Environmental Agents

Fetal Alcohol Spectrum Disorders

Prenatal Onset of Growth Deficiency, Microcephaly, Short Palpebral Fissures

In 1968, Lemoine of Nantes, France, recognized the multiple effects that alcohol can have on the developing fetus. Lemoine’s report was not well accepted, and the disorder was independently rediscovered in 1973 by Jones and colleagues and was referred to as fetal alcohol syndrome (FAS). In 1996, an Institute of Medicine (IOM) report suggested that prenatal alcohol exposure results in a spectrum of defects now referred to as fetal alcohol spectrum disorders (FASD). FAS is at one end of the spectrum and alcohol related neurodevelopmental disorder (ARND) at the other. In between are partial FAS (PFAS) and alcohol related birth defects (see Comment below). To facilitate the practical applications of the criteria, Hoyme and colleagues set forth a clarification of the IOM report in 2005 (updated in 2016), and in 2010 Jones and colleagues extended the range of structural defects in order to provide a better appreciation of the total spectrum of FAS. It is now recognized that only 10% of children diagnosed with an FASD have FAS. The vast majority of affected individuals have a diagnosis of ARND. Based on a study published in 2018 in four communities in the United States, the most conservative prevalence estimate of FASD was 1.1% to 5.0%. Alcohol is now appreciated as the most common teratogen to which the fetus is liable to be exposed. It is of major public health concern.


Variable features from among the following:

  • Growth. Prenatal and postnatal onset of growth deficiency.

  • Performance. Average IQ of 65, with a range of 20 to 120; fine motor dysfunction manifested by weak grasp, poor eye-hand coordination, or tremulousness; irritability in infancy, hyperactivity in childhood. Problems with executive function, working memory, and spatial processing; poor impulse control, problems in social perception, deficits in higher level of receptive and expressive language.

  • Craniofacial. Mild-to-moderate microcephaly, short palpebral fissures, maxillary hypoplasia. Short nose, smooth philtrum with thin and smooth upper lip.

  • Skeletal. Joint anomalies, including abnormal position or function, altered palmar crease patterns, small distal phalanges, small fifth fingernails.

  • Cardiac. Heart murmur, frequently disappearing by 1 year of age; ventricular septal defect is most common, followed by atrial septal defect.

Occasional Abnormalities

Ptosis of eyelid, frank microphthalmia, cleft lip with or without cleft palate, micrognathia, protruding auricles, prominent ear crus extending from the root of the helix across the concha, mildly webbed neck, short neck, cervical vertebral malformations (10% to 20%), rib anomalies, tetralogy of Fallot, coarctation of the aorta, strawberry hemangiomata, hypoplastic labia majora, short fourth and fifth metacarpal bones, decreased elbow pronation/supination, incomplete extension of one or more fingers. Other joint contractures, hockey stick palmar crease, meningomyelocele, hydrocephalus. Characteristic neuropathologic features, including abnormalities of the corpus callosum, volume reduction of the cranial, cerebral, and cerebellar vaults, particularly the parietal lobe, portions of the frontal lobe, and the basal ganglia, although only the caudate is disproportionally reduced.

Natural History

There may be tremulousness in the early neonatal period. Postnatal linear growth tends to remain retarded, and the adipose tissue is thin. This often creates an appearance of “failure to thrive.” These individuals tend to be irritable as young infants, hyperactive as children, and more social as young adults. Problems with dental malalignment and malocclusion, eustachian tube dysfunction, and myopia develop with time. Specific abnormalities have been documented on tests of language, verbal learning and memory, academic skills, fine-motor speed, and visual-motor integration. Poor school performance is the rule even in children with IQ scores within the normal range.


The cause of this disorder is prenatal exposure to alcohol. Risky drinking during pregnancy has been defined as one or more of the following: (1) six drinks or more per week for two2 or more weeks during pregnancy; (2) three or more drinks per occasion on two or more occasions during pregnancy; (3) documentation of alcohol-related social or legal problems in proximity to the index pregnancy; (4) documentation of intoxication during pregnancy; (5) positive testing with established alcohol-exposure biomarkers during pregnancy; (6) increased risk associated with drinking during pregnancy as assessed by a validated screening tool.

The risk of a serious problem in the offspring of a chronically alcoholic woman has been estimated to be 30% to 50%.


Partial Fetal Alcohol Syndrome: Diagnosis of PFAS with documented prenatal alcohol exposure includes two or more of the characteristic facial features, including short palpebral fissures, smooth philtrum and thin vermilion border of upper lip plus neurobehavioral impairment (see below).

Diagnosis of PFAS without prenatal alcohol exposure includes two or more of the characteristic facial feature, plus growth deficiency or deficient brain growth, structural anomalies of the brain or abnormal neurophysiology defined as one or more of the following: Head circumference ≤ 10%, structural brain anomalies, or recurrent nonfebrile seizures, plus neurobehavioral impairment (see below).

Alcohol-Related Neurodevelopmental Disorder: Diagnosis of ARND requires documented prenatal alcohol exposure plus neurobehavioral impairment that includes A or B below and can be diagnosed in children only after 3 years of age.

  • A


    • Evidence of global impairment (general conceptual ability ≥ 1.5 SD below the mean, or performance IQ or verbal IQ or spatial IQ ≥ 1.5 SD below the mean).


    • Cognitive deficit in at least two neurobehavioral domains ≥ 1.5 SD below the mean (executive functioning, specific learning impairment, memory impairment, or visual spatial impairment).

  • B


    • Evidence of behavioral deficit in at least two domains ≥ 1.5 SD below the mean, including impairments of self-regulation (mood or behavioral regulation, attention deficit, or impulse control).


  • Lemoine P, et al: Les enfants de parents alcoholiques, Ovest Med 21:476, 1968.

  • Jones KL, et al: Pattern of malformation in offspring of chronic alcoholic mothers, Lancet 1:1267, 1973.

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

  • Jones KL, et al: Outcome in offspring of chronic alcoholic women, Lancet 1:1076, 1974.

  • Clarren SK, Smith DW: The fetal alcohol syndrome: A review of the world literature, N Engl J Med 198:1063, 1978.

  • Streissguth AP, et al: Fetal alcohol syndrome in adolescents and adults, JAMA 265:1961, 1991.

  • Stratton KR, et al, editors: Fetal Alcohol Syndrome: Diagnosis, Epidemiology, Prevention and Treatment , Washington DC, 1996, National Academy Press.

  • Jones KL: From recognition to responsibility: Josef Warkany, David Smith, and the fetal alcohol syndrome in the 21st century, Birth Defects Res A Clin Mol Teratol 67:13, 2003.

  • Guerri C, et al: Foetal alcohol spectrum disorders and alterations in brain development, Alcohol Alcohol 44:108, 2009.

  • Jones KL, et al: Fetal alcohol spectrum disorders: Extending the spectrum of structural defects, Am J Med Genet 152:2731, 2010.

  • Hoyme HE, et al: Updated clinical guidelines for diagnosing fetal alcohol spectrum disorders, Pediatrics 138:e20154256, 2016.

  • May P,: Prevalence of fetal alcohol spectrum disorders in 4 US communities, JAMA 319:474, 2018.

    FIGURE 1

    Fetal alcohol syndrome.

    Affected children of women with chronic alcoholism. A and B, Same child at 4 months and 8 years of age. C and D, Same child at birth and at 4 years of age. Note the short palpebral fissures; long, smooth philtrum with smooth vermilion border; and hirsutism in the newborn.

    A and B, From Jones KL: Birth Defects Res A Clin Mol Teratol 67:13, 2003, with permission; C and D, From Jones KL, Smith DW: Lancet 2:999, 1973, with permission.

    FIGURE 2

    A–E , Note the short palpebral fissures; long, smooth philtrum; thin vermilion border; maxillary hypoplasia; and ptosis.

    A and C, From Jones KL: Birth Defects Res A Clin Mol Teratol 67:13, 2003, with permission; B, D, and E, from Jones KL, Smith DW: Lancet 2:999, 1973, with permission.

    FIGURE 3

    A , Short right leg secondary to congenital hip dislocation. B, Camptodactyly.

    From Jones KL: Birth Defects Res A Clin Mol Teratol 67:13, 2003, with permission.

Fetal Hydantoin Syndrome (Fetal Dilantin Syndrome)

Although data suggesting the possible teratogenic effects of anticonvulsants were first presented by Meadow in 1968, convincing epidemiologic evidence of the association between hydantoins and congenital abnormalities awaited the studies of Fedrick and of Monson and colleagues. Further studies by Speidel and Meadow and by Hill and colleagues revealed a pattern of malformation that may include digit and nail hypoplasia, unusual facies, and growth and intellectual disabilities.


  • Growth. Mild-to-moderate growth deficiency, usually of prenatal onset, but may be

  • accentuated in the early postnatal months.

  • Performance. Occasional borderline to mild intellectual disability; performance in childhood may be better than that anticipated from progress in early infancy.

  • Craniofacial. Wide anterior fontanel; metopic ridging; ocular hypertelorism; broad, depressed nasal bridge; short nose with bowed upper lip; broad alveolar ridge; cleft lip and palate.

  • Limbs. Stiff, tapered fingers; hypoplasia of distal phalanges with small nails, especially postaxial digits; low-arch dermal ridge patterning of hypoplastic fingertips; digitalized thumb; shortened distal phalanges and metacarpals and cone-shaped epiphyses; dislocation of hip.

  • Other. Short neck, rib anomalies, widely spaced small nipples, umbilical and inguinal hernias, pilonidal sinus, coarse profuse scalp hair, hirsutism, low-set hairline, abnormal palmar crease, strabismus.

Occasional Abnormalities

Microcephaly, brachycephaly, positional foot deformities, strabismus, coloboma, ptosis, slanted palpebral fissures, webbed neck, pulmonary or aortic valvular stenosis, coarctation of aorta, patent ductus arteriosus, cardiac septal defects, single umbilical artery, pyloric stenosis, duodenal atresia, anal atresia, renal malformation, hypospadias, micropenis, ambiguous genitalia, cryptorchidism, symphalangism, syndactyly, terminal transverse limb defect, cleft hand, holoprosencephaly.

Natural History

It is not uncommon for infants to have relative failure to thrive during the early months; the reasons for this are unknown. IQ has been within the normal range. In a group of 48 three-year-olds who had been prenatally exposed to hydantoin, mean IQ was 99 with a range from 94 to 104. In another study conducted on prenatally exposed 6-year-olds, mean IQ was 108.Verbal abilities were lower than nonverbal abilities. However, no dose-response effect was noted.


The cause of this disorder is prenatal exposure to phenytoin (Dilantin) or one of its metabolites. The risk of a hydantoin-exposed fetus having fetal hydantoin syndrome is approximately 10%. No dose-response curve has been demonstrated, and no “safe” dose has been found below which there is no increased teratogenic risk.


Similar craniofacial features referred to as the “anticonvulsant facies” are associated with prenatal exposure to carbamazepine, hydantoin, primidone, and phenobarbital. In addition, an increased risk for meningomyelocele has been associated with prenatal exposure to carbamazepine; an increased risk for oral clefts has been associated with prenatal exposure to hydantoins and carbamazepine; and an increased risk for congenital cardiac defects has been associated with prenatal exposure to phenobarbital and carbamazepine. Good evidence indicates that exposure to a combination of the anticonvulsants (polytherapy) may increase the risk to the fetus. It has been suggested that the teratogenicity of these agents is associated with cardiac rhythm disturbances secondary to their propensity to inhibit a specific ion current (IKr) and subsequent hypoxic damage. IKr is critical for embryonic cardiac repolarization and rhythm regulation. Studies in early mouse embryo culture suggest a greater risk exists for malformation in association with polytherapy than monotherapy and that the risk is linked to disturbances in cardiac rhythm.


  • Meadow SR: Anticonvulsant drugs and congenital abnormalities, Lancet 2:1296, 1968.

  • Aase JM: Anticonvulsant drugs and congenital abnormalities, Am J Dis Child 127:758, 1970.

  • Speidel BD, Meadow SR: Maternal epilepsy and abnormalities of the fetus and newborn, Lancet 2:839, 1972.

  • Fedrick J: Epilepsy and pregnancy: A report from the Oxford Record Linkage Study, BMJ 2:442, 1973.

  • Monson RR, et al: Diphenylhydantoin and selected congenital malformations, N Engl J Med 289:1049, 1973.

  • Hill RM, et al: Infants exposed in utero to antiepileptic drugs, Am J Dis Child 127:645, 1974.

  • Hanson JW, Smith DW: The fetal hydantoin syndrome, J Pediatr 87:285, 1975.

  • Hanson JW, et al: Risks to the offspring of women treated with hydantoin anticonvulsant, with emphasis on the fetal hydantoin syndrome, J Pediatr 89:662, 1976.

  • Phelen MC, et al: Discordant expression of fetal hydantoin syndrome in heteropaternal dizygotic twins, N Engl J Med 307:99, 1982.

  • Finnell RH, Chernoff GF: Editorial comment. Genetic background: The elusive component in the fetal hydantoin syndrome, Am J Med Genet 19:459, 1984.

  • Strickler SM, et al: Genetic predisposition to phenytoin-induced birth defects, Lancet 2:746, 1985.

  • Jones KL, et al: Pattern of malformation in the children of women treated with carbamazepine during pregnancy, N Engl J Med 320:1661, 1989.

  • Holmes LB, et al: The teratogenicity of anticonvulsant drugs, N Engl J Med 344:1132, 2001.

  • Holmes LB, et al: The correlation of deficits in IQ with midface and digit hypoplasia in children exposed in utero to anticonvulsant drugs, J Pediatr 146:118, 2005.

  • Danielsson C, et al: Polytherapy with hERG-blocking antiepileptic drugs: Increased risk for embryonic cardiac arrhythmia and teratogenicity, Birth Defects Res A Clin Mol Teratol 79:595, 2007.

  • Meador K, et al: Cognitive function at 3 years of age after fetal exposure to antiepileptic drugs, N Engl J Med 360:1597, 2009.

  • Meador KJ, et al: Foetal antiepileptic drug exposure and verbal versus non-verbal abilities at three years of age, Brain 134:396, 2011.

  • Meador K, et al: Fetal antiepileptic drug exposure and cognitive outcomes at age 6 years (NEAD study): A prospective observational study, Lancet Neurol 12:244, 2013.

  • Tomson T, et al: Comparative risk of major congenital malformations with eight different antiepileptic drugs: A prospective cohort study of the EURAP registry, Lancet Neurol 17:530. 2018.

    FIGURE 1

    Fetal hydantoin syndrome.

    A and B, A 3-month-old infant with growth and intellectual disabilities whose mother took diphenylhydantoin throughout pregnancy. Note the hypoplastic nails and phalanges, and the relatively low and broad nasal bridge.

Fetal Valproate Syndrome

Concern was raised regarding prenatal valproic acid exposure in 1982 by Robert and Guiband, who documented an association between maternal ingestion of valproic acid and meningomyelocele in the offspring. DiLiberti and colleagues and Hanson and colleagues set forth a broader pattern of malformation in 1984.


  • Performance. Delayed development. At 3 years of age, poor cognitive development; verbal abilities lower than nonverbal abilities.

  • Craniofacial. Narrow bifrontal diameter; metopic ridging; larger cephalic index (disproportionate increased width of the skull relative to a shortened anterior-posterior length); high forehead; epicanthal folds connecting with an infraorbital crease or groove; ocular hypertelorism; broad, low nasal bridge with short nose and anteverted nostrils; midface hypoplasia; long smooth philtrum with a thin vermilion border; relatively small mouth; micrognathia.

  • Cardiovascular. Aortic coarctation, hypoplastic left heart, aortic valve stenosis, interrupted aortic arch, secundum type atrial septal defect, pulmonary atresia without ventricular septal defect, perimembranous ventricular septal defect.

  • Limbs. Long, thin fingers and toes; joint laxity; hyperconvex fingernails; talipes equinovarus.

Occasional Abnormalities

Growth delay, neural tube closure defects, autism spectrum disorder, brain atrophy, cyst of septum pellucidum, septooptic dysplasia, esotropia, nystagmus, tear duct anomalies, microphthalmia, iris defects, cataracts, corneal opacities, cleft palate, hearing loss, supernumerary nipples, hemangiomas, pigmentary abnormalities, hypospadias, inguinal and umbilical hernias, omphalocele, broad chest, bifid rib, postaxial polydactyly, radial ray defects, nail hypoplasia, preaxial defects of feet, triphalangeal thumbs, tracheomalacia, lung hypoplasia, laryngeal hypoplasia, renal hypoplasia, abnormal collecting system, hydronephrosis, hypospadias, poor bladder control.

Natural History

Increasing concern exists regarding the long-term cognitive effects of prenatal valproate exposure. A significant performance decline in motor functioning, adaptive functioning (as measured by parental ratings), and social skills, as well as an increased risk for attention-deficit disorders, has been documented. Behavioral problems are common, and many of the affected children require educational support. Impairments vary based on age. Cognitive, speech, and motor development problems are common in infancy, and IQ, language, memory, attention problems, and difficulties in executive function are more problematic at school age and beyond. Monotherapy with valproate has been associated with significantly more neurodevelopmental/behavioral problems than monotherapy with other antiepileptic drugs. Polytherapy that includes valproate is associated with significantly lower cognitive abilities and greater risk for structural malformations. Cognitive and neuropsychological deficits often occur without all or even any of the physical features.


The cause of this disorder is prenatal valproic acid exposure.


  • Robert E, Guiband P: Maternal valproic acid and congenital neural tube defects, Lancet 2:934, 1982.

  • DiLiberti JH, et al: The fetal valproate syndrome, Am J Med Genet 19:473, 1984.

  • Hanson JW, et al: Effects of valproic acid on the fetus, Pediatr Res 18:306A, 1984.

  • Ardinger HH, et al: Cardiac malformations associated with fetal valproic acid exposure, Proceedings of the Greenwood Genet Center 5:162, 1986.

  • Jager-Roman E, et al: Fetal growth, major malformations, and minor anomalies in infants born to women receiving valproic acid, J Pediatr 108:997, 1986.

  • Sharony R, et al: Preaxial ray reduction defects as part of valproic acid embryofetopathy, Prenat Diagn 13:909, 1991.

  • Omtzigt JGC, et al: The risk of spina bifida aperta after first-trimester exposure to valproate in a prenatal cohort, Neurology 42(Suppl 5):119, 1992.

  • Kozma C, et al: Valproic acid embryopathy: Report of two siblings with further expansion of the phenotypic abnormalities and a review of the literature, Am J Med Genet 98:168, 2001.

  • Viinikainen K, et al: The effects of valproate exposure in utero on behavior and the need for educational support in school-aged children, Epilepsy Behavior 9:636, 2006.

  • Meador KJ, et al: Cognitive function at 3 years of age after fetal exposure to antiepileptic drugs, N Engl J Med 360:1597, 2009.

  • Cohen MJ, et al: Fetal antiepileptic drug exposure: Motor, adaptive, and emotional/behavioral functioning at age 3 years, Epilepsy Behavior 22:240, 2011.

  • Meador KJ, et al: Foetal antiepileptic drug exposure and verbal versus non-verbal abilities at three years of age, Brain 134:396, 2011.

  • Stadelmaier R, et al: Exposure to sodium valproate during pregnancy: Facial features and signs of autism, Birth Defects Res 109A, 1134, 2017.

  • Clayton-Smith J, et al: Diagnosis and management of individuals with fetal Valproate Spectrum Disorder: a consensus statement from the European Reference Network for Congenital Malformations and Intellectual Disability, Orphanet J Rare Dis. 14:180, 2019.

    FIGURE 1

    Fetal valproate syndrome.

    A and B, A 3-year-old girl with high forehead, broad nasal bridge, short nose, anteverted nares, and long philtrum.

Fetal Warfarin Syndrome (Warfarin Embryopathy, Fetal Coumarin Syndrome)

Nasal Hypoplasia, Stippled Epiphyses, Coumarin Derivative Exposure in First Trimester

Isolated reports of infants who, in retrospect, were affected by warfarin were followed in 1975 by simultaneous recognition of this association in five infants. A number of infants are known to have been affected.


Following Prenatal Exposure from 6 to 9 Weeks

  • Facies. Nasal hypoplasia and depressed nasal bridge, often with a deep groove between the alae nasi and nasal tip.

  • Skeletal. Stippling of uncalcified epiphyses, particularly of axial skeleton (vertebrae and pelvis), at the proximal femora and in the calcanei; stippling disappears after the first year.

  • Limbs. Hypoplastic distal phalanges shaped like inverted triangles with the apices pointing proximally.

  • Growth. Low birthweight; most demonstrate catch-up growth.

Occasional Abnormalities

Choanal atresia, cleft lip and palate, lung hypoplasia, severe rhizomelia; scoliosis; congenital heart defect; vertebral anomalies, asplenia, renal agenesis, hypospadias. Structural defects of brain development.

Natural History

Infants often present with upper airway obstruction, which is relieved by the placement of an oral airway. Cervical spine abnormalities with resultant instability have led to severe neurologic dysfunction and even sudden death in some cases. The majority of affected children have done well with normal cognitive development except for persistent cosmetic malformation of the nose. The stippling is incorporated into the calcifying epiphyses and has resulted in few problems.

Following Prenatal Exposure from 14 to 20 Weeks

  • Central Nervous System (CNS). Microcephaly, hydrocephalus, Dandy-Walker malformation, agenesis of corpus callosum, midline cerebellar atrophy, seizures and spasticity, intellectual disability, speech difficulties.

  • Eye. Optic atrophy, cataracts, microphthalmia, Peters anomaly.

  • Other. Intrauterine growth retardation, scoliosis, tethered skin in the sacrococcygeal region.


This disorder is caused by prenatal exposure to the vitamin K antagonist warfarin (Coumarin, Coumadin). The critical period of exposure relative to the classic facial and skeletal features of the warfarin embryopathy is between 6 and 9 weeks’ gestation. Warfarin functions by blocking the enzyme vitamin k epoxide reductase. As a result gamma-glutamyl carboxylation of vitamin k-dependent clotting factors does not occur. Because vitamin K–dependent clotting factors are absent at 6 to 9 weeks’ gestation, another mechanism most likely related to the effect of coumadin on other vitamin k-dependent proteins containing carboxylated glutamyl residues must result in the warfarin embryopathy. In the majority of cases CNS abnormalities and intellectual disability are associated with exposure limited to the second and third trimesters, likely as a consequence of disruption secondary to fetal hemorrhage (Judith G. Hall, personal communication). In addition, warfarin can lead, in some cases, to structural defects in CNS development following first-trimester exposure, implying that it has a direct effect on CNS structural development as well. The incidence of warfarin-induced fetal complications has been estimated to be 6.4% of live born infants who were prenatally exposed.


Two additional disorders with similar clinical features have been associated with disturbances of vitamin K metabolism. Both pseudo-warfarin embryopathy, as the result of a defect of vitamin K epoxide reductase and severe maternal malabsorption resulting in fetal vitamin K deficiency, are associated with a similar phenotype. In addition, identical clinical features are seen in X-linked recessive chondrodysplasia punctata (CDPX). In vitro studies have shown that warfarin inhibits arylsulfatase E (ARSE) activity, a deficiency of which is responsible for the clinical phenotype of X-linked recessive chondrodysplasia punctata, thus explaining the phenotypic similarity.


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Jun 28, 2021 | Posted by in PEDIATRICS | Comments Off on Environmental Agents

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