INTRODUCTION

For centuries, observations all over the world have shown that maternal drinking during pregnancy can have serious adverse effects on the health of the newborn and knowledge of alcohol-related birth defects dates back to old Biblical times: "Behold, thou shalt conceive and bear a son and now drink no wine or strong drink!" (1). Furthermore, in ancient Carthage and Sparta there were even laws prohibiting the use of alcohol by newly married couples in order to prevent conception during intoxication(2).

Much closer to modern times, in the 1720's, when the "gin epidemic" was rife in Britain, the Royal College of Physicians reported to the Parliament that parental drinking was a cause of "weak, feeble and distempered children"(3).

It took well over a hundred years before the House of Commons reacted, and finally came out with a paper entitled "Effects of Drunkenness on the Nation", which also contained a report on the effects of maternal alcohol consumption on the newborn, stating: "They tend to be born starved, shrivelled and imperfect in form" (4).

However it was not until 1967, in France, that Lemoine and his team first described in scientific terms a group of children affected by maternal alcohol abuse, which included defective intra-uterine and post-partum growth, unusual facial features, congenital malformations, such as cardiac defects, cleft palate etc. combined with mental subnormality (5).

These findings in France and, five years later, independent observations by Dr Jones and his colleagues from the United States, led finally to a recognition of a distinct dysmorphic condition associated with maternal gestational alcoholism named as Fetal Alcohol Syndrome (FAS), which has since become a clearly established clinical entity. (6-36)

Fetal Alcohol Syndrome

The most common characteristics of children born with FAS are as follows:

Growth abnormalities: Prenatal growth deficiency can be significant and includes all three of the following parameters of growth, weight, length and head circumference (2,20-24). Frequently the growth deficiencies are so severe that the newborn has to be hospitalised because of obvious failure to thrive (20). Postnatal growth and weight retardation is also significant and this continues for life despite the infant being reared in an ideal nutritional and social environment (21).

Craniofacial abnormalities: The eyes of the affected children are often small with exaggerated inner epicanthic folds, and squints are common in later years (21). The nasal bridge is usually poorly formed, giving the nose a small 'retrousse' appearance. The vertical groove running from the nose down to the upper lip tends to be shallow or absent, and the upper lip itself is often narrow. The ears tend to be large and somewhat simple in form (2,20-24). Cleft palate may also be present (21).

Musculoskeletal abnormalities: Variable musculoskeletal and limb defects are found in approximately 40% of cases, ranging in severity from minor problems such as contractures of the finger joints to more severe lesions, such as congenital hip dislocations and thoracic cage abnormalities (24). Genital abnormalities are also frequent, such as undescended testes and malformations of the lower wall of the urithera in males and hypoplastic labia in females. Minor kidney abnormalities have also been detected (21).

Cardiac abnormalities: Congenital heart disease is found in 29-50% of reported cases (26). They are commonly atrical or ventricular septal defects, but also complex and sometimes lethal cardiac abnormalities can occur (2,20-26).

Nervous system abnormalities: When first delivered, the affected infants may show clear evidence of alcohol withdrawal, with signs similar to delirium tremens in adults (27). They are often fretful, tremulous, have a weak grasp, poor eye-hand coordination and frequently a great difficulty with sucking and feeding. Cerebellar damage is also common, resulting later on in excessive clumsiness and even in recurrent seizures (21).

Neuro-developmental delay or mental deficiency: The average IQ in children born with FAS is around 65, indicating moderate mental handicap. Mental retardation also occurs frequently in varying degrees (21,28-30). In fact FAS is now recognised as the leading known cause of mental retardation, surpassing Down's syndrome and spina bifida (2,31,32). Around 70% of children with FAS are severely hyperactive, frequently engaging in disturbing self-stimulating behaviours such as body rocking, head banging or head rolling (22,33- 36). Without exception all children with FAS suffer from severe developmental disabilities. With the onset of school, these severe IQ and attention deficits, combined with various behavioural problems, emerge as serious intellectual and learning disabilities (22,28-30,33-39).

Adolescents/Adults with FAS: The natural history of FAS has now been traced into adulthood (39-41). When children with FAS approach adolescence, the specific craniofacial features associated with the syndrome are not as noticeable as in infancy. However, the short stature and microcephaly seem to be permanent. The average academic functioning of these adolescents and adults does not seem ever seem to develop beyond early school grade level, even though in one sample of 61 studied, 42% had IQ levels above 70 and all had received constant remedial help at school. A particular deficit was found in arithmetic skills and extreme difficulties with abstractions like time and space, cause and effect, as well generalising from one situation to another. The most noticeable behaviour problems were found to be with comprehension, judgement and attention skills, causing these adults born with FAS to experience major psychosocial and adjustment problems for the rest of their lives (41).

THE TERATOGENIC EFFECTS OF ALCOHOL:

Alcohol is a teratogen (2,42-48). There has been no teratogenic agent yet studied in man which has shown a clear threshold effect, i.e. where the substance could be considered safe at a particular level, beyond which its teratogenic effect begins to take hold, and alcohol is no exception (43).

That being the case, the teratogenic effects of alcohol can also induce fetal malformations both at the earliest, as well as at the lowest level of intake, its effectiveness spreading differentially over the whole spectrum of reproduction, affecting the developing fetus in varying degrees, in both extent and severity, depending on the dosage and timing.

This explains also why maternal alcohol consumption can affect the offspring through all gradations of teratogenesis, ranging from transient to very mildly affected, and from moderately affected right up to the full blown Fetal Alcohol Syndrome.

During transient teratogenesis the impact of the agent on the fetal tissue may not inflict permanent damage, as the substance can be degraded by the mother and fetal tissue in time, depending on genetic influences, susceptibility and maternal nutritional status (43).

Alcohol teratogenesis on structural development: Alcohol is a low molecular substance and is therefore quite capable of crossing the placental barrier and entering the fetus, causing the level of alcohol in the fetus to be approximate to that of the mother (48). In the first 21 days of the fetal development the preliminary cell organisation of the embryo begins to take place. If an excessive amount of alcohol is consumed before the blastocyst is embedded in the uterus, the impact can be so severe that the fetus is miscarried (45). By the end of the 36th day, often long before the woman even realises that she is pregnant, the neural tube is clearly present and open, and most of the rudimentary organs have already been formed, such as limbs, heart, brain, eyes, mouth, digestive tract etc.

It is therefore obvious that if a teratogenic substance such as alcohol is consumed during this most critical period of rapid growth of cell development and organ formation, this can result in various forms of malformation in the newborn, such as defective heart, musculoskeletal abnormalities, mental handicap etc., without any specific outward signs of FAS.

Even though it is considered that the first three months of gestation is the most critical period for alcohol-induced malformations to occur, both human and animal experiments have been able to demonstrate that the teratogenic effects of alcohol continues throughout the whole gestational period, affecting at the later stage particularly the brain development and function (20,42,45).

Alcohol teratogenesis in brain development:

Alcohol has the most detrimental effect on both brain development and function (45-50). The infant is not only born with a brain smaller in size, but the teratogenic effect of alcohol both reduces the number of brain neurons, as well as alters their distributution, resulting in mental deficiency in varying degrees, from milder behavioural problems to obvious mental handicap(21,29,48-50).

Animal studies have shown that while many areas of the brain are affected by maternal alcohol exposure, its effects seem to be particularly detrimental on the hippocampus (51-54), where it produces marked changes in its mossy fibres and 20% reduction in the pyramidal cells in the CA1 region, as well as a sparsity in the number of dendritic spines in the CA1 pyramidal neurons(51).

It has been therefore speculated that both the intellectual decrements and the behavioural deficits seen in infants born to mothers using alcohol during pregnancy may result directly from these specific hippocampal structural alterations (53).

Hundreds of experiments have been able to confirm that maternal alcohol consumption indeed causes irreversible brain alterations in both human and non-human infants, which also include abnormalities in EEG patterns (55-57), abnormal visual evoked responses (58), and both defective auditory brain stem (59) and spatial learning developments (60,61).

Autopsy reports on deceased patients with FAS have shown widespread anomalies, many of which have been associated with disruption in the migration and integration of neural and glial cells during embryogenesis(62).

In addition, other autopsy studies have shown that the nature and degree of brain malformations in children of alcoholic and heavy drinking mothers are extremely variable, suggesting that a wide variety of broad spectrum neurologic, behavioural and intellectual deficits would therefore also be found in survivors (62).

As only about half of the autopsied cases studied had enough physical characteristics to warrant a diagnosis of FAS, it seems now quite obvious that alcohol-related brain damage, as well as learning and behavioural deficits, do occur frequently in the absence of any external signs of FAS (62).

FETAL ALCOHOL EFFECTS:
The teratogenic effects of alcohol spreads differentially over the whole spectrum of reproduction, varying only in the extent and degree. At one end of the spectrum are the children warranting a firm diagnosis of FAS, and at the other end of the spectrum are the children who lack the common physical characteristics of FAS but who, nevertheless, have some subtle or marked physical and/or mental deficiencies by being exposed to varying amounts of alcohol in utero.

It is now widely accepted that the classical diagnosis of FAS is totally inadequate as for every child born with FAS there are thousands of others whose lives are partially handicapped , or limited, by being exposed to alcohol during gestational development. These children, without sufficient physical stigmata for firm diagnosis of FAS, are now identified as suffering from Fetal Alcohol Effects (FAE) (33).

Over the years a number of epidemiological studies have investigated both the physical and neurobehavioural effects of varying levels of prenatal alcohol exposure on both human and non-human infants. One of the foremost experts and contemporary researchers in this field is Dr Ann P. Streissguth, of the Department of Psychiatry and Behavioral Sciences at the University of Washington, who has researched, published and lectured widely on the teratogenic effects of maternal alcohol consumption (18,22,28,29,30,35,36,38,39,41,48,50,63,64,73,79,83,84,85,87,89,120).

From the year 1974 Dr Streissguth and her team began a seven and half year longitudinal, prospective, population-based study, examining the long term effects of moderate prenatal alcohol exposure on 486 infants born to mothers who had reported no major problems with alcohol but were, nevertheless, social drinkers i.e. reported consuming on average two or more drinks most days during pregnancy, or reported a "binge- pattern" of drinking e.g. consuming five or more drinks per any occasion in the month before pregnancy recognition. Only six out of the mothers interviewed felt that they might have used alcohol excessively during pregnancy.

The mothers were primarily white, married, middle class, and at low risk for adverse pregnancy outcome, and all were receiving prenatal care by the fifth month of pregnancy (63). This cohort sample of children, which included 261 boys and 225 girls, were first examined and evaluated on the first and second day after birth, and then approximately at eight and eighteen months, at four years, and at seven and at seven and a half years after birth(64).

FAE in infants and preschool children:

Most of these infants were born basically within normal limits as a group. However, the more the mothers had reported consuming alcohol, the poorer the overall performance of the newborns. Already, on the first day of life, the infants of the mothers who had been drinking more during pregnancy functioned significantly worse. They were usually born with lighter weight (65-68) and were more jittery and tremulous (66,69). They had difficulties with habituation, which is the ability to turn off redundant stimuli, considered as a basic nervous system function of the newborn (70-73).

On the second day of life they had a longer latency to begin sucking and had a weaker suck as measured on a pressure transducer with non-nutritive nipple (74,75). They also suffered from disrupted sleep patterns (76-78), low level of arousal, unusual body orientation, abnormal reflexes, hypotonia and excessive mouthing (48).

By eight months, and then onwards, these infants seemed to continue suffering from disrupted sleep-wake patterns, poorer balance and motor control, longer latency to respond, poorer attention, visual recognition and memory, decrements in mental development, spoken language and verbal comprehension, including lower IQ scores (36,79-86). As references indicate, these findings have also been confirmed independently by other workers.

FAE in young school-age children:

After seven years Dr Streissguth and her team re-examined the cohort of 486 children (48,64,87,88). The results showed that learning problems and classroom behaviour which were most negatively related to moderate alcohol exposure in utero were: co-operation, sustained attention, retention of information, comprehension of words, impulsiveness, tactfulness, word recall and organisational skills, all indicating increased risk of learning disabilities.

In fact, even though these children were within an average range of intelligence, their overall performance on arithmetic and reading tests were negative. It also became apparent that maternal drinking of two or more drinks per day on average, after statistically adjusting for appropriate covariates, was related to a 7-point decrement in IQ in these seven year olds.

Furthermore, that children of women who reported never drinking five or more drinks on any occasion in the month before pregnancy recognition, were on average one to three months behind in reading and arithmetic skills.

In addition 24% of these children were participating in special remedial programmes at school, compared to 15% of children of abstainers. This represents 9% excess of learning disabilities for children of mothers who had never been drinking five or more drinks on one occasion prior to pregnancy recognition.

These children were also found to have higher learning problem score of 17% compared to children of abstainers which was 7%.

The conclusion of this study was that two maternal alcohol use patterns have now been identified as being particularly detrimental to the offspring i.e. two or more drinks an average per day during pregnancy, and "binge-pattern" of alcohol consumption, e.g. five or more drinks on any occasion, particularly when consumed in the month so before pregnancy recognition, as both can lead to marked behaviour and learning disabilities in school-age children.

It was also concluded that these alcohol-related behaviour and attention decrements seem to have been already clearly observable from an early infancy, long before academic learning had even occurred.

Half an year later, Professor Streissguth and her team selected from the cohort study of 482 children, 384 subjects (89). The reason for the selection was because some tests were either added or modified after the initial testing had begun, therefore not all tests had been administered to all the 482 children.

One of the tests added was Children's Memory Test blocks, which had been completed only by these 384 children. The results showed that low-level prenatal alcohol consumption is most strongly related to attention and memory deficits across both verbal and visual modalities, poor integration and quality responses, as well as to negative behaviour patterns involving distractibility, inflexibility, and poor organisational skills. Also inadequate perceptual motor functioning was apparent.

This wide pattern of performance deficits uniformly occurred despite the presence of average IQ, suggesting that maternal alcohol induced behaviour decrements in the offspring seem to be a more sensitive indicator of central nervous system damage than the IQ scale itself. The study concluded that maternal social drinking seemed to result in the offspring having similar, but less severe consequences than those seen in children born with FAS, indicating in both cases, the clear occurrence of alcohol-induced permanent and irreversible central nervous system damage during critical stages of fetal development. FAE in adolescents and adults: As with children born with FAS, population based studies carried out on the offspring born to socially drinking mothers have shown that, on maturation, these children can still show subtle and permanent alcohol-related neurobehavioural deficits, IQ and achievement decrements, combined with various attention, memory and learning problems (36,39).

ALCOHOL AND MALE REPRODUCTION:

Alcohol is a direct testicular toxin (90). It causes atrophy of semeniferous tubules, loss of sperm cells, and an increase in abnormal sperms (91). Alcohol is also known to be a strong Leydig cell toxin (92), and it can have an adverse effect on the synthesis and secretion of testosterone (93,94). Alcohol can cause significant deterioration in sperm concentration, sperm output and motility (95,96). Semen samples of men consuming excessive amounts of alcohol have shown distinct morphological abnormalities (97,98). It has been also established that approximately 80% of chronic alcoholic men are sterile (99) and, furthermore, that alcohol is one of the most common causes of male impotence (100).

ALCOHOL AND NUTRITIONAL STATUS:

Numerous animal studies of experimental alcoholism, where nutritional status has been well controlled, have shown that the damage to the developing fetus, such as low birth weight, central nervous system impairment and congenital abnormalities, are caused as a direct consequence of the teratogenic effects of alcohol. In addition, some of these studies have also been able to show a clear continuum effect; the higher the blood alcohol of the mother, the greater the damage to the developing fetus (2,66,101-111).

Even though the direct connection between alcohol intake and birth defects is now indisputable, other etiological factors associated with maternal drinking must also be considered as contributing to adverse pregnancy outcome.

The most important of these secondary factors is alcohol-induced malnutrition, as nutritional deficiencies occur frequently with alcohol intake, due to reduced appetite. However, in cases where nutritional food intake is adequate, alcohol still considerably reduces nutritional status by directly interfering with nutrition utilization, digestion and absorption, as well as greatly increasing urinary excretion of both vitamins and minerals. Alcohol-induced zinc depletion is particularly well documented (112-115). This could be of a particular importance, as some studies on human pregnancies have shown a positive correlation with reduced zinc status and low birth weight and fetal malformations, suggesting that inadequate zinc nutriture could also act independently as a teratogenic agent (115-118).

In addition, folic acid deficiency, which results from alcohol-induced urinary excretion, has been linked directly with the occurrence of spina bifida (119). Besides direct malnutrition, other secondary metabolic disturbances due to alcohol consumption may also contribute to an adverse pregnancy outcome, such as alcohol-induced hypoglycaemia, ketoacidosis, as well as various alterations in both lipid, and amino acid metabolism.

SUMMARY:

There is now an ever-increasing recognition that alcohol is the most common chemical teratogen presently causing malformations and mental deficiency in the human offspring (20).

In 1977 the following statement was made by Dr Ernest Noble, Director of the National Institute of Alcohol Abuse and Alcoholism of the United States: "The Fetal Alcohol Syndrome is the third leading cause of mental retardation and neurological problems in infants, ranking after Down's syndrome and spina bifida" (31). Several other investigators have also recognised maternal alcohol abuse as being one of the leading causes for the occurrence of mental retardation in children in the Western world (6,33,42,66,120-122).

In addition, it has been estimated that maternal alcoholism may be responsible for at least 10% of all infant congenital malformations (20,42). The true figures of maternal alcohol- induced infant damage is obviously difficult to assess, especially in cases of Fetal Alcohol Effects, where the deterioration is infinitely more subtle than seen in the cases of Fetal Alcohol Syndrome.

However, it has been estimated that the incidence of Fetal Alcohol Effects occurs in at least 3-5 of 1000 live births, whereas Fetal Alcohol Syndrome has been found to be present in approximately 1-2 of 1000 live births (32,120,123).

As stated previously, alcohol is a poison at all levels, and therefore no totally safe level of alcohol use during pregnancy can be established. Alcohol-related damage to the fetus has been linked with every form of drinking pattern, from heavy drinking to intermittent as well as moderate social drinking i.e. one or two drinks daily most days during pregnancy; and from very infrequent, but relatively heavy, drinking to one single drinking binge prior to pregnancy recognition.

The teratogenic effects of maternal "social drinking" is considered less detrimental to the fetus than that of abusive drinking, but it can still nevertheless affect the infant, maybe in a less serious but much more subtle manner.

The infant may be born with lighter weight, suffer from difficulties with habituation, feeding, and disrupted sleep-wake patterns. By eight months onwards to young school age, the children born to social drinkers seem to show poorer balance, motor control, attention, visual recognition, memory, sleep patterns and mental development than infants born to non-drinking mothers. When at school, the academic performance and IQ of these children seem to be generally below average. In addition, overall classroom behaviour of these children have been found to be negatively related to: co-operation, retention of information, comprehension of words, memory, impulsiveness, tactfulness, word recall, organisation, as well as attention skills, all indicating increased risk in learning abilities.

On maturation and as adults, these children born to social drinkers showed still subtle, but permanent, alcohol-related neurobehavioural deficits, including IQ and achievement decrements, as well as attention, memory and learning difficulties.

In summary, it now seems to be evident that maternal social drinking results in the offspring having similar, but less severe consequences, than those seen in children born with Fetal Alcohol Syndrome. This finding is not unexpected, as the toxic effect of alcohol can damage the fetus permanently and irreversibly through all gradations of teratogenesis.

During the 1990 Betty Ford Lecture Dr Streissguth stated: " In summary, every community should know the following about alcohol and pregnancy: There is no known safe level of alcohol consumption during pregnancy. Pregnant women should be advised to abstain from drinking during pregnancy and when they are planning a pregnancy. Even social drinking during pregnancy, or before pregnancy recognition, can put children at increased risk for learning problems at school, even though their mothers did not report any serious alcohol related problems..." (120)

CONCLUSION:

Patterns of alcohol use are changing, with more and more teenagers consuming alcohol regularly. There is all the more cause for concern as research has shown that, in recent years, regular alcohol consumption has increased alarmingly among the female population, and particularly among younger women and teen-age girls. Because of this sharp rise in alcohol consumption among women in childbearing years, information and advice about the dangers of maternal alcohol intake must be widely disseminated among the general public.

In order to achieve this, the following steps should be taken forthwith:

1. Local Education Authorities should include in their health education curricula specific information about the dangers of alcohol consumption during pregnancy.

2. Information leaflets about the potential risks to the fetus associated with maternal and paternal alcohol consumption should be widely distributed and available in all doctors' surgeries, hospital waiting rooms, family planning clinics etc.

3. The Government should instruct the alcohol industry to display clear warning labels, similar to those seen today on cigarette packets, indicating that alcohol damages the unborn baby.

The most salient point that can be made about alcohol induced fetal damage is that it is totally preventable, and by informing both prospective parents of the potential dangers of alcohol consumption before conception, and particularly all women during pregnancy, we can hope to control the problem. It is frightening to realize how long the knowledge has been there that alcohol indeed damages the unborn child, without anyone seemingly worrying about it. If we could effectively foster the simple fact that "mothering from conception is direct mothering", and therefore that everything the mother consumes during pregnancy is also consumed by the developing child, some of these tragedies might be more easily avoided. This would also be a major philosophical advance towards the great importance of preventive medicine.

ACKNOWLEDGEMENTS

This study was supported by a grant from FORESIGHT, The Association for the Promotion of Preconceptual Care, 28 The Paddock, Godalming, Surrey GU17 1XD. A special recognition is given to Dr Ann P. Streissguth who has fought tirelessly to draw attention to the dangers of maternal alcohol intake during fetal development.

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