Test-Tube-Trauma for IVF-Babies
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By Martina Lenzen-Schulte
Submitted by Ingrid Schneider, ReproKult, Germany
Developmental disturbances and malformations are more frequent in babies after In-Vitro-Fertilization than in naturally conceived babies. Doctors require critical surveillance of new techniques.
The first reports in the end of the 1970s that babies had been conceived outside their mothers` bodies appalled many people and caused reservation among doctors. The birth of a test-tube baby no longer makes the headlines. Test-tube conception is a medical technique regarded as a proven way of helping a couple have children when their chances of conceiving naturally are clearly reduced.
Since Louise Brown was born as the first test-tube baby 25 years ago in summer 1978 more than one million test-tube babies were born worldwide. The first test-tube baby in Germany was born in 1982 in Erlangen.
Every year, over 400,000 treatments take place worldwide. Doctors take egg cells from the mother and inseminate them artificially in a test-tube with sperm cells from the father. The fertilized egg cells are then reimplanted into the mother`s womb.
In Germany, 2 to 3 per cent of all newborn babies were conceived through artificial fertilisation. Almost 10,000 test-tube babies were born in 2001 in Germany.
For many years there was no reliable knowledge about how healthy or ill these test-tube babies are. Initial investigations gave favourable results and confirmed the parents´ euphoria. More recently, warnings have been growing not only from paediatricians and epidemiologists, but also from those, who apply reproductive techniques themselves. It seems that the risks for test-tube babies have been underestimated.
There are four publications that have addressed the problem of malformation-rate in test-tube babies and raised concern. Some of these publications make a difference between children arising from “conventional” in vitro-fertilization (IVF) – where sperm cells and egg cells are simply “mixed” in a test tube – and a technique called “intracytoplasmatic sperm injection (ICSI)”: one single sperm cell is directly injected by a micro-pipette into an egg cell.
Scientists from the National Centre for Research and Development (Stakes) in Helsinki (Finland) found a 1.4 times higher risk for inborn malformations for the whole collective of test-tube babies. Researchers at the University of Western Australia in Perth found twice as high a risk of malformation both for babies after ICSI and after conventional IVF. In a recent study from Germany including 95 fertility centers the risk for malformations was 1.25 for ICSI babies. The birth register in Mainz which documents all malformations in babies in the Mainz area even found a three-fold higher risk: while this was at 5% in naturally conceived babies, malformations ran at 16% among ICSI babies.
These malformations included:
Cleft lip and cleft palate, hydrocephalus, spina bifida, malformations of the heart, the kidneys, pancreas and reproductive organs, fistulas between rectum and vagina and a completely atretic anus.
Chromosomal aberrations (such as in Downs syndrome) also occurred more frequently.
To date it is unclear how the major differences in the data reported by various scientists can be interpreted. Partly, this might be due to differences in data capture. Partly, different characteristics of the parents might play a role.
Presumably, some very rare genetic diseases are more frequent after artificial fertilization. American scientists found a six-fold higher risk for the Beckwith-Wiedemann syndrome after artificial fertilization. An English study found a four-fold increase. The sick children are born with gross overweight, and the internal organs are bigger than normal.
Typically, their tongue is too big and protrudes out of the mouth, requiring surgical intervention for the children to be able to learn to talk. The small patients are highly susceptible for a malignant tumour of the kidneys, the Wilms tumour.
Another extremely rare disease is the Angelmann syndrome, showing severe mental retardation. The children move like robots and are unable to talk. It was Bernhard Horstehmke from the department of human genetics at the university of Essen who - in cooperation with American scientists – showed a suspected correlation between the Angelmann syndrome and ICSI.
Risks of rare diseases
An overall increase of the prevalence of malignant tumours in test-tube babies is currently discussed. Two years ago, doctors from the Hadassah medical university in Israel reported an increase of major eye diseases among small children conceived through artificial fertilization. Among others they saw an increase of retinoblastomas, a malignant tumour of the retina which occurs mainly during the first years of life. Just recently, retinoblastomas again have been arising attention: Annette Moll from the University of Amsterdam found a disproportionately high prevalence of this tumour among test-tube children. Although individually these are tragic cases for the children and their families, these are all relatively rare events. They do not affect most test-tube babies.
However, nobody really knows at present if the higher risk is not just the tip of an iceberg; it may be that more health problems will come to light in a later period of life. This makes it mandatory to research possible causalities.
Essentially, there are two main risks which seem to play a major role. Firstly, the genetic background of the parents may not be favourable. Secondly, technical manipulation and unnatural conditions during artificial fertilization could cause developmental disturbance.
Obviously, the risk of parents transferring their genetic defects is higher with artificial fertilization. The seminal fluid of men who want children through ICSI contains up to 70 per cent chromosomal aberrations. Frequently, this concerns the sex chromosomes. In such a case the body cells of a man have one Y- and two instead of one X-chromosomes, the so-called Klinefelter syndrome. These men have more feminine features, breasts, a small penis and are less hairy. Eventually, they show mental retardation. In Germany there are about 80,000 Klinefelter-patients living, but only about 6 - 7 per cent of them get medical treatment. Klinefelter patients rarely have positive knowledge that they are ill. Among those men who want artificial fertilization, these and other genetic defects which lead to reduced fertility occur more frequently. This fact alone increases the risk of getting children with genetic aberrations after artificial fertilization.
ICSI: a technique under suspicion
The actual risk of transferring genetic abnormalities depends also on the specific technique. During natural conception, more than a million sperm cells are involved. For in vitro fertilization, between 50,000 and 100,000 sperm cells are used. For ICSI, the laboratory technicians choose one single sperm cells which is injected into the egg cell through a extremely fine needle. It is in fact possible to exclude abnormally functioning or abnormally moving sperm cells just by their apperance. However, the normal visible form does not guarantee the sperm cell contains normal genes.
The sperm charges used for IVF contain increased numbers of genetically abnormal sperm cells. Consequently, the risk of selecting just such an abnormal cell is higher. Therefore, guidelines for IVF in Germany explicitly require a consultation about the increased genetic risks of ICSI.
The technical manipulations that occur during sperm cell injection are considered to be a possible source for defects. The head of the sperm cell is surrounded by a so-called acrosom, which contains enzymes and works as a chemical “drilling machine”. During natural conception, only the cell nucleus and the tail of the sperm cell, but not the acrosom can reach the cytoplasm of the egg cell. During ICSI, the acrosom also reaches the egg cell cytoplasm. There are some hints that conception is retarded until the falsely incorporated acrosom has been decomposed.
Moreover it seems possible that during ICSI the extremely fine spindle, along which the chromosomes are arranged in a distinct order before they are separated, is disrupted. This would certainly disturb the last steps during meiosis which – during two cell divisions – normally reduces the chromosome number from 46 to 23.
Before conception takes place the chromosomes - in preparation for these divisions – are sorted in pairs, but they finally separate only after the sperm cell could penetrate into the egg cell. The spindle is invisible through a routine light microscope and could easily be damaged or even disrupted during ICSI. There are some coarse hints how to avoid the damage, but this is not entirely reliable. A better orientation is achieved using polarized light in the microscope.
However, malformations are found not only after ICSI, but also after standard IVF. So, the various processes taking place wherever artificial fertilization is applied have to be checked scrupulously. It is thought that the “environmental” conditions in the glass tube which in many aspects are different from the biological conditions could cause the defects. This has been stated frequently by veterinarians who investigated animal models. When the fertilized egg moves slowly through the Fallopian tube on its way to the womb the cells inside are already dividing and start forming the embryo. On the way they receive a lot of signals and get support from the Fallopian tube cells. For example, the tube cells secrete specific sugar molecules, the so-called glykoproteins. These glykoproteins stick the embryonic cells together (like some sort of glue). The formerly loose formation of embryonic cells becomes a more compact lump, a process called “compaction”. Obviously, compaction is a very important step during embryonic development. The Fallopian tube cells have a detoxicating effect and they protect the embryo against oxygen radicals.
It has been investigated if Fallopian tube cells from apes or cows could take on that supportive function, but the results were not encouraging.
The addition of blood serum to the glass tube is now regarded as problematic. Blood serum contains proteins, among them albumin. Albumin should support the growth of the embryo.
However, other components of the blood serum presumably disturb the so-called “imprinting”. Imprinting is a process where the function of some genes is not only due to the inherited sequence of the DNA but also mainly influenced by environmental conditions during embryonic development. For example, imprinting allows to switch off maternal genes, and to switch on the corresponding paternal genes, and vice versa. So, this genetic “flexibility” helps to control embryonic growth and development.
It was found that a syndrome in animals which is very similar to the human Beckwith-Wiedemann-syndrome was based on switching on or off the wrong genes during embryonic development. Uncontrolled growth is certainly somehow related to the development of tumours. So, imprinting errors could be the cause of cancer. Additionally, imprinting errors are not only the cause for too much growth and overweight but also for growth retardation and underweight.
One of the investigations which are repeatedly cited in this context was published by Laura Schieve from the Health Centre in Atlanta, Georgia. According to her findings, test-tube babies are 2.6 times more frequently underweight than naturally conceived babies, their birth weight is below 2.500 g, even if their were born as mature babies around the expected date. A first clue to a possible cause came form a German lab. Annette Queißer-Luft and her team from the children’s hospital at the university in Mainz found an imprinting defect on chromosome number 11 among underweight test-tube babies. Actually, this cannot be taken as proven evidence. However, important genes which control the growth of the body are arranged just on that part of chromosome number 11. And it was just on the same part of the chromosome where imprinting defects causing the Angelmann syndrome were found.
Freezing the embryos in their very early stages can cause damage, too. The survival rate of frozen embryos after thawing them is lower than that of fresh embryos. The zona pellucida, the rather stiff surface skin which protects the egg can rupture during the process of freezing. Antifreeze liquids – they contain alcohol which is toxic for cells – are added to prevent the formation of dangerous intracellular ice crystals inside the egg. It has not been proven yet if ultrafast freezing techniques – on the long run - cause less damage.
In Germany it is forbidden to store embryos. Consequently, it is not allowed to freeze them. It is only allowed to breed just as many as one wants to implant into the mother’s uterus. Before the cell nuclei of sperm cell and egg cell have not yet been unified, the cell complex is – per definition – not yet an embryo. These Pre-Stage-Embryos may be frozen in Germany for later implantation, when the implantation of fresh embryos was unsuccessful. Some 10000 of these pre-Stage-Embryos are stored presently in German fertility hospitals. In the year 2000, about 9500 embryo transfers were performed after thawing frozen embryos. The subsequent rate of pregnancies was considerably lower.
The last-named aspects have recently been recognized as risk factors. However, it has been known since a long time that multiple pregnancies – which indee are much more frequent compared to malformations - cause additional risk. The female body is not constructed for more than one baby in the womb. After natural conception twins are born only in 1.19 per cent of all pregnancies. Artificial fertilization has increased that number by a factor of 20. More than 2 babies per pregnancy are even some hundred times as frequent than after natural conception. Globally - even in Germany – up to 40 per cent of the newborn babies after artificial fertilization are twins, triplets or more.
The birth of these children frequently takes place long before the expected date and coincides often with malformations which are a burden for the whole life of the newborn.
In October 2003, a report was published considering the development of children with a birth weight of less than 1000 g, comprising results from Canada, USA, the Netherlands and Bavaria/Germany. More than 50 per cent of these children had major problems in school. In detail, they showed deficiencies in paying attention and concentrating on a subject. Also, they showed hallucinations, day-dreaming and social problems in dealing with other children of their age.
A study from the USA showed that about 50 per cent of extremely premature children had at least one major neurological defect such as paralysis, blindness or deafness. Children from triple births had a nearly 50 times more frequent occurrence of cerebral paralysis than children from single pregnancies. A Swedish study found that the risk for spastic or other cerebral paralysis was 2.8 times higher for test-tube babies, and even 3.7 times higher for those out of multiple pregnancies. Recently, scientists in Israel reported a disproportionately increased rate of cerebral bleeding for premature and test-tube babies. They assume that artificial fertilization is a risk factor on its own for this severe complication.
There is now common agreement that most health problems among test-tube babies are due to the multiple pregnancies. Experts called the Infertility therapy-associated multiple pregnancies and births an “ongoing epidemic”. It has been claimed in England recently that the hospitals which perform the reproductive techniques should pay partly for the enormous costs of public health care caused by the test-tube babies. The more embryos are re-implanted into the mother’s womb, the better are the chances for an embryo to grow. This unquestioned dogma of reproductive medicine has – mainly in the USA – for a long time lead to the fact that more than three embryos were re-implanted from the test-tube. When doctors learnt about the numerous complications threatening already three embryos, they killed the surplus embryos. This so-called fetocide – which in the USA is an accepted routine method to reduce the number of embryos in the uterus – leads to additional risks for the remaining fetuses. Depending on the number of killed embryos, every 12th to 6th pregnancy ends then spontaneously.
Scientists have learnt now that a high number of re-implanted embryos does not guarantee better rates of pregnancy. It seems to be much more important to have a small number of embryos of “high quality”. Just now Tarun Jain and collegues from the Harvard Medical School reported in the New England Journal of Medicine, that even under the most liberal conditions in the United States the self-regulation of the infertility centers helped to install a trend towards fewer and fewer embryos being transferred today. Since 1999 the rate of triplet and higher-order multiple births stabilized for the first time in at least 18 years in the United States.
For a long time the risks of artificial conception for the babies have been unknown to the public, Reproductive techniques have helped some hundred thousands of couples worldwide to have children. However, experts now demand much more restraint for the use of reproductive techniques.
Gerald Schatten from the University of Pittsburgh, Pennsylvania, one of the outstanding experts in reproductive technology world-wide, required– on the occasion of the 25th anniversary of IVF-techniques - a so-called “ARTsilomar”. By this he was referring to IVF-techniques (Assisted Reproductive Technology) and to the conference in Asilomar (Monterey, California) where experts in genomics in 1975 agreed on a memorandum that not everything which could be done should be done.
His famous colleague Robert Winston from Hammersmith Hospital in London warns about shrugging off these recent findings as mere statistical over-subtlety. He sees dark clouds coming up. These warnings are also about experiments where the safety of the technique has hardly been checked yet. Experts criticize experiments about using using immature sperm cells as merely adventurous. Equally critical – to their opinion - are experiments to rejuvenate egg cells of older women using the egg cell cytoplasm of young women, so called cytoplasmatic transfer, to increase the chances for pregnancy. The FDA intervened after children with genetic malformations had been born.
Jennifer Kurinczuk, an epidemiologist from the University of Leicester (England) claimed that unpleasant results should not be pushed under the carpet any longer. She now requires a detailed consultation of couples: they should know all the risks before they decide.
However, such a consultation is not always easy when couples are determined to have a child. These couples tend to accept even major risks. Anja Pinborg from the university in Copenhagen found that women refused to a second multiple pregnancy only when they already had severely disabled children from a first pregnancy.
According to a study in the Netherlands, every second couple insisted to have reproductive technology applied even when they knew that the father had chromosomal anomalies which were likely to be inherited to the children.
Some infertile couples even preferred to have multiple birth despite the risks.
A plea for more restraint and more profound studies
Meanwhile, not only paediatricians see multiple births as one of the worst disasters in our time. In Germany it was Henning Beier, director of the Department of Anatomy and Reproductive Biology in Aachen, who warned already in 1997, that the immense health risks and social problems arising from multiple births should not be subordinated to the single goal to have a higher success, in other words a higher pregnancy rate, after artifical fertilization. In part due to his report, a rule was established in Germany that only two instead of the routinely used three embryos should be re-implanted when women were younger than 35.
Raymond Lambert from the Universite´ Laval in Quebec (Canada) blaimed his colleagues for their irresponsibility when they supported multiple pregnancies and multiple births in such big numbers. He stated that the re-implantation of a high number of embryos should never have become daily clinical routine. However, there is absolutely no consent among doctors working in the filed of reproductive technology: Norbert Gleicher from the Center of Human Reproduction in Chicago rejected this reproach and insisted that only the parents had the right to make a decision.
The way in which the problem of safety risks is discussed clearly shows the widespread uncertainty among scientists. Even considering all positive evidence one must not overlook that besides in-vitro fertilization itself there could easily be other causes. Robert Edwards, one of the “fathers” of Louise Brown, stated in an analysis of the health risks of test tube babies that a considerable risk could come from unfavourable conditions inside the maternal body. Recently, Lambert rated the maternal infertility in itself as a main risk factor for an unfavourable outcome of the test-tube babies.
Intensive research seems now even more essential. Alastair Sutcliffe from the Center for Community Child Health in London was one of the first paediatricians who looked for possible defects among test-tube babies. In an article in one of the 2002 issues of the British Medical Journal he required to perform really meaningful studies to get reliable answers to the problem of health risks. He claimed that it would be difficult to admit to test-tube babies that they could have been exposed to a higher risk. What if these children would understand one day that their safety was not the most important precept for the doctors who helped their parents to conceive?
The author is a medical doctor and publishes as a medical journalist.
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Article translated from the German „Spektrum der Wissenschaft“, 12/2003.