Background and Introduction

Alcohol is a known human teratogen that produces a constellation of physical abnormalities and problems in behavior and cognition. Other teratogens which have received widespread attention include ionizing radiation; lead; polychlorinated biphenyls or PCBs, a group of synthetic hydrocarbons used as electrical insulating fluid in heat exchangers, plastics, transformers, and carbonless copy paper); diphenylhydrantoin, a prescription medicine used to treat seizures associated with epilepsy; substances of abuse (e.g., nicotine and cocaine), and infectious agents such as rubella virus. Although the effects of exposure to many of these compounds are well described, the mechanisms of action are not. Teratogens differ in their periods of susceptibility, the duration of exposure required to cause adverse fetal outcome, and the manifestations of

the insult.1

Fetal alcohol syndrome (FAS) was initially described in the medical literature in France by Lemoine in 1968.2 However, the term ÒFetal Alcohol SyndromeÓ was first coined by Jones and Smith in 1973 when they published their landmark report describing a constellation of birth defects in children born to alcoholic mothers.3

Alcohol exposure in utero produces a wide spectrum of craniofacial abnormalities and central nervous system dysfunction ranging from the subtle to very severe deficits. Because of the variable pattern of anomalies, the Institute of Medicine (IOM) developed five diagnostic cagtegories1 (Table 1 on next page) which have helped to provide consistency in the terminology used to describe the problems associated with prenatal alcohol exposure. The first two categories pertain to FAS itself. The other categories address the various aspects of alcohol-related effects.1

The exact prevalence of FAS is not known and has been difficult to characterize because

of significant variations in study populations and methods of data collection. Centers

for Disease Control (CDC) studies have documented FAS prevalence rates ranging from two to 15 cases per 10,000 live births in the United States.4 This article reviews the pathophysiology, clinical and orofacial manifestations, and management concerns arising in children afflicted with FAS.

Pathophysiology

Alcohol-induced fetal toxicity has been well established although the underlying mechanisms are not completely known. Currrent research on FAS has attempted to delineate the specific mechanisms of damage to the fetus as well as the conditions that determine the extent of this damage. Numerous factors, however, have complicated this research. First, the process of human development itself is complex and not yet fully understood. Second, multiple mechanisms work simultaneously and sequentially along different biochemical pathways and at different physical sites in the developing embryo. And third, the ways in which alcohol-induced mechanisms produce damage to the fetus depend on a number of variables, including the timing, frequency, and amount of maternal drinking during pregnancy, the motherÕs health status and habits, and the genetic make-up of the mother and fetus.

A central doctrine of teratology is that an organ is most susceptible during the period of its most rapid development. For most organs, this is the first trimester. The brain, however, appears to be vulnerable throughout the pregnancy since it begins forming in the first trimester and continues developing and maturing beyond delivery. Therefore, CNS deficits are a striking feature of FAS.

A safe level of alcohol consumption during pregnancy, if any, has not been determined. The alcohol molecule is small and fat-soluble and readily crosses the placenta and the fetal blood/brain barrier. This results in nearly equal fetal and maternal alcohol levels.5 The fetus has an immature liver with a limited ability to metabolize alcohol, and therefore the other developing organs are extremely vulnerable to any alcohol exposure.6

Although alcohol does not have any nutrient value, the energy from its metabolism can satisfy the bodyÕs caloric needs, depriving the body of essential nutrients present in food.

It is conceivable, therefore, that some of the anomalies seen in FAS are actually secondary effects of alcohol-related malnutrition. In addition, the metabolism of alcohol results in the production of acetaldehyde, a potent teratogen. The phenotype of FAS may be further complicated by the presence of this toxic compound.7

Clinical Manifestations

Diagnostic criteria for FAS developed by IOM (Table 1) have made the task of identification of classic FAS cases much easier. When the phenotype is less than classic or atypical, confirming the diagnosis becomes difficult, if not impossible.

There are other considerations that can also lead to errors in diagnosis. Maternal alcohol use during pregnancy may not be documented. Additionally, the use of other drugs (e.g., cocaine, marijuana, nicotine) often accompanies alcohol consumption. Delineation of FAS becomes difficult in such cases where polysubstance use is present. The clinical features of this syndrome can be subtle, and the characteristic facial features of FAS are often difficult to identify in neonates. Further, some of the neurologic effects may not be evident at birth. Diagnosis of FAS can be challenging under these circumstances, moreso

because no specific diagnostic tests are available.

A severe disturbance of growth is the hallmark of this syndrome, and one of the first indications of possible FAS is low birth weight. The growth deficiency persists postnatally and is not appreciably altered with changes in nutrition or a stable home setting.

Disturbance of the CNS is the most serious feature of the syndrome and is represented by microcephaly with resultant delayed neurological development. In most cases, the severity of the mental retardation correlates closely with the severity of the dysmorphic features.

The facial abnormalities are distinctive (Figure 1) and include short palpebral fissures, presence of epicanthal folds, low nasal bridge with short or upturned nose, and a smooth philtrum with a thin upper lip.5 In these patients, the upper lip also lacks the classic CupidÕs bow indentation at the edge of the vermilion border.8 Paralleling the somatic growth deficiencies, FAS patients also have narrow foreheads with flat midfaces and hypoplastic maxillas/mandibles.9,10  Very often these patients can also have wide palatal defects including cleft lip or palate. It has also been reported that FAS spectrum patients may have microdontia.9 Minor outer ear anomalies have been noted and include poorly formed pinnae, low-set ears, prominence, and retroversion.7 Less common anomalies are ptosis, strabismus, and antimongoloid slant of the eyes.5,7

A variety of limb anomalies occur, and include abnormal palmar creases and minor joint abnormalities. The latter include inability to completely extend the elbows, comptodactyly, and clinodactyly.5

Cardiac lesions occur with less frequency and are usually not severe. The majority have consisted of atrial rather than ventricular septal defects.5  An atrial septal defect is an opening in the septum between the two atria of the heart that is distinct from a patent foramen ovale. The communication allows a left-to-right shunt, though usually no significant pressure differences are detected between the atria. The classification

of atrial septal defect depends on the anatomic location of the defect. The most common type of atrial septal defect is at the fossa ovalis (ostium secundum), which accounts for 70 percent of these defects.11

A ventricular septal defect is an opening in the septum that separates the two ventricles, and is a common form of congenital heart disease. It constitutes about 10 percent of the congenital cardiac malformations found among adults. The opening allows a left-to-right shunting of blood, the extent and consequence depending on the size of the opening. Small ventricular septal defects are generally of little physiologic consequence. However, the larger the opening, the more shunting occurs. This equalizes ventricular systolic pressures and increases pulmonary arterial pressure with resulting severe congestive heart failare.11 The common clinical manifestations of FAS are listed in Table 3.

Craniofacial anomalies become less pronounced while cognitive and behavioral aspects of the syndrome gain more prominence as the infant grows. Hyperactivity, attention deficits, and language problems are particularly noticeable. Reduction in general intellectual functioning and academic skills as well as deficits in verbal learning, reasoning, and social skills become more prominent during childhood and adolescence. Behavioral problems continue and often worsen during teenage years and adulthood, particularly social functioning and peer relationships. These deficits have far-reaching consequences because they are pervasive and persist throughout the individualÕs life.5

Implications of FAS in Dentistry

Important considerations of FAS that may affect treatment rendered by dental clinicians include multiple facial deformities contributing to mouth breathing and corresponding dry mouth. Intuitively, mouth breathers tend to have a higher incidence of caries and gingivitis due to loss of the buffering capacity of saliva and gingival irritation due to drying. In these patients, it is paramount to stress the importance of impeccable oral hygiene.

FAS patients are also prone to have speech disorders which are multifactorial in nature, and referral to a speech pathologist must be considered to facilitate treatment.12

The orofacial manifestations that dentists should be concerned with include CNS and oral/motor deficits, poor tongue thrusting, temporomandibular joint (TMJ) disorders, cleft lip/palate, and dental malocclusions.

Systemically administered nitrous oxide and all general anesthetics contain N-methyl-D-aspartate (NMDA) antagonist and/or gamma aminobutyric acid (GABA) with mimetic properties much like ethanol. These qualities can trigger a neurodegeneration in the developing fetus.13 The clinician must be aware of these properties for prolonged procedures and operating room cases, especially in mothers who have a known history of substance abuse, so as not to potentiate any unintended adverse fetal alcohol effects.

Dental Management Concerns

The first step in the management of a dental patient with FAS is recognition of the condition. This is best accomplished via the medical history and open discussion with the patient or family members. Once a patient with FAS is identified, the dental practitioner must learn as much as possible about the history of the patient, including type and extent of systemic manifestations, current medications, frequency of physician visits, degree of control, and any known contributing factors.11

Consultation with the patientÕs physician is suggested before dental care is provided to patients with systemic problems resulting from FAS. Problems generally do not occur in providing outpatient dental care if the patientÕs systemic complications are well controlled and conservative medical care is being provided. However, if the patient is in the advanced stages of organ failure from complications of FAS or has other systemic diseases (e.g., CNS disturbances, diabetes mellitus, hypertension, or congestive heart failure), dental care may best be provided after physician consultations and in a hospital-like setting. Deferral of treatment may be required until adequate control is obtained.11 If

the person is to be treated as an outpatient, vital signs including blood pressure should be closely monitored before and during the procedure. Any atrial and/or ventricular septal defects may need special precautions and management.11

In children, an atrial septal defect is often asymptomatic. However, symptoms may increase with age, and by age 40 the majority of individuals will display symptoms of the defect. Infective endocarditis is rare in patients with an unrepaired atrial septal defect; therefore antibiotic prophylaxis is not required for an unrepaired secundum atrial septal defect or for one that has been surgically repaired if more than six months have passed since the repair and no residual shunting occurs.11

Surgical closure of a ventricular septal defect is necessary for moderate or large openings and is usually performed before the patient is two years old. The risk of infective endocarditis in patients with an uncomplicated, unrepaired defect is between four percent and ten percent for the first 30 years of life. It is very important to be aware that in contrast to atrial septal defects, all patients with unrepaired moderate to large ventricular septal defects require endocarditis prophylaxis. Patients with a surgically repaired ventricular septal defect do not require antibiotic prophylaxis if more than six months have passed since the repair and no residual shunting exists.11

In patients with orofacial infection, aggressive management is necessary, with the possibility of using culture and sensitivity tests for the selection of appropriate antibiotics. When surgical procedures are undertaken, meticulous attention to good surgical technique is necessary to decrease the risks of excessive bleeding and infection. The dentist should consult with the physician to determine the need for antibiotics when invasive procedures are planned. Alteration in drug dosage may be needed based on the amount of kidney function present.11

One of the major problems in treating a patient with FAS is that of drug therapy. Of concern are drugs excreted primarily by the kidney or that are nephrotoxic, and those that have an effect on the CNS. As a general rule, drugs excreted by the kidney are eliminated twofold less efficiently when the glomerular filtration rate (GFR) drops to 50 ml/min and thus may reach toxic levels at lower GFR. In these circumstances, drug dosage needs to be reduced and timing of administration needs to be prolonged.11 Nephrotoxic drugs such as acyclovir, aminoglycosides, aspirin, non-steroidal anti-inflammatory drugs, and tetracycline may require special dosage adjustments. Acetaminophen is also nephrotoxic and can cause renal tubular necrosis at high doses, but it is probably safer than aspirin in these patients due to metabolism in the liver.11

Although nitrous oxide-oxygen and diazepam are anti-anxiety drugs that require little modification for use in patients with FAS, the hematocrit or hemoglobin concentration should be measured before intravenous sedation to ensure adequte oxygenation. In addition, drugs that depress the central nervous system (barbiturates, narcotics) are best avoided in FAS because the blood/brain barrier may not be intact and excessive sedation may result.11

Seizures in FAS patients can usually be effectively controlled with anticonvulsant drugs and are therefore not a contraindication to normal routine dental care. In some instances, however, the history may reveal a degree of seizure activity that suggests non-compliance or a severe seizure disorder that does not respond to anticonvulsants. For these patients, a consultation with the physician is advised before dental treatment is rendered. A patient with poorly controlled disease may require additional anticonvulsant or sedative medication, as directed by the physician.11

In spite of appropriate preventive measures taken by the dentist and patient, the possibility always exists that an epileptic patient may have a generalized tonic-clonic convulsion in the dental office. The dentist and staff should anticipate this occurrence and be prepared for it. Preventive measures include knowing the patientÕs history, scheduling the patient at a time within a few hours of taking the anticonvulsant medication, using a mouth prop, removing dentures, and discussing with the patient the urgency of mentioning an aura as soon as it is sensed.

The clinician should also be aware that irritability is often a symptom of impending seizure. If the patient has a seizure while in the dental chair, the primary task of management is to protect the patient and try to prevent injury.11 Because gingival overgrowth is associated with phentoin administration, every effort should be made to maintain the patient at an optimum level of oral hygiene. This may require frequent visits for monitoring progress. If significant gingival overgrowth exists, surgical reduction will be necessary. However, this must be accompanied with an increased awareness of oral hygiene needs and a positive commitment by the patient to maintain oral cleanliness.11

Patients who are taking anticonvulsants may suffer from the toxic effects of these drugs, and the dentist should be aware of their manifestations. In addition to the more common adverse effects such as a rash, immune-mediated disorders such as erythema multiforme or Stevens-Johnson syndrome may present. Phenytoin, carbamazepine, and valproid acid can cause bone marrow suppression, leukopenia, and thrombocytopenia, resulting in an increased incidence of microbial infection, delayed healing, and gingival and postoperative bleeding. Valproic acid can decrease platelet aggregation, leading to spontaneous hemorrhage and petechiae.11

Treatment Planning Modifications

The goal of dental care for patients with FAS is to restore the mouth to the healthiest condition possible and to eliminate possible sources of infection (Table 4). Oral physiotherapy training is important for the maintenance of long-term oral health. Recall appointments may need to be more frequent when salivary flow rates are diminished to reduce the development of oral infections, periodontal disease, and caries. Once an acceptable level of oral hygiene has been established, no contraindication exits to routine

dental care.11

In addition, many of these patientsÕ diets contain food or drinks that increase the risk for dental disease. The dental treatment plan should contain the following elements. The daily oral hygiene procedures must be identifed. The treatment plan must be realistic for the patientÕs overall CNS, psychiatric manifestations, and physical status. For example, a patient with FAS may be more anxious, hostile, and uncooperative in the dental office that will make dental care more difficult.11 Prosthetic appliances may be misplaced, lost, or improperly worn. In advanced cases, removable prosthetic devices may need to be taken from the patient because of the danger of self-injury. Complex dental procedures should be performed only when the patient is in a stable condition. The treatment plan should minimize any stress of the dental visit. This can best be accomplished by effective patient management efforts and the use of non-verbal communication.

The dental team should communicate to the patient and the family members a positive, hopeful attitude toward maintenance of the patientÕs oral health. The dental team should determine if the patient is legally able to make rational decisions. This should be discussed with the patient and/or parents or a guardian. Treatment planning often will

involve input and permission from a parent/guardian so that decisions can be made.11

The last aspect of the treatment plan deals with the selection of medications to be used in the dental treatment of the patient. Certain agents may need to be avoided, while others will require a reduction in their usual dosage. Liver enzyme induction and central nervous sytem effects of alcohol in patients with FAS can require increased amounts of local anesthetic or additional anxiolytic procedures to be used. Appointments with these patients may therefore require more time if this manifestation was not anticipated. Most importantly in FAS patients, medical consultation is suggested to establish the patientÕs current status, confirm the medications the patient is taking, and identify any complications that may be present.11

References

            1. Stratton K, Howe C, Battaglia F eds. Institute of Medicine. Fetal alcohol syndome. Diagnosis, epidemiology, prevention, and treatment. Washington, D.C.: National Academy Press, 1996; pages 4-5, 33.

            2. Lemoine P, Harousseu H, Borteryu JP, Menuet JC. Les enfants de parents alcooliques: Anomalies observees a propos de 127 cas. [The children of alcoholic parents: Anomalies observed in 127 cases.] Quest medicale 1968;21:476-82.

            3. Jones KL, Smith DW. Recognition of the fetal alcohol syndrome in early infancy. Lancet 1973;2:999-1001.

            4. Centers for Disease Control and Prevention (2002). Monitoring fetal alcohol syndrome [Online]. Retrieved from ttp://www.cdc.gov/ncbddd/factsheets/

monitoring fas.pdf.

            5. Volpe JJ. Neurology of the Newborn, Fourth Edition. Philadelphia: WB Saunders, 2001;pages 867-68.

            6. Gardner J. Fetal alcohol syndrome: Recognition and intervention. MCN Am J Matern Child Nurs 1997;22(6):318-22.7.

            7. Abel EL. Fetal Alcohol Syndrome. New Jersey: Medical Economics Co. Inc. 1990; pages 40-1,55-87.

            8. West JR, Perrotta DM, Ericson CK. Fetal alcohol syndrome. A review for Texas physicians. Tex Med 1998;94(7):61-7.

            9. Zachman RD, Grummer MA. The interaction of ethanol and vitamin A as a potential mechanism for the pathogenesis of fetal alcohol syndrome. Alcohol Clin Exp Res 1998;22(7):1,544-56.

            10. Eustace LW, Kang D-H, Coombs D. Fetal alcohol syndrome: a growing concern for health care professionals. J Obstet Gynecol Neontal Nurs 2003;32:215-21.

            11. Little JW, Falace DA, Miller CS, Rhodus NL. Dental Management of the Medically Compromised Patient, Sixth Edition. St. Louis: CV Mosby Co. 2002;pages 181-83, 468-75,

419-22.

            12. Church MW, Abel EL. Fetal alcohol syndrome. Hearing, speech, language, and vestibular disorders. Obstet Gynecol Clin North Am 1998;25(1):85-97.