Teratology – Medical Background

Professor A. Ornoy, M.D.

Director of Teratology Unit

Hebrew University and Hadassah School of Medicine

Jerusalem

Birth Defects (Teratology) – Medical Background

Introduction

Teratology is the study of birth defects. Human birth defects, like those found in animals, can be caused by both genetic and environmental factors, and in most cases they are caused by a combination of the two. Teratology focuses more on the environmental factors which may affect the normal development of the human fetus.

According to medical literature, in most societies about 3% of all live babies are born with what are termed “major anomalies” – serious defects requiring medical correction or treatment (which is not always successful). The question which has occupied researchers for many years is: how does the environment affect the development of the fetus, and when can damage be caused to it?

I shall be dealing with some of the ethical problems associated with this topic, but I shall present more questions than answers.

Stages of Fetal Development

We must firstly ask a biological question: Does the human fetus develop along a single continuum from the moment of fertilization and throughout its development in the uterus, such that it is impossible to differentiate between various stages of what we may term the prospective human being – i.e. its potential to become a complete human being, or may we differentiate between the various stages of development and say that up to a certain point we are dealing with a “pre-fetus,” and from that point onwards it becomes more recognizable as a potential human being, and has a higher legal and halachic status?

From the biological point of view the earliest stage in the development of the fetus is the moment when a sperm cell penetrates an ovum and begins the process of fertilization. From this point onwards this cell starts to divide, and soon afterwards – about a week after fertilization – an embryo consisting of a large number of cells is formed.  Some will form part of the fetus itself while others will become its various support systems – the placenta, amniotic sac, etc.

At  about six days after fertilization, the embryo is already situated inside the uterus, and for the first time biological contact is made with the mother by means of the embryo attaching itself to the inner wall of the uterus; it penetrates the mucosa and starts to be nourished by the mother. Thereafter, further development takes place.  The embryo implants itself in the mucosa and creates real organic contact with the tissues of the mother during days 8, 9 and 10.

Is there a difference between the status of the embryo before and after its implantation in the uterus?

The embryonic cells are still identical and possess a very general potential. In fact until the third week after fertilization we can remove this lump of embryonic cells and separate it into different groups; from each group a complete, normal fetus can be created, identical to the babies that will be born from each of the other groups. The biological basis for the creation of identical twins or triplets is actually at this early stage of embryonic development.

Around day 17-18 following fertilization, we start to see the beginning of a process that is unique to humans: the beginning of the development of the organs. Until now the human embryo is very similar to that of most mammals, and also bears some resemblance to the embryos of more primitive animals. But on the 17th or 18th day after fertilization, there is something that differentiates the human embryo from that of other animals.  Is the embryo more of a prospective human being now than it was before? It was with this consideration in mind that the British Parliament legislated a law in 1990 stating that from a biological point of view there is a difference between an embryo before this stage – the creation of the “primitive streak,” the stage when the various organs begin to develop – and after it. According to the British legislators the difference is so great that they allowed experiments on human embryos up to this stage with appropriate permits. 

Is this correct from a biological point of view? There is room for considerable doubt.

Hereafter other organs begin to develop. A human embryo in its fourth week measures all of 4mm, but has certain characteristics: a facial area, a heart, and the beginnings of a digestive system. On the other hand, at least visually, the embryo still does not resemble a human being. The difference between the embryo's appearance at this stage and its appearance in the eighth week is vast.  An embryo in its sixth week, measuring about 12mm, already bears some resemblance to a fetus. We can already distinguish the area of the head, the eye sockets, the developing brain, limbs and internal organs.

Is this embryo different biologically from an embryo in its third week? In principle, no. The sole difference is that the organs which began to develop in the third week, continue to do so and can now be seen with greater clarity. 

It is important to remember that we have been speaking of a length of 12mm. But in the eighth week, when the embryo measures 20-22mm, most of the organs have passed their early stages of development. In effect we are speaking of the first forty days of development. What characterizes an embryo at this stage is that on the one hand it already has most of its organs, but on the other hand they are not yet capable of functioning independently. The cerebral cortex is only just beginning to develop. Some say that the main difference between man and lower animal life is specifically the impressive development of the cerebral cortex. An additional characteristic of the embryo in the eighth week is that the bones of the limbs and skeleton begin to develop.

From a purely embryological point of view this is an extremely important transitional stage, during which – according to the traditional definition – the embryo becomes a fetus. The transition here is purely medical; from a biological point of view all of this development follows one single continuum. There are qualitative differences at various stages with regard to the fetus's ability to function or survive, but there are no biological barriers dividing the stages of development. This is important to remember.

I would like to add at this point the fact that during the 1950's and early 1960's a “stillborn infant” was medically defined as such only after the 28th week of pregnancy, because it was generally accepted that only after 28 weeks could a baby survive. Within quite a short time, by the end of the 1960's, this was reduced to 26 weeks, and today a stillborn infant is defined as a baby born dead after the 24th week of pregnancy. It is difficult to tell today whether within another five, ten or twenty years the age of a fetus capable of surviving will not be reduced even further. Today we are able to grow cultures of mammalian embryos outside of the body. In fact, we can grow such embryos in the laboratory, outside of the body, through almost the entire course of the pregnancy. It follows that the definition of a mammalian embryo capable of surviving may well go down to a very early age of pregnancy indeed. In human fetuses, too, the age representing the lower limit of survival has changed from generation to generation, and will almost certainly continue to change in the future. This may lend additional weight to the biological fact that we are speaking of one developmental continuum, and that from a biological point of view it is difficult to draw a line and say that an embryo at an early stage is different in its potential to be born from an embryo at a later stage.

Parallel to this process of normal development is abnormal or pathological development of embryos at almost every stage. We are able to distinguish various defects in aborted embryos at a very young age. For example, in an embryo at the end of the fifth week of pregnancy we can already distinguish defects in the facial area; in the sixth week we can distinguish defects of the limbs and problems in the abdominal area and the heart.

Swedish Law

If we accept the fact that the process of fetal development is one continuous biological continuum, we may understand why various countries have legislated their own laws in this regard.  I would like to mention the law in Sweden, where pregnancies may be legally terminated. In fact, an abortion can be performed there until the 18th week of pregnancy, if the woman so wishes, and Swedish law does not reflect any biological barriers during the course of the pregnancy. From the 17th to the 22nd week the decision with regard to termination of the pregnancy must be taken by a medical committee, a concept quite widely recognized in other countries too. In other countries the limit is even 24 weeks. Although no such law exists in Israel, in practice pregnancies are not terminated beyond the 22nd week, even if defects are discovered in the fetus.

It should be noted that it was only in 1990 that a law was legislated in the Scandinavian countries stating from what fetal age an aborted fetus is to be legally treated as a cadaver. In Scandinavia cadavers are cremated.

Live Babies Resulting from Attempted Abortion

Some very interesting ethical questions arise in connection with abortions, for example: What should be done in the case of an attempted abortion which failed,  resulting in the birth of a live, breathing baby? This generally happens when an abortion is carried out during the 20th to 22nd week or later. In Israel there have already been three or four such cases in recent years, and of course they raise legal and ethical questions.

I have already mentioned the change in the definition of “stillborn infants” from 28 to 24 weeks, and the possibility that in future the definition will be 20 weeks or even less. Anyone dealing with termination of pregnancies must be aware of the concept of the continuity of intrauterine life from a biological point of view with all its halachic and legal ramifications.

National Center for Teratological Counseling

The teratology laboratory of the School of Medicine has operated a national center for teratological counseling for the past seven years. Anyone – pregnant women, doctors, paramedics, nurses, social workers and others – may call with questions concerning possible exposure of the fetus to outside factors which may affect it. To date (July 1993) we have handled around 7,000 such calls, with the number rising each year. We began in 1987 with 150 calls, in 1991 there were 1,500 and in 1992 about 2,000. 60% of the callers were women, mostly pregnant, and 30% were doctors, including many calls from abortion committees. I think that this increase has been a very positive development. 10% of the calls were from paramedics, mostly from nurses at Family Health centers.

As to the reasons for the calls, in most cases (67%) there was some type of medicine administered throughout the pregnancy or for shorter periods during the course of the pregnancy. 13% of the cases involved X-rays while the others dealt with such questions as infections or illnesses suffered by the mother during the pregnancy, vaccinations, etc. What characterized a large number of the women who called us was that they wished to continue their pregnancy, but had heard that the development of their fetus was in serious danger. With regard to the stage of pregnancy when they called, most callers (70%) were in their first trimester  because it is during this period that the embryo is  most sensitive to the influences of outside factors. This seems to be a widely known fact, not only among doctors but also amongst the general population. There are also some who call before falling pregnant (about 8%) in situations where they are planning on having some type of recommended medicinal treatment during the pregnancy. There are some medicines which harm the fetus, but there are usually alternatives which do not cause any damage. Some of the callers were in their second trimester, and a smaller number in their third.

Distribution of Dangers to Fetuses

What characterized all the women who called was a state of fear, and in a large number of cases the fear was caused by information they had previously received. In our responses – which are given over the telephone and then followed up by written confirmation – we divide the percentage of risk to the fetus into several categories: A very small danger which cannot be calculated is defined as less than 1%, a slightly greater risk is between 1% and 5%, an even larger risk is between 5% and 10% and a very serious danger is more than 10%. This division allows us to follow up and see, in another few years, the results of our counseling. Was there really exposure of the fetus such that it led to the development of defects? Remember that  there are cases where we cannot know if there was any danger at all since we did not have sufficient information; other times we know that there was some danger but we do not know the extent of it.

Until the end of 1991, in 74% of 3,429 cases the exposure of the fetus to a certain factor did not in itself present any danger to the pregnancy. Many of these women were afraid of things that they thought they knew or that they had been told. In 16% of the cases there was a small risk (less than 1%). We are quite flexible in defining this area, because we include within this category some relatively new medicines about which not enough is yet known, but which in theory should almost certainly not be harmful.

I would not hesitate to combine the first two categories and say that in about 90% of the cases the exposure presented almost no additional danger to the fetus.  (By this I mean in addition to the basic level of 3% defects which exists amongst the general population.) In 4% of the cases there was a danger of between 1% and 5%. In a tiny percentage of cases there was really considerable danger – above 5% – and this includes one or two cases where the danger was between 20% and 30%. This category represents 28 cases – less than 1% of the 3,439 that we handled. From 1987 until 1993 there were altogether some 8,000 cases. Here again there was no change in the percentages: There were still 74% with no danger, 17% with a danger of less than 1%, 4% with a slightly larger danger (up to 5%), and only very few with a high risk  percentage to the fetus. We can say today with confidence that most environmental factors do not present a danger to the development of the fetus.

We also keep our own records and generally receive the results of the women's check-ups. Anyone who calls is requested to inform us in writing after the birth, or after the termination of pregnancy, as to what happened. The occurrence of major anomalies in those babies carried to full term was found to be exactly the same as the occurrence of such birth defects amongst the general population.

8% of the callers terminated their pregnancies. It should be noted that some of these abortions were performed on women whose risk factor for damage to the fetus was less than 1%. We do not involve ourselves in the families' decisions, nor do we make recommendations as to whether or not the pregnancy should be terminated. We simply supply information on the risk factor.

Spontaneous miscarriages occur with the same frequency in these cases as amongst the general population – about 15% – and generally during the early stages of the pregnancy. It should be remembered that most of the women who call the center are in their first trimester.

Ethical Dilemmas in Teratology Counseling

All these statistics look simple and clear-cut, but they involve many ethical dilemmas. Perhaps these problems do not affect us directly – after all, our task is simply to calculate the risk to the fetus – but when this information is translated into a decision as to whether or not the pregnancy should continue, we are faced with several very significant questions.

For example, there are two types of intrauterine infection: (1) those which do not harm the fetus while affecting the mother during pregnancy (flu, or a cold) – in which case there is no problem; and (2) other infections including German measles, CMV and toxoplasmosis which cause harm to the fetus in 10%, 20%, 30% or perhaps even 40% of cases. The difference between these two categories is enormous.

But there are other questions in this area. For example, what are we to do following a viral infection where the risk factor to the fetus is very low – around half a percent, or 1%, as in the case of herpes simplex, where the infection is caused by an EBV virus – which can also cause infectious mononucleosis?

There is also a category of diseases carried by the mother which, if left untreated, can cause very serious damage to the fetus. For example, where toxoplasmosis or syphilis is not treated with antibiotics, 10% to 15% of fetuses are affected. But if the mother's illness is located early enough in the pregnancy and she is treated with antibiotics, most of the damage can be avoided. What happens with infections which have the potential to cause serious harm during the first trimester, and where the danger during the second trimester is less, but still exists? What do we decide with regard to continuing the pregnancy in the second trimester?

Should women carrying infections such as CMV be allowed to become pregnant with the knowledge that a small number of fetuses are harmed by such viruses in the mother's body? What should we do when during the course of the pregnancy the mother has suffered from some infection of the blood (sepsis)? We know that such a situation can lead to fetal defects.

Moreover, teratology has reached the point of being able to detect a great number of birth defects while the fetus is still in the uterus. What should be done when we detect defects which can be treated, e.g. cleft palate or hare lip? Or when we discover, in the 20th or 21st week, a heart defect that can be corrected surgically? Or when there are cosmetic or even functional problems of some degree – e.g. extra fingers, fingers which are joined to each other, etc.? There is also sometimes a situation of amputation (where part of a limb is missing from the fetus) which is discovered at a stage of pregnancy where by law an abortion may still be performed. And what is to be done when an ultrasound examination (which every pregnant woman today is recommended to undergo) reveals anatomical defects which we may assume can be corrected, but which may also be new anatomical defects, about which we still have more to learn? Today a strong controversy exists with regard to the proper attitude towards an ultrasound indication of swelling in the area of the fetus's neck. This is a relatively common finding, and in some cases the situation corrects itself without intervention.

Hence we see that this area has no lack of ethical dilemmas, especially when we discover birth defects or genetic problems before the birth, or slight changes in chromosomes which may lead to disease of an unknown level of seriousness. When the situation involves fertility problems and a long-awaited pregnancy, is this enough to change the decision to abort, when there is a certain risk to the fetus? What should be done when during the course of the pregnancy we detect serious illness in the fetus, which will eventually be fatal, but which will start developing only in adulthood, at the age of 30 or 40? Is Huntington's Chorea (a degenerative illness which develops at age 30-40 but which may be detected during pregnancy) different from progressive muscular dystrophy (a muscular disease which appears mostly in young boys)? Why, in the latter case, is there generally no hesitation in agreeing to termination of the pregnancy, while in the case of Huntington's Chorea there is a serious dilemma?

Summary

Teratology and the study of genetics have progressed to the point where we no longer speak of percentages of risk to the development of fetus, but we are also able to detect a large number of the defects and factors which affect the fetus at an early stage of development. The dilemma, therefore, is not – as it was ten or twenty years ago – whether there is a danger, and if so to what degree, but rather that once we have found a defect in the fetus: Is it serious enough to justify termination of the pregnancy, or is there a good chance of correcting it?

Who decides what constitutes a serious defect or a slight one? Who decides when termination of the pregnancy is justified and when it is not?

In another ten or twenty years we may well have the answers to these questions, and we may be asking new ones. It seems that that is the trend when it comes to science in general and medicine in particular. Each time we find answers to earlier questions, new questions immediately confront us.