Prevention, Recognition and Management of Fetal Alcohol Spectrum Disorders

This book presents clinical assessment and management solutions for those people who are exposed to Alcohol in Pregnancy. Over the last few decades we have begun to understand the enduring effects of prenatal alcohol exposure on the developing fetus. The consequence of prenatal alcohol exposure - Fetal Alcohol Spectrum Disorders is a lifelong disorder and affects children and adults. It is a condition which is significantly under-recognised for many reasons. Assessment and diagnosis requires the input of multiple different professionals, and referral pathways are often poorly developed or non-existent.  Information to support and guide these professionals in practical ways, what to do and how to help, remains limited. This book seeks to fill some of that gap by offering professionals, clear and useable research-based information and guidance that will help in their practice whilst also being a useful resource for anyone new to this increasingly recognised area of work.

The book is divided into four broad areas bringing together chapters authored by experts in their field including those with lived experiences. Part one focuses on presenting an overview of the condition, and approaching women about their alcohol use and risk followed by part two focusing more around diagnostic issues. Part three follows with management advice, and part four revolves around policy and health prevention in general. Each chapter is designed to offer insight but also practical tips and support in an accessible manner. The book offers an essential guide for a broad range of health and social care professionals working with this condition.

• Language: English
• Publisher: Springer
• Release date: Jul 31, 2021
• ISBN: 9783030739669

Book preview

Part IIt Starts at the Very Beginning

© Springer Nature Switzerland AG 2021

R. A. S. Mukherjee, N. Aiton (eds.)Prevention, Recognition and Management of Fetal Alcohol Spectrum Disordershttps://doi.org/10.1007/978-3-030-73966-9_1

1. Section 1 Overview: The Importance of Stories

Neil Aiton¹   and Raja A. S. Mukherjee²  

(1)

The One Stop Clinic, Royal Sussex County Hospital, Brighton, UK

(2)

National FASD Specialist Behaviour Clinic, Surrey, UK

Neil Aiton

Email: [e-mail]

Raja A. S. Mukherjee (Corresponding author)

Email: [e-mail]

1.1 FASD: The Stories Which Need to Be Told …

History is who we are and how we are made. (David McCullough)

History is important—for individuals and for cultures, as well as for civilisations. Storytelling has become part of the innate way we, as humans, respond to and interact with each other. Stories by their nature have to be understood, remembered and shared. The storage and gradual accretion—as well as the shared understanding of those memories—are what build us into who we are as individuals and help define how we relate to others and to the world around us. The shared experiences re-lived in the telling of common stories of special or significant events help bind us together in society.

Books often contain stories, and in many ways, although this book is not a story book—as well as containing a collection of different stories—it does indeed tell its own powerful story: the story of FASD. Amongst the scientific references, the research studies and the prose lie glimpses of the real people whose stories need to be told. The centrepiece of that story is, of course, how these peoples’ lives are continuing to be affected by the lifelong consequences of exposure to alcohol during fetal life. We are especially grateful to one individual, Lee, for contributing a chapter describing his own perspective. However, his story, although unique, can be seen in part, as representative of so many others. The individual chapters when taken as a whole unveil the way that prenatal alcohol exposure impacts so many aspects of the way we function and interact as humans, and the challenges that arise—not only in assessment and diagnosis but also in understanding the unique nature of each individual who has been affected.

Then there is the story of the research itself and how that is progressing in so many different areas, so that we are able to find better ways to understand, prevent, diagnose and help those who are affected. Unfortunately, a book such as this only tells the story up to a certain point, but this story is continuing. Behind all of these research studies also lie the researchers themselves who have their own stories too, about how they first became involved and captivated by the importance of studying and researching this subject, as well as motivated to continue in the field.

Of course, the fundamental point of telling the story about FASD is to lead us to the position where we are able to prevent the problem from happening in the first place. Stories and experiences from other conditions where there are important adverse outcomes (death or lifetime disability) from a theoretically preventable problem such as leprosy, smallpox or TB have taken decades to progress. In a similar way, the societal change over the attitudes, prevalence and legal framework regarding smoking has taken decades to achieve since the severe adverse outcomes first became known in the 1960s and 1970s.

Chapter 2 begins with the story of how the historical understanding has developed regarding the effect of alcohol on the unborn child during pregnancy. Although most accounts about the historical aspect of FASD start with the classic paper by Jones et al. from 1973 [1] (and often ignoring a prior paper by Lemoine [2] because that story was told in a different language), it is likely that the dangers of alcohol consumption in pregnancy were not widely known earlier than this, just as even now this is not universal knowledge. There were concerns in the UK prior to the introduction of the gin laws in the 1750s, and also in Victorian times, although these were mostly around morality and social disorder. The story about the introduction of the gin laws and associated taxation has also largely been forgotten but this narrative can be compared very closely to modern attitudes and potential impacts with respect to the relatively recent arguments concerning the ‘minimum unit pricing’ taxation of alcohol [3, 4]. Of course, this is why these stories need to be told along with the ones in this book, so that we don’t ‘forget’ again, and so that understanding and attitudes can eventually be changed.

Our own collective, cumulative, shared knowledge and experience in the field of FASD brings a moral imperative to strive to do anything we can to prevent this problem and overcome the barriers to change. Chapter 3 introduces the issues involved when considering the balance between the rights of the developing fetus and that of the mother, which have to be carefully considered as we attempt to address this problem: in particular to avoid the risk of unintentional harm to the fetus or the mother. Confusion over what the research shows and how this can be interpreted from different standpoints brings many challenges to how that conversation progresses. The importance of hearing others’ perspective, as well as their stories, in the process of telling our own is highlighted—leading to a position of mutual understanding from which beneficial change can grow. If we wish to successfully invoke change, we must make sure that despite any sense of frustration, we hold back from ‘shouting’ our stories too loudly and respect the positions of others. In telling our stories, we must also learn to frame them in ways which are mostly likely to be receptive to and gain traction with those whom we are addressing—in other words, pay more attention to the art of storytelling.

Sometimes, perhaps researchers are not particularly good at communicating their stories—it is after all a different skill. However, in competing against other priorities within the cacophony of all the other stories, it is important that the story presented is crafted well and able to stand out against the competition, whether applying for funding or in disseminating findings. There are others who are well-versed in the craft of ‘storytelling’ such as journalists who can help, but we must remember that they will be viewing the topic through a completely different lens, looking for the best angle, the most newsworthy detail or an interesting ‘hook’ to give a story greater character—and thus all the better when told and re-told. The party game when a message is passed around a circle in whispers (also called the ‘telephone game’) is well known but illustrates the point that after a story has been told, there is no control over what happens to it. For researchers who are struggling to discover and establish ‘truth’, particularly when findings are small and incremental, this apparent distortion of their normal paradigm can cause significant discomfort. It can also lead to miscommunication as in the example at the end of Chap. 3.

Consider, too, the far-reaching implications when there are gaps in our stories. Those who work within the field of ‘children, looked after’ within the care system and adoption will know this very well, along with those who may have been adopted themselves. As humans, we naturally search for meaning and context in our lives. The journey we are travelling on through life is one that has to have a beginning as well as an end: where did we come from and where are we going? What if we don’t have people around us who are able to tell us our early stories, or even those stories that preceded them, to fill in the gaps before we developed our own conscious memories? Aside from the existential questions, it is clear that when that beginning is missing, there are powerful urges to try to fill in those gaps. Later chapters on children in care and adoption touch on some of these issues and the problems springing from lost information in trying to help these children in the best way as they face the challenges of growing up and establish their own new independent story.

Continuing the same theme, there has been increasing evidence that our early stories right at the start of lives are so important in shaping us, and that we can live out the consequences of these experiences for the rest of our lives [5]. These early events can cause changes in the nervous and endocrine systems which respond and adapt to those experiences way before the development of conscious memory, and possibly even during prenatal life as well [6]. Although our current state of knowledge in this area is in its infancy, it is extremely likely that prenatal alcohol exposure has a significant additional part to play in addition to the resulting neurobiology which has already been uncovered. The product of these changes means that those individuals face their future life with a nervous system which is ‘wired differently’ and therefore responds differently to external events compared with others, with additional long-term impacts on mental health through the lifespan. There is also a chapter looking at how those early stories are intertwined with parenting and combine to influence the process of attachment which can also have far-reaching implications down to the next generation.

How we parent our children is the product of many complex factors, but those who work with pregnant women and in the fields of substance use cannot escape the observation that a great many of the women who are dependent on alcohol or use alcohol as a coping strategy in daily life themselves have complex and often traumatic early stories to tell. These stories really do need to be heard more widely in society, so that we can move away from a culture which very easily tends to blame and victimises ‘women who choose to drink’ towards one which is able to understand, support and encourage change. Statistics and figures about alcohol and deprivation (it is a common misapprehension that these two words are always associated) are important to collect, from a public health and political perspective because unless we understand the nature and size of problems, it is difficult to gauge progress when trying to effect change. The danger which can arise from just looking at statistics alone is that of de-personalisation and discrimination: here, individual stories can help with a wider understanding because they bring out the personal experiences and humanity of those managing to live, thrive and survive (or perhaps not?) despite significant adversity.

Of course, we don’t have a right to hear people’s private stories: we all own our own stories and can make choices about who to share them with. Often these stories are too intimate and private to be shared widely, and to share these type of stories takes trust. Many women who have used alcohol and/or other substances over long periods of time have experienced significant discrimination. This discrimination can be personal or institutional and intended or unintended. They have often learned to become suspicious and highly sensitive to what they perceive to be discrimination as well as judgemental attitudes. This leads to mistrust of professionals and institutions, and with that an understandable reluctance to share their story, or even part of their story. A common narrative for this type of experience is ‘I’ve been let down before, why should this be any different?’ There is a great need to understand and attempt to break down these barriers, but this is impossible unless there is provision for their stories to be heard.

The chapter on talking to pregnant women provides practical advice on trying to communicate, be ‘real’, show empathy and encourage women to ‘tell their story’, so that we can have a true and honest conversation with them about their pregnancy, and most importantly—for those individuals who may need it—how we can offer to help. It must also be remembered that because alcohol is so ubiquitous in our society, the knowledge that drinking alcohol in pregnancy can have profound and long-lasting effects is by no means universally known. Hence the importance of asking at initial pregnancy booking—not just about the current pattern but also about their knowledge and understanding, remembering that even women who do not drink alcohol regularly may drink significant amounts on special occasions or crises without the knowledge they could inadvertently be causing harm.

During pregnancy, how the fetus develops is itself a seemingly miraculous story about carefully choreographed patterns of cellular growth, any of which can be potentially interrupted or altered by the presence of alcohol. It is those within the nervous system which have the greatest impact and long-standing consequences as told in many of the chapters in this book. Detailed knowledge of fetal development helps us understand the timing of impacts and give better understanding of the relationship of exposure to potential future outcome.

There is an irony that although the first descriptions about FAS were of newborns [1], it is currently extremely difficult to diagnose this problem in the new-born period using the currently available diagnostic frameworks. There is an urgent need for more detailed longer-term follow-up studies to investigate the relationship between exposure, early findings and biomarkers, which will help as useful predictors of future outcome. The encouragement to pursue this is the emerging evidence that earlier identification of FASD can help improve outcome. So the ending of stories isn’t necessarily already determined at the beginning but has the potential to be changed along the way, rebutting a commonly held nihilistic fallacy (often used to justify inertia) that ‘there’s nothing thing that can be done anyway’.

Finally, we do like stories to have a ‘happy ending’. The moral imperative to find better answers, to help those affected by alcohol in pregnancy as well as those affected by FASD in better ways, and to be better at preventing this problem in the first place means that this is an unfinished journey. A common journey on which all of us who have been impacted by our experience and understanding about FASD are bound together. We are privileged to build on the stories of those pioneers who first opened our eyes to this topic (too many to mention, and with the potential risk of accidental omission!). Looking back from the future to this present time, we too will be considered to have played our part in that journey—but will we have done enough? History will eventually have to make that judgement, but in the meantime, there is increasing hope, and still much to be done. The true happy ending to this story will be when (like polio) this problem has been virtually eliminated.

References

1.

Jones KL, Smith DW. Recognition of the fetal alcohol syndrome in early infancy. Lancet. 1973;302(7836):999–1001. https://​doi.​org/​10.​1016/​s0140-6736(73)91092-1. PMID: 4127281.CrossrefPubMed

2.

Lemoine P, et al. Les Enfants des parents alcholiques: anomalies observes a propos de 127 cas [The children of alcoholic parents: anomalies observed in 127 cases]. Quert Med. 1968;8:476–82.

3.

Abel EL. The gin epidemic: much ado about what? Alcohol Alcohol. 2001;36(5):401–5. https://​doi.​org/​10.​1093/​alcalc/​36.​5.​401.CrossrefPubMed

4.

Dillon P. Gin: the much lamented death of madam Geneva the Eighteenth Century gin craze. London: Justin, Charles & Co; 2004. p. 263. ISBN 1-932112-25-1.

5.

Larkin H, Shields JJ, Anda RF. The Health and Social Consequences of Adverse Childhood Experiences (ACE) Across the lifespan: an introduction to prevention and intervention in the community. J Pre Interv Commun. 2012;40(4):263–70. https://​doi.​org/​10.​1080/​10852352.​2012.​707439.Crossref

6.

Brandon AR, Pitts S, Denton WH, Stringer CA, Evans HM. A history of the theory of prenatal attachment. J Prenat Perinat Psychol Health. 2009;23(4):201–22.PubMedPubMedCentral

© Springer Nature Switzerland AG 2021

R. A. S. Mukherjee, N. Aiton (eds.)Prevention, Recognition and Management of Fetal Alcohol Spectrum Disordershttps://doi.org/10.1007/978-3-030-73966-9_2

2. Overview of FASD: How Our Understanding of FASD Has Progressed

Alan D. Price¹  

(1)

School of Health and Society, University of Salford, Salford, England

Alan D. Price

Email: [e-mail]

Chapter Highlights

Provides an overview of the background and history of fetal alcohol spectrum disorder (FASD)

Reviews the mechanisms by which prenatal alcohol exposure can lead to FASD

Describes evidence on low-level exposure and social determinants of alcohol-exposed pregnancies

The contemporary investigation into the impact of prenatal alcohol exposure is most often traced back to a series of articles by Kenneth Jones and colleagues at the University of Washington in the early 1970s [1–3], and to a lesser extent, to an article published in French 5 years earlier [4]. However, these publications have been described as rediscoveries of the harmful effects of alcohol on pregnancy, and such knowledge may have existed for hundreds or even thousands of years.

The earliest known warning concerning alcohol and pregnancy appears in the Old Testament Book of Judges, which is thought to have been written during or before the sixth century bce. The Angel of the Lord appears to the Wife of Manoah to inform her that she will become pregnant, and warns her, amongst other instructions, to ‘… drink no wine, nor other fermented drink …’ [5]. The woman gives birth to Samson, who becomes renowned for his strength and intellect. Whilst some have suggested that this represents knowledge of the harmful impact that alcohol may have on an unborn baby [6], others have argued that this may not be the case, and that the instructions were most probably given to ensure that proper religious rites were followed [5, 7].

Similarly, the following quote has been attributed to Aristotle (384–322 bce): ‘Foolish, drunken, or haire brain women most often bring forth children like unto themselves, morose and feeble’ [8], and has often been held as evidence that the Ancient Greeks had at least a rudimentary knowledge of the ill effects of alcohol consumed during pregnancy [4, 9]. However, it later became apparent that renaissance scholar Robert Burton fabricated the quote, along with several others, in The Anatomy of Melancholy (1621). Aristotle did in fact discuss the influence of alcohol on conception in Problemata (reprinted 1927), but only in terms of its effect on the male libido, and that as a result of cooling the male body prior to intercourse, a couple might have the ‘misfortune’ to conceive a girl [7, 8].

There is little evidence of attention to the issue of prenatal alcohol exposure between these ancient clues and the end of the 1600s, when the abolishment of a monopoly on distillation in England coincided with a levy on the import of French brandy. By the early 1720s, the price of domestically produced gin had fallen so sharply that the working classes could afford to consume several pints each of the strong liquor per year [9, 10]. During the next 30 years, the widely documented public drunkenness on the streets of the English capital became known as the ‘London gin epidemic’. Several observations [9] have been documented from that era, which appear to show that physicians were well aware of the harm that alcohol was having on unborn babies:

Half the train of chronical diseases with which we see children afflicted are only the secondary sighs and groanings … of parentive ill-spent life. These consequences … will be brought on infants by the debauchery of the Mother. [11]

What must become an infant, who is conceived in gin? With the poisonous distillations of which it is nourished, both in the womb and at the breast. [12]

… the enormous use of spirituous liquors … renders such infants as are born meagre and sickly, and unable to pass through the first stages of life. [13]

Such quotes have generally been held as fairly strong evidence that the dangers of prenatal exposure to alcohol, or at least to gin, were well known during the early to mid-1700s [9, 14, 15]. Others have noted that these complaints about drunkenness only applied to the ‘inferior classes’ [16, 17]. Many social and economic forces influenced the lives of the working classes, the health of their children, and how they were perceived by upper-class physicians and politicians. It is also interesting to note that cheap, home-made gin was widely available on the black market, especially after a tax rise in 1736, which often contained additives such as sulphuric acid, lime oil and turpentine [18], and that prenatal exposure to turpentine has recently been shown to damage neurobehavioural functions in rats [19]. Exposure to turpentine, or other chemicals in bootleg gin, during the eighteenth century could, therefore, go some way to explain the problems seen in working-class children born during this time.

During the nineteenth century, public attitude towards alcohol in Europe and North America became more negative, fuelled in part by the temperance movement. The first epidemiological studies on alcohol’s harmful effects were published, such as Sullivan’s [20] study of 120 pregnant inmates at a Liverpool women’s prison. Maternal alcoholism was found to be associated with a higher rate of stillbirth or infant mortality than in cases where mothers had been denied alcohol. Sullivan also noted that paternal and grandparental alcoholism were less damaging than maternal exposure [7]. Such research was supported by, and conducted in support of, the temperance movement, whose attitude towards alcohol was based primarily on religious teachings [7]. Prohibition of alcohol in the United States was accompanied by often sensational claims about the harms of alcohol and dependency, so much so that following the end of prohibition in 1933, warnings about the harmful effects of alcohol were largely denounced as propaganda. Any previous research that supported the temperance view of alcohol was effectively discredited, and more recent findings pertaining to prenatal alcohol exposure were met with some incredulity by clinicians [7, 10].

In the second half of the twentieth century, a doctoral thesis and a related journal article, both written in French [4, 21], described physical and behavioural deficits in over 200 babies born to alcoholic mothers. The authors noted the impact of prenatal exposure to alcohol on the developing foetuses, but neither article managed to make an impact [6, 22]. The issue remained hidden until 1970, when Christie Ulleland, a junior paediatrician at the University of Washington School of Medicine, noticed that maternal alcoholism was a factor in a significant number of infants suffering with failure to thrive. She wrote that:

These observations indicate that infants of alcoholic mothers are at high risk for pre- and post-natal growth and developmental failure, and suggest that greater attention should be given to alcoholic women during the child bearing years. [23]

This brief statement is arguably the true source of the modern investigation into the effects of prenatal exposure to alcohol. Eight of those infants from alcoholic mothers suffered from microcephaly, stunted growth, developmental delay, short palpebral fissures, joint anomalies and small jaws. This collection of defects was given the name Fetal Alcohol Syndrome and received global recognition in a series of articles written by Ulleland’s colleagues Kenneth Jones and David Smith, whose names have become synonymous with the first descriptions of Fetal Alcohol Syndrome [1–3].

There was initial scepticism that such a ubiquitous substance as alcohol could do so much damage without having come to the attention of medical professionals. Since alcoholism frequently coincides with malnutrition, poverty and a chaotic home environment, many suggested that these environmental risks could explain a range of birth defects just as easily as alcohol [2, 10]. A steady increase in research attention mostly diminished these concerns, although the interaction between prenatal alcohol exposure and early environmental risk is still not fully understood [24]. Animal models provided experimental evidence of the harmful effects of alcohol [25, 26], even finding the same distinctive facial anomalies in mouse pups as those described by Jones and colleagues in human infants. Meanwhile, human epidemiological studies [27–29] provided evidence of prevalence, range of outcomes, and began to demonstrate a link between the level of consumption and the severity of outcome.

In the time since this increase in attention to the issue, the harmful effects of alcohol used during pregnancy have become better understood and widely known to the general public, at least in societies where alcohol is widely used. Government warnings to reduce or avoid alcohol consumption during pregnancy in the United States in the 1970s and 1980s were followed by similar warnings in other Western countries, but the extent to which these warnings are having the desired effect is the subject of some debate [10, 30].

Alcohol is a teratogen—an agent that causes malformation to an embryo or fetus. There are several mechanisms by which alcohol can impact fetal development, as well as an increasing number of techniques that may be used to investigate these effects. Prenatal alcohol exposure (PAE) can impact the development of the whole fetus, and exposed individuals can present with structural damage to such areas as the digestive system [31], skeleton [32], heart [33], eyes [34] and the immune and endocrine systems [35].

Alcohol consumed during pregnancy enters the mother’s bloodstream, passes freely though the placenta, and into the fetus and amniotic fluid [36]. In adults, alcohol is metabolised by a pair of enzymes called cytosolic alcohol dehydrogenase (ADH) and hepatic CYP2E1. These enzymes begin to appear in the individual during gestation, but do not reach maximum efficacy until well into childhood [37]. Instead, the main elimination method available to the fetus is transfer of alcohol back into the maternal bloodstream, but this is a complex process which can be impeded by alcohol-related constriction of blood vessels [36]. For these reasons, elimination of alcohol from the fetal compartment only occurs at around 3–4% of the maternal rate, which leads to prolonged fetal exposure [38].

Whilst in the fetal compartment, alcohol can disrupt the development of the fetus via a number of mechanisms. Apoptosis is the process of programmed cell death, which is usually beneficial and necessary in organic growth, but this process can be inappropriately initiated or supressed by some diseases or exposures to exogenous substances including alcohol [39, 40]. Apoptotic cell death due to alcohol exposure has been demonstrated in animal fetus models [41, 42], animal infant models [43, 44] and in vitro cell culture experiments [45, 46]. This process is seen in the adult human liver following alcohol consumption [47], but may be particularly harmful during fetal development since alcohol here is metabolised more slowly and since damage to cells during organogenesis can lead to improper development of those organs [36].

Alcohol can induce apoptosis by promoting the generation or inhibiting the elimination of reactive oxygen species (ROS)—unstable molecules formed during metabolic processes, which can react with many other molecules including those involved with cellular processes such as DNA and proteins [47]. Moreover, alcohol exposure can reduce the number of antioxidant cells, whose functions include elimination of ROS [47]. Raised levels of ROS can lead to uncontrolled apoptosis, and animal models have suggested this as a mechanism for the characteristic craniofacial and neurodevelopmental abnormalities seen in FAS [48, 49]. Linked to this is the effect of alcohol on mitochondria, which are organelles present in all cells and are crucial to oxygen and energy production within the cell. There is evidence from rodent models that prenatal alcohol exposure can lead to apoptosis via mitochondria damage [50].

Besides direct impact on cellular processes, PAE may affect gene expression. DNA molecules are present in every type of cell, and contain essentially the same information, most of which will be unnecessary to the functioning of a given cell. Epigenetic markers are molecules that develop during gestation and attach to DNA molecules, and whose role is to activate or inhibit certain genes or groups of genes, ultimately controlling gene activity [51]. Various environmental factors can influence epigenetic markers and gene expression, sometimes resulting in adverse outcomes such as cancers [51]. There is emerging evidence from animal fetus and cell culture studies that PAE can alter epigenetic markers, resulting in widespread changes in gene expression [52]. Moreover, recent human clinical studies have shown expected epigenetic differences in children with fetal alcohol spectrum disorder (FASD), which support the role of epigenetics as a mechanism for PAE-related harm in humans [53, 54].

Alcohol-related damage to cells in the developing fetus is especially harmful for the developing brain, which develops throughout gestation and is therefore vulnerable to alcohol exposure during the entire pregnancy. Within the brain, however, different structures may be especially at risk during different periods, and this may explain some differences in FASD presentation. The rudimentary structures of the brain and nervous system begin to develop during the embryonic period, which lasts from conception to about 8 weeks gestation. The primitive brain provides the basic plan for development but continues to develop across the whole pregnancy and into the postnatal period. The brain first begins to form as a tube, which forms into sections that become the forebrain, midbrain and hindbrain. At around 4–8 weeks gestation, the first fissure of the brain starts to form, and this separation produces the two hemispheres of the cortex. The further sulci and gyri (grooves and ridges) of the cortex continue to develop until the late stages of pregnancy, at Weeks 23–35 [55]. The brain areas whose development is more active during the first trimester, such as the midbrain and the limbic system, which are associated with emotional and instinctive processes, may be more susceptible to harm during this time, whereas the cortical areas, which undergo more development later on, may be more at risk during the second or third trimesters. Some evidence for this comes from studies of the timing and pattern of alcohol exposure in humans. Alcohol consumption during the first, rather than second or third trimesters, has been shown to be associated with increased emotional difficulties [56, 57]. Craniofacial effects such as the thin vermillion border, smooth philtrum and microcephaly have been shown to be dependent on specific exposure times, such as gestational days 19 and 20 in non-human primates [58] and in the second 6 weeks of gestation in humans [59].

Children prenatally exposed to alcohol can present with a wide variety of physical, cognitive and behavioural problems, and to varying degrees. The relative breadth and severity of deficits are associated with a number of risk and protective factors which contribute to the impact of alcohol on a developing fetus. The most influential of these is the drinking behaviour of the expectant mother. Consistently high levels of alcohol consumption throughout pregnancy and/or episodes of binge-drinking (more than 6 units per session for women [60]) are associated with severe cognitive deficits [61], behavioural disorders [62] and structural cortical abnormalities [63] in humans. Animal models have shown that high-dose alcohol exposure causes severe neurodevelopmental deficits in primates and rodents [64]. Results from studies into the impact of mild to moderate PAE in humans are less consistent, with some studies failing to find a significant detrimental effect on pregnancy outcome [65] or cognitive and behavioural development [66]. However, a recent meta-analysis found a small association between moderate PAE and behavioural issues in children [61], and a meta-analysis of high-quality studies showed an effect on cognitive outcomes and birthweight [67].

The mixed results of studies into low to moderate PAE may be partly due to the influence of confounding variables. True experiments in humans, where pregnant women are randomly assigned to consume alcohol, would be deeply unethical. Therefore, research is limited to observational designs such as case-control or cohort studies, which are susceptible to confounding variables [68]. For example, women who drink low to moderate amounts of alcohol during pregnancy tend to be more affluent than women who never drink and women who drink more heavily, and affluence is associated with advantages in offspring such as higher levels of intelligence and academic achievement [69]. Factors such as affluence could, therefore, partly explain the mixed results of studies into low to moderate alcohol exposure on cognitive functioning in school-age children. One technique that can bridge the gap between observational studies and experimental studies in humans is Mendelian randomisation. Named after early geneticist Gregor Mendel, this technique relies on the random distribution of genes from each parent to their offspring. This leads to random variation within the population of genetic determinants of behaviour, including alcohol consumption. Variations of a gene that controls the production of alcohol dehydrogenase—rs1229984 (ADH1B)—have been shown to predict alcohol consumption before and during pregnancy [70] and are considered the most useful tool to conduct quasi-randomisation to conditions of varying PAE in humans [71]. Studies that have employed this technique have demonstrated significant incremental differences between moderate, low and zero alcohol exposure in pregnancy, where higher exposures were associated with deficits in intelligence and academic achievement [71], early-onset persistent conduct problems [72] and atopic conditions such as asthma, hay fever and eczema [73].

There is some evidence of a genetic component in the teratogenic effects of alcohol. For example, PAE has been experimentally shown to have differing effects on five distinct inbred strains of mice [74]. One strain showed severe global physical defects following maternal prenatal intubation of alcohol, whereas another strain showed no teratogenesis and the remaining three strains showed intermediate effects. A mechanism for these kinds of results may be the variation in the rate of maternal or fetal metabolism of alcohol; the efficacy of enzymes such as those mentioned above—ADH and CYP2E1—may be largely the result of genetic variation in humans as well as animals [75]. At least one human twin study has supported the role of genetics, with monozygotic alcohol-exposed twin pairs showing significantly greater concordance in terms of IQ and diagnosis than between dizygotic pairs [76], but these kinds of studies are scarce.

Increased or decreased exposure to other substances can also negatively impact fetal development. Risks relating to exposure to exogenous substances such as tobacco and street drugs are well known [77, 78], and there is some evidence that prenatal polydrug use, combined with alcohol exposure, may be more harmful than alcohol exposure alone [79]. Many women who consume alcohol during pregnancy, especially those who struggle with addiction, can be further affected by polydrug exposure [80], as well as other related issues such as malnutrition. Maternal diet or nutrient deficiency may also intensify the impact of PAE—low levels of iron [81] and zinc [82] in maternal blood have been shown to exacerbate the teratogenic effects of alcohol in animal models. Choline supplementation may be useful as an intervention during pregnancy and early childhood as this has been shown to moderate the impact of PAE in rats [83] and humans [84], and multivitamin supplements have shown a similar effect in humans [85].

Much of the research into the specific dangers and mechanisms of alcohol-related harm to a developing fetus is necessarily conducted using either in vitro tissue samples or animal model research methods. True experiments using human participants would clearly be harmful and unethical, so it is not possible to design a PAE study in humans where all relevant variables—genetics, drug exposure, pattern of alcohol exposure, environmental influences and so on—can be effectively controlled. Studies using tissue samples are useful under particular circumstances, and this method can be tightly controlled, uncomplicated and cost-effective, which can allow for multiple internally valid experiments [86]. However, tissue studies are limited in terms of their ability to demonstrate the impact of PAE, which necessarily involves intact animals during pregnancy, with a digestive system and many bodily influences on alcohol consumed and its eventual impact on the fetus [86]. Studies using live animals bridge this gap, and although no animal is a perfect surrogate for the human body, different animals can provide useful models for different research questions [87]. Smaller animals such as rodents are suitable for neurobiological or genetic studies, and their shorter gestation period allows for a greater turnover of results [88]. Larger animals such as sheep and pigs provide a gestation period and some behaviours similar to humans, whereas non-human primates offer the most similar model to humans in terms of genetics, neurological and cognitive development and social behaviours [87, 89]. There are, of course, ethical issues inherent in the use of animals in this kind of research, but the impact that these studies can have on our understanding of PAE is substantial [90]. Where observational studies of humans have provided tentative findings, the use of various animal models has been invaluable in the process of supporting evidence in a manner which would otherwise be unrealistic [86].

Early evidence of the physical impact of PAE on the human brain came entirely from post-mortem investigations of children born to alcoholic mothers following heavy PAE [91]. By the late 1970s, alcohol had become widely accepted as a teratogen responsible for growth deficiency, craniofacial abnormalities, joint or skeletal defects, microcephaly, cardiac problems and mental deficiency [92]. Further studies during this time began to produce more specific neurological findings including hydrocephalus (excess fluid in the brain), extensive neuroanatomical disorganisation and leptomeningeal neuroglial heterotopia (an abnormal sheet of neural or glial tissue) around the meninges, cerebellum and brainstem [93]. Such studies highlight the extent to which heavy PAE can impact brain development, often leading to stillbirth or infant mortality, but these findings may not be representative of the full range of deficits, especially those seen following moderate alcohol exposure [59]. More recently, advances in brain imaging technologies have allowed the assessment of brain structure and function in live human patients. Magnetic resonance imaging (MRI) has shown that reductions in overall brain volume and surface area as well as malformations are common, but that some brain structures are more often damaged than others. These include the cerebellum, basal ganglia, hippocampus, the frontal and parietal lobes of the cortex, and the corpus callosum [94, 95]. The corpus callosum, the central bundle of neural fibres connecting the two hemispheres of the brain, which is responsible for integration of cognitive, sensory and motor functioning, appears to be particularly vulnerable to prenatal alcohol exposure. There is also an association between corpus callosum dysmorphology and the characteristic facial anomalies seen in FAS, which could potentially be used by clinicians to determine the extent of neurostructural damage [96]. Related to this neuroanatomical damage is the impact of PAE on the endocrine system. Animal models and human observational studies have demonstrated a link between PAE, hormone imbalance and an increased stress-response [97, 98], which implicates the hypothalamic-pituitary-adrenal (HPA) axis [99]. The HPA axis is formed of the hypothalamus and pituitary gland in the brain, and the adrenal glands which are located next to each kidney. The stress response begins with activation of the hypothalamus, and results in the release of cortisol, epinephrine and norepinephrine into the bloodstream. These hormones increase heart rate and glucose levels, which may be needed during the stressful situation [100]. PAE can increase activation of the HPA axis in humans [97], which means that individuals exposed to alcohol prenatally may be more susceptible to damage caused by stressful events during childhood or adulthood. Little research has been conducted on the relationship between prenatal alcohol and postnatal trauma, but an emerging pattern is that children with both of these exposures are more similar in terms of cognitive and behavioural functioning to children with just prenatal alcohol, than they are to children with just postnatal trauma [101]. This suggests that, rather than a synergistic effect of dual exposure, prenatal alcohol appears to be the driving force behind developmental difficulties in children with both exposures.

Fathers’ drinking behaviour can also affect their unborn offspring, through both biological and environmental means. Alcohol consumption by biological fathers in the week leading up to IVF sperm collection has been found to predict failure to achieve live birth and spontaneous miscarriage, possibly due to the impact of alcohol on sperm count or quality [102]. In a mouse model, males who were intubated with alcohol prior to mating were more likely than non-exposed controls to produce pups with teratogenic and developmental deficits [103]. Sperm quality was also suggested as an explanation for these effects, but the authors report that such mechanisms are poorly understood. Transgenerational epigenetic inheritance—the biological inheritance of acquired characteristics from the previous generation via epigenetic means—has been suggested as a mechanism for passing on drug-seeking behaviours from male mice to their offspring [104]. Epigenetic inheritance is also seen in plants and smaller animals such as nematodes, but the extent to which it may occur in mammals is poorly understood [105, 106]. Studies in humans have found associations between preconception paternal alcohol consumption and low birthweight [107], cognitive deficit [108], congenital heart defect [109] and leukaemia [110], but sperm quality is currently a better explanation for such effects than transgenerational epigenetic inheritance.

Aside from biological mechanisms, there appears to be a significant social effect on alcohol consumption in pregnancy, and particularly from the impact of male partners. A recent cross-cultural study of English and Swedish mothers [111] found that Swedish participants viewed women who drink during pregnancy as unfit mothers and were less likely to drink during pregnancy themselves, whereas English women emphasised alcohol as a social device and felt that drinking small amounts on special occasions was acceptable. The same study found that partners often reduced or abstained from alcohol during their partner’s pregnancy, and this appeared to facilitate reduction or abstinence in the pregnant women. Women who drink during pregnancy have been shown to be more likely to live with a male partner who consumed alcohol [102], and women whose male partner was a heavy drinker were more likely to continue to drink during pregnancy [112]. The quality of a woman’s relationship with her male partner has also been shown to influence her alcohol behaviour during pregnancy; women who reported higher relationship satisfaction were less likely to consume alcohol during pregnancy [112], and when fathers were involved in pregnancy care protocols, their female partners were less likely to drink during pregnancy [102]. Unfortunately, many of the findings relating to male partners’ impact on FASD are taken from only a small number of high-quality studies, and there appear to have been no studies into the prenatal influence of female partners on maternal alcohol consumption [113]. The focus of investigations into the mechanisms of FASD has understandably been on in utero biological factors which necessarily implicate the biological mother, but there has been some concern that women have been unfairly villainised here, while the role of fathers, partners and wider society has been overlooked [113, 114].

There has been a huge increase during the last half century in the understanding of the impact of alcohol on many different biological mechanisms in the developing fetus. We have come to realise many different ways that the fetus can be affected by alcohol and how this might impact future growth and development. Although there is much more we need to learn, evidence from human, animal and cell tissue studies converges to provide strong and detailed evidence of the harmful impact of prenatal alcohol exposure. The infant can emerge from the uterus with biological and behavioural changes which can significantly affect adaptation to the postnatal environment.

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