The Expanding World of Multiple Gestations

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Hans van der Slikke, MD, PhD: “It’s April 2003, we’re in Berlin at the Controversies in Obstetrics, Gynaecology and Infertility Conference and next to me are two world-leading experts on multiple pregnancy. Please could you introduce yourselves?”

Professor Isaac Blickstein, MD: “Well, I would like to introduce my friend, Louis Keith, who is a Professor at Northwestern University, Chicago. He is running the Centre of Multiple Births in Chicago with his twin brother, Donald, and currently he is the Co-President of the ICS International Society of Twin Studies, author of a zillion papers related to multiple pregnancy and also with me on two books now and a lot of papers in the past and in the future.”

Professor Louis Keith, MD: “My friend Isaac Blickstein is Professor of Obstetrics and Gynaecology at the Hebrew University in Jerusalem, a professorship which he just got this last year and, I must say, a professorship which is long overdue based on his acknowledged leadership in the world of multiple pregnancies and those publications I’ve worked with him on; this is our third book and it has been a pleasure, Isaac.”

Professor Isaac Blickstein, MD: “Thank you.”

Hans van der Slikke, MD, PhD: “Could you both tell me, you have almost a lifelong history of collaboration, when and especially how did it start?”

Professor Louis Keith, MD: “Well, it began in Helsingborg, Sweden, where we met for the first time. It continued in Israel at a meeting that he was chairman of, but it really began in Copenhagen, Denmark, when I looked at Isaac and I said, 'Isaac, it’s time that you edit a book for your career' and then what did you say, Isaac?”

Professor Isaac Blickstein, MD: “The idea came forth and the layout of this book, Iatrogenic Multiple Pregnancy, was written on napkins of SAS. It was conceived on the ground but born in the air.”

Professor Louis Keith, MD: “Exactly, because when I suggested it to Isaac, he said somehow or other in the words that came out, the words iatrogenic pregnancy came out, and I said, that’s it, that is your book and he looked at me like I was insane, probably many of the viewers would say, yes, you’re right, Isaac, he’s nuts, but aside from that, that was a topic that became obvious to us because there was nothing on it in a monograph form and then came the flight to Dusseldorf to see a mutual colleague, Hugo Verhoeven, for dinner and by the time we landed, we put the pile of napkins on the plate and said, Hugo, what do you think, this is the outline for the new book on iatrogenic pregnancies and it came to pass.”

Professor Isaac Blickstein, MD: “Yeah, and then we continued with the collaboration on the triplet book which was published a few months ago and this idea came from Louis actually, because we witnessed this tremendous increase in triplets in the United States. This kind of multiple pregnancy, this kind of obstetric challenge, is indeed the most important thing now in perinatal medicine.

The most important, in our view at least, and Louis got the collaboration with the company in the United States that sponsored our research, extensive research of their database and I think without their help and without knowing the material at hand, nobody before could analyse samples of more than 60 triplets, 100 triplets, and for the first time we analysed 3,000 sets of triplets and it is the cornerstone of this triplet book.”

Professor Louis Keith, MD: “Yes, and when the company asked us to do the analysis, I remember saying to them distinctly, well, we could do the analysis, I know the right person, meaning you, but the question is how do you present it so that it isn’t just another paper that lies on your desk and the way to do it was to build a book around this analysis in which we tried to do everything we could to get the world’s best authorities to write about every aspect of triplet pregnancies and it’s about 600 pages this book, something like that.”

Professor Isaac Blickstein, MD: “And then we come to revision of your first book and I think it will be the textbook on multiple pregnancy, forthcoming next year.”

Professor Louis Keith, MD: “Next year, 2004, if everybody is willing and able to contribute their chapter on time. It will have 84 chapters.”

Professor Isaac Blickstein, MD: “At least.”

Professor Louis Keith, MD: “At least, and it will represent not a revision but a complete re-write with very few carry-overs from the first book. Obviously, the chapter on conjoined twins isn’t going to change except we are going to add to that a chapter by a young man in Poland who was instrumental in the successful separation of a set of twins and it shows you really what can be done now by internet and e-mail because the analysis of the children pre-operatively was directed by a Doctor Scott Adsik at the Children’s Hospital of Philadelphia in a series of e-mails to a former student of mine in Lublin, Poland, who got every one of the tests performed in Lublin, digitised all the results, sent them by e-mail, they were downloaded in Philadelphia, interpreted in Philadelphia, the most complex types of tele-medicine that you could imagine, and then the children were brought over courtesy of LOT Airlines, met at the airport by the Polish counsel, whisked through customs and everything, every courtesy was given, and they were ultimately successfully separated at the Children’s Hospital of Philadelphia.

At the time, they were very skittish about having the newspapers know and there was no publicity, but now that it’s over and now that the children are running around like two other children of their age with very minimal scars, this is going to be added to that chapter. But the rest of the chapters are essentially new.”

Professor Isaac Blickstein, MD: “Yes, I agree, because everything changed during the last decade, since 1995, when your first book appeared because I think there are few topics in medicine that got so much energy in it from all parts involved. I mean reproductive medicine is nothing similar to what it was ten years ago. Neonatal medicine is nothing similar to what it was ten years ago and perinatal medicine, ultrasound, everything, is nothing like what it was before, so we had to change, even if the outline is approximately similar, every chapter would be totally revised where we would recognise or developed previously.”

Professor Louis Keith, MD: “And I think that the situation with multiples, of which twins are clearly the most common, is a worldwide epidemic, there is no other terminology to explain it. Not only are women older when they want to get pregnant, but many of them need help and, of course, you have all of these twins.

When I’ve been studying the literature on twins since the mid-70s, you know, a dataset of a 1,000 sets of twins in the mid-70s was an astronomical number, but now there are many community hospitals when they want to review their data internally, they have a 1,000 sets of twins in the last decade, so you just have to put all this information together in a compendium.”

Professor Isaac Blickstein, MD: “I totally agree with you. I suppose that is what happened in terms of higher-order multiples. I think that in one year, there were more high-order multiples delivered in the United States than in the previous decade and 1998 was the hallmark of the triplets. In 1998 alone there were more triplets born to mothers over 35 than in the entire decade before and no other adjective like epidemic can describe it. I mean, it is also contagious because it comes from one country to another and from one developing country to another developing country and now all countries have their own rate of infertility and couples want their children and the risk of high-order multiples or multiples with infertility treatment is equal, whether it is in the United States or in India, it is the same risk.”

Professor Louis Keith, MD: “And I think that’s one of the points that we’re going to bring out very clearly in this revision, that it is absolutely crucial that when women go to any form of assisted reproductive technology that they be thoroughly informed of these risks. Not only should they go for some of the more sophisticated manipulative types of therapy, but when they get the simple drugs like clomiphene citrate, people don’t realise when they go to the PDR in the United States and look at clomiphene citrate, it will give you the dose but unless you read the fine, fine print, you won’t realise that the references for which this dosing is made are forty years old.

Now, when you think about that, we certainly know that the results that we’re getting with clomiphene today are not the results that were originally given to the FDA forty years ago, but this doesn’t come out. It will certainly come out in the book.”

Professor Isaac Blickstein, MD: “Yes, sure, but I mean in iatrogenic pregnancies, that’s two kinds of iatrogenic multiples, those who may be avoidable and those who may not be avoidable. I think that once you stimulate the ovary, whether with clomiphene citrate or with gonadotrophins, the ovary is stimulated and unless you abort the cycle, you cannot know exactly how many multiples will come out or if it will be a singleton at all.

However, the avoidable cases are those in which you are yourself putting in the number, you are deciding on the number of embryo transfers during an assisted reproductive technology cycle. For example, in IVF, you are in charge of how many embryos will be transferred and now the trend is in Scandinavia, for example, is to minimise the risk of multiple pregnancy, more cycles with less embryo transfer as opposed to doing everything necessary in order to achieve a pregnancy and, in many ways, it is existentialistic position of the IVF centres.

They must have success. If they are not successful in getting a pregnancy, they don’t have any role in medicine and, at certain times, it may result in a higher rate of multiple pregnancies which are a complication of the treatment.”

Professor Louis Keith, MD: “But this need to have success, I can certainly understand from the point of view of the IVF centre. But in the last two or three years, there has been a very critical review of what is success. We were both in Australia and heard a paper from the people in Sydney, called IVF Sydney, where they were so alarmed at their 41% twinning rate with, I think it was two embryo transfers, they decided to do a trial where they only put in one embryo and they got almost the same success rate in terms of total pregnancy rate, but they brought the twinning rate down to 6%.

Now, in that regard, there have been some papers that are in the process of being written now in the UK, which looks at all of the data for the entire country and there they have shown it is absolutely economically feasible to put an upper limit on the number of embryos transferred and spend the extra money on giving more cycles because they will save so many days in the NICU units and the costs that are associated with that, that it would pay the National Health Service of England to give out more cycles and they would still save money rather than paying these astronomical NICU bills because in the end, it is society that pays the NICU bills.

We think of a couple in Israel or in Chicago or wherever, going to an IVF centre, public or private, they pay or they don’t pay, and you can cost out this at X, but that’s a given thing and that’s what people have in their mind. They don’t think about two additional costs: Y and Z. Y is the neonatal intensive care costs and Z is the lifetime cost of bringing up children who may be neurologically impaired and whether we want to, we certainly don’t say that this is wonderful, but we have to admit the truth of it. Not every higher-order multiple child survives without neurological impairment and you have done some studies to that effect.”

Professor Isaac Blickstein, MD: “Yes. We calculated the risk of cerebral palsy, the quadriplegic type, which means the baby or the child can’t move anything except his head and living in the wheelchair for his lifetime, and the risk is about sixfold increased when there is transferred three embryos and this idea was picked up by John Kiley from the National Centre of Health Statistics and he did a study with me and it seems that assisted reproductive technology in the United States adds 8% to the cerebral palsy rate and if we do everything for it, every pregnancy, we do seeing them daily, we do ultrasound weekly, we screen for every virus, every bacteria, we do whatever is needed for pregnancy, amniocentesis, whatever we do, we cannot reduce the cerebral palsy rate by 1%. However, with assisted reproductive technology, we increase the numbers tremendously, 8% increase, because the main idea is that we cannot avoid prematurity in these high-order multiples and prematurity is definitely associated with neurological handicap.”

Professor Louis Keith, MD: “And with that, perhaps, we ought to bring this interview to a close and say to our listeners if you want to know more . . .

Professor Isaac Blickstein, MD: “Buy our book.”

Professor Louis Keith, MD: “Well, it isn’t a question of buying our book, it’s a question of looking forward to the publication. Let’s hope that we both survive going through these 80 chapters to get it out on time in 2004. Thank you, Isaac.”

Professor Isaac Blickstein, MD: “Thank you very much.”

Hans van der Slikke, MD, PhD: “Gentlemen, thank you very much.”