this infertility journey I came to know what surrogacy means!  How to explain my parents and relatives who are scientifically ignorant, what surrogacy is ! If  you can, try and do it! Rajender’s face was full of confusion. I was taken aback.

How did we make Rajender’s parents understand what surrogacy is, was it that difficult ? Keep reading :)

I will never ever carry a baby

I need a surrogate. This is the only thought running in my mind after I lost my children. It was dark and cold in Germany. I was longing for the warmth of a little one.  All my post-pregnancy hormonal fluctuations made coping even more difficult. I was in tears and full of fear.  All I needed is a baby as quick as possible!

Immediately after losing our twins we decided to go back to India. I had my own fears about shifting to India but my hubby (Rajender) was very adamant. Rajender’s coping mechanism was very different than that of mine. He needed to keep quiet and be within himself. For me, I needed to talk all my fears to someone; I needed words, comforting words. Although few thoughtful friends dropped in some time, everyone had to look after their life too. I am very thankful for the ones who came with their little ones. Those were the times of solace for both of us, a little oasis in the horrible desert we were in. There are friends who never came. I understood them too. Many are even afraid to face us, didn’t know what to tell us. But the truth is, when someone is going through difficult time in their life, the best thing you can do is to spend some time with them. Your time and comforting words are the best gift you can give someone during such times.

As time went on, I saw the truth in Rajender’s words; staying back in Germany will only make the situation worse. We needed the warmth of sun. We needed our parents so badly. In India, the situation for our parents was not any better. They wanted to see us, wanted to keep us within their wings.  I would say, Rajender took the most appropriate decision and I followed him.

The only idea that was brewing in my mind is to use a surrogate. Not only that, I was so greedy and unreasonable too. You will understand that when I explain what I actually wanted. I was constantly pestering Rajender for surrogacy. I told him, if I get pregnant again and if I have to lose the baby, I will no more survive. I never intended these words as blackmail; it’s the way I felt. He tried a lot to make me see the situation in a better way. He asked me, in your quest for your baby, will you exploit another woman. I told him, I am not exploiting anyone, I am going to give money which they need and I will have my little one. He looked at me eye to eye and asked, ‘what is the guarantee that you will have a baby with surrogate?  What will we do if the surrogate loses her life in the process, although it is unlikely, there is no assurance that it will not happen.  If something like that happens how will we be able live with such a huge guilt?’ I was shocked. All I can do is to cry. But this didn’t deter my spirit of pursuing surrogacy. I saw so many blogs where surrogacy gave the couples their much needed baby. I was so adamant and crying every day. I had only one more soul who could help me decide – my Dr! I asked Dr. Malpani’s opinion. All he said was to wait until the grieving period ends. He said, ‘whatever you decide now may not be correct. I never tell anyone what to do.  It is your life and only you have to decide’. I had no mood to listen to his wise words; all I needed was a path in front of my eye, the path to a baby so that I can remain peaceful. At last seeing my pain and agony, Rajender told me: ‘Manju, you are the one who has to carry the baby. If I can carry the baby I would do so happily. I will leave the decision in your hands. Whatever you decide I will support you. If you think surrogacy is the best option for you let us pursue that’. I should have been happy with those words, right? But unfortunately not!  I wanted from Rajender one more thing too; I told him that I will never ever do ovarian stimulation again. I have no strength to go through that roller coaster. If the remaining two frozen embies do not stick to surrogate’s womb then we will opt for donor eggs. He was shocked beyond belief. He said, why you think so far. First let us transfer the two embies, and then let us decide. But, the adamant, greedy person within me was not satisfied. Rajender didn’t yield to my unreasonable demand. He told me clearly that, if those two embies do not stick, we will adopt. I am not against adoption; all I wanted is a baby to spend my time with when my maternal instincts are high. But I thought, if not my genes, why not I have at least Rajender’s genes in my child – I know how animal instinct rules us but I perceived the power of it!

                            ....... A new beginning, will update whenever possible :)

How do you deal with a friend's pregnancy ?

Recently I received a mail from one of my blog reader (I would proudly call her my friend now), she asked me, how I deal with a friend's pregnancy! My simple answer would be, by sharing her happiness. I can't imagine myself crying and fretting over someone's pregnancy. For me, it equals to insulting my soul, not respecting or loving myself. This question is a great chance to put in words what I think and how I deal with the pregnancy of people around me. Thanks V !

Dear V,

You write so beautifully. It would be nice if you write a blog, it will help many.

Yes, it was a very hard time. Losing our twins have changed the way we view life. Seeing the death of our most precious children and not able to do anything about it has taught many harsh realities of life. Although I have recovered a lot, still the fear of uncertainty is haunting me many a time. But V, time heals many things, so hopefully we are getting better and trying hard to face life with the same enthusiasm. We spent 6 months in India, the sun and the love from our relatives has helped us a lot. I want to believe that this suffering will make me better, but sometimes too much of hard time can make a person as hard as a rock so that nothing grows on it ( no positive emotions too ! ) I just pray God that he doesn't take me to that situation. 

V, so many women get pregnant everyday. Getting pregnant is such a natural thing which is unfortunately denied to us. We are humans and it is  very natural to feel hurt when we hear that someone close to us is pregnant. Have you watched children ? When there are two children and when you ignore one child and give a chocolate to the other, how will the neglected child feel ? The first reaction would be sorrow, a feeling of hurt ( the child cries ), when the crying is over there will be anger,  then it turns as jealousy,  then the child might fight with the other child for the chocolate, at the end it might even hit the other child and try to take away the chocolate by force. Children are not corrupted with anything ( they do not know good or bad ) , they just reflect the basic human mentality. We are grown ups, that's true, but we are humans.  There is nothing to feel guilty about how we feel about our friends pregnancy. This doesn't mean we are mean. We are not intending any harm to them. We just feel sorry for ourselves.

Now the question is, how long and how far we can nurture this feeling ? For me it is important to kill it in the beginning so that I feel comfortable and good about myself. I am not a child who has no control over his emotions . I know the consequences of negative emotions. If I grow it, it is going to affect me as well as the friendship. Above all, it is will make me to feel bad about myself. 

How do I deal with the pregnancy of a friend ? Nowadays it has become much easier. Might be I am much more mature than I was before. In the beginning when all our friends start getting pregnant, I used to ask my husband, whether it hurts. He used to give a very funny reply - when I am not responsible for that pregnancy why should I worry :) But nowadays I know it hurts him more. I tell him, every life is different and this is our life. If we do not have children and if we have to fight hard for that, there must be a reason to it. At least we have the money to take such costly treatments. There are so many who cannot afford treatment. More than everything, there so many other horrible sufferings in this world, we are spared of that. So we should be thankful for that.

I don't lie that I don't get hurt. But only for a moment ( my inability hurts ), then I do try to be genuinely happy for my friend. Since I have undergone so much to have a child, I know what a blessing it is. Instead of being sorry for myself, it is better to be happy for the pregnant woman. In that way I feel proud and good about myself. I appreciate myself :)

Once I was talking with my sister who has two cute boys, she is a gynaecologist too. I was telling how great motherhood is. She replied, even pigs give birth to so many children. I was dumbfounded by her reply. But when you think deeply, other than motherhood, it takes much more to be a woman, to be a human. Our society has hyped motherhood out of proportion. I don't think there is something to feel inferior if our reproductive system is defective. Only when we feel defective we get easily affected by other's pregnancy news. Just believe that your turn will come, even if it doesn't there are so many other ways to become a mom. Carrying alone doesn't make anyone a mom, caring does ! I sincerely wish, when you meet your friend you don't feel inferior or lose your real self and confidence. Hope what I wrote helps you in someway, I am not sure though :)

Manju

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 !