Fetal alcohol spectrum disorder

• 1. Introduction

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  Fetal alcohol spectrum disorder affects an estimated 7.7 out of every 1000 people worldwide, and it is highly misdiagnosed and underdiagnosed. The condition arises in people who were exposed to alcohol before they were born. A child can look entirely typical at birth. The intellectual effects may not surface until the child starts school. Even then, not every infant exposed to alcohol in the womb develops a detectable disorder, and no one can fully explain the difference. This documentary traces the condition from ancient advice to modern clinics. Why did doctors dismiss the link between drinking and damaged children as superstition? How does alcohol reach a developing fetus, and why can the fetus not clear it? And how do specialists diagnose a disorder that sometimes leaves no mark on the face?

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• 2. Old Warnings, Long Silence

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  Plato, in his Laws from the fourth century B.C., wrote that both bride and bridegroom should be sober, so that a child might spring from sober parents. The Talmud, from the sixth century AD, says that "One who drinks intoxicating liquor will have ungainly children." Some readers see early awareness of fetal harm in such lines. Yet ancient sources rarely separate a mother's drinking from a father's, and they care more about conception than pregnancy. Many simply express heredity, the belief that children grow up like their alcoholic parents.

  In 1725, during the Gin Craze, British physicians petitioned the House of Commons about strong drink and pregnant women. They called such drinking "too often the cause of weak, feeble, and distempered children." William Hogarth's print Gin Lane tied gin to stillbirth and infant mortality. His print Beer Street shows commerce and happiness, which suggests that the alcohol in beer was not yet thought harmful.

  In the 19th century, Benjamin Rush and Thomas Trotter lobbied against drinking in pregnancy, warning of dependence and mental deficiency in children. The teetotalism and temperance movements spread these claims, along with reports of alcohol's harmful effects on animal embryos. But the claims were so often sensationalized that any finding of harm was largely denounced as propaganda.

  In 1899, Dr. William Sullivan, a prison physician in Liverpool, noted higher stillbirth rates among 120 alcoholic female prisoners than among their sober female relatives. He suggested that alcohol was the cause. That cut against the prevailing belief that heredity explained intellectual disability, poverty and criminal behavior. Henry H. Goddard's popular early-1900s case study of the Kallikak family reflected the older view. Later researchers suggested the Kallikaks almost certainly had fetal alcohol syndrome.

  Through the mid-1900s, studies of alcoholism leaned on the heredity argument. Many researchers were temperance advocates funded by groups such as the Anti-Saloon League, so clinicians read their work with heavy skepticism. The temperance movement effectively shut down serious research on the subject for nearly 50 years after Prohibition. By the 1940s the idea was generally dismissed as superstition. Within a generation, though, some doctors would go further than ignoring alcohol in pregnancy. They would administer it.

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• 3. Alcohol as Medicine

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  From the 1960s to the 1980s, alcohol was commonly used as a tocolytic, a treatment meant to stop preterm labor, meaning birth before 37 weeks of gestation. The method originated with Dr. Fritz Fuchs, chairman of obstetrics and gynecology at Cornell University Medical College. Doctors recommended a small amount of alcohol to calm the uterus during early contractions, including Braxton Hicks contractions.

  Later in pregnancy, the alcohol was given intravenously, and often in large amounts. Women experienced intoxication, nausea, vomiting and potential alcohol poisoning, followed by hangovers when the alcohol stopped. Vomiting put the mother at high risk of aspiration. One account calls the procedure "a brutal procedure for all involved."

  Because the alcohol went in through a vein, a doctor could keep treating a mother long after she had passed out. She could end up more intoxicated than would otherwise be possible. Such heavy intoxication was highly likely to contribute to fetal alcohol spectrum disorder.

  A 2015 review judged ethanol no better than a placebo of sugar water at suppressing preterm birth and neonatal mortality. It was also worse than other tocolytic drugs, called beta-mimetics, at postponing birth. Babies faced a higher rate of low birth weight, breathing problems at birth and neonatal death. Meanwhile, in France and the United States, a few researchers had already begun describing children whose mothers were alcoholic.

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• 4. Naming the Syndrome

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  In 1957, in France, Jacqueline Rouquette described 100 children of alcoholic parents in a thesis that was never published. Her mentor, Paul Lemoine of Nantes, said she gave a good description of the facial appearance in certain cases. In 1968, Lemoine himself published a study in a French medical journal on children with distinctive features whose mothers were alcoholic.

  Independently, across the Atlantic, Christy Ulleland of the University of Washington Medical School ran an 18-month study in 1968-69 of the offspring of 11 alcoholic mothers. Her colleagues, the dysmorphologists Kenneth Lyons Jones and David Weyhe Smith, examined the infants. In eight children they identified a pattern of "craniofacial, limb, and cardiovascular defects associated with prenatal onset growth deficiency and developmental delay." The pattern showed that the damage began before birth. The Ulleland study is arguably the true source of the modern understanding.

  Most syndromes are named after the physician who first reported them. Smith chose differently and named this one after its cause: fetal alcohol syndrome. He reasoned that if people knew maternal drinking caused it, abstinence would follow from education and public awareness. The news shocked some people, while others were skeptical.

  By 1978, within nine years of the Washington discovery, animal studies had confirmed that alcohol is a teratogen, a cause of birth defects. They included monkey studies by Sterling Clarren at the University of Washington Primate Center. That year, 245 cases had been reported, and the syndrome was described as the most frequent known cause of intellectual disability. In 1979, a research group in Gothenburg, Sweden, confirmed the Washington and Nantes findings. Researchers in France, Sweden and the United States were struck by how alike the unrelated children looked. They also noted the same unfocused, hyperactive behavior.

  Over time, experience suggested that a range of effects could follow prenatal exposure. The term fetal alcohol effects, or FAE, described people with confirmed or unknown exposure who showed damage but no obvious physical anomalies. In 1981, Smith called it an "extremely important concept" because it highlighted brain damage regardless of growth or facial features. Clinicians dropped the term in the 1990s. The public often read it as milder than the syndrome, when its effects could be just as damaging.

  In 1996, the replacement terms alcohol-related brain damage and alcohol-related neurodevelopmental disorder were introduced. In 2002, the US Congress ordered the Centers for Disease Control to develop diagnostic guidelines for fetal alcohol syndrome. In 2004, the term fetal alcohol spectrum disorder was formally adopted. Some had already used it in the 1990s. It covers the syndrome and other conditions caused by prenatal exposure. In 2013, the American Psychiatric Association introduced neurobehavioral disorder associated with prenatal alcohol exposure. Of all these names, only fetal alcohol syndrome is defined by the International Statistical Classification of Diseases and Related Health Problems.

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• 5. The Placental Pathway

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  After a pregnant woman drinks, alcohol crosses the placenta and umbilical cord to reach the developing fetus. It breaks down slowly there and stays far longer than it would in an adult. A fetus appears to face a triple risk.

  First, the so-called placental barrier is practically absent for ethanol. The alcohol and a toxic byproduct called acetaldehyde pass freely into the fetal compartment. Second, the developing nervous system is especially sensitive to ethanol. The alcohol interferes with cell proliferation, differentiation, neuronal migration, axonal outgrowth and the fine-tuning of synaptic networks. Third, fetal tissues cannot clear the toxin the way adult tissues do.

  In adults the liver is the main detoxifying organ. The fetal liver cannot detoxify ethanol, because the enzymes ADH and ALDH have not yet been expressed. Up to term, fetal tissues have little capacity for the job. The fetus stays exposed to ethanol in the amniotic fluid for periods far longer than ethanol lingers in the mother's circulation. Fetal tissues also hold much lower quantities of antioxidant enzymes such as SOD, so antioxidant protection is much less effective.

  Even so, the exact biological mechanisms behind fetal alcohol syndrome and its spectrum remain unknown. One proposed route involves retinoic acid. Acetaldehyde can compete with retinaldehyde and prevent its oxidation into retinoic acid. Different ethnic groups also show considerable genetic variation in the liver enzymes that detoxify ethanol, which makes universal conclusions hard. Genetic examinations have revealed long-lasting molecular effects that depend on both timing and dose, and even moderate amounts can cause alterations.

  Between conception and the third week, the brain, spinal cord and heart are the most susceptible systems. During the third week, alcohol can also damage the central nervous system. The fourth week is when the limbs form, along with the eyes and ears. Alcohol at that point can affect arms, legs, fingers and toes.

  By the sixth week the teeth and palate are forming. Alcohol in that window is responsible for many of the facial characteristics of fetal alcohol syndrome. By the twelfth week, frequent exposure can harm brain development, affecting cognitive, learning and behavioral skills before birth. By the 20th week, organs and organ systems are well developed, yet the fetus remains vulnerable. In the second trimester, ethanol reduces blood flow through the umbilical artery to the fetal brain. That lowers nutrition levels and can disturb the endocrine system of both fetus and mother.

  Alcohol is also a known folic acid antagonist. Heavy drinking and binge drinking during the first 12 weeks, when the lip and palate form, have been linked to orofacial cleft.

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• 6. The Diagnostic Maze

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  Four diagnostic systems were developed in North America. The Institute of Medicine's guidelines came first and standardized how people with prenatal alcohol exposure were diagnosed. The University of Washington's 4-Digit Diagnostic Code scores four key features on a scale of one to four. That yields 256 descriptive codes, grouped into 22 clinical categories. The Centers for Disease Control guidelines set a consensus for fetal alcohol syndrome but deferred other conditions. Canadian guidelines then harmonized most differences between the Institute of Medicine and Washington systems.

  All four systems assess growth, facial features, the central nervous system and alcohol exposure. A diagnosis of fetal alcohol syndrome needs a positive finding on all four. For the wider spectrum, central nervous system damage plus alcohol exposure is enough in every system. No single specialist does this alone. A physician usually judges growth and facial features, while psychological, speech-language and occupational therapy assessments establish brain impairment.

  Growth deficiency means height or weight at or below the 10th percentile of standardized charts. The 4-Digit Code marks the severe level at or below the 3rd percentile. Yet growth became a criterion partly by accident. In the first studies that described the syndrome, growth deficiency was required for inclusion, so every original case showed it. Canadian guidelines updated in 2016 deleted growth as a criterion.

  Three facial features define fetal alcohol syndrome. The first is a smooth philtrum, the groove between nose and upper lip. The second is a thin upper lip, called thin vermilion. The third is small palpebral fissures, meaning narrow eye openings. A trained physician rates lip and philtrum with the Lip-Philtrum Guide, a five-point scale of photographs running from normal at 1 to severe at 5. Eye width is measured in millimeters with calipers or a clear ruler, then compared with a University of Washington growth chart.

  Brain damage is the primary feature of any diagnosis, and it can be structural, neurological or functional. Structural problems include microcephaly and abnormalities such as agenesis of the corpus callosum. Imaging is expensive and inaccessible to most people, so microcephaly dominates structural diagnoses. A Minnesota team proposed the Ten Brain Domains to standardize functional assessment. They include achievement, attention, memory, language and motor skills. The state's Fetal Alcohol Diagnostic Program looks for performance 1.5 or more standard deviations from average in three or more domains.

  As of 2002, only 25 autopsy reports existed for infants known to have the syndrome. The first, in 1973, involved an infant who died shortly after birth and showed extensive brain damage. In 1977, Clarren described a second infant, born to a binge-drinking mother, who died ten days after birth. That autopsy showed severe hydrocephalus and a small corpus callosum.

  Exposure is established by interviewing the biological mother or relatives and by reviewing prenatal, birth, court and treatment records. For many adopted adults and children in foster care, such records are unavailable. Exposure is then labeled unknown, and a diagnosis is still possible. The 4-Digit Code defines high-risk exposure as a blood alcohol concentration of 100 mg/dL or more, delivered at least weekly in early pregnancy. A 55 kg woman typically reaches that level with six to eight beers in one sitting. Chemical biomarkers, such as fatty acid ethyl esters in a newborn's first stool, remain insufficiently proven.

  The Centers for Disease Control reviewed nine syndromes with overlapping features, among them Aarskog, Williams and Noonan syndromes. None includes all three facial features, and none results from prenatal alcohol exposure. Behavior causes a different confusion, since most people with the disorder have been misdiagnosed with ADHD. As of 2016, Sweden's Agency for Health Technology Assessment and Assessment of Social Services accepts only fetal alcohol syndrome. It calls the evidence for other types inconclusive and doubts that identifying them benefits the person diagnosed.

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• 7. How Much Is Too Much

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  No safe level of fetal alcohol exposure has been established. Alcohol is a known teratogen, so randomized controlled trials on pregnant women would be unethical. Among women who drink any quantity during pregnancy, the risk of a child with the disorder is about 15%, and of a child with fetal alcohol syndrome about 1.5%. Two standard drinks a day, or six in a short time, carries a 4.3% risk of a syndrome birth. That is one in 23 heavy-drinking pregnant women. Svetlana Popova has stated that "binge drinking is the direct cause of FAS or FASD."

  The evidence on low-to-moderate drinking, such as less than 12 grams of ethanol per day, is inconsistent and contradictory. Many studies find no significant effect, some find beneficial associations, and others find harm, even on the same outcomes. Definitions of low consumption vary widely. Residual confounding likely remains and may be larger than any observed effect.

  Fathers have entered the debate too. Alcohol use before conception may contribute through long-term epigenetic modification of the father's sperm. That idea has been challenged, and evidence that it can cause the complete syndrome is inconclusive.

  The Surgeon General of the United States, the Centers for Disease Control, the American College of Obstetricians and Gynecologists and the American Academy of Pediatrics all advise abstaining during pregnancy. So do the World Health Organization and the United Kingdom's National Institute for Health and Clinical Excellence. Because a woman may not know she has conceived until several weeks in, the advice also covers women trying to conceive. Since 1988, the Alcoholic Beverage Labeling Act has required warning labels on alcoholic beverage containers in the United States.

  Elizabeth Armstrong has questioned the zero-tolerance approach, calling it a moral panic. Critics note that the UK's abstinence advice was chosen as simple guidance that ensured nobody underestimated the risk, rather than on scientific evidence. Tennessee's 2014 fetal assault law, which expired in 2016, criminalized opioid use during pregnancy. It led women to avoid professional medical care for fear of prosecution.

  Stigma shapes the debate as well. Current advocacy perspectives hold that a focus on prevention alone further stigmatizes people with the disorder and their birth parents. Advocates argue that supporting people already living with it spreads the awareness that prevention needs, summed up as "Intervention is Prevention." Poverty, malnutrition, poor social support and generational trauma all shape the effects of exposure.

  Globally, one in 10 women drinks alcohol during pregnancy, and 20% of them binge with four or more drinks on one occasion. The five countries with the highest rates of alcohol use in pregnancy are Ireland at 60%, Belarus at 47%, Denmark at 46%, the UK at 41% and the Russian Federation at 37%. In one recent count, any form of the disorder affected 1 person in 20. Some estimate it could be as high as 1 in 7.

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• 8. Life With FASD

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  A University of Washington study of 473 people diagnosed with the syndrome, the partial syndrome or alcohol-related neurodevelopmental disorder mapped what comes later. Over 90% had mental health problems such as ADHD or clinical depression. Among those aged 12 and older, 60% had disrupted schooling and 60% had trouble with the law. About 50% had been confined in psychiatric care, chemical dependency care or prison, and 35% had alcohol and drug problems. Among those aged 21 and older, 80% lived in dependent settings and 80% had employment problems.

  These are called secondary disabilities, because they emerge when a person's primary difficulties meet the world's expectations. Primary disabilities come directly from brain damage and are often mistaken for behavior problems. Animal studies link learning impairments to damaged dendrites of the hippocampus and impaired motor development to a smaller cerebellum. They link hyperactivity to a smaller corpus callosum.

  One study found an average life span of 34 years for people with the syndrome. Of the deaths, 44% had an external cause, and 15% were suicides. In 2019, another study found a higher risk of hypertension in people with the disorder, independent of race, ethnicity and obesity.

  The costs are large. A 2015 review estimated the overall cost to Canada at $9.7 billion, counting crime, healthcare and education. In 2002, the Centers for Disease Control estimated the lifetime cost per child with the syndrome in the United States at $2 million. That amounts to over $4 billion nationally.

  The same Washington study identified eight protective factors. They include living in a stable and nurturing home for over 73% of life, being diagnosed before age six, and never experiencing violence. Others include staying in each living situation for at least 2.8 years and being found eligible for developmental disability services. A diagnosis of fetal alcohol syndrome itself, rather than another condition on the spectrum, also protected.

  Malbin, in 2002, identified strengths that often stand out. They include music, art, spelling, reading, computers, mechanics, woodworking and skilled trades such as welding. Non-impact sports and physical fitness also suit many people.

  The condition has no available cure, but treatment can improve outcomes. Early intervention from birth to age 3 improves development. A developmental approach tailors help to a person's delayed stages. Practiced instruction on tying shoelaces, or slip-on shoes, are examples. The advocacy model adds someone, such as a family member or case manager, who explains the disability to schools and others and helps set attainable goals. Medications such as stimulants and antidepressants treat specific symptoms rather than the disorder itself.

  Between 2017 and 2019, researchers reported a possible cure using neural stem cells. They proposed that applied to a newborn, it could reverse the damage and prevent lasting effects.

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