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Effects of drugs & chemicals on baby's brain: Psychoteratology
Author Paul Kenyon

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Overview:
newborn babyThis lecture addresses an important practical question:

What safeguards are in place to detect medicines that might harm a baby if they were taken during pregnancy?

This is an important issue in the light of the thalidomide tragedy. We begin by trying to gauge the size of the threat by examining the proportion of pregnant women that take medicines, and the type of medicines that are most frequently prescribed in pregnancy.

We move on to consider critical periods in human in utero development - this may give insight into which behavioural systems might be affected by drug ingestion at various stages of gestation.

The heart of the lecture is a discussion of the tests that are used to detect behavioural teratogens - chemicals that could compromise a child's subsequent behavioural development. As psychologists you should be able to form an opinion on the relative usefulness of these tests. We consider the evidence that substances taken during pregnancy interfere with psychosexual differentiation in animal models. This possibility does not appear to be seriously considered in current tests of human medicines. You already know quite a lot about the psychosexual differentiation from your earlier lectures.

I hope you will begin to appreciate how your theoretical understanding can be brought to bear on this important issue that concerns everyone - the health and happiness of the new-born child. Of course you should be aware of the social, political and economic implications of these findings.

Learning Objectives
After studying the material on this page you should be able to:
  • Describe the scope of psychoteratology
  • List four teratogens
  • Recognize the symptoms of Foetal Alcohol Syndrome
  • Explain why it is difficult to detect the effect(s) of a psychoteratogen in the general population
  • Describe the general effects of teratogens on the body
  • Explain why the unborn child may be at psychoteratogenic risk
  • Recognize the critical periods for organ development in the embryo and foetus
  • Compare international guidelines for testing drug safety in animals
  • Explain how drug exposure could effect psychosexual differentiation
  • Critical evaluate Anand and Van Thiel's (1982) study of the effects of cimetidine on male rat sexual behaviour
  • Describe the effects of perinatal stress, alcohol, and dopaminergic drugs on sexually dimorphic behaviours in animals
  • Critically evaluate the risk to the new-born child of damage caused by chemical exposure in utero

What is psychoteratology?

The Neurobehavioural Teratology Society describes neurobehavioural teratology as

"...the study of functional brain deficits (like learning disorders) that result from something going wrong during development. Whether it is a genetic defect that is inherited, or exposure to some substance or circumstance during pregnancy, the result can be some form of functional birth defect that may occur without an obvious visible sign. It involves studying those birth defects related to the development of the brain that may not be visible to the naked eye, but are disabling to that person."

teratogens

Some of the known causes of birth defects are:

  • alcohol
  • hormones
  • diseases
  • heavy metals

These substances are transferred from the mother's blood, across the placenta into the fetal system, where they cause malformations and defects.


Alcohol is a teratogen and the cause of a pattern of malformations known as Fetal Alcohol Syndrome (FAS). The syndrome has become the leading cause of mental retardation arising from the action of known teratogenic agents. It is characterized by a group of physical and mental birth defects that are the direct result of drinking alcohol during pregnancy. This condition continues to represent a substantial public health problem, as well as an economic burden to society. None the less, FAS is 100% preventable. This information is adapted from the Texas Genetics Network Newsletter that has a very useful article on FAS Fetal Alcohol Syndrome

Detection of behavioural teratogens

The effects of behavioural teratogens may be very difficult to detect in humans because subtle effects can be impossible to detect against a background of significant variation in behaviour across the population.

Imagine that a new teratogen has the effect of reducing each affected child's IQ by five points.

However a teratogen that decreased IQ by 5 points in the population would lead to

However - because both these groups form such a small proportion (0.25%) of the normal population - the effect of the teratogen would remain undetected in studies of the whole population.

IQ affected by teratogen differential effect on tails of normal distribution
Figures based on Slotkin (1998)  

 

Principles of teratology
Teratologists have discovered the following principles from studies in animals and humans:


Frequency of taking medicines during pregnancy

The frequency, number and range of drugs taken in pregnancy is higher than you might expect. Psychoactive drugs may have to be taken in pregnancy; their mode of action involves effects on neurotransmitters - what is the effect of this on the developing brain?

In the 1960's, thalidomide was used as an anti-nausea agent, causing several thousand european children to be born with limb and body malformations. Thalidomide had a major impact on the attitudes of pharmaceutical companies and governments towards drug safety. Despite the obvious deformities suffered by these children, it was not immediately obvious that the drug was responsible because similar deformities can occur in the absence of exposure to thalidomide. In other words this is not a completely new condition - it occurs at a certain level in the population.

This reinforces the point made earlier that it is difficult to detect teratogens

Despite the thalimide tragedy, the average number of medicines taken by each woman during pregnancy rose between 1963 and 1973.

thalidomide effects drug intake 1963-73

Frequency of taking medicines during pregnancy

In a survey of 156 women carried out in 1971, Nelson & Forfar found that nearly all women were taking medicines during pregnancy. The majority of women were also taking self-prescribed medications. The table below is a comparison of drug useage, average number of drugs taken per woman, and self medication in Scotland (Nelson & Forfar, 1971), USA (Heineman et al, 1977, Doering & Stewart, 1978), Belguim (Meire et al, 1979) and the Netherlands (Eskes et al, 1983).

Scotland USA Belguim Netherlands
% Drug usage 97% 94% 93% 99% 83 to 71%
Average number per woman 3.5 11 3.8 4.4 2.4 to 2.3
Self-medication 65%     18% 11 to 7%



Types of medicines taken during pregnancy

Types of medicines taken during pregnancy

This figure shows the specific types of medication taken during pregnancy in a study of 911 women carried out by Forfar & Nelson in Scotland in 1970.

  • iron - used to treat anaemia which causes a reduction in the blood's ability to transport oxygen
  • analgesics - pain killers
  • barbiturates - early type of anti-anxiety drug - rarely used nowadays
  • diuretics - increase urine production
  • anti-emetics - reduce nausea
  • antibiotics - combat infections
  • antihistamines - treat allergies
  • hormone -e.g. diethyl stilbestrol (DES) given to reduce the risk of miscarriage

 


Critical periods in human development

There are critical periods for the development of various systems in the embryo and fetus. This knowledge can be used to track down the effect of teratogens and alert doctors and women to the dangers of exposure to particular drugs at various stages of pregnancy.

The CNS (central nervous system) is at particular risk during the early weeks of pregnancy - weeks 3-6.

Weeks 7 to 12 are thought to be the sensitive period for the development of the external genitalia.

 

Legend

  • highly sensitive period marker = highly sensitive period to teratogenic effects
  • less sensitive period marker = less sensitive period


Figure drawn from data in Krauer et al (1984)

Follow this link to the Oregon Museum of Science & Industry site which has pictures showing the development various systems in the human embryo.


Schematic illustration of critical periods in human development
Weeks of pregnancy
3
4 5 6 7 8 12 16 20 38
CNS
Heart
Arms
Eyes
Legs
Teeth
Palate
External

genitalia

Ear

Testing drug safety in animals: International Guidelines

Experience with thalidomide prompted a review of drug safety testing guidelines. Before any medicine is licensed for use in humans it must be tested in animals. These tests examine the effects of the drug on

In these tests pregnant female animals are treated during the last third of pregnancy and during lactation up to weaning. Offspring are monitored for growth and development after birth.

The main and most important difference between countries is the requirement in Japan and Canada for behavioural observation of offspring. In the US, UK, and Scandanavian countries, behavioural testing is not mandatory. This table is taken from Riley & Vorhees.

Comparison of International Guidelines
  U.S Canada Scandanavia U.K. Japan
Number of species 1 1 2 1 1
Number of  doses 2 3 3 3 3
Number of  animals 20 20   12 20
Are behavioural observations required? No Yes No No Yes

In addition it must be demonstrated that animals that have been exposed to the drug 'in utero' are capable of reproducing.

However I have argued that

There are a number of ways in which drug exposure could effect psychosexual differentiation

  1. by antagonising the effects of testosterone on target tissues within the CNS
  2. by interfering with neurotransmitters that are thought to mediate the organisational effects of hormones on the brain
  3. by inducing hepatic (liver) enzyme systems in the neonate and thereby reducing androgen levels during the critical period of brain development

For a fuller discussion of this issue see Kenyon & Malinek (1984).


 

Effects of cimetidine on male rat sexual behaviour

There is a strong body of information that testosterone is involved in the psychosexual differentiation of the mammalian brain. Follow these links to related pages on psychosexual differentiation and the effects of hormones on sexual behaviour .

An antiandrogen might interfere with psychosexual differentiation. Cimetidine (Tagamet) is used drug for the treatment of stomach ulcers - it is now available OTC (over-the-counter i.e. without prescription ) it is a weak antiandrogen. Anand & Van Thiel (1982) claimed that cimetidine interferes with psychosexual differentiation in animals.

These graphs show the effects of perinatal (pre- and neonatal) exposure to cimetidine on the sexual behaviour of adult male rats (Anand & Van Thiel, 1982)

Male rats exposed to cimetidine in utero, and whilst suckling showed:

  • increased mount latency
  • reduced mounting behaviour

when they were exposed to a sexually receptive female rat for a 15 minute test of their sexual behaviours

cimeditine increases mount latency cimetidine reduces number of mounts
Anand & Van Thiel interpreted these results as indicating that cimetidine significantly reduced
  • sexual motivation (mount latency) and
  • sexual performance (number of mounts)

Can you see that this interpretation is flawed because the increase in mount latency will inevitably lead to a reduction in the number of mounts that can be made in a test session of fixed duration? There were a number of other weaknesses in this study that make it difficult to conclude that cimetidine poses a risk to human health.

Nevertheless Anand & Van Thiel have highlighted the possibility that ingestion of antiandrogens in pregnancy may threaten the process of psychosexual differentiation.


Testing drug safety in animals: Behavioural tests

What is surprising about Anand & van Thiel's paper is that the research was carried out after the drug was released for use in humans. In other words, their work may highlight a weakness in drug testing procedures. Contemporary guidelines do not appear to acknowledge the possibility that a drug taken in pregnancy could interfere with the psychosexual differentiation of the unborn child. The realization of this danger prompted me to ask the question:

What types of behaviour are examined by behavioural teratologists?

It appears that simple tests that are quick and cheap to administer are favoured.

The table below presents the results of a survey of japanese and american teratologists reported by Buelke-Sam & Kimmel (1979).

Behavioural tests used by teratologists in Japan & U.S.
Percentage of labs using test in:
Type of test Japan n=60 U.S. n=69 Sex difference on test?
General behaviour 68% 33%
Motor coordination 82% 51%
Reflex 86% 49%
Activity 35% 57% Yes
Emotionality 90% 33% Yes
Maze tests 76% 43% Yes
Avoidance 41% 38% Yes
Operant schedules 2% 25% Yes
Aggression 0% 9% Yes
Sexual behaviour 0% 9% Yes

This table shows how important it is to use both male and female offspring - rather than just one sex- on behavioural tests in order to detect any behavioural change arising from an effect on psychosexual differentiation.

The argument for this position is strengthened by studies showing that prenatal exposure alcohol,stress, and drugs that interfere with dopamine neurotransmission, affect psychosexual differentiation.


Prenatal stress feminises and demasculinises the behaviour of male rats

Ward et al, (1972) exposed female rats to stress whilst they were pregnant (prenatal stress) or in the period after birth when they were suckling their offspring (postnatal stress). The adult male offspring of these stressed mothers were given six opportunities to copulate with an estrous female. The diagrams show the percentage of these perinatally stressed male rats that ejaculated or copulated on at least one of six these tests.
prenatal stress reduces male copulation prenatal stress reduces male ejaculation prenatal stress increases male lordosis
Results:
  • Many of the prenatally stressed rats failed to copulate with female rats, and very few of these males ejaculated.
  • Prenataly stressed male rats showed high levels of the typically female behaviour 'lordosis'.
  • Postnatal stress had no effect.

Conclusion:

These results suggest that prenatal stress feminizes and demasculinizes the behaviour of male rats. Stress may cause a decrease in the release of testosterone in the developing male rat fetus.

This explanation is supported by the observation that prenatal stress reduces testosterone in the male rat fetus (Ward In Adler et al (Eds.) Handbook of Behavioural Neurobiology, Volume 7. Reproduction)

Effect of prenatal stress on testosterone levels

Recent research suggests that prenatal stress does not have such dramatic effects on the gender role behavior of girls and boys (Hines et al 2002)


Prenatal alcohol exposure alters adult expression of sexually dimorphic behaviour in the rat

McGiven et al (1984) found that saccharin preference was altered in adult male and female rats that had been exposed to alcohol during gestation.

The sexual dimorphism normally observed in this behaviour was absent in fetal alcohol-exposed rats.

The lack of dimorphism appears to result from a masculinisation of the exposed females and a feminisation of the exposed males.

Because this is a fairly complex experiment, click here to :

  1. use the 'Separator Tool' to examine saccharine preference in male and female control and alcohol-exposed groups 'one-group-at-a-time'
  2. use the 'Overlayer Tool' to understand the differential impact of alcohol-exposure on male and female rats.
Prenatal alcohol exposure and saccharin preference

 


Perinatal dopamine-related drugs demasculinise rats

Hull et al (1984) reported that the administration of haloperidol - a common neuroleptic drug -to pregnant or lactating rats impaired the masculine sex behaviour of their male offspring.

Prenatal haloperidol did not affect testosterone concentration in fetuses.

Maternal administration of apomorphine, a dopamine agonist, and of AMPT (alpha-methyl-para-tyrosine), a DA synthesis inhibitor, also demasculinised male behaviour but did not lower testosterone in adulthood.

The authors conclude that these drugs may act directly on neurons that control masculine sexual behaviour, without lowering testosterone prenatally or in adulthood.

Perinatal dopamine drugs demasculinises rats

Point to ponder
Can you think of any animal models that could be used to test the safety of medicines taken in pregnancy? How would you experimentally verify their efficacy?


References & online resources

 

Supplementary reading

 

Doskoch (2001) Which is more toxic to a fetus - antidepressants or maternal depression? Neuropsychiatry Review 2/5 2001.

"Ten years ago, many clinicians considered prescribing antidepressants to a pregnant woman to be foolhardy. But recent data increasingly suggest otherwise. Most studies indicate that antidepressants do not increase the risk of obstetrical complications or birth defects (though more long-term behavioral studies are needed). Conversely, evidence now suggests that untreated maternal depression can have deleterious effects on offspring, both by altering their neurobiology during fetal development and by compromising care after birth."



The Chicago Project News - Fall 1996, The Effects of Prenatal Exposure to Tobacco, Alcohol, and Cocaine,
by Daniel J. Kindlon, Ph.D. & Felton Earls, M.D.
"According to recent statistics, 17 percent of mothers report having smoked cigarettes during pregnancy and 20 percent report having used alcohol at some point during pregnancy (Ventura et al, 1994). When during development are the various effects of prenatal exposure to tobacco, alcohol, or cocaine seen and what are these effects? Does exposure relate to the development of academic difficulties and behavior problems later? How might exposure interact with family and neighborhood characteristics in producing such negative outcomes? These are some of the questions being explored by the Project on Human Development in Chicago Neighborhoods' Infant Study as they assess the cognition, temperament, physical health, and caretaker's characteristics of approximately 400-500 six-month old infants. In preparation for this investigation, we prepared a literature review for the National Institute of Justice on prenatal exposure to tobacco, alcohol, and cocaine, including information gathered from recent comprehensive reviews of research on both humans and animals. Our aim is to expand on this base of knowledge as we complete data collection for the study we have undertaken."

Cocaine Use During Pregnancy: Its Effects On Infant Development and Implications for Adoptive Parents
by Judith Schaffer, M.A.
"Prospective adoptive parents, as well as parents who have recently adopted infants, need to be aware that when a pregnant woman uses cocaine during her pregnancy, it crosses the placenta and causes considerable damage to the developing fetus. Although cocaine is thought to damage many organ systems, the developing central nervous system of the fetus is especially sensitive to this powerful stimulant. Such damage has been implicated in a variety of developmental problems for the infant and later for the child.
A lack of knowledge about the symptoms associated with damage to the central nervous system can lead parents and others to mistakenly attribute them to psychological problems associated with foster care and adoption. It is therefore important that families who adopt infants, as well as agency workers and others who place them, be familiar with the growing research about the unique characteristics of these infants. It is also important to be familiar with the kinds of evaluations available which may help you to determine whether or not an infant has been cocaine-exposed, the special needs of these infants, and the intensive parenting that they appear to require."
Behavioral Studies of Drug-Exposed Offspring: Methodological Issues in Human and Animal Research

National Institute on Drug Abuse Monograph 164:

COCAINE AND PREGNANCY ,
by Phillip Coffin of The Lindesmith Center.
"The rise in cocaine use and appearance of crack cocaine in the 1980s spurred fears about its effects on the developing fetus. Cocaine use during pregnancy is certainly inadvisable, yet many of the initial reports cited dangers that later studies do not support, and policies fostered during those years may have caused more harm than good. Recent press and politics have not reflected changes seen in the scientific realm. "
Organization of Teratology Information Services
publishes a number of useful Fact Sheets, including one on Prozac with answers to questions that many mothers will ask, for example
Will taking Prozac have any effect on my baby's behavior and development?
"Studies have begun to look at the possible long-term effects on infants exposed to Prozac during pregnancy. Prozac affects the mother by changing chemical levels in the brain. These changes could also have an effect on fetal brain development. One study examined development in children averaging three years of age and did not find differences between exposed and unexposed children. The first completed study of behavior and development was reassuring, however, more studies are needed before we can be certain of the effects on the fetal brain."
Fetal Alcohol Syndrome
"In 1973, Jones and Smith coined the term "fetal alcohol syndrome" (FAS) to describe a pattern of abnormalities observed in children born to alcoholic mothers. It was originally postulated that malnutrition might be responsible for these defects. However, the pattern of malformation associated with FAS is not seen in children born to malnourished women, and alcohol has been found to be acutely toxic to the fetus independently of the effects of malnutrition ."
Evolution of Our Understanding of Methylmercury as a Health Threat ,
Chiho Watanabe and Hiroshi Satoh, Department of Environmental Health Sciences, Tohoku University School of Medicine, Sendai, Japan
"Methylmercury (MeHg) is recognized as one of the most hazardous environmental pollutants, primarily due to endemic disasters that have occurred repeatedly. A review of the earlier literature on the Minamata outbreak shows how large-scale poisoning occurred and why it could not be prevented. With the repeated occurrences of MeHg poisoning, it gradually became clear that the fetus is much more susceptible to the toxicity of this compound than the adult. Thus, recent epidemiologic studies in several fish-eating populations have focused on the effects of in utero exposure to MeHg. Also, there have been many studies on neurobehavioral effects of in utero exposure to methylmercury in rodents and nonhuman primates. The results of these studies revealed that the effects encompass a wide range of behavioral categories without clear identification of the functional categories distinctively susceptible to MeHg. The overall neurotoxicity of MeHg in humans, nonhuman primates, and rodents appears to have similarities. However, several gaps exist between the human and animal studies. By using the large body of neurotoxicologic data obtained in human populations and filling in such gaps, we can use MeHg as a model agent for developing a specific battery of tests of animal behavior to predict human risks resulting from in utero exposure to other chemicals with unknown neurotoxicity. Approaches developing such a battery are also discussed. -- Environ Health Perspect 104(Suppl 2):367-379 (1996) "
Appropriate End Points for the Characterization of Behavioral Changes in Developmental Toxicology,
Vincenzo Cuomo (1), Maria A. De Salvia (1), Simona Petruzzi (2), and Enrico Alleva (2) (1)Institute of Pharmacology, University of Bari, Bari, Italy; (2)Behavioral Pathophysiology Section, Istituto Superiore di Sanità, Rome, Italy
"The present paper is devoted to second- and higher-tier test methods for the characterization of behavioral changes produced in rodents by exposure to noxious agents during development. The paper analyzes a series of end points that are informative about specific processes and underlying regulatory mechanisms but require greater technical sophisti cation and larger investments than first-tier end points. This applies to ultrasonic emissions in successive postnatal periods; to mother-pup interactions, including appropriate cross-fostering controls; to social (including sexual) interaction tests from the infantile to the young adult stage; and to a variety of conditioning and learning tests u sing both positive and negative reinforcement. -- Environ Health Perspect 104(Suppl 2):307-315 (1996) "
Neurobehavioral Aspects of Developmental Toxicity Testing,
Beate Ulbrich(1) and Anthony K. Palmer(2), (1) Bundesinstitut für Arzneimittel und Medizinprodukte, Berlin, Germany; (2) Huntingdon Research Centre, Huntingdon, Cambridgeshire, Great Britain
"Tests for detection of neurobehavioral changes in the offspring have been a regulatory requirement in developmental toxicity testing of drugs for almost 20 years. Keeping their purpose of hazard identification and risk assessment for humans in mind, investigators and agency reviewers have become deeply ingrained with some stereotyped behaviors with respect to such relevant issues as choice of animal species and data evaluation. Other problematic areas of study design and conduct, selection of litter representatives for testing, what methods to combine in a testing battery, and statistical treatment of results and their interpretation, will need more research and discussion in the future. -- Environ Health Perspect 104(Suppl 2):407-412 (1996)"
Animal Models in Alcohol Research
"Animals are used in alcoholism research for the same reasons that they are used in all medical research: to understand the causes of disease and to develop new treatments. Animals are used in three principal ways in research on alcoholism: to model the drinking behavior of human alcoholics, to learn from the brain and other organs of drinking animals how brain chemistry leads to a drinking behavior, and to study how alcohol damages organs. No animal model completely reproduces all the features of the human disease. On the other hand, individual features of alcoholism can be studied in animals in great detail. Moreover, the researcher has full control over experimental conditions such as nutrition, environment, species, and ancestry. This Alcohol Alert reviews animal research designed to answer questions pertaining to human alcohol use and abuse. "
The health and psychological consequences of cannabis use
"The following are the major possible adverse effects of chronic, heavy cannabis use which remain to be confirmed by further research:
  • an increased risk of developing cancers of the aerodigestive tract, i.e. oral cavity, pharynx, and oesophagus;
  • an increased risk of leukemia among offspring exposed while in utero;
  • a decline in occupational performance marked by underachievement in adults in occupations requiring high level cognitive skills, and impaired educational attainment in adolescents;
  • birth defects occurring among children of women who used cannabis during their pregnancies."
Profet, M. 1992. Pregnancy sickness as adaptation: A deterrent to maternal ingestion of teratogens. In Barkow, J. H., Cosmides, L., and Tooby, J. (eds.) The Adapted Mind: Evolutioanry Psychology and the Generation of Culture. Oxford University Press, NY.

Profet argues that "pregnancy sickness" (a.k.a., "morning sickness") is not a sickness at all, but an adaptive response to avoid potential teratogens. Its sympoms all cause the avoidance of aromatic foods. The aromatic nature of these foods was originally a signal that such foods contain compounds which can be dangerous.

Here is an abstract of Profet's argument

Copyright Dr. C.A.P. Kenyon 1994-2006