Teratogenic Causes of Malformation

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Review:

Teratogenic Causes of Malformations

Enid Gilbert-BarnessDepartment of Pathology, Tampa General Hospital and University of South Florida College of Medicine,Tampa, Florida

Abstract. Crucial morphogenetic processes during the blastogenesis period, which extends throughoutthe first 4 wk of development, from fertilization until the end of the gastrulation stage (days 27 to 28postconception), can be altered and result in structural abnormalities, including patterns of multiple

congenital anomalies (MCAs) arising from developmental field defects. Severe damage may cause deathof the product of conception or, because of the pluripotential nature of the cells, the damage may becompensated allowing development to continue in a normal fashion. Most investigators believe that theall-or-none rule applies to the first 2 wk of development. Because the fetus is less susceptible to morphologicalterations when the developmental process of the majority of organs has been completed, the mostcommon anomalies associated with teratogenic exposures during the fetal period are fetal growth restriction(intrauterine growth retardation) and mild errors of morphogenesis (abnormalities of phenogenesis), suchas epicanthic folds, clinodactyly, and others. us, teratogenic exposures result in a wide variety of effectsthat range from infertility, prenatal onset growth restriction, structural defects, and functional CNSabnormalities to miscarriage or fetal death.

Keywords: teratogens, malformations, disruptions, morphogenesis, environmental exposures

Introduction

It is estimated that approximately 10-15% ofcongenital structural anomalies are the result ofthe adverse effect of environmental factors onprenatal development [1]. is means thatapproximately 1 in 250 newborn infants havestructural defects caused by an environmentalexposure and, presumably, a larger number of

children have growth retardation or functionalabnormalities resulting from nongenetic causes, inother words, from the effects of teratogens. Ateratogen is defined as any environmental factorthat can produce a permanent abnormality in

structure or function, restriction of growth, ordeath of the embryo or fetus. A dose-responserelationship should be demonstrated in animals orhumans so that the greater the exposure duringpregnancy, the more severe the phenotypic effectson the fetus [2]. Factors comprise medications,drugs, chemicals, and maternal conditions ordiseases, including infections. Time of exposureand specificity are shown in Table 1. is

manuscript discusses the teratogenic effects of well-documented environmental factors. Brent [1] noted that it is inappropriate to label

an agent as teratogenic without characterizing thedose, route of exposure, and stage of pregnancy

when the exposure occurred. is is because, as haslong been recognized, the effects of an environ-mental agent on the embryo or fetus depend on thechemical or physical nature of the agent and severalother factors, such as dose, route, and length of

Address correspondence to Enid Gilbert-Barness, M.D.,Tampa General Hospital, 1 Tampa General Circle, Tampa, FL33606, USA; tel 813 844 7565; fax 813 844 1427; [email protected].

0091-7370/10/0200-0099. $5.60. © 2010 by the Association of Clinical Scientists, Inc.

Annals of Clinical & Laboratory Science, vol . 40, no. 2, 2010

Available online at ww w.annclinlabsci.org

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exposure; the developmental stage at which theexposure occurs; the genetic susceptibility of themother and embryo or fetus; and the presence andnature of concurrent exposures [3].

Teratogenic exposures during prenatal develop-

ment cause disruptions regardless of the develop-mental stage or site of action. Most structuraldefects caused by teratogenic exposures occurduring the embryonic period, which is when criticaldevelopmental events are taking place and thefoundations of organ systems are being established[4]. Different organ systems have different periodsof susceptibility to exogenous agents.

Radiation

Ionizing radiation can injure the developingembryo due to cell death or chromosome injury.ere is no proof that human congenital malfor-mations have been caused by diagnostic levels ofradiation. e most critical exposure period is 8-15 wk after fertilization [5,6]. Before implantation,the mammalian embryo is insensitive to theteratogenic and growth-retarding effects ofradiation and sensitive to the lethal effects [7-9].e risks of 1-rad (0.10Gy) or 5-rad (0.05Gy) acuteexposure are far below the spontaneous risks of the

developing embryo because 15% of human embryosabort, 2.7 - 3.0% of human embryos have majormalformations, 4% have intrauterine growthretardation, and 8-10% have early- or late-stageonset genetic disease. Permanent growth retardationis more severe after midgestation radiation.

Because of its extended periods of organogenesisand histogenesis, the central nervous system (CNS)retains the greatest sensitivity of all organ systemsto the detrimental effects of radiation through thelater fetal stages. In utero radiation produces micro-

cephaly and mental retardation. Later in life thereis increased incidence of hematopoietic malig-nancies and leukemia [10].

Infectious Agents

e lethal or developmental effects of infectiousagents are the result of mitotic inhibition, directcytotoxic effects, or a vascular disruptive event onthe embryo or fetus. However, a repair process mayresult in scarring or calcification, which causes

further damage by interfering with histogenesis[11,12]. Infections that do not result in congenitalmalformations but do cause fetal or neonatal deathinclude enteroviruses (coxsackievirus, poliovirus,and echovirus) and hepatitis, variola, vaccina, andmumps viruses [13,14]. Non-radioactive in-situhybridization of formalin-fixed, paraffin-embeddedplacental and fetal tissue, using virus-specific DNAor RNA probes, is helpful for diagnosing fetal virusinfections such as cytomegalovirus, parvovirusB-19, and varicella-zoster virus that cause fetal

hydrops, placentitis, and abortion [15].

Varicella. Varicella (or chickenpox) is a highlyinfectious disease, usually occurring in childhood.By adulthood, more than 95 percent of Americanshave had chickenpox. Eighty-five to ninety-five

Table 1. Time specificity of action of some human teratogens [190].

Teratogen Fertil ization Age (days) Malformation

Rubella virus 0-60 Cataract or heart diseases more likely 0->129 Deafnessalidomide 21-40 Reduction defects of extremitiesHyperthermia 18-30 Anencephaly Male hormones (androgens) 90 Clitoral hypert rophy Warfarin (coumadin) 100 Possible mental retardation >14 50% vaginal adenosis >98 30% vaginal adenosis >126 10% vaginal adenosisRadioiodine therapy >65-70 Fetal thyroidectomy Goitrogens and iodides >180 Fetal goiterTetracycline >120 Dental enamel staining of primary teeth >150 Staining of crowns of permanent teeth

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percent of pregnant women are immune tochickenpox, which means that there is no need tobe concerned about this during pregnancy, even ifthe woman is exposed to someone with chickenpox.Nearly seven women out of 10,000 will develop

chickenpox during pregnancy, however, becausethey are not immune [16]. e disease is caused by the varicella-zostervirus (VZV), which is a form of the herpes virus.Transmission occurs from person-to-person bydirect contact or through the air. Chickenpox iscontagious from 1 to 2 days before the appearanceof the rash until the blisters have dried and becomescabs. Once a person is exposed to the virus,chickenpox may take up to 14 to 18 days to develop.

When a woman has a varicella infection during the

first 20 wk of pregnancy, there is a 2% chance thatthe baby will have a group of defects called thecongenital varicella syndrome [16], which includesscars, defects of muscle and bone, malformed andparalyzed limbs, small head size, blindness,seizures, and mental retardation. is syndrome israrely seen if the infection occurs after 20 wk ofpregnancy.

Another time that there is a concern about avaricella infection is in the newborn period, if themother develops the rash during the period from 5

days before to 2 days after delivery. Between 25%and 50% of newborns will be infected in this case,and they develop a rash between 5 and 10 daysafter birth. Up to 30% of infected babies will die ifnot treated. If the mother develops a rash between6 and 21 days before delivery, the baby faces somerisk of mild infection [17]. If the baby is treated immediately after birth with an injection of VZIG (varicella-zoster immuneglobulin), the infection can be prevented or theseverity lessened [16]. If a pregnant woman has

been exposed to someone with chickenpox, VZIGcan be given within 96 hr to prevent chickenpox orlessen the severity [16]. It is important for pregnant

women to avoid exposure to anyone withchickenpox if they are unsure that they are immuneto this infection.

Mumps virus. Mumps virus during pregnancydoes not cause malformations, but endocardialfibroelastosis has been noted in infants with a

positive mumps antigen skin test; this relationshiphas not been consistent [18].

Influenza virus. ere is no compelling evidenceto incriminate influenza virus infection during

pregnancy as a cause of malformations [18].

Parvovirus. Human parvovirus B-19 is able tocross the placenta and results in fetal infection,

which may occur whether the mother is symp-tomatic or asymptomatic. It is associated with ahigher than average fetal loss and may lead tospontaneous abortion in the first trimester, hydropsfetalis in the second trimester, and stillbirth atterm [19,20]. Generalized myocarditis, myositis ofskeletal muscles, and abnormalities of the eyes are

reported [21]. Human parvovirus B-19 has anaffinity for the erythropoietic tissue of the host andis therefor associated with fetal anemia leading tocardiac failure.

Other viral infections. Other viruses have notresulted in congenital anomalies but have causedsignificant fetal pathology. Poliovirus has beenassociated with abortion, stillbirth, and meningo-myelitis [22]; echovirus with disseminated viremia[23]; variola and vaccinia with necrotizingcutaneous and visceral infection; and hepatitis

virus with neonatal hepatitis [24].

Syphilis. It is believed that the fetus cannot beinfected with syphilis early in pregnancy because acytotrophoblastic layer of cells in the chorionic villiof the placenta prevents the spirochete from passingfrom maternal to fetal blood. is cell layerdisappears at the sixth month. Since the spirocheteusually does not reach the conceptus during thefirst trimester, it is usually not a cause of abortion[25]. However, there has been a report of syphilitic

endometritis causing first trimester abortion as apotential infectious cause of fetal morbidity inearly gestation [26]. In untreated maternal syphilis of less than 2 yrduration, about half of the infants are live-born

without infection. In untreated maternal syphilisin the primary or secondary stages, 50% arestillborn or die within 4 wk after birth. Inuntreated maternal syphilis in the early part of thetertiary stage, 20% to 60% of infants are normal,

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40% have congenital syphilis, 20% are bornprematurely, and 16% are stillborn or die within 4 wk after birth. In untreated syphilis in the latepart of the tertiary stage, 75% of babies areunaffected, 10% have congenital syphilis, 9% are

born prematurely, 10% are stillborn, and 1% die within 4 wk after birth [27].

Toxoplasmosis. Primary maternal infection withToxoplasma gondii occurs in 1 per 1000 pregnanciesin the United States [28]. Infection is disseminatedthrough the placenta to the offspring in 40%, withmaternal infection through the placenta. Malfor-mations do not occur; however, hydrocephalus andmicrocephaly result from chronic destructivemeningoencephalitis. Chorioretinitis may progress

to scarring and loss of vision. Hydrocephalus andcerebral calcifications, hepatitis, and lymphadeno-pathy are the most common complications ininfants infected prenatally [29]. Organisms havebeen recovered from the brain of a congenitallyinfected infant after 5 yr.

ermodisruptions

Hyperthermia is defined as a body temperature ofat least 38.9°C and is an antimitotic teratogen after

exposure between weeks 4 and 14 [30-32]. In aretrospective study, Smith et al [33] presented 21patients who had been exposed during pregnancyto hyperthermia caused by infections or by saunabathing. Severe mental deficiency, seizures ininfancy, microphthalmia, midface hypoplasia, andmild distal limb abnormalities were associated with hyperthermia [33]. Infants exposed tomaternal hyperthermia at 7 to 16 wk of gestationhave hypotonia, neurogenic arthrogryposis, orCNS dysgenesis [34]. Shiota [34] studied 100

embryos with CNS defects and found that 18% ofmothers of anencephalic infants had experiencedhyperthermia at the critical embryonic stage [34].Occipital encephalocele has also been related tohyperthermia [35]. Embryonic studies in guineapigs and rats have highlighted the sensitivity ofbrain growth to elevated temperatures [36-38].

Hypothermia is defined as a core body temperatureof less than 35°C. Cardiopulmonary bypass in a

pregnant patient is associated with a fetal mortalityrate of 16% to 33%. One infant with multiplecongenital defects has been described. Anotherinfant had severe disruptive defects of the brainand distal spinal cord, suggesting hypoperfusion

injuries related to hypothermia [39].

Toxic Metals

Lead. A woman who has had lead poisoning canpass lead on to her fetus if she becomes pregnant,even if she no longer is exposed to lead. ishappens because more than 90% of the lead maybe stored in bone and released into the bloodstreamyears later. Blood Pb levels of ≥10 µg/dl areconsidered to be elevated but not dangerously high.

e term “lead poisoning” refers to blood Pb levels≥50 µg/dl. Deleterious effects of lead exposure havenot been convincingly shown to occur at blood Pblevels ≤20 µg/dl. Lead crosses the placenta as earlyas the 12th to 14th weeks of gestation andaccumulates in fetal tissue [40-42]. e adverseeffects of lead include spontaneous abortion andstillbirth. A small but significant increase in minormalformations, including hemangiomas, lymph-angiomas, hydroceles, skin tags, skin papillae, andundescended testes, was seen in infants with highlead levels in the umbilical blood [41-44]. eVACTERL (vertebral, anal, cardiac, tracheo-esophageal fistula, renal and limb abnormalities)association has been reported with prenatalexposure to high lead levels, similar to animalmodels of lead teratogenicity [45].

Mercury. Organic forms of mercury are more toxicthan the inorganic forms. Methylmercury, themost toxic organic form, causes severe braindamage, as in Minamata disease, which occurred

in epidemic proportions on the Japanese island ofMinamata after maternal ingestion (by bothhumans and cats) of methlymercury-contaminatedshellfish [46]. A similar exposure occurred in Iraqafter the ingestion of bread prepared from wheattreated with methylmercury that was used as afungicide [47]. e blood Hg assay measuresexposure to all types of mercury, but becausemercury remains in the bloodstream for only a fewdays after exposure, the test should be done soon



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after exposure. Most non-exposed people haveblood Hg levels of 0 to 2 µg/dl. Levels >2.8 µg/dlare required to be reported to the state healthdepartment. e assay can be influenced by eatingfish that contain mercury. Early effects of mercury

toxicity have been found when the blood Hg levelexceeds 3 µg/dl [48]. Methylmercury poisoningproduces atrophy of the granular layer of thecerebellum and spongiose softening in the visualcortex and other cortical areas of the brain [47];polyneuritis can also occur.

Lithium is used in the treatment of bipolar disorder.If possible lithium should be withheld during thefirst trimester of pregnancy and women takinglithium should not breast feed their infants. e

ratio of lithium concentrations in umbilical cordblood to maternal blood is uniform (mean 1.05 ±0.13). Infants with high lithium concentrations(>0.64 mmol/L) at delivery have significantly lower

Apgar scores. High lithium concentrations atdelivery are associated with perinatal complications,and lithium concentrations can be reduced by briefsuspension of therapy proximate to delivery.Cardiovascular malformations, in particularEbstein anomaly and tricuspid atresia, have beenrelated to lithium exposure [49-52]. Infants exposed

in utero to lithium may experience transientlethargy, hypotonia, cyanosis, poor feeding, andpoor respiratory efforts during the early neonatalperiod [49]. Other defects that have been noted ininfants exposed to lithium in utero includemalformations of the CNS, ear, and ureter, alteredthyroid and cardiac function, and congenital goiter[53]. Some abnormalities (mainly heart defectssuch as Ebstein malformation) in the newbornoccur in 6% to 10% of pregnancies involving first-trimester exposure to lithium [54,55].

Chemical Exposures

Polychlorinated and polybrominated biphenyls(PCBs). PCBs have been used for more than 40years as insulating fluids, heat exchangers,plasticizers, and chemical additives, and they areknown to be worldwide pollutants. ey have beenpresent in game fish caught in PCB-contaminated

waters [56]. Placental transfer of PCBs occurs inhumans [57]. Women suffering from PCB

poisoning have infants with parchment-like skin with desquamation and brown discoloration (“colababy”), dark colored nails, conjunctivitis, lowbirthweight, exophthalmos, and natal teeth.Reduced birthweight and small head size with

hypotonicity and hyporeflexia are associated withhigher levels of exposure. ere is no evidence ofreproductive risk to humans as long as occupationalexposures to PCBs are below the recommendedairborne levels of 0.0001 mg/m3 [58]. PCBs mayinterfere with male reproductive function byexerting estrogenic agonist/antagonist activity.

Toluene. Standards for a permissible exposure limit(PEL) for toluene have been set by the U.S.Occupational Safety and Health Administration(OSHA) at 100 ppm (375 mg/m3), calculated as atime weighted average over an 8-hr workday.Toluene embryopathy includes prenatal andpostnatal growth deficiency, microcephaly,anencephaly, developmental delay, cardiac andlimb defects, and craniofacial anomalies similar tofetal alcohol syndrome (FAS) [57,59-67]. Pheno-typic facial abnormalities similar to those of FASsuggest a common mechanism of craniofacialteratogenesis for toluene and alcohol attributed todeficiency of craniofacial neuropeithelium andmesodermal components due to increased

embryonic cell death [67].

Maternal Conditions

Obesity. During pregnancy, obesity is associated with adverse outcomes that include macrosomia,hypertension, pre-eclampsia, gestational diabetesmellitus (GDM), and fetal death [68-72]. Inaddition, many investigators have reported anincreased risk of birth defects.

Diabetes mellitus. Although hyperglycemia maybe key in the pathogenesis of diabetic embryopathy,other factors contained in diabetic serum may alsocontribute to the embryopathy [73]. Hyperglycemialeads to inhibition of the myoinositol uptake that isessential for embryonic development duringgastrulation and neurulation stages of embryo-genesis [74,75]. Deficiency of myoinositol appearsto cause perturbations in the phosphoinositidesystem that lead to abnormalities in the arachidonicacid-prostaglandin pathway. e gastrulation and



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neurulation stages of development are particularlysensitive to hypoglycemia and result in growthretardation as well as cranial and caudal neuraltube defects (NTDs). Obesity that occurs with anumber of metabolic abnormalities, including

abnormal glucose metabolism, is associated with ahigher risk of malformations. A possible role offree oxygen radicals in diabetic teratogenicity hasbeen suggested. e pathogenesis of diabeticembryopathy is heterogeneous [73,74]; mainten-ance of glucose homeostasis is important for theprevention of diabetic embryopathy.

ere is a correlation between elevatedhemoglobin A1c (HbA1c) levels and the incidenceof major congenital anomalies in infants of diabeticmothers (IDMs) [76-80]. HbA1c is a normal,

minor hemoglobin that differs from HbA by theaddition of a glucose moiety to the amino-terminalvaline of the beta chain. Glycosylation ofhemoglobin A occurs during circulation of the redcell and depends on the average concentration ofglucose to which the red cell is exposed during itslife cycle [81]. Measurement of HbA1c provides anindex of chronic glucose elevation, and therefore ofdiabetes control [82]. HbA1c levels duringpregnancy that exceed 11.5% are associated withcongenital abnormalities in 66% of the offspring,

but levels below 9.5% are not associated withincreased frequency of anomalies in infants ofdiabetic mothers [83]. Defects of the heart, centralnervous system (CNS), kidneys, and skeletonpredominate. Transposition of the great vessels,ventricular septal defect (VSD), and dextrocardiaoccur with greatest frequency. Anencephaly, spinabifida, and hydrocephaly are the major CNSmalformations. Rare malformations include situsinversus and caudal dysplasia, vertebral and renalanomalies, imperforate anus, radius aplasia, renalabnormalities including agenesis and dysplasia,and other defects. Brain development is oftenimpaired and anomalies include those observed inthe VACTERL association. Minor physicalabnormalities include anteverted nares, flattenednasal bridge, excess skin folds on the neck, andtapered fingers with hyperconvex nails. Othercomplications include hyperbilirubinemia, hypo-calcemia, vascular thromboses (eg, renal veinthrombosis), and respiratory distress syndrome.

Caudal dysplasia syndrome, with varying degreesof sacral agenesis, is sometimes associated withdefects of the palate and branchial arches andoccurs in 1% of diabetic offspring [84,85].

Hypothyroidism in infants occurs when the fetalthyroid gland has been suppressed by antithyroiddrugs (propylthiouracil, carbimazole, iodides),radioactive iodine [86] or possibly maternalantibodies [87]. Transfer of maternal thyroxin tothe fetus is negligible during early pregnancy.During the final weeks of pregnancy, thyroid-binding globulin (TBG) may compete for thyroxin.Triiodothyronine is less bound by TBG and canmore freely cross the placenta.

Hyperthyroidism during pregnancy is usually dueto Graves disease. e presence of thyroid-stimulating globulins may result in thyrotoxicity inthe fetus and newborn regardless of the treatmentof maternal disease. Neonatal thyrotoxicosis isusually a transient phenomenon lasting severalmonths. Affected infants have goiter, exophthalmos,restlessness, tachycardia, periorbital edema,ravenous appetite, hyperthermia, cardiomegaly,cardiac failure, and hepatosplenomegaly [88].

Hyperparathyroidism. Infants of mothers withuntreated hypoparathyroidism may have transienthyperparathyroidism during the fetal and neonatalperiods [89]. e fetal parathyroid hyperplasia thatoccurs in response to low maternal and fetal serumcalcium concentration is mediated by the maternalparathyroid dysfunction. Bone demineralizationand subperiosteal reabsorption occurs in the longbones. IUGR, pulmonary artery stenosis, VSD,and muscle hypotonia also occur.

Cretinism and iodine deficiency. Iodine deficiencyis the cause of endemic goiter and cretinism due todeficiency or of insufficient availability of thyroxineat the feto-placental level. ere is a role of maternalT4 in neurological embryogenesis, before the onsetof fetal thyroid function and, therefore, itsprotective role in fetal thyroid failure. In earlypregnancy, iodine deficiency induces a criticaldecrease of T4 levels with consequent TSH increaseresponsible for hypothyroidism in about 50% ofiodine-deficient pregnant women. Congenital



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hypothryoidism associated with deafness andmental retardation is found in the offspring ofhypothyroid mothers. Deafness persists in spite ofthyroid replacement therapy. Developmental

changes in the brain and cerebellum have beendescribed [90]. Fetal iodine deficiency results in cretinismcharacterized by mental retardation, spasticdiplegia, deafness, and strabismus [91,92]. Itrequires severe maternal iodine deficiency (lessthan 20 µg/day) during the first half of gestation, which occurs primarily in Northern Italy and inmountainous areas of New Guinea, the Himalayas,and the Andes.

Myotonic dystrophy. e myotonic dystrophy genecontains a segment of CTG repeats that tends toamplify in each generation [87-89]. Infants bornof women with myotonic dystrophy may show fetal

hypokinesia and generalized weakness, and mayexperience difficulty in respiration and feeding.e facies characteristically shows tenting of theupper lip, ptosis, absence of movement, andanterior cupping of the pinnas. Clubfoot is oftenpresent and postnatal growth is slow.

Phenylketonuria . Maternal phenylketonuria(PKU) leads to defects that include intrauterine

Table 2. Characterist ics of the fetal alcohol syndrome [191]

Affected System Frequent Anoma lies Occa sional Anoma lies

Growth Deficiency Prenatal


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and postnatal growth retardation, cardiovasculardefects, dislocated hips, and other anomalies [93-95]. Infants of mothers with PKU are heterozygous,and because phenylketonuric heterozygotes aregenerally normal, the defect in the fetus must be

attributed to the maternal metabolic disturbance.ese effects are directly related to the maternalphenylalalnine level. When the level exceeds 20mg/ml, 92% of infants have mental retardation;73%, microcephaly; 40%, IUGR; and 12%,cardiac malformations. One-fourth of pregnanciesabort spontaneously.

Ethanol, Smoking, and Various Drugs

Fetal Alcohol Syndrome (FAS). Patients with FAS

must have three characteristics: prenatal andpostnatal growth retardation (>2 SD for lengthand weight), facial anomalies, and CNS dysfunction(Table 2). e full picture of FAS usually occurs inbabies born to alcoholic mothers, or those whodrink regularly or binge-drink. However, noamount of alcohol is safe. Even light or moderatedrinking can affect the developing fetus.

Acetaldehyde is implicated as the cause of FASthrough its inhibiting effects on DNA synthesis,placental amino acid transport, and development

of the fetal brain [96-98]. e biologic basis forFAS is related to genetic polymorphisms identifiedfor alcohol dehydrogenase (ADH), which convertsalcohol to acetaldehyde, and acetaldehydedehydrogenase (ALDH2), which converts acetalde-hyde to acetate. Genetic differences in ADH allelesmake some infants exposed to the same level ofalcohol in utero more likely to have longer or higherlevels of exposure to acetaldehyde. is mayexplain the greater frequency in American blacksand Native Americans.

Structural and functional impairments occurin up to one half of infants born to alcoholic women who drink heavily. Functional and growthdisturbances without other morphologic changescan occur in infants whose mothers drinkmoderately (1 to 2 oz of absolute ethanol daily). Nomalformations have been documented in infants ofmothers who drink


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of the limbs, eyes, CNS, and arthrogryposis maybe present [112]. e assessment of the effects ofLSD use during pregnancy has been difficult, sincethe women’s lifestyle may include use of alcoholand other drugs, poor medical care, andmalnutrition. ere is no indication that the risk ofcongenital anomalies is great [113]. LSD-induced

chromosomal damage may last up to 2 years but issometimes transient [114,115]. ere is no evidencethat paternal exposure to LSD in small doses beforeconception is associated with increased rates ofspontaneous abortion, premature birth, or birthdefects [116,117].

Sedatives. Increased frequencies of cleft lip, cleftpalate, and congenital heart disease have beenreported after maternal phenobarbital exposure[118]. Benzodiazepine-containing drugs, taken inlarge amounts, may produce IUGR, cleft lip, and

facial features that resemble the findings of FAS[2,119], although studies have shown little or noincrease in congenital anomalies.

Isotretinoin (accutane, retin-A, retinoic acid)(Table 3). e risk of fetal abnormality whenisotretinoin is taken by a pregnant woman is 25%[118]. e critical period of exposure is 4 to 10 wkof gestation. e defects include hydrocephalus,microcephaly, cerebellar dysgenesis, depressednasal bridge, microtia or absent external ears, cleft

palate, anomalies of the aortic arch, cardiac defects(including ventricular septal defect, atrial septaldefect, tetralogy of Fallot), and hypoplastic adrenalcortex [120-122]. Spontaneous abortion is alsoincreased. A pregnancy-prevention program hasbeen implemented in women of child-bearing agereceiving isotreitinoin [123]. Use of topical retinoicacid has not been associated with fetal malfor-mations. Like its congener isotretinoin, etretinatecan cause CNS, cardiovascular, and skeletal

Table 3. Manifestations in isotretinoin embryopathy [192].

Abnormality Manifestations

Brain Hydrocephalus, leptomeningeal, heterotopias, vermis hypoplasia, Dandy-Walker, corticospinal tract malformationsBrain (occasional) Gyral defects including grade 3 lissencephaly, regional pachygyria, subcortical heterotopias

Brain funct ion Severe or profound mental retardation, hypotonia, diminished deep tendon reflexes (absent or abnormal) Craniofacial Low-set, small or atretic, malformed ears; small or atretic external auditory meatus; microphthalmia; telecanthus;

epicanthal folds; low nasal bridge; small jaw, sometimes with U-shaped cleft palate (Robin sequence) Heart Ventricular septal defect, truncus arteriosus, double-outlet right ventricle; interrupted aortic arch; patent ductus arteriosus

Table 4. Abnormal ities in tha lidomide embryopathy [193]

Skeletal defects Absent radii

Hand Limited extension, club hand, hypoplastic or fused phalanges, finger syndactyly, carpal hypoplasia or fusion, radial deviation Ulna Short and malformed, unilaterally or bilaterally absent Humerus

Hypoplastic, absent Shoulder girdle Abnormal ly formed with absent glenoid, fossa and acromion process, hypoplastic scapula and clavicle Hips Unilaterally or bilaterally dislocated Legs Coxa valga , femoral torsion, tibial torsion, bilatera l or unilateral stiff knee, abnormal tibiofibular joint, dislocated patella(e) Feet Overriding fifth toe, calcaneovalgus deformity Ribs Asymmetric first rib, cervical rib Spine Cervical spina bifida, fused cervical spine Mandibular hypoplasia Maxillary hypoplasia Cardiac anomalies Tetratology of Fallot, atrial septal defect, patent foramen ovale, dextrocardia, congestive heart failure leading to death Systolic murmur, cardiomegaly Suspected congenital heart disease Other abnormalities Apparently low-set ears, malformations extending to microtia Urogenital anomalies Micrognathia Meckel diverticulum Uterine anomalies

malformations [124]. In contrast to isotretinoin,etretinate is bound to lipoproteins and persists inthe circulation for years after use. Talidomide (Table 4). alidomide was usedclinically in the 1960s. It caused limb reductiondefects, facial hemangiomas, esophageal and

duodenal atresia, cardiac defects (eg, tetralogy ofFallot), renal agenesis, urinary tract anomalies,



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genital defects, dental anomalies, ear anomalies,facial palsy, ophthalmoplegia, anophthalmia,microphthalmia, and coloboma [125,126]. Cleftpalate was a rare occurence and the CNS was notaffected. e children had normal intelligence.e sensitive period for production of humanthalidomide birth defects was 23 to 28 days post-conception, with the critical period no longer than14 days. About 20% of pregnancies exposed duringthis period resulted in infants with anomalies, themost notable of which were limb defects rangingfrom triphalangeal thumb to tetra-amelia orphocomelia of the upper and lower limbs, at times

with preaxial polydactyly of six or seven toes perfoot [125].

McCredie [127-129] postulated interference

with neural crest-based sclerotomal organization asthe pathogenetic basis of the limb malformations.McCredie and coworkers [125,130] expanded theirstudies of the visceral anomalies in infants whodied with multiple congenital anomalies withlongitudinal limb defects by attempting todetermine whether neural crest injury wouldimpair development of structures supplied by thesensory autonomic nerves derived from the injuredzone of the neural crest. Application of sclerotomaland viscerotomal maps to the autopsy data showed

a neuroanatomic correlation in 89% of cases. eauthors proposed a developmental correlation

within a multiple congenital anomaly syndromeon the basis of neurotomes or embryonicdevelopmental fields with common regionalinnervation. alidomide is an inhibitor ofangiogenesis; its antiangiogenic activity correlates

with its teratogenicity [131].

Folic acid deficiency and folic acid antagonists. Folic acid deficiency has been observed in a high

percentage of women who have had infants with aneural tube defect (NTD); folic acid antagonistsalso may result in NTDs. Deficiency of folic acidappears to result in up to 70% of NTDs, particularlyanencephaly [132]. e US Food and Drug

Administration (FDA) recommends fortifyingfood with adequate levels of folic acid. Peri-conceptional daily intake of 0.4 mg of folic acid(the dose commonly contained in over-the-countermultivitamin preparations) reduces the risk of

NTDs by approximately 60% [133]. e US PublicHealth Service (PHS) recommends that all womenof childbearing age in the United States who arecapable of becoming pregnant should consume 0.4mg of folic acid per day in order to reduce their riskof having a pregnancy affected with spina bifida orother NTDs [134]. Because the effects of highintakes are not well known but include maskingthe diagnosis of vitamin B12 deficiency, care shouldbe taken to keep total folate consumption at


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disruption [144]. Cocaine-exposed fetuses alsohave increased incidences of prematurity, micro-cephaly, and sudden infant death [145].

Phenytoin (hydantoin, dilantin). Phenytoin is amedication used to treat epilepsy. If taken by themother in the first trimester, there is a small risk fora combination of birth defects known as the fetalhydantoin syndrome. e pattern of anomaliesconsists of developmental delay or frank mentaldeficiency, dysmorphic craniofacial features, andhypoplasia of the distal phalanges. e presence ofmajor phenytoin-associated birth defects in a childcorrelates with an inability of lymphocytes todetoxify the drug. ere appears to be geneticsusceptibility to phenytoin fetal toxicity. Twins

have been discordant for manifestations of thehydantoin syndrome [146]. e risk of develop-mental disturbance in phenytoin-exposed childrenranges from 1% to 11%. Chronic exposure presentsa maximum of 10% risk for the full syndrome anda maximum of 30% risk for some anomalies[147,148].

Trimethadioine, paramethadione. Maternal use ofthese drugs results in spontaneous abortion in one-fourth of pregnancies. Most liveborn infants have

prenatal and postnatal growth deficiency, develop-mental delay, malformations, and distinctive facies,including brachycephaly with midfacial hypoplasia,V-shaped eyebrows with or without synophrys,broad nasal bridge, arched or cleft palate, andmalpositioned ears, with anterior cupping and/orexcessive folding of the superior helices [149].Cardiovascular defects, particularly septal defectsand tetralogy of Fallot, renal malformations,tracheoesophageal anomalies, hernias, and hypo-spadias are common. Survivors often have mild to

moderate mental retardation and speech impair-ment [149].

Warfarin (dicumarol, coumarin derivatives). Women with a history of thromboembolic diseaseor artificial heart valves often require long-termanticoagulant therapy. ere is an estimated 25%risk for affected infants after exposure during theperiod from 8 to 14 weeks of pregnancy. Warfarininhibits the formation of carboxyglutamyl from

glutamyl residues, decreasing the ability of proteinsto bind calcium [150]. Choanal stenosis may occur.Calcific stippling occurs primarily in the tarsals,proximal femurs, and paravertebral processes.Brachydactyly and small nails, with greater severityin the upper limbs, has been present in about one-half of affected infants. Optic atrophy, micro-phthalmia and blindness can result from exposureduring the first or second trimester. Brain anomaliesinclude microcephaly, optic atrophy, visual impair-ment, seizures, hypotonia, and mental retardation.Inhibition of calcium binding by proteins during acritical period of ossification may explain the nasalhypoplasia, stippled calcification, and skeletalabnormalities of warfarin embryopathy [150].

Angiotensin-converting enzyme (ACE) inhibitors.Captopril crosses the human placenta. Its use andthat of other ACE inhibitors is associated withspontaneous abortions, intrauterine and neonataldeaths, neonatal respiratory distress, limb andCNS defects, patent ductus arteriosus (PDA),oligohydramnios, and calcarial hypoplasia, as wellas renal tubular dysplasia [151].

Statins. e statins are hypolipidemic drugs usedto lower serum cholesterol levels in people who

have or are at risk for cardiovascular disease[152,153]. Statins inhibit 3-hydroxy-3-methy-glutaryl coenzyme A (HMG-CoA) reductase, theenzyme that catalyzes formation of mevalonatefrom HMG-CoA, the rate-limiting step in themevalonate pathway of cholesterol biosynthesis.Cholesterol, an integral part of cell membranes, iscritical for embryonic and fetal development. Italso is the precursor of steroid hormones and isessential for the activation and propagation ofhedgehog signaling, which regulates critical events

during development, including patterning of theCNS [154-157]. e FDA designated these drugsin pregnancy category X [153] and, therefore, theiruse is contraindicated in women who are or maybecome pregnant. Because approximately 50% ofpregnancies in the United States are unplanned[158-160], early pregnancies may be unknowinglyexposed to them. Because of the recognition of various patternsof congenital abnormalities (CA) resulting from



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