A diagnosis can be made by an evaluation of medical history and clinical observation. The  Beighton criteria  are widely used to assess the degree of joint hypermobility. DNA and biochemical studies can help identify affected people. Diagnostic tests include collagen gene-variant testing, collagen typing via skin biopsy, echocardiogram, and lysyl hydroxylase or oxidase activity, but these tests are not able to confirm all cases, especially in instances of an unmapped variation, so clinical evaluation remains important. If multiple members of a family are affected, prenatal diagnosis may be possible using a DNA information technique known as a linkage study. [ 109 ]  Knowledge about EDS among all kinds of practitioners is poor. [ 110 ] [ 111 ]  Research is ongoing to identify genetic markers for all types. [ 112 ]


Because no single gene has been identified as the sole cause of the most common type of EDS, hypermobile type, obtaining a diagnosis is often difficult. [ 113 ]  The 2017 diagnostic criteria are as follows:


In such cases where all criteria are met, a patient can be diagnosed with hEDS according to The International Consortium on Ehlers-Danlos Syndromes and Hypermobility Spectrum Disorders [ 114 ]


Several disorders share some characteristics with EDS. For example, in  cutis laxa , the skin is loose, hanging, and wrinkled. In EDS, the skin can be pulled away from the body, but is elastic and returns to normal when let go. In  Marfan syndrome , the joints are very mobile, and similar cardiovascular complications occur. People with a " marfanoid " appearance are often tall and thin with long arms and legs and "spidery" fingers while EDS phenotypes vary considerably. Certain subtypes of EDS may involve short stature, large eyes, and the appearance of a small mouth and chin, due to a small palate. The palate can have a high arch, causing dental crowding. Blood vessels can sometimes be easily seen through translucent skin, especially on the chest. The genetic connective tissue disorder  Loeys–Dietz syndrome  also has symptoms that overlap with EDS. [ 115 ]


In the past,  Menkes disease , a copper metabolism disorder, was thought to be a form of EDS. People are commonly misdiagnosed with  fibromyalgia ,  bleeding disorders , or other disorders that can mimic EDS symptoms. Because of these similar disorders and complications that can arise from an unmonitored case of EDS, a correct diagnosis is important. [ 116 ]   Pseudoxanthoma elasticum  is worth consideration in diagnosis. [ 117 ]


No cure for Ehlers–Danlos syndrome is known, and treatment is supportive. Close monitoring of the cardiovascular system, physiotherapy, occupational therapy, and orthopedic instruments (e.g., wheelchairs, bracing, casting) may be helpful. This can help stabilize the joints and prevent injury. Orthopedic instruments are helpful for the prevention of further joint damage, especially for long distances. People should avoid activities that cause the joint to lock or overextend. [ 118 ]


A physician may prescribe casting to stabilize joints. Physicians may refer a person to an orthotist for  orthotic treatment  (bracing). Physicians may also consult a physical and/or occupational therapist to help strengthen muscles and teach people how to properly use and preserve their joints. [ 119 ] [ 120 ]


Aquatic therapy  promotes muscular development and coordination. [ 121 ]  With manual therapy, the joint is gently mobilized within the range of motion and/or manipulations. [ 119 ] [ 120 ]  If conservative therapy is not helpful, surgical joint repair may be necessary. Medication to decrease pain or manage cardiac, digestive, or other related conditions may be prescribed. To decrease  bruising  and improve wound healing, some people have responded to  vitamin C . [ 122 ]  Medical care workers often take special precautions because of the sheer number of complications that tend to arise in people with EDS. In vascular EDS, signs of chest or abdominal pain are considered trauma situations. [ 123 ]


Cannabinoids  and medical marijuana have shown some efficacy in reducing pain levels. [ 124 ]


In general, medical intervention is limited to symptomatic therapy. Before pregnancy, people with EDS may be recommended to have genetic counseling and to familiarize themselves with the risks pregnancy poses. Children with EDS should be given information about the disorder so they can understand why they should avoid contact sports and other physically stressful activities. Children should be taught that they should not demonstrate the unusual positions they can maintain due to loose joints, as this may cause early degeneration of the joints. Emotional support along with behavioral and psychological therapy can be useful. Support groups can be immensely helpful for people dealing with major lifestyle changes and poor health. Family members, teachers, and friends should be informed about EDS so they can accept and assist the child. [ 125 ]


Successful treatment of chronic pain in EDS requires a multidisciplinary team. The ways to manage pain can be to modify pain management techniques used in the normal population. Pain is classified into several types. One is  nociceptive , which is caused by an injury sustained to tissues. Another is  neuropathic pain , caused by abnormal signals by the nervous system. In many cases, the pain individuals experience is an unequal mix of the two.  Physiotherapy  (exercise rehabilitation) can be helpful, especially in stabilizing the core and the joints. Stretching exercises must be reduced to slow and gentle stretching to reduce the risks of dislocations or subluxations. Usable methods may include posture reeducation, muscle release, joint mobilization, trunk stabilization, and manual therapy for overworked muscles.  Cognitive behavioural therapy  is used in many chronic pain patients, especially those who have severe, chronic, life-controlling pain that is unresponsive to treatment. It has not been checked for efficiency in clinical trials. The state of pain management with EDS is considered insufficient. [ 106 ]


Nonsteroidal anti-inflammatory drugs ( NSAIDs ) may help if the pain is caused by inflammation. However, long-term use of NSAIDs is often a risk factor for gastrointestinal, renal, and blood-related side effects. It can worsen symptoms of  mast cell activation syndrome , a disease that may be associated with EDS.  Acetaminophen  can be used to avoid the bleeding-related side effects of NSAIDs. [ 106 ]


Lidocaine  can be applied topically after subluxations and painful gums. It can also be injected into painful areas in the case of musculoskeletal pain. [ 106 ]


If the pain is neuropathic in origin,  tricyclic antidepressants  in low doses,  anticonvulsants , and  selective norepinephrine reuptake inhibitors  can be used. [ 106 ]


When a dislocation or subluxation does occur, muscle spasms and stress tend to occur, increasing pain and reducing the chances of the dislocation/subluxation naturally relieving. Methods to support a joint after such an incident include the usage of a sling to hold the joint in place and allow it to relax. Orthopedic casts are not advised as there could be pain if unrelaxed muscles are still trying to spasm out against the cast. Other solutions to promote relaxation are heat, gentle massaging, and mental distractions. [ 126 ]


The instability of joints, leading to subluxations and joint pain, often requires surgical intervention in people with EDS. Instability of almost all joints can happen, but appears most often in the lower and upper extremities, with the wrist, fingers, shoulder, knee, hip, and ankle being most common. [ 119 ]


Common surgical procedures are joint  debridement , tendon replacements, capsulorrhaphy, and  arthroplasty .  Aortic dissection  and other such complications of  vascular EDS  will mandate surgical intervention. After surgery, the degree of stabilization, pain reduction, and people's satisfaction can improve, but surgery does not guarantee an optimal result; affected people and surgeons report being dissatisfied with the results. The consensus is that conservative treatment is more effective than surgery, [ 61 ]  particularly since people have extra risks of surgical complications due to the disease. Three basic surgical problems arise due to EDS – the strength of the tissues is decreased, which makes the tissue less suitable for surgery; the fragility of the blood vessels can cause problems during surgery; and wound healing is often delayed or incomplete. [ 119 ]  If considering surgical intervention, seeking care from a surgeon with extensive knowledge and experience in treating people with EDS and joint hypermobility issues would be prudent. [ 127 ]


Local anesthetics,  arterial catheters , and  central venous catheters  cause a higher risk of  bruise formation  in people with EDS. Some people with EDS also show a resistance to local anaesthetics. [ 128 ]  Resistance to  lidocaine  and  bupivacaine  is not uncommon, and  mepivacaine  tends to work better in people with EDS. Special recommendations for anesthesia are given for people with EDS. [ citation needed ]  Detailed recommendations for anesthesia and perioperative care of people with EDS should be used to improve safety. [ 127 ]


Surgery in people with EDS requires careful tissue handling and a longer immobilization afterward. [ 129 ]


The outcome for individuals with EDS depends on the specific type of EDS they have. Symptoms vary in severity, even in the same disorder, and the frequency of complications varies. Some people have negligible symptoms, while others are severely restricted in daily life. Extreme joint instability, chronic musculoskeletal pain, degenerative joint disease, frequent injuries, and spinal deformities may limit mobility. Severe spinal deformities may affect breathing. In the case of extreme joint instability, dislocations may result from simple tasks such as rolling over in bed or turning a doorknob. Secondary conditions such as autonomic dysfunction or cardiovascular problems, occurring in any type, can affect prognosis and quality of life. Severe mobility-related disability is seen more often in hEDS than in classical EDS or vascular EDS. [ 130 ]


Although all types of EDS are potentially life-threatening, [ 11 ] [ 12 ] [ 13 ]  most people have a normal lifespan. Those with blood vessel fragility, though, have a high risk of fatal complications, including spontaneous arterial rupture, which is the most common cause of sudden death. The median life expectancy in the population with vascular EDS is 48 years. [ 131 ]


Ehlers–Danlos syndromes are estimated to occur in about one in 5,000 births worldwide. Initially, prevalence estimates ranged from one in 250,000 to 500,000 people, but these were soon found to be low, as medical professionals became more adept at diagnosis. EDS may be far more common than the currently accepted estimate due to the wide range of severities with which the disorder presents. [ 133 ]


The prevalence of the disorders differs dramatically. The most common is hypermobile EDS, followed by classical EDS. The others are very rare. For example, fewer than 10 infants and children with dermatosparaxis EDS have been described worldwide.


Some types of EDS are more common in  Ashkenazi Jews . For example, the chance of being a carrier for dermatosparaxis EDS is one in 2,000 in the general population but one in 248 among Ashkenazi Jews. [ 134 ]


Some recent studies have found that EDS is significantly more prevalent in people who identify as  transgender  or  gender-diverse , or who suffer from  gender dysphoria . One review, of a pediatric EDS clinic in the  American Midwest  between 2020 and 2022, found that 17% of patients identified as trans or gender-diverse, 89% of whom were  assigned female at birth . [ 135 ]  By comparison, roughly 1-2% of adolescents identify as trans or gender-diverse in the US overall. [ 136 ]  Meanwhile, a 2020 analysis found that among adults undergoing gender-affirming surgery, 2.6% had a diagnosis of EDS—130 times the highest reported prevalence of EDS in the general population. [ 137 ]


Until 1997, the classification system for EDS included ten specific types and acknowledged that other rarer types existed. At this time, the classification system underwent an overhaul and was reduced to six major types using descriptive titles. Genetic specialists recognize that other types of this condition exist but have only been documented in single families. Except for  hypermobility  (type 3), the most common type of all ten types, some of the specific variations involved have been identified, and they can be precisely identified by  genetic testing ; this is valuable due to a great deal of variation in individual cases. Negative genetic test results do not rule out the diagnosis since not all variations have been discovered; therefore, the clinical presentation is crucial. [ 138 ]


Forms of EDS in this category may present with soft, mildly stretchable skin, shortened bones, chronic  diarrhea , joint hypermobility and dislocation, bladder rupture, or poor wound healing. Inheritance patterns in this group include X-linked recessive, autosomal dominant, and autosomal recessive. Examples of types of related syndromes other than those above reported in the medical literature include: [ 139 ]


EDS may have contributed to the virtuoso violinist  Niccolò Paganini 's skill, as he was able to play wider fingerings than a typical violinist. [ 140 ]


Many  sideshow  performers have EDS. Several of them were billed as the Elastic Skin Man, the India Rubber Man, and Frog Boy. They included such well-known individuals (in their time) as Felix Wehrle, James Morris, and Avery Childs. Two performers with EDS currently hold world records. Contortionist  Daniel Browning Smith  has hypermobile EDS and holds the current  Guinness World Record  for the most flexible man as of 2018, while  Gary "Stretch" Turner , sideshow performer in the Circus Of Horrors, has held the current Guinness World Record for the most elastic skin since 1999, for his ability to stretch the skin on his stomach 6.25 inches. [ 141 ]


The fantasy novel  Fourth Wing  by  Rebecca Yarros  presents a main character, Violet Sorrengail, who has an unnamed chronic condition that aligns closely with EDS symptoms. When asked about this connection Rebecca Yarros agrees with the connection but says EDS goes unnamed due to the level of medical knowledge present in her story's world. Yarros has EDS and included it as a representation of her condition. [ 158 ]


Grey's Anatomy , a long-running TV series, approached the topic of EDS in their  13th season . In the episode " Falling Slowly ", the show's doctors are confronted with confusion when met with diagnosing a patient. Due to complex and contradicting symptoms presented by the patient, the show's doctors ultimately give the diagnosis of EDS. This episode was based on conversations held by producers who talked with a patient and doctor who have EDS. [ 159 ]


Ehlers–Danlos–like syndromes are hereditary in  Himalayan cats , some domestic shorthair cats, [ 160 ]  and certain breeds of cattle. [ 161 ]  It is seen as a sporadic condition in domestic dogs, with higher frequency in  English Springers . [ 162 ]  It has a similar treatment and prognosis. Animals with the condition should not be bred, as the condition can be inherited. [ 163 ]


Degenerative suspensory ligament desmitis  is a similar condition seen in many breeds of  horses . [ 164 ]  It was originally notated in the  Peruvian Paso  and thought to be a condition of overwork and older age, but it is being recognized in all age groups and all activity levels. It has been noted in newborn foals.


Endocardial fibroelastosis  ( EFE ) is a rare  heart  disorder usually occurring in children two years old and younger. [ 1 ]  It may also be considered a reaction to stress, not necessarily a specific disease. [ 2 ]


It should not be confused with  endomyocardial fibrosis . [ citation needed ]


EFE is characterized by a thickening of the innermost lining of the heart chambers (the  endocardium ) due to an increase in the amount of supporting connective tissue and elastic fibres. It is an uncommon cause of unexplained  heart failure  in infants and children, and is one component of  HEC syndrome . Fibroelastosis is strongly seen as a primary cause of  restrictive cardiomyopathy  in children, along with  cardiac amyloidosis , which is more commonly seen in progressive multiple myeloma patients and the elderly. [ citation needed ]


A review cites references to 31 different diseases and other stresses associated with the EFE reaction. [ 2 ]  These include infections, cardiomyopathies, immunologic diseases, congenital malformations, even electrocution by lightning strike. EFE has two distinct  genetic  forms, each having a different mode of  inheritance . An  X-linked recessive  form, [ 3 ]  and an  autosomal   recessive  form [ 4 ]  have both been observed.


A Cardiac MRI can show eccentric patchy thickening of  endocardium which is a non-specific finding. Myocardial biopsy is a definitive test. [ citation needed ]


The cause should be identified and, where possible, the treatment should be directed to that cause. A last resort form of treatment is  heart transplant . [ 5 ]


An infant with dilated, failing heart was no rarity on the pediatric wards of hospitals in the mid-twentieth century. On autopsy, most of these patients' hearts showed the thickened endocardial layer noted above. This was thought to be a disease affecting both the heart muscle and the endocardium and it was given various names such as: idiopathic hypertrophy of the heart, endocardial sclerosis, cardiac enlargement of unknown cause, etc. Some of these hearts also had overt congenital anomalies, especially aortic stenosis and coarctation of the aorta. [ citation needed ]


The term "endocardial fibroelastosis" was introduced by Weinberg and Himmelfarb in 1943. [ 6 ]  In their pathology laboratory they noted that usually the  endocardium  was pearly white or opaque instead of normally thin and transparent and microscopically showed a systematic layering of collagenous and  elastic fibers . They felt their new term was more adequately descriptive, and, indeed it was quickly and widely adopted. Clinicians began applying it to any infant with a dilated, failing heart, in spite of the fact that the only way to definitively establish the presence of EFE was to see it at autopsy. EFE had quickly become the name of a disease, and it continues to be used by many physicians in this way, though many patients with identical symptoms do not have the endocardial reaction of EFE. [ citation needed ]


In the latter decades of the twentieth century, new discoveries and new thinking about heart muscle disease gave rise to the term "cardiomyopathy". Many of the cases of infantile cardiac failure were accordingly called "primary cardiomyopathy" as well as "primary EFE", while those with identifiable congenital anomalies stressing the heart were called "secondary EFE". In 1957 Black-Schaffer proposed a unitary explanation that stress on the ventricle, of any kind, may trigger the endocardial reaction, so that all EFE could be thought of as secondary. [ 7 ]


Evidence gradually accumulated as to the role of infection as one such type of stress. The studies of Fruhling and colleagues in 1962 were critical. [ 8 ]  They followed a series of epidemics of  Coxsackie virus  infection in their part of France. After each epidemic there were increased numbers of cases with EFE coming to autopsy. On closer study there were cases of pure acute myocarditis, cases of mixed myocarditis and EFE, and cases where myocarditis had healed, leaving just EFE. They were able to culture Coxsackie virus from the tissues of many of the cases at all stages  of this apparent progression. A similar progression from myocarditis to EFE was later observed at Johns Hopkins but no virology was done. [ 9 ]


Noren and colleagues at the  University of Minnesota , acting on an idea floated at a pediatric meeting, were able to show a relation between exposure to maternal  mumps  in fetal life, EFE, and a positive skin test for mumps in infants. [ 10 ]  This brought on a large ongoing controversy and finally prompted a virologist colleague of theirs to inject embryonated eggs with  mumps virus . [ 11 ]  The chicks at first showed the changes of myocarditis, about a year later, typical EFE, and transitional changes in between. Despite this, the controversy about the role of mumps continued as the actual incidence of EFE plummeted. The proponents of mumps as a cause pointed to this as the effect of the recent implementation of widespread mumps immunization. [ citation needed ]


Evidence that  viral  infection may play a role as a cause or trigger of EFE was greatly reinforced by the study directed by Towbin in the virus laboratory of  Texas Children's Hospital . [ 12 ]  They applied the methods of today's genetics to old preserved specimens from autopsies of patients with EFE done well before mumps immunization began and found mumps genome in the tissues of over 80% of these patients. It seems undeniable that transplacental mumps infection had been in the past the major cause of EFE, and that immunization was indeed the cause of EFE having become rare. [ citation needed ]


Non-infectious causes of EFE have also been studied, spurred by the opening of new avenues of genetics research. Now there are specific named genes associated with certain cardiomyopathies, some of which show the characteristic reaction of EFE. A typical example is Barth syndrome and the responsible gene, tafazzin. [ 13 ]


Developments in echocardiography, both the technology of the machines and the skill of the operators, have made it no longer necessary to see the endocardium at autopsy. EFE can now be found non-invasively by the recording of increased endocardial echos.  Fetal echocardiography has shown that EFE can begin to accumulate as early as 14 weeks of gestation, and increase with incredible rapidity [ 14 ]  and even that it can be reversed if the stress can be removed early in fetal life. [ 15 ]


The North American Pediatric Cardiomyopathy Registry was founded in 2000 and has been supported since by the National Heart, Lung and Blood Institute. Because of the logic of the diagnostic tree, where EFE applies to many branches of the tree and thus cannot occupy a branch, it is not listed by the Registry as a cause but rather, "with EFE" is a modifier that can be applied to any cause. [ 16 ]


Thus, the past half-century has seen EFE evolve from a mysterious but frequently observed disease to a rare but much better understood reaction to many diseases and other stresses. [ citation needed ]


Ethmocephaly  is a type of  cephalic disorder  caused by  holoprosencephaly . Ethmocephaly is the rarest phenotypic variant of a group of defects called the holoprosencephaly (HPE) malformation sequence; other variants include cebocephaly, cyclopia, and median cleft palate. [ 1 ]   It consists of a  proboscis  separating narrow-set eyes with an absent nose and  microphthalmia  (abnormal smallness of one or both eyes).  Cebocephaly , another facial anomaly, is characterized by a small, flattened nose with a single  nostril  situated below incomplete or underdeveloped closely set eyes.


The least severe in the spectrum of facial anomalies is the median  cleft lip , also called  premaxillary agenesis .


Although the causes of most cases of holoprosencephaly remain unknown, some may be due to   dominant  or  chromosome  causes. Such chromosomal anomalies as  trisomy 13  and  trisomy 18  have been found in association with holoprosencephaly, or other  neural tube defects .  Genetic counseling  and  genetic testing , such as  amniocentesis , is usually offered during a pregnancy if holoprosencephaly is detected.  The recurrence risk depends on the underlying cause.  If no cause is identified and the fetal chromosomes are normal, the chance to have another pregnancy affected with holoprosencephaly is about 6%.


There is no treatment for holoprosencephaly and the prognosis for individuals with the disorder is poor. Most of those who survive show no significant developmental gains. For children who survive, treatment is symptomatic. It is possible that improved management of diabetic pregnancies may help prevent holoprosencephaly, however there is no means of primary prevention.


EUROCAT  is a network of population-based  congenital anomaly  registries across  Europe  for the  monitoring , surveillance and  research  of congenital anomalies. It was founded in 1979.


As of January 2023, the network has 43 member registries from 23 countries covering more than 25% of  European  births per year. The detailed registry descriptions can be found on the EUROCAT website [ 1 ] [ 2 ]


EUROCAT's objectives are to:


EUROCAT was founded in 1979 as the  European Concerted Action on Congenital Anomalies and Twins. [ 3 ]  The EUROCAT Central Registry was based in  Brussels  from 1979 to 1999 and at the  University of Ulster  from 2000 to 2014.


In 2015 the Central Registry was transferred to the European Commission's  Joint Research Centre  (JRC) in  Ispra ,  Italy , [ 4 ]  and it is now an integral part of the European Platform on Rare Disease Registration. [ 5 ]


Leadership is provided by the JRC-EUROCAT Management Committee, comprising elected members from the EUROCAT congenital anomaly registries and representatives from the JRC.


All EUROCAT member registries use multiple sources of information to ascertain cases in live births, late  fetal deaths  (>20 weeks gestational age) and terminations of pregnancy for fetal anomaly at any  gestational age .


EUROCAT has achieved a high level of data harmonisation and  interoperability  between registries through the standardisation of definitions, diagnoses and  terminology , principally by the development of the EUROCAT Guides [ 6 ]  and software for data management. The EUROCAT  methodology  is recognized worldwide and is used by many research groups.


The role of the JRC-EUROCAT Central Registry is (i) to maintain and further develop the EUROCAT Central Database, (ii) to ensure secure  data transmission  and (iii) to facilitate  data management  in all registries.


Data management includes  data validation , data harmonization and  quality assessment  using validated international classification systems where possible, which are defined in the EUROCAT Guide 1.5. [ 6 ]


Data are transmitted by individual registries to the JRC-EUROCAT Central Registry twice a year, in February and October, via a secure  web-portal.  The validated data included in the Central Database are used by the Central Registry to perform routine  statistical analyses  for  epidemiological surveillance . The Central Registry also provides data for research and surveillance purposes and supports the coordination and dissemination activities of the network.


One key function of EUROCAT is to publish annual statistics on  prevalence [ 7 ]  and prenatal detection rates [ 8 ]  for a wide range of major  congenital anomalies . The data covers all  pregnancy  outcomes (including terminations) from 20 weeks  gestation .


The JRC-EUROCAT Central Registry also performs a  statistical analysis  of temporal clusters and pan-European trends [ 9 ]  in prevalence of congenital anomalies.


A  facial cleft  is an opening or gap in the  face , or a malformation of a part of the face. Facial clefts is a collective term for all sorts of clefts. All structures like bone, soft tissue, skin etc. can be affected. Facial clefts are extremely rare  congenital anomalies . There are many variations of a type of clefting and classifications are needed to describe and classify all types of clefting. Facial clefts hardly ever occur isolated; most of the time there is an overlap of adjacent facial clefts. [ 1 ]


There are different classifications about facial clefts. Two of the most used classifications are the  Tessier classification [ 2 ]  and the  Van der Meulen classification . [ 3 ]  Tessier is based on the anatomical position of the cleft and Van der Meulen classification is based on the embryogenesis.


In 1976  Paul Tessier  published a classification on facial clefts based on the anatomical position of the clefts. The different types of Tessier clefts are numbered 0 to 14. These 15 different types of clefts can be put into 4 groups, based on their position: [ 4 ]  midline clefts, paramedian clefts, orbital clefts and lateral clefts. The Tessier classification describes the clefts at soft tissue level as well as at bone level, because it appears that the soft tissue clefts can have a slightly different location on the face than the bony clefts. [ citation needed ]


The midline clefts are Tessier number 0 ("median craniofacial dysplasia"), number 14 ( frontonasal dysplasia ), and number 30 ("lower midline facial cleft", also known as "median mandibular cleft"). These clefts bisect the face vertically through the midline. Tessier number 0 bisects the  maxilla  and the nose, Tessier number 14 comes between the nose and the  frontal bone . The Tessier number 30 facial cleft is through the tongue, lower lip and  mandible . The tongue may be absent, hypoplastic, bifid, or even duplicated. [ 5 ]  People with this condition may be  tongue-tied . [ 5 ]


Tessier number 1, 2, 12 and 13 are the paramedian clefts. These clefts are quite similar to the midline clefts, but they are further away from the midline of the face. Tessier number 1 and 2 both come through the maxilla and the nose, in which Tessier number 2 is further from the midline ( lateral ) than number 1. Tessier number 12 is in extent of number 2, positioned between nose and frontal bone, while Tessier number 13 is in extent of number 1, also running between nose and forehead. Both 12 and 13 run between the midline and the orbit. [ citation needed ]


Tessier number 3, 4, 5, 9, 10 and 11 are orbital clefts. These clefts all have the involvement of the  orbit . Tessier number 3, 4, and 5 are positioned through the maxilla and the orbital floor. Tessier number 9, 10 and 11 are positioned between the upper side of the orbit and the forehead or between the upper side of the orbit and the  temple  of the head.
Like the other clefts, Tessier number 11 is in extent to number 3, number 10 is in extent to number 4 and number 9 is in extent to number 5.


The lateral clefts are the clefts which are positioned horizontally on the face. These are Tessier number 6, 7 and 8. Tessier number 6 runs from the orbit to the cheek bone. Tessier number 7 is positioned on the line between the corner of the mouth and the ear. A possible lateral cleft comes from the corner of the mouth towards the ear, which gives the impression that the mouth is bigger. It's also possible that the cleft begins at the ear and runs towards the mouth. Tessier number 8 runs from the outer corner of the eye towards the ear.
The combination of a Tessier number 6-7-8 is seen in the  Treacher Collins syndrome . Tessier number 7 is more related to  hemifacial microsomia  and number 8 is more related to  Goldenhar syndrome .


Van der Meulen classification divides different types of clefts based on where the development arrest occurs in the  embryogenesis . A primary cleft can occur in an early stage of the development of the face (17 mm length of the embryo). The developments arrests can be divided in four different location groups: internasal,  nasal , nasalmaxillar and maxillar. The maxillar location can be subdivided in  median  and lateral clefts.


Internasal  dysplasia  is caused by a development arrest before the union of the two nasal halves. These clefts are characterized by a median cleft lip, a median notch of the  cupid's bow  or a duplication of the labial  frenulum . Besides the median cleft lip,  hypertelorism  can be seen in these clefts. Also sometimes there can be an underdevelopment of the  premaxilla .


Nasal dysplasia or nasoschisis is caused by a development arrest of the lateral side of the nose, resulting in a cleft in one of the nasal halves. The nasal septum and cavity can be involved, though this is rare. Nasoschisis is also characterized by hypertelorism.


Nasomaxillary dysplasia is caused by a development arrest at the junction of the lateral side of the nose and the maxilla, which results in a complete or non-complete cleft between the nose and the orbital floor (nasoocular cleft) or between the mouth, nose and the orbital floor (oronasal-ocular cleft). The development of the lip is normal.


Maxillary dysplasia can manifest itself on two different locations in the maxilla: in the medial or the lateral part of the maxilla.


It is possible that facial clefts are caused by a disorder in the migration of  neural crest cells . [ 6 ]


Another theory is that facial clefts are caused by failure of the fusion process and failure of inwards growth of the  mesoderm .


Other theories are that genetics play a part in the development of facial clefts [ 7 ]  or that they are caused by amniotic bands. [ 8 ]


Around one in 700 individuals are born with craniofacial clefts. [ 9 ]  There are multiple genetic and environmental factors which contribute to craniofacial development. Within craniofacial disorders and  abnormalities , orofacial clefts, and specifically  cleft lip  (CL) and  cleft palate  (CP) are the most common in humans. [ 9 ]  Occurrences of CL/P are most often (around seventy percent of cases) isolated and nonsyndromic, meaning they are not associated with a syndrome or inherited genetic conditions. [ 9 ] [ 10 ]  Around thirty percent occur with other structural variances, and over 500 syndromes have been identified in which clefting is a principal feature. [ 9 ] [ 10 ]  Clefting can result from  teratogens , an agent that disrupts embryo development such as, radiation, maternal infection, chemicals, or drugs. [ 9 ] [ 10 ]   Chromosomal abnormalities  or  mutations  at single gene loci have also contributed to clefting development. [ 9 ] [ 10 ]  Genetic causes are linked with most craniofacial syndromes, and CL/P and other orofacial clefts are recognized as  heterogeneous disorders , meaning there are multiple recognized causes. [ 9 ] [ 11 ]  Orofacial clefts have great phenotypic diversity, and their associated genetic environments have called for vast research and investigation.


Craniofacial disorders have high variance in phenotypic expression, and researchers have suggested this variance could be due to interactions between the mutated/deviated genes and other genes, along with interactions with environmental factors. [ 12 ] [ 13 ]  Environmental causes have been found to contribute to craniofacial clefting, however, these are still influenced by and supported by genetic factors. Many studies, for example, have linked maternal smoking to increased CLP risk; however, the increased risk suggests that genes in metabolic pathways could still contribute to susceptibility or formation of CL/P. [ 14 ]


The craniofacial complex begins its progress in the fourth week of development, and results from  neural crest  cells migrating to form and fuse the facial primordia. [ 9 ] [ 10 ]  Failures or deviations in this process result in craniofacial clefts, either CL or CP. [ 6 ]  The range of variation in phenotype aligns with ancestry. [ 9 ] [ 14 ]  Studies have found increased amounts of clefting in the relatives of patients with clefts, suggesting genetic factors are the underlying cause for CL/P. [ 9 ]  Inheritance has a known and significant role in human craniofacial morphology. This is supported through cephalometric and anthropometric comparisons of family members including between triplets, twins, siblings, and parents and children. [ 15 ]


Genetic factors of craniofacial clefting can be investigated and tracked through several methods including  sequencing  in humans,  Genome-wide association studies  (GWAs),  fate mapping , expression analysis, and animal studies (knockout experiments or models with clefting from chemical mutagenesis). [ 16 ]   Twin studies  and familial clustering have also revealed that facial structure and formation are genetically linked. Several genes have been associated with craniofacial disorders through experimentation, including sequencing Mendelian clefting syndromes. [ 9 ]  Over 25 loci have been identified as potential influencers of craniofacial clefts across populations. [ 12 ]


The  transforming growth factor  ( TGF ) family has provided multiple candidate genes linked with craniofacial development and malformation. [ 17 ] [ 18 ] [ 14 ] [ 10 ]   TGF  is involved in cell migration, differentiation, and proliferation, as well as regulating the extracellular matrix. [ 17 ]  Another gene that has been flagged as causal for craniofacial disorders, including CL/P, is  interferon regulatory factor 6  or,  IRF6 . [ 9 ] [ 14 ] [ 19 ]  Mutations in  IRF6  cause  Van der Woude syndrome , the most common clefting syndrome. [ 9 ]   Ventral anterior homeobox 1 ,  VAX1,  and  noggin ,  NOG , were identified with genome-wide significance for contributing to CL/P. [ 14 ]  Additionally, mutations in  SPECC1L  have recently been identified as influential to facial structure formation, and as causal for syndromic facial clefting. [ 19 ] [ 20 ]  Nonsyndromic CL/P has been associated with the transcription factor  forkhead box protein E1  ( FOXE1 ), as mutations have resulted in cases of CL/P in mice. [ 10 ]  Other genes which have been found to interact with or contribute to craniofacial clefting include  FGFR s,  TWIST ,  MSX s,  GREM1 ,  TCOF1 ,  PAX s,  MAFB ,  ABCA4,  and  WNT  allowing great cause for more research into the genetic basis for craniofacial disorders. [ 11 ] [ 18 ] [ 12 ] [ 13 ] [ 14 ]


Because the cause of facial clefts still is unclear, it is difficult to say what may prevent children being born with facial clefts. It seems that  folic acid  contributes to lowering the risk of a child being born with a facial cleft. [ 21 ]


There is no single strategy for treatment of facial clefts, because of the large amount of variation in these clefts. Which kind of surgery is used depends on the type of clefting and which structures are involved. There is much discussion about the timing of reconstruction of bone and soft tissue. The problem with early reconstruction is the recurrence of the deformity due to the intrinsic restricted growth. This requires additional operations at a later age to make sure all parts of the face are in proportion. [ 22 ]  A disadvantage of early bone reconstruction is the chance to damage the tooth germs, which are located in the maxilla, just under the orbit. The soft tissue reconstruction can be done at an early age, but only if the used skin flap can be used again during a second operation. The timing of the operation depends on the urgency of the underlying condition. If the operation is necessary to function properly, it should be done at early age. The best aesthetic result is achieved when the incisions are positioned in areas which attract the least attention (they cover up the scars). If, however, the function of a part of the face isn't damaged, the operation depends on psychological factors and the facial area of reconstruction.


The treatment plan of a facial cleft is planned right after diagnosis. This plan includes every operation needed in the first 18 years of the patients life to reconstruct the face fully.
In this plan, a difference is made between problems that need to be solved to improve the health of the patient (coloboma) and problems that need to be solved for a better cosmetic result (hypertelorism).


The treatment of the facial clefts can be divided in different areas of the face: the cranial anomalies, the orbital and eye anomalies, the nose anomalies, the midface anomalies and the mouth anomalies.


The most common cranial anomaly seen in combination with facial clefts is  encephalocele .


The treatment of encephalocele is based on surgery to repair the bony gap and provide adequate protection of the underlying brain. The question remains if the external brain tissue should be put back into the skull or if it is possible to cut off that piece of brain tissue, because its claimed that the external piece of brain tissue often isn't functional, [ 23 ]  with the exception of a basal encephalocele, in which the pituitary gland can be found in the mouth.


The most common orbital /eye anomalies seen in children with facial clefts are colobomas and vertical dystopia.


The coloboma which occurs often in facial clefts is a cleft in the lower or upper eyelid. This should be closed as soon as possible, to prevent drought of the eye and a consecutive loss of vision. [ 24 ]


Vertical orbital dystopia can occur in facial clefts when the orbital floor and/or the maxilla is involved in the cleft. Vertical orbital dystopia means that the eyes do not lay on the same horizontal line in the face (one eye is positioned lower than the other). The treatment is based on the reconstruction of this orbital floor, by either closing the boney cleft or reconstructing the orbital floor using a  bone graft . [ 25 ]


There are many types of operations which can be performed to treat a hypertelorism. 2 options are: box osteotomy and facial bipartition [ 26 ]  (also referred to as a median fasciotomy).
The goal of the box osteotomy is to bring the orbits closer together by removing a part of the bone between the orbits, to detach both orbits from the surrounding bone structures and move both orbits more to the centre of the face.
The goal of the facial bipartition is not only to bring the orbits closer together, but also to create more space in the maxilla. This can be done by splitting the maxilla and the frontal bone, remove a triangular shaped piece of bone from the forehead and nasal bones and pulling the two pieces of forehead together. Not only will the hypertelorism be solved by pulling the frontal bone closer together, but because of this pulling, the space between the both parts of the maxilla will become wider.


The nose anomalies found in facial clefts vary. The main goal of the treatment is to reconstruct the nose to get a functional and esthetic acceptable result. A few possible treatment options are to reconstruct the nose with a forehead flap or reconstruct the nasal dorsum with a bone graft, for example a rib graft. The  nasal reconstruction  with a forehead flap is based on the repositioning of a skin flap from the forehead to the nose. A possible downside of this reconstruction is that once you performed it at a younger age, you can't lengthen the flap at a later stage. A second operation is often needed if the operation is done on early age, because the nose has a restricted growth in the cleft area. Repair of the  ala  (wing of the nose) often requires the inset of cartilage graft, commonly taken from the ear. [ 27 ]


The treatment of soft tissue parts of midface anomalies is often a reconstruction from a skin flap of the cheek. This skinflap can be used for other operations in the further, as it can be raised again and transposed again. In the treatment of midface anomalies there are generally more operations needed. Bone tissue reconstruction of the midface often occurs later than the soft tissue reconstruction. The most common method to reconstruct the midface is by using the fracture/ incision lines described by  René Le Fort . When the cleft involves the maxilla, it is likely that the impaired growth will result in a smaller maxillary bone in all 3 dimensions (height, projection, width).


There are several options for treatment of mouth anomalies like Tessier cleft number 2-3-7 . These clefts are also seen in various syndromes like Treacher Collins syndrome and hemifacial microsomia, which makes the treatment much more complicated. In this case, treatment of mouth anomalies is a part of the treatment of the syndrome.


Related articles


Syndromes


Facial femoral syndrome  is a rare  congenital disorder . [ 1 ]  It is also known as femoral dysgenesis, bilateral femoral dysgenesis, bilateral-Robin anomaly and femoral hypoplasia-unusual facies syndrome. The main features of this disorder are underdeveloped thigh bones ( femurs ) and unusual  facial features . [ 2 ]


Of note intellectual development typically is normal.


The cause of this condition is not known. A  genetic  basis is suspected. More than one case have been reported in three families. [ citation needed ]  It seems to be correlated to  maternal   diabetes mellitus  in about a third of patients. There also have been links to maternal drug exposure,  viral infections ,  radiation , and  oligohydramnios . [ 3 ]


The diagnosis is based on the combination of unusual facial features and the  dysplastic  or absent  femurs . [ 3 ]


Diagnosis may be made antenatally. [ 4 ]


There is no known specific treatment for this condition. Management is supportive. [ 3 ]


This is a rare disorder with 92 cases reported up to 2017. [ 1 ]


This condition was first described in 1975. [ 5 ]


Faciocardiorenal syndrome  is a rare  genetic disorder  characterized by facial dysmorphisms, congenital heart defects, and the presence of a  horseshoe kidney , alongside  intellectual disabilities . [ 2 ]  Facial dysmorphisms include  protruding ears , narrowing of the mouth,  cleft palate ,  hypertelorism , etc. [ 3 ]  Only 4 cases from the United States, [ 4 ]   Northern Ireland , [ 5 ]  and Mexico [ 6 ]  have been described in the medical literature. [ 7 ]  Transmission is, presumably,  autosomal recessive . [ 2 ]


Familial male-limited precocious puberty , often abbreviated as  FMPP , also known as  familial sexual precocity  or  gonadotropin-independent testotoxicosis , [ 1 ]  is a form of  gonadotropin -independent  precocious puberty  in which boys experience early onset and progression of  puberty . [ 2 ]  Signs of puberty can develop as early as an age of 1 year. [ citation needed ]


The spinal length in boys may be short due to a rapid advance in epiphyseal maturation. It is an  autosomal dominant [ 1 ]  condition with a  mutation  of the  luteinizing hormone (LH) receptor . As FMPP is a gonadotropin-independent form of precocious puberty,  gonadotropin-releasing hormone agonists  (GnRH agonists) are ineffective. Treatment is with drugs that suppress or block the effects of gonadal  steroidogenesis , such as  cyproterone acetate ,  ketoconazole ,  spironolactone , and  testolactone . [ 3 ]  Alternatively, the combination of the  androgen receptor   antagonist   bicalutamide  and the  aromatase inhibitor   anastrozole  may be used. [ 4 ]


Robert King Stone , personal physician to American president  Abraham Lincoln , described the first case of FMPP in 1852. [ 5 ]


Femur-fibula-ulna syndrome  (FFU syndrome)  is a very rare syndrome characterized by abnormalities of the  femur  (thigh bone),  fibula  (calf bone) and the  ulna  (forearm bone). There have been suggestions that FFU complex may be the same as  proximal femoral focal deficiency  (PFFD) although authors are currently in disagreement over whether or not the disorders are in fact separate. The breadth of the abnormality and number of limbs involved is considered sporadic although upper limbs are more affected than lower limbs and right side malformation is more prevalent than the left. [ 1 ]  The condition was first noted by Lenz and Feldman in 1977. [ 2 ]


This article about a disease of musculoskeletal and connective tissue is a  stub . You can help Wikipedia by  expanding it .


Fetal alcohol spectrum disorders  ( FASDs ) are a group of conditions that can occur in a person who is exposed to  alcohol  during  gestation . [ 1 ]  FASD affects 1 in 20 Americans, but is highly mis- and under-diagnosed. [ 9 ]


The several forms of the condition (in order of most severe to least severe) are:  fetal alcohol syndrome  (FAS), partial fetal alcohol syndrome (pFAS),  alcohol-related neurodevelopmental disorder  (ARND), [ 1 ]  and neurobehavioral disorder associated with prenatal alcohol exposure (ND-PAE). [ 10 ]  Other terms used are fetal alcohol effects (FAE), partial fetal alcohol effects (PFAE), alcohol-related birth defects (ARBD), [ 1 ] [ 11 ]  and static  encephalopathy , [ 12 ]  but these terms have fallen out of favor and are no longer considered part of the spectrum. [ 13 ]


Not all infants exposed to alcohol in utero will have detectable FASD or pregnancy complications. The risk of FASD increases with amount consumed, the frequency of consumption, and the longer duration of alcohol consumption during pregnancy, particularly  binge drinking . The variance seen in outcomes of alcohol consumption during pregnancy is poorly understood. Diagnosis is based on an assessment of growth, facial features, central nervous system, and alcohol exposure by a multi-disciplinary team of professionals. The main criteria for diagnosis of FASD is nervous system damage and alcohol exposure, with FAS including congenital malformations of the lips and growth deficiency. FASD is often misdiagnosed as or comorbid with ADHD.


Almost all experts recommend that the mother abstain from alcohol use during pregnancy to prevent FASDs. As the woman may not become aware that she has conceived until several weeks into the pregnancy, it is also recommended to abstain while attempting to become pregnant. Although the condition has no known cure, treatment can improve outcomes. Treatment needs vary but include psychoactive medications, behavioral interventions, tailored accommodations, case management, and public resources.
Globally, one in 10 women drink alcohol during pregnancy, and the prevalence of having any FASD disorder is estimated to be at least 1 in 20. The rates of alcohol use, FAS, and FASD are likely to be underestimated, because of the difficulty in making the diagnosis and the reluctance of clinicians to label children and mothers. Some have argued that the FAS label stigmatizes alcohol use, while authorities point out that the risk is real. The condition has appeared in several works of fiction.


The key signs of fetal alcohol syndrome (FAS) required for diagnosis include:


Popova et al. identified 428  ICD-10  conditions as co-occurring in individuals with FAS. Excluding conditions used in FAS diagnosis, co-occurring conditions with 50% prevalence or greater include: [ 16 ]


Other FASD conditions are partial expressions of FAS where the central nervous system shows clinical deficits. In these other FASD conditions, an individual may be at greater risk for adverse outcomes because brain damage is present without associated visual cues of poor growth or the "FAS face" that might ordinarily trigger an FASD evaluation. Such individuals may be misdiagnosed with primary  mental health disorders  such as  ADHD  or  oppositional defiance disorder  without appreciation that brain damage is the underlying cause of these disorders, which requires a different treatment paradigm than typical mental health disorders. While other FASD conditions may not yet be included as an  ICD  or  DSM-IV-TR  diagnosis, they nonetheless pose significant impairment in  functional behavior  because of underlying brain damage. [ 17 ]  Many indications of fetal alcohol spectrum disorders are developmental. Therefore, although a child may appear 'normal' at birth, intellectual disabilities caused by alcohol before birth may not appear until the child begins school. [ 18 ]


More broadly, alcohol use during pregnancy is also associated with: [ 1 ] [ 19 ]


Alcohol can also harm the fertility of women who are planning for pregnancy. Adverse effects of alcohol can lead to malnutrition, seizures, vomiting and dehydration. The mother can suffer from anxiety and depression which can result in child abuse/neglect. It has also been observed that when the pregnant mother withdraws from alcohol, its effects are visible on the infant as well. The baby remains in an irritated mood, cries frequently, does not sleep properly, weakening of sucking ability and increased hunger. [ 26 ]


In 2019, a study found that individuals with FASD have a higher risk of  hypertension  independent of race/ethnicity and obesity. [ 27 ]


Fetal alcohol spectrum disorders are caused by alcohol exposure during gestational development. [ 1 ]  If an individual was not exposed to alcohol before birth, they will not have FASD. [ 28 ]  However, not all infants exposed to alcohol in utero will have detectable FAS, FASD, or pregnancy complications. [ 29 ]


No safe level of fetal alcohol exposure has been established. [ 30 ]  Because alcohol is a known  teratogen , it is considered unethical to do randomized controlled trials on pregnant women to determine the precise toxicity effects of alcohol. [ 31 ]  Among women who consume any quantity of alcohol during pregnancy, the risk of giving birth to a child with FASD is about 15%, and to a child with FAS about 1.5%. Drinking 2  standard drinks  a day, or 6 standard drinks in a short time, carries a 4.3% risk of a FAS birth (i.e. one of every 23 heavy-drinking pregnant women will deliver a child with FAS). Furthermore, alcohol-related congenital abnormalities occur at an incidence of roughly one out of 67 women who drink alcohol during pregnancy. [ 29 ]  Among those mothers who have an alcohol use disorder, an estimated one-third of their children have FAS. [ 32 ]  The variance seen in outcomes of alcohol consumption during pregnancy is poorly understood. Aggravating factors may include  advanced maternal age ,  smoking , poor diet, [ 33 ] [ 34 ]  genetics, and social risk factors. [ 35 ]


The risk of FASD increases with amount consumed, the frequency of consumption, and longer duration of alcohol consumption during pregnancy. [ 35 ] [ 34 ] [ 36 ]   Blood alcohol concentration  has been identified as a relevant factor. [ 37 ]  All forms of alcohol, such as beer, wine, and liquor, pose similar risk. [ 38 ]   Binge drinking  increases the chances and severity of FASD to such an extent that Svetlana Popova has stated that "binge drinking is the direct cause of FAS or FASD". [ 39 ]   Small amounts of alcohol may not cause an abnormal appearance, however, small amounts of alcohol consumption while pregnant may cause behavioral problems and also increases the risk of miscarriage. [ 40 ] [ 32 ] [ 41 ] [ 42 ]  Quasi-experimental studies provide moderately strong evidence that prenatal alcohol exposure causes detrimental cognitive outcomes, and some evidence of reduced birthweight, although no study was fully rated at low risk of bias and quantity of studies was limited. [ 43 ]


The evidence is inconsistent and contradictory regarding the effects of low-to-moderate drinking, for example less than 12 grams of ethanol per day. [ 44 ]  Many studies find no significant effect, but some find beneficial associations, and others find detrimental associations, even on the same outcomes. Summarizing studies by country shows some similarity in results, due to using the same data sources. The definition of low alcohol consumption varies significantly among studies and often fails to incorporate all aspects of timing, dose, and duration. Recall bias and socioeconomic and psychosocial factors have been controlled for in most studies, but it is likely that residual confounding due to missing factors and variation in methods still exists and is larger than any observed effects. [ 45 ] [ 46 ] [ 32 ] [ 47 ] [ 23 ] [ 19 ]


Fathers who consume alcohol prior to conception may contribute to FAS through long term  epigenetic  modification of the father's sperm. [ 32 ] [ 48 ] [ 49 ]


Almost all experts recommend that the mother abstain from alcohol use during pregnancy to prevent FASDs. [ 4 ] [ 13 ] [ 50 ]  A pregnant woman may not become aware that she has conceived until several weeks into the pregnancy, so it is also recommended to abstain from alcohol while attempting to become pregnant. [ 51 ]  The recommendations of abstaining from alcohol during pregnancy and while attempting to become have been made by the  Surgeon General of the United States , [ 52 ] [ 51 ]  the Centers for Disease Control, [ 23 ]  the American College of Obstetricians and Gynecologists, the  American Academy of Pediatrics , [ 38 ]  the  World Health Organization , [ 53 ]  the United Kingdom's  National Institute for Health and Clinical Excellence , [ 54 ]  and many others. [ 38 ]  In the United States, federal legislation has required that warning labels be placed on all alcoholic beverage containers since 1988 under the  Alcoholic Beverage Labeling Act . [ 55 ]


The most current advocacy perspectives encourage people and systems to approach FASD with interventions and support for individuals who are already living with FASD. Focusing on prevention often only further stigmatizes individuals with FASD and their birth parents. Advocates say, if a person is supporting people currently living with FASD then that person is spreading the awareness needed for successful prevention efforts; "Intervention is Prevention". Many  social determinants of health  impact the effects of PAE: [ 56 ]


Women can experience serious symptoms that accompany alcohol withdrawal during pregnancy. According to the World Health Organization, these symptoms can be treated during pregnancy with brief use of  benzodiazepine   tranquilizers . [ 21 ]  Currently, the FDA has approved three medications—naltrexone, acamprosate, and disulfiram—for the treatment of  alcohol use disorder  (AUD).  However, there is insufficient data regarding the safety of these medications for pregnant women. [ 57 ]


American Psychiatric Association  guidelines recommend that medications not be used to treat alcohol use disorder in pregnant women except in cases of acute alcohol withdrawals or other co-existing conditions. [ 61 ]  Instead, behavioral interventions are usually preferred as treatments for pregnant women with AUD. Medications should only be used for pregnant women after carefully considering potential risks and harms of the medications versus the benefits of alcohol cessation. [ 57 ]


After a pregnant woman consumes alcohol, the alcohol crosses through the placenta and umbilical cord to the developing fetus. Alcohol metabolizes slowly in the fetus and remains for a long time when compared to an adult. [ 62 ] [ 37 ]  A human fetus appears to be at triple risk from maternal alcohol consumption: [ 63 ] [ 64 ]


Although alcohol is known to be a  teratogen  (causing birth defects), the exact biological mechanisms for the development of FAS or FASD are unknown. However, clinical and animal studies have identified a broad spectrum of pathways through which maternal alcohol can negatively affect the outcome of a pregnancy. Clear conclusions with universal validity are difficult to draw, since different ethnic groups show considerable  genetic polymorphism  for the hepatic enzymes responsible for ethanol detoxification. [ 65 ]  Genetic examinations have revealed a continuum of long-lasting molecular effects that are not only timing specific but are also dosage specific; with even moderate amounts being able to cause alterations. [ 66 ]  Additionally, ethanol may alter fetal development by interfering with  retinoic acid  signaling as acetaldehyde can compete with retinaldehyde and prevents its oxidation to retinoic acid. [ 67 ]


Different body systems in the infant grow, mature and develop at specific times during gestation. The effect of consumption of alcohol differs during each of these developmental stages: [ 18 ]


Fetal alcohol spectrum disorders encompass a range of  physical  and  neurodevelopmental  problems which can result from prenatal alcohol exposure. Diagnosis is based on the signs and symptoms in the person and evidence of alcohol use. [ 1 ]  These diagnoses of fetal alcohol spectrum disorders are currently recognized:


As of 2016, the  Swedish Agency for Health Technology Assessment and Assessment of Social Services  accepts only FAS as a diagnosis, seeing the evidence as inconclusive with respect to other types. The agency feels it is unclear if identifying a FASD-related condition benefits the diagnosed individual. [ 70 ]


Presently, four FASD diagnostic systems that diagnose FAS and other FASD conditions have been developed in North America:


Each diagnostic system requires an assessment of four key features: growth, facial features, central nervous system, and alcohol exposure. To determine any FASD condition, a  multi-disciplinary  evaluation is necessary to assess each of the four key features for assessment. Generally, a trained  physician  will determine growth deficiency and FAS facial features. While a qualified physician may also assess central nervous system structural abnormalities or neurological problems, usually central nervous system damage is determined through  psychological ,  speech-language , and  occupational therapy  assessments to ascertain clinically significant impairments in three or more of the Ten Brain Domains. [ 73 ]  Prenatal alcohol exposure risk may be assessed by a qualified physician,  psychologist ,  social worker , or chemical health counselor. These professionals work together as a team to assess and interpret data of each key feature for assessment and develop an integrative, multi-disciplinary report to diagnose FAS (or other FASD conditions) in an individual. [ 74 ]


A positive finding on all four features is required for a diagnosis of FAS, and the four diagnostic systems essentially agree on criteria for fetal alcohol syndrome (FAS). However, there are differences among systems when full criteria for FAS are not met. Prenatal alcohol exposure and central nervous system damage are the critical elements of the spectrum of FASD, and a positive finding in these two features is sufficient for an FASD diagnosis in all FASD systems. [ 75 ]  But different researchers and systems may use a wide variety of terminology to describe an individual's FASD condition, as the nomenclature is still evolving. Most individuals with deficits resulting from prenatal alcohol exposure do not express all features of FAS and fall into other FASD conditions. [ 19 ]  The Canadian guidelines recommend the assessment and descriptive approach of the "4-Digit Diagnostic Code" for each key feature of FASD and the terminology of the IOM in diagnostic categories, excepting ARBD. [ 2 ]


The most severe condition is called Fetal Alcohol Syndrome (FAS), [ 1 ]  which refers to individuals who have a specific set of birth defects and neurodevelopmental disorders characteristic of the diagnosis. [ 22 ]  The following criteria must be fully met for an FAS diagnosis: [ 2 ] [ 19 ] [ 71 ] [ 72 ]


FAS is the only expression of FASD that has garnered consensus among experts to become an official  ICD-9  and  ICD-10  diagnosis.


Partial FAS (pFAS) was previously known as atypical FAS in the 1997 edition of the "4-Digit Diagnostic Code". People with pFAS have a confirmed history of prenatal alcohol exposure, but may lack growth deficiency or the complete facial stigmata. Central nervous system damage is present at the same level as FAS. These individuals have the same functional disabilities but "look" less like FAS. [ 76 ]


The following criteria must be fully met for a diagnosis of Partial FAS: [ 2 ] [ 19 ] [ 71 ]


Growth or height may range from normal to deficient. [ 14 ]


Alcohol-related neurodevelopmental disorder (ARND) is the specific diagnosis of the non-dysmorphic type of FASD, where a majority of the symptoms are witnessed. [ 77 ]  The diagnosis was initially suggested by the Institute of Medicine to replace the terms FAE (fetal alcohol effects). It focuses on central nervous system damage, rather than growth deficiency or FAS facial features. The Canadian guidelines also use this diagnosis and the same criteria. While the "4-Digit Diagnostic Code" includes these criteria for three of its diagnostic categories, it refers to this condition as  static encephalopathy . The behavioral effects of ARND are not necessarily unique to alcohol however, so use of the term must be within the context of confirmed prenatal alcohol exposure. [ 13 ]  ARND may be gaining acceptance over the terms FAE and ARBD to describe FASD conditions with central nervous system abnormalities or behavioral or cognitive abnormalities or both due to prenatal alcohol exposure without regard to growth deficiency or FAS facial features. [ 13 ] [ 78 ]


The following criteria must be fully met for a diagnosis of ARND or static encephalopathy: [ 2 ] [ 19 ] [ 71 ]


Growth or height may range from normal to minimally deficient. [ 14 ]


Neurobehavioral disorder associated with prenatal alcohol exposure (ND-PAE) is the spectrum-wide term for the psychiatric, behavioral, and neurological symptoms of all FASDs. It was introduced into the DSM-V as a "condition for further study" and as a specified condition under, "other specified neurodevelopmental disorders" as a way to better study the behavioral aspects of all FASD disorders. [ 77 ]


In terms of FASD,  growth  deficiency is defined as significantly below average  height ,  weight  or both due to prenatal alcohol exposure and can be assessed at any point in the  lifespan . Growth measurements must be adjusted for parental height,  gestational age  (for a  premature infant ), and other  postnatal  insults (e.g.,  poor nutrition ), although birth height and weight are the preferred measurements. [ 71 ]  Deficiencies are documented when height or weight falls at or below the 10th percentile of standardized growth charts appropriate to the population. [ 14 ]  Prenatal or postnatal presentation of growth deficits can occur, but are most often postnatal. [ 79 ]


Criteria for FASD are least specific in the  Institute of Medicine  (IOM) diagnostic system ("low birth weight..., decelerating weight not due to nutrition..., [or] disproportional low weight to height" p. 4 of executive summary), [ 19 ]  while the CDC use the 10th percentile as a cut-off to determine growth deficiency. [ 72 ]  The "4-Digit Diagnostic Code" allows for mid-range gradations in growth deficiency (between the 3rd and 10th percentiles) and severe growth deficiency at or below the 3rd percentile. [ 71 ]  Growth deficiency (at severe, moderate, or mild levels) contributes to diagnoses of FAS and pFAS, but not ARND or static encephalopathy. [ citation needed ]


The "4-Digit Diagnostic Code" from 2004 ranks growth deficiency as follows: [ 71 ]


In the initial studies that described FAS, growth deficiency was a requirement for inclusion in the studies; thus, all the original people with FAS had growth deficiency as an  artifact  of  sampling  characteristics used to establish criteria for the syndrome. [ citation needed ]  That is, growth deficiency is a key feature of FASD because growth deficiency was a criterion for inclusion in the study that defined FAS. Growth deficiency may be less critical for understanding the disabilities of FASD than the neurobehavioral sequelae to the brain damage. [ 19 ]  Canadian guidelines updated in 2016 deleted growth as a diagnostic criterion. [ 80 ]


Several characteristic  craniofacial  abnormalities are often visible in individuals with FAS. [ 81 ]  The presence of FAS facial features indicates  brain damage , although brain damage may also exist in their absence. FAS facial features (and most other visible, but non-diagnostic, deformities) are believed to be caused mainly during the 10th to 20th week of gestation. [ 82 ]


Refinements in diagnostic criteria since 1975 have yielded three distinctive and diagnostically significant facial features which distinguish FAS from other disorders with partially overlapping characteristics. [ 83 ] [ 84 ]  The three FAS facial features are:


Measurement of FAS facial features uses criteria developed by the  University of Washington . The lip and philtrum are measured by a trained physician with the Lip-Philtrum Guide, [ 85 ]  a five-point  Likert scale  with representative photographs of lip and philtrum combinations ranging from normal (ranked 1) to severe (ranked 5). Palpebral fissure length (PFL) is measured in millimeters with either  calipers  or a clear ruler and then compared to a PFL growth chart, also developed by the University of Washington. [ 15 ]


Ranking FAS facial features is complicated because the three separate facial features can be affected independently by prenatal alcohol. A summary of the criteria follows: [ 71 ] [ 86 ]


Central nervous system  (CNS) damage is the primary feature of any FASD diagnosis. Prenatal alcohol exposure, which is classified as a  teratogen , can damage the brain across a continuum of gross to subtle impairments, depending on the amount, timing, and frequency of the exposure as well as genetic predispositions of the fetus and mother. [ 19 ] [ 87 ]  While functional abnormalities are the behavioral and cognitive expressions of the FASD disability, CNS damage can be assessed in three areas: structural, neurological, and functional impairments. [ citation needed ]


All four diagnostic systems allow for assessment of CNS damage in these areas, but criteria vary. The IOM system requires structural or neurological impairment for a diagnosis of FAS, but also allows a "complex pattern" of functional anomalies for diagnosing PFAS and ARND. [ 19 ]  The "4-Digit Diagnostic Code" and CDC guidelines allow for a positive CNS finding in any of the three areas for any FASD diagnosis, but functional anomalies must measure at two standard deviations or worse in three or more functional domains for a diagnosis of FAS, PFAS, and ARND. [ 71 ] [ 72 ]  The "4-Digit Diagnostic Code" also allows for an FASD diagnosis when only two functional domains are measured at two standard deviations or worse. [ 71 ]  The "4-Digit Diagnostic Code" further elaborates the degree of CNS damage according to four ranks:


Structural abnormalities of the brain are observable, physical damage to the brain or brain structures caused by prenatal alcohol exposure. Structural impairments may include  microcephaly  (small head size) of two or more standard deviations below the average, or other abnormalities in brain structure (e.g.,  agenesis of the corpus callosum ,  cerebellar hypoplasia ). [ 19 ]


Microcephaly is determined by comparing head circumference (often called occipitofrontal circumference, or OFC) to appropriate OFC growth charts. [ 14 ]  Other structural impairments must be observed through  medical imaging  techniques by a trained physician. Because imaging procedures are expensive and relatively inaccessible to most people, diagnosis of FAS is not frequently made via structural impairments, except for microcephaly. [ citation needed ]


Evidence of a CNS structural impairment due to prenatal alcohol exposure will result in a diagnosis of FAS, and neurological and functional impairments are highly likely. [ 2 ] [ 19 ] [ 71 ] [ 72 ]


During the first trimester of pregnancy, alcohol interferes with the migration and organization of  brain cells , which can create structural deformities or deficits within the brain. [ 88 ]  During the third trimester, damage can be caused to the  hippocampus , which plays a role in memory, learning, emotion, and encoding visual and auditory information, all of which can create neurological and functional CNS impairments as well. [ 89 ]


As of 2002, there were 25 reports of  autopsies  on infants known to have FAS. The first was in 1973, on an infant who died shortly after birth. [ 90 ]  The examination revealed extensive brain damage, including microcephaly, migration anomalies,  corpus callosum  dysgenesis, and a massive  neuroglial ,  leptomeningeal   heterotopia  covering the left hemisphere. [ 91 ]


In 1977, Clarren described a second infant whose mother was a binge drinker. The infant died ten days after birth. The autopsy showed severe  hydrocephalus , abnormal neuronal migration, and a small corpus callosum. [ 91 ]  FAS has also been linked to  brainstem  and cerebellar changes, agenesis of the corpus callosum and  anterior commissure , neuronal migration errors, absent  olfactory bulbs ,  meningomyelocele , and  porencephaly . [ 91 ]


When structural impairments are not observable or do not exist, neurological impairments are assessed. In the context of FASD,  neurological impairments  are caused by prenatal alcohol exposure which causes general neurological damage to the  central nervous system  (CNS), the  peripheral nervous system , or the  autonomic nervous system . A determination of a neurological problem must be made by a trained physician, and must not be due to a postnatal insult, such as  meningitis ,  concussion ,  traumatic brain injury , etc. [ citation needed ]


All four diagnostic systems show virtual agreement on their criteria for CNS damage at the neurological level, and evidence of a CNS neurological impairment due to prenatal alcohol exposure will result in a diagnosis of FAS or pFAS, and functional impairments are highly likely. [ 2 ] [ 19 ] [ 71 ] [ 72 ]


Neurological problems are expressed as either hard signs, or diagnosable disorders, such as  epilepsy  or other  seizure disorders , or soft signs. Soft signs are broader, nonspecific neurological impairments, or symptoms, such as impaired  fine motor skills ,  neurosensory   hearing loss , poor  gait ,  clumsiness , and poor  eye–hand coordination . Many soft signs have  norm-referenced criteria , while others are determined through clinical judgment. "Clinical judgment" is only as good as the clinician, and soft signs should be assessed by either a pediatric neurologist, a pediatric neuropsychologist, or both. [ citation needed ]


When structural or neurological impairments are not observed, all four diagnostic systems allow CNS damage due to prenatal alcohol exposure to be assessed in terms of functional impairments. [ 2 ] [ 19 ] [ 71 ] [ 72 ]  Functional impairments are deficits, problems, delays, or abnormalities due to prenatal alcohol exposure (rather than hereditary causes or postnatal insults) in observable and measurable domains related to daily functioning, often referred to as  developmental disabilities . There is no consensus on a specific pattern of functional impairments due to prenatal alcohol exposure [ 19 ]  and only CDC guidelines label developmental delays as such, [ 72 ]  so criteria (and FASD diagnoses) vary somewhat across diagnostic systems.


The four diagnostic systems list various CNS domains that can qualify for functional impairment that can determine an FASD diagnosis:


A recent [ when? ]  effort to standardize assessment of functional CNS damage has been suggested by an experienced FASD diagnostic team in Minnesota. The proposed framework attempts to harmonize IOM, 4-Digit Diagnostic Code, CDC, and Canadian guidelines for measuring CNS damage vis-à-vis FASD evaluations and diagnosis. The standardized approach is referred to as the Ten Brain Domains and encompasses aspects of all four diagnostic systems' recommendations for assessing CNS damage due to prenatal alcohol exposure. The framework provides clear definitions of brain dysfunction, specifies empirical data needed for accurate diagnosis, and defines intervention considerations that address the complex nature of FASD with the intention to avoid common secondary disabilities. [ 73 ]


The proposed Ten Brain Domains include: [ 73 ]


The Fetal Alcohol Diagnostic Program (FADP) uses unpublished Minnesota state criteria of performance at 1.5 or more  standard deviations  on  standardized testing  in three or more of the Ten Brain Domains to determine CNS damage. However, the Ten Brain Domains are easily incorporated into any of the four diagnostic systems' CNS damage criteria, as the framework only proposes the domains, rather than the cut-off criteria for FASD. [ 92 ]


Prenatal alcohol exposure is determined by interview of the biological mother or other family members knowledgeable of the mother's alcohol use during the pregnancy (if available), prenatal health records (if available), and review of available birth records, court records (if applicable),  chemical dependency treatment  records (if applicable), chemical biomarkers, [ 93 ]  or other reliable sources.


Exposure level is assessed as  confirmed exposure ,  unknown exposure , and  confirmed absence of exposure  by the IOM, CDC and Canadian diagnostic systems. The "4-Digit Diagnostic Code" further distinguishes confirmed exposure as  High Risk  and  Some Risk : [ citation needed ]


Evidence is insufficient for the use of chemical biomarkers to detect prenatal alcohol exposure. [ 95 ]  Biomarkers being studied include fatty acid ethyl esters (FAEE) detected in the meconium (first feces of an infant) and hair. FAEE may be present if chronic alcohol exposure occurs during the second and third trimester since this is when the meconium begins to form. Concentrations of FAEE can be influence by medication use, diet, and individual genetic variations in FAEE metabolism however. [ 93 ] [ 96 ]


The CDC reviewed nine  syndromes  that have overlapping features with FAS; however, none of these syndromes include all three FAS facial features, and none are the result of prenatal alcohol exposure: [ 72 ]


Other disorders that have overlapping behavioral symptoms that might be comorbid to fetal alcohol spectrum disorder might include: [ 97 ]


Most people with an FASD have most often been misdiagnosed with ADHD due to the large overlap between their behavioral deficits.


Although the condition has no available cure, treatment can improve outcomes. [ 1 ] [ 3 ]  Because CNS damage, symptoms, secondary disabilities, and needs vary widely by individual, there is no one treatment type that works for everyone. [ 33 ]


Between 2017 and 2019 researchers made a breakthrough when they discovered a possible cure using neural stem cells (NSCs); they propose that if applied to a newborn, the damage can be reversed and prevent any lasting effects in the future. [ 98 ]


Psychoactive drugs  are frequently tried as many FASD symptoms are mistaken for or overlap with other disorders, most notably  ADHD . Medications are used to specifically treat symptoms of FASDs and not FAS entirely. Some of the medications used are antidepressants, stimulants, neuroleptics and anti-anxiety drugs. [ 99 ]


Early intervention  from birth to age 3 has been shown to improve the development of a child born with FASD. [ 96 ]  Interventions may include  parent–child interaction therapy , efforts to modify child behavior, and drugs. [ 5 ]   Behavioral  interventions are based on the  learning theory , which is the basis for many parenting and  professional  strategies and interventions. [ 78 ]  Along with ordinary  parenting styles , such strategies are frequently used by default for treating those with FAS, as the diagnoses  oppositional defiance disorder  (ODD),  conduct disorder ,  reactive attachment disorder  (RAD) often overlap with FAS (along with  ADHD ), and these are sometimes thought to benefit from behavioral interventions. Frequently, a person's poor academic achievement results in  special education  services, which also utilizes principles of  learning theory ,  behavior modification , and  outcome-based education . [ citation needed ]


Children with FAS benefit from behavioral and functional training, social skill training and tutoring. Support groups and talk therapy not only help the children suffering from FAS, but also help the parents and siblings of these children. [ citation needed ]


Many books and handouts on FAS recommend a developmental approach, based on  developmental psychology , even though most do not specify it as such and provide little theoretical background. Optimal human development generally occurs in identifiable stages (e.g.,  Jean Piaget 's  theory of cognitive development ,  Erik Erikson 's  stages of psychosocial development ,  John Bowlby 's  attachment framework , and other  developmental stage theories ). FAS interferes with normal development, [ 100 ]  which may cause stages to be delayed, skipped, or immaturely developed. Over time, an unaffected child can negotiate the increasing demands of life by progressing through stages of development normally, but not so for a child with FAS. [ 100 ]


By knowing what developmental stages and tasks children follow, treatment and interventions for FAS can be tailored to helping a person meet developmental tasks and demands successfully. [ 100 ]  If a person is delayed in the  adaptive behavior  domain, for instance, then interventions would be recommended to target specific delays through additional education and practice (e.g., practiced instruction on tying shoelaces), giving reminders, or making accommodations (e.g., using slip-on shoes) to support the desired functioning level. This approach is an advance over behavioral interventions, because it takes the person's developmental context into account while developing interventions. [ citation needed ]


The  advocacy  model takes the point of view that someone is needed to actively mediate between the environment and the person with FAS. [ 13 ]  Advocacy activities are conducted by an advocate (for example, a family member, friend, or  case manager ) and fall into three basic categories. An advocate for FAS: (1) interprets FAS and the disabilities that arise from it and explains it to the environment in which the person operates, (2) engenders change or accommodation on behalf of the person, and (3) assists the person in developing and reaching attainable goals. [ 13 ]


The advocacy model is often recommended, for example, when developing an  individualized education program  (IEP) for the person's progress at school. [ 99 ]


An understanding of the developmental framework would presumably inform and enhance the advocacy model, but advocacy also implies interventions at a systems level as well, such as educating schools, social workers, and so forth on best practices for FAS. However, several organizations devoted to FAS also use the advocacy model at a  community practice  level as well. [ 101 ]


Treating FAS at the  public health  and  public policy  level promotes FAS prevention and diversion of  public resources  to assist those with FAS. [ 13 ]  It is related to the advocacy model but promoted at a systems level (rather than with the individual or family), such as developing community education and supports, state or province level prevention efforts (e.g., screening for maternal alcohol use during  OB/GYN  or prenatal medical care visits), or national awareness programs. Several organizations and state agencies in the U.S. are dedicated to this type of intervention. [ 101 ]


The prognosis of FASD is variable depending on the type, severity, and if treatment is issued. [ citation needed ]  Prognostic disabilities are divided into primary and secondary disabilities.


The primary disabilities of FAS are the functional difficulties with which the child is born as a result of CNS damage due to prenatal alcohol exposure. [ 102 ]


Often, primary disabilities are mistaken as  behavior problems , but the underlying CNS damage is the originating source of a functional difficulty, [ 103 ]  rather than a mental health condition, which is considered a secondary disability. The exact mechanisms for functional problems of primary disabilities are not always fully understood, but  animal studies  have begun to shed light on some correlates between functional problems and brain structures damaged by prenatal alcohol exposure. [ 13 ]  Representative examples include:


Functional difficulties may result from CNS damage in more than one domain, but common functional difficulties by domain include: [ 13 ] [ 78 ] [ 100 ] [ 103 ]  Note that this is not an exhaustive list of difficulties.


The secondary disabilities of FAS are those that arise later in life secondary to CNS damage. These disabilities often emerge over time due to a mismatch between the primary disabilities and environmental expectations; secondary disabilities can be ameliorated with early interventions and appropriate supportive services. [ 102 ]


Six main secondary disabilities were identified in a University of Washington research study of 473 subjects diagnosed with FAS, PFAS (partial fetal alcohol syndrome), and ARND (alcohol-related neurodevelopmental disorder): [ 13 ] [ 102 ]


Two additional secondary disabilities exist for adults: [ 13 ] [ 102 ]


Eight factors were identified in the same study as universal protective factors that reduced the incidence rate of the secondary disabilities: [ 13 ] [ 102 ]


Malbin (2002) has identified the following areas of interests and talents as strengths that often stand out for those with FASD and should be utilized, like any strength, in treatment planning: [ 78 ]


One study found that the people with FAS had a significantly shorter  life expectancy . [ 6 ]  With the average life span of 34 years old, a study found that 44% of the deaths were of "external cause", with 15% of deaths being suicides.


Globally, one in 10 women drink alcohol during pregnancy. Out of this population, 20%  binge drink  and have four or more alcoholic drinks per single occasion. [ 39 ]  The use of alcohol during pregnancy occurs at different rates across the world, potentially due to various cultural differences and legislation. The five countries with the highest prevalence of alcohol use during pregnancy are Ireland (60%), Belarus (47%), Denmark (46%), the UK (41%), and the Russian Federation (37%). [ 29 ]


In a recent count, the prevalence of having any FASD disorder was 1 person out of 20, but some people estimate it could be as high as 1 in 7. [ 7 ]  The rates of FAS and FASD are likely to be underestimated, because of the difficulty in making the diagnosis and the reluctance of clinicians to label children and mothers. [ 107 ]


FASD among  Australian  youth is more common in  indigenous Australians . [ 108 ]  The only states that have registered birth defects in Australian youth are  Western Australia ,  New South Wales ,  Victoria  and  South Australia . [ 109 ]  In Australia, only 12% of Australian health professionals are aware of the diagnostics and symptoms of FASD. [ 108 ]  In Western Australia, the rate of births resulting in FASD is 0.02 per 1,000 births for non-Indigenous Australians, however among indigenous births the rate is 2.76 per 1,000 births. [ 109 ]  In Victoria, there have been no registered FASD related births for indigenous Australians, but the rate for the general population in Victoria is 0.01–0.03 per 1000 births. [ 109 ]  There have been no dedicated FASD clinics within Western Australia, but there are also no nationally supported diagnostic criteria anywhere in Australia. [ 110 ]  Passive surveillance is a prevention technique used within Australia to assist in monitoring and establishing detectable defects during pregnancy and childhood. [ 109 ]


A 2015 review article estimated the overall costs to Canada from FASD at $9.7 billion (including from crime, healthcare, education, etc.). [ 111 ]


In South Africa, some populations have rates as high as 9%. [ 11 ]


In the United States, alcohol use at some point during  pregnancy  is common and appears to be rising in prevalence. [ 112 ] [ 113 ] [ 114 ] [ 35 ]  In 2006–2010, an estimated 7.6% of pregnant women used alcohol, while 1.4% of pregnant women reported binge drinking during their pregnancy. The highest prevalence estimates of reported alcohol use during pregnancy were among women who are aged 35–44 years (14.3%), white (8.3%), college graduates (10.0%), or employed (9.6%). [ 115 ]  In 2015, about 10% of pregnant women drank alcohol in the past month, and 20% to 30% drank at some point during the pregnancy. [ 34 ]  Of pregnant American women, 3.6% met criteria for an alcohol use disorder in a 2001 epidemiological study. [ 40 ]  As of 2016, the US Centers for Disease Control estimated 3 million women in the United States are at risk of having a baby with FASD. [ 116 ]


FASD is estimated to affect between 1-2% and 5% of people in the United States and Western Europe. [ 117 ]  FAS is believed to occur in between 0.2 and 9 per 1,000 live births in the United States. [ 117 ]  Using medical and other records, CDC studies have identified 0.2 to 1.5 infants with FAS for every 1,000 live births in certain areas of the United States. [ 118 ]  A more recent CDC study of 2010 data analyzed medical and other records and found FAS in 0.3 out of 1,000 children from 7 to 9 years of age. [ 119 ]


The lifetime cost per child with FAS in the United States was estimated at $2 million (for an overall cost across the country of over $4 billion) by the  CDC  in 2002. [ 117 ]


Some hold that ancient sources describe the negative effects of alcohol during pregnancy, [ 11 ]  identifying admonitions from  ancient Greek ,  Roman , the  Talmud , and the  Bible . [ 120 ]  For example,  Plato  writes in his fourth-century B.C.  Laws  (6.775): "Drinking to excess is a practice that is nowhere seemly ... nor yet safe. ... It behooves both bride and bridegroom to be sober ... in order to ensure, as far as possible, in every case that the child that is begotten may be sprung from the loins of sober parents." The sixth-century AD  Talmud  ( Kethuboth  60b) cautions, "One who drinks intoxicating liquor will have ungainly children." However, ancient sources rarely if ever distinguish maternal alcohol consumption from paternal, and are more concerned with conception than pregnancy. The sources can often be viewed as expressing  heredity , that children are likely to turn out like their (alcoholic) parents, rather than presenting the modern viewpoint that alcohol itself has an impact. [ 121 ] [ 90 ]


In 1725, in the midst of the  Gin Craze , British physicians petitioned the  House of Commons  on the effects of strong drink when consumed by pregnant women saying that such drinking is "too often the cause of weak, feeble, and distempered children, who must be, instead of an advantage and strength, a charge to their country". [ 122 ]  There are many other such historical references during that period. [ 123 ]  Gin specifically was implicated as affecting children's health and causing stillbirth and infant mortality, as depicted in William Hogarth's  Gin Lane . In contrast, Hogarth's  Beer Street  shows commerce and happiness, suggesting that the alcohol in beer was not known to have deleterious effects at this time. [ 121 ]


In Gaelic Scotland, according to  Martin Martin , the mother and nurse were not allowed to consume  ale  during pregnancy and breastfeeding. [ citation needed ]


In the 19th century,  Benjamin Rush  and  Thomas Trotter  lobbied against alcohol consumption during pregnancy to avoid dependence and mental deficiency in children. [ 121 ]  The  teetotalism  and  temperance movements  popularized these and other claims, [ 124 ] [ 125 ]  including the teratogenic effects of alcohol on animal embryos, [ 121 ]  but they were often sensationalized, so much so that any finding that alcohol was harmful was largely denounced as propaganda. [ 123 ]  A prominent observation of possible links between maternal alcohol use and fetal damage was made in 1899 by Dr. William Sullivan, a  Liverpool  prison physician who noted higher rates of  stillbirth  for 120 alcoholic female prisoners than their sober female relatives. He suggested the causal agent to be alcohol use. [ 126 ]  This contradicted the predominating belief at the time that heredity caused intellectual disability, poverty, and criminal behavior, which contemporary studies on the subjects usually concluded. [ 13 ]  A case study by  Henry H. Goddard  of  the Kallikak family —popular in the early 1900s—represents this earlier perspective, [ 127 ]  though later researchers have suggested that the Kallikaks almost certainly had FAS. [ 128 ]  General studies and discussions on alcoholism throughout the mid-1900s were typically based on a heredity argument. [ 129 ]  Researchers were often temperance advocates and funded by like-minded organizations such as the  Anti-Saloon League , so clinicians viewed all such research with heavy skepticism. The temperance movement effectively shut down serious research into the subject for nearly 50 years after Prohibition. [ 121 ]


From the 1960s to the 1980s, alcohol was commonly used as a  tocolytic , a method to stop preterm labor (born at less than 37 weeks gestation). The method originated with Dr.  Fritz Fuchs , the chairman of the department of obstetrics and gynecology at Cornell University Medical College. [ 130 ] [ 131 ]  Doctors recommended a small amount of alcohol to calm the uterus during contractions in early pregnancy or Braxton Hicks contractions. In later stages of pregnancy, the alcohol was administered intravenously and often in large amounts. "Women experienced similar effects as occur with oral ingestion, including intoxication, nausea and vomiting, and potential alcohol poisoning, followed by hangovers when the alcohol was discontinued." [ 132 ]  Vomiting put the mother at a high risk for aspiration and was "a brutal procedure for all involved". [ 130 ]  Because the alcohol was being given intravenously, the doctor could continue giving the treatment to the mother long after she had passed out, resulting in her being more intoxicated than would otherwise be possible. Such heavy intoxication was highly likely to contribute to FASD. [ 130 ]  In a 2015 review, ethanol was found to be no better than placebo (sugar water) in suppressing preterm birth and neonatal mortality. Not only was ethanol worse than other beta-mimetic drugs (tocolytic agents) at postponing birth, it also led to a higher rate of low birthweight babies, babies with breathing problems at birth, and neonatal death. [ 133 ]


In France in 1957, Jacqueline Rouquette had described 100 children whose parents were alcoholics in a thesis, which was not published. "She gave a good description in certain cases of the facies" according to her mentor, Paul Lemoine. [ 134 ]
In 1968, Paul Lemoine of  Nantes , himself published a study in a French medical journal about children with distinctive features whose mothers were alcoholics. [ 135 ]


Independently, in the U.S., Christy Ulleland at  University of Washington  Medical School conducted an 18-month study in 1968–1969 documenting the risk of maternal alcohol consumption among the offspring of 11 alcoholic mothers. [ 136 ]  This study is arguably the true source of the modern understanding. [ 123 ]  The infants were studied by  dysmorphologists  Kenneth Lyons Jones and  David Weyhe Smith , colleagues of Ulleland at University of Washington, [ 123 ]  who identified a pattern of "craniofacial, limb, and cardiovascular defects associated with prenatal onset growth deficiency and developmental delay" in eight children. The pattern of malformations indicated that the damage was prenatal. They named these defects "fetal alcohol syndrome". [ 137 ]  News of the discovery shocked some, while others were skeptical of the findings. [ 138 ]  While many  syndromes  are  eponymous , i.e. named after the physician first reporting the association of symptoms, Smith named FAS after the causal agent of the symptoms. [ 139 ]  He reasoned that doing so would encourage prevention, believing that if people knew maternal alcohol consumption caused the syndrome, then abstinence during pregnancy would follow from  patient education  and public awareness. [ 139 ]  At the time, nobody was aware of the full range of possible birth defects from FAS or its rate of prevalence. [ 139 ]


In 1978, within nine years of the Washington discovery, animal studies, including non-human monkey studies carried out at the University of Washington Primate Center by  Sterling Clarren , had confirmed that alcohol was a  teratogen . By 1978, 245 cases of FAS had been reported by medical researchers, and the syndrome began to be described as the most frequent known cause of  intellectual disability . [ citation needed ]  In 1979, the Washington and Nantes findings were confirmed by a research group in  Gothenburg , Sweden. [ 140 ]  Researchers in France, Sweden, and the United States were struck by how similar these children looked, though they were not related, and how they behaved in the same unfocused and  hyperactive  manner. [ 140 ]


Over time, subsequent research and clinical experience suggested that a range of effects could arise from prenatal alcohol exposure. The term  fetal alcohol effects  (FAE) was used for alcohol-related neurodevelopmental disorder and alcohol-related birth defects. [ 1 ]  It was initially used in research studies to describe humans and animals in whom teratogenic effects were seen after confirmed prenatal alcohol exposure (or unknown exposure for humans), but without obvious physical anomalies. [ 141 ]  Smith (1981) described FAE as an "extremely important concept" to highlight the debilitating effects of brain damage, regardless of the growth or facial features. [ 142 ]  This term fell out of favor with clinicians in the 1990s because it was often regarded by the public as a less severe disability than FAS, when in fact its effects could be just as detrimental. [ 143 ]  In 1996 the replacement terms ARBD and ARND were introduced. In 2002, the US Congress mandated that the CDC develop diagnostic guidelines for FAS and in 2004 a definition of a term that already had been used by some in the nineties, the Fetal Alcohol Spectrum Disorder (FASD) was adopted, [ 38 ] > to include FAS as well as other conditions resulting from prenatal alcohol exposure. [ 139 ]
Currently, FAS [ 19 ] [ 141 ] [ 137 ]  is the only expression of prenatal alcohol exposure defined by the  International Statistical Classification of Diseases and Related Health Problems  and assigned  ICD-9  and diagnoses. [ citation needed ]


Alcohol-related birth defects (ARBD), formerly known as possible fetal alcohol effect (PFAE), [ 141 ]  was a term proposed as an alternative to FAE and PFAE. [ 144 ]  The IOM presents ARBD as a list of congenital anomalies that are linked to maternal alcohol use but have no key features of FASD. [ 19 ]  PFAE and ARBD have fallen out of favor because these anomalies are not necessarily specific to maternal alcohol consumption and are not criteria for diagnosis of FASD. [ 13 ]


In 2013, the  American Psychiatric Association  introduced neurobehavioral disorder associated with prenatal alcohol exposure (ND-PAE). [ 77 ]