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PartV

Fetal Infections and Teratogenesis

Developmental toxicology, drugs,and fetal teratogenesisRobert L. Brent and Lynda B. Fawcett

Reproductive problems encompass a multiplicity of diseases including sterility, infer-tility, abortion, stillbirth, congenital malformations, fetal growth retardation, andprematurity. It is estimated that the majority of all conceptions are lost before term,many within the first 3 weeks of development. Severe congenital malformationsoccur in 3% of births, and include those birth defects that cause death, hospital-ization and mental retardation and those that necessitate significant or repeated sur-gical procedures, are disfiguring, or interfere with physical performance. Theseclinical problems occur commonly in the general population and, therefore, envi-ronmental causes are not always easy to corroborate (Table 13.1).

Basic principles of teratology

To label an environmental exposure as teratogenic, it is necessary to characterizethe exposure with regard to the dose, route of exposure, and the stage of pregnancywhen the exposure occurred. Labeling an agent as teratogenic indicates only that itmay have the potential to produce congenital malformations. When evaluatinghuman and animal studies on the reproductive effects of environmental agents,several important principles should be followed, as outlined in Table 13.2.

The etiology of congenital malformations

The etiology of congenital malformations can be divided into three categories:unknown, genetic, and environmental (Table 13.3). A significant proportion of con-genital malformations of unknown etiology are likely to have an important geneticcomponent. Malformations with an increased recurrent risk such as cleft lip andpalate, anencephaly, spina bifida, certain congenital heart diseases, pyloric stenosis,hypospadias, inguinal hernia, talipes equinovarus, and congenital dislocation of thehip fit into the category of multifactorial disease as well as the category of poly-genic inherited disease.

Handbook of Clinical Obstetrics: The Fetus & Mother, Third EditionE. Albert Reece, John C. Hobbins

Copyright © 2007 by Blackwell Publishing Ltd

Factors that affect susceptibility to developmental toxicants

A basic tenet of environmentally produced malformations is that teratogens, or ateratogenic milieu, have certain characteristics in common and follow certain basicprinciples. These principles determine the quantitative and qualitative aspects ofenvironmentally produced malformations.

Stage of exposureThe risk of an exposure to a developmental toxicant resulting in morphologicalanomalies or intrauterine death varies, depending on the embryonic or fetal stageat which the exposure occurs. The period of sensitivity may be narrow or broad,

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Table 13.1 Background reproductive risks in pregnancy.

Reproductive risk Frequency

Immunologically and clinically diagnosed spontaneous abortions per 350000million conceptions

Clinically recognized spontaneous abortions per million clinically 150000recognized pregnancies

Genetic diseases per million births: 110000Multifactorial or polygenic genetic environmental interactions 90000

(i.e., neural tube defects, cleft lip, hypospadias, hyperlipidemia, diabetes)

Dominantly inherited disease (i.e., achondroplasia, Huntington’s 10000chorea, neurofibromatosis)

Autosomal and sex-linked genetic disease (i.e., cystic fibrosis, 1200hemophilia, sickle-cell disease, thalassemia)

Cytogenetic (chromosomal abnormalities) (i.e., Down syndrome 5000(trisomy 21), trisomies 13 and 18, Turner syndrome, 22q deletion, etc.)

New mutations* 3000Severe congenital malformations† per million births (resulting from all 30000

causes of birth defects: genetic, unknown, environmental)Prematurity per million births 40000Fetal growth retardation per million births 30000Stillbirths (> 20 weeks) per million births 2000–20900Infertility 15% of couples

Modified from: Beckman D, Fawcett L, Brent RL. Developmental toxicology. In: MassaroE, ed. Handbook of human toxicology. New York: CRC Press; 1997:1007–1084.*The mutation rate for many genetic diseases can be calculated; this can be readilyperformed with dominantly inherited diseases when offspring are born with a dominantgenetic disease and neither parent has the disease.†Congenital malformations have multiple etiologies, including a significant proportion thatare genetic.

depending on the environmental agent and the malformation in question. Theembryo is most sensitive to the lethal effects of drugs and chemicals during theperiod of embryonic development from fertilization through the early postimplan-tation stage. Surviving embryos have malformation rates similar to control subjectsbecause significant cell loss or chromosome abnormalities at these stages have a highlikelihood of resulting in embryonic death, not because malformations cannot beproduced at this stage.

The period of organogenesis (from day 18 through about day 40 post conceptionin the human) is the period of greatest sensitivity to teratogens when most grossanatomic malformations can be induced. Most environmentally produced majormalformations occur before the 36th day post conception in the human. The excep-tions are malformations of the genito-urinary system, the palate, the brain, or defor-mations resulting from problems of constraint, disruption, or destruction.

DEVELOPMENTAL TOXICOLOGY, DRUGS, AND FETAL TERATOGENESIS

75

Table 13.2 Basic scientific principles of teratology.

Principle Description

Exposure to teratogens There is a threshold below which no teratogenicfollows a toxicological effect will be observed. As the dose of the dose–response curve teratogen is increased, both the severity and

frequency of reproductive effects will increase(Fig. 13.1)

The embryonic stage at which Some teratogens have a broad period of exposure occurs will determine embryonic sensitivity whereas others have a what effects, if any, a teratogen very narrow period of sensitivitywill have

Most teratogens have a confined Known teratogens may be presumptively group of congenital implicated by the spectrum of malformationsmalformations referred to as they produce. It is easier to exclude an agentthe syndrome of the agent’s effects as a cause of a birth defect than to definitively

prove it was responsible because of the existence of genocopies of some teratogenic syndromes

No teratogen can produce every The presence of certain malformations can type of malformation eliminate the possibility that a particular

teratogenic agent was responsible because those malformations have not been demonstrated to be part of the syndrome caused by the teratogen, or because productionof the malformation is not biologically plausiblefor that particular alleged teratogen

Based on concepts from: Brent R. Methods of evaluating the alleged teratogenicity ofenvironmental agents. In: Sever J, Brent RL, eds. Teratogen update: environmentallyinduced birth defect risks. New York: Alan R Liss; 1986:199–201.

Agents that result in cell depletion, vascular disruption, necrosis, specific tissueor organ pathology, physiological decompensation, or severe growth retardationhave the potential to cause deleterious effects throughout gestation.

Dose or magnitude of the exposure and threshold doseThe quantitative correlation between the magnitude of the embryopathic effects andthe dose of a drug, chemical, or other agent is referred to as the dose–response rela-tionship. The dose–response relationship of a toxicant should be interpreted care-fully. A substance given in large enough amounts to cause maternal toxicity is alsolikely to have deleterious effects on the embryo such as death, growth retardation,or retarded development. Several considerations affect the interpretation ofdose–response relationships (Table 13.4).

The threshold dose is the dosage below which the incidence of death, malforma-tion, growth retardation, or functional deficit is not statistically greater than that

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Table 13.3 Etiology of human congenital malformations observed during the first year of life.

Suspected cause Percent of total

Unknown 65–75PolygenicMultifactorial (gene–environment interactions)Spontaneous errors of developmentSynergistic interactions of teratogens

Genetic 15–25Autosomal and sex-linked inherited genetic diseaseCytogenetic (chromosomal abnormalities)New mutations

Environmental 10Maternal conditions: alcoholism, diabetes, endocrinopathies, 4

phenylketonuria, smoking and nicotine, starvation, nutritional deficits

Infectious agents: rubella, toxoplasmosis, syphilis, herpes simplex, 3cytomegalovirus, varicella zoster, Venezuelan equine encephalitis, parvovirus B19

Mechanical problems (deformations): amniotic band constrictions, 1–2umbilical cord constraint, disparity in uterine size and uterine contents

Chemicals, prescription drugs, high-dose ionizing radiation, < 1hyperthermia

Modified from: Brent R. Environmental factors: miscellaneous. In: Brent R, Harris M, eds.Prevention of embryonic, fetal and perinatal disease. Bethesda, MD: John E. FogartyInternational Center for Advanced Study in the Health Sciences, NIH; 1976:211.

of control subjects. The threshold level of exposure usually varies between less thanone and up to two orders of magnitude below the teratogenic or embryopathic doseof drugs and chemicals that kill or malform one-half of the embryos. An exogenousteratogenic agent, therefore, has a no-effect dose compared with mutagens or car-cinogens, which have a stochastic dose–response curve (Table 13.5, Fig. 13.1). Theincidence and severity of malformations produced by every exogenous teratogenicagent that has been appropriately studied have exhibited threshold phenomenaduring organogenesis.

Pharmacokinetics and metabolism of the drug or chemicalPhysiological alterations in pregnancy as well as the bioconversion of compoundscan significantly influence the teratogenic effects of drugs and chemicals. Tables 13.6and 13.7 outline the physiological alterations that occur in the mother and the fetus,respectively, during pregnancy and that affect the pharmacokinetics of drugs.Although other organs, including the placenta, can be involved in the metabolismof drugs or chemicals, the major site of bioconversion of chemicals in vivo is likelyto be the maternal liver. Bioconversion has been shown to be important in the ter-atogenic activity of several xenobiotics.

Placental transportIt has been alleged that the placental barrier is protective and that harmful sub-stances do not reach the embryo; however, it is now clear that there is no “placen-tal barrier” per se, and most drugs and chemicals do cross the placenta. Factors thatdetermine the ability of a drug or chemical to cross the placenta and reach the


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Table 13.4 Considerations that affect the interpretation of dose–response relationships.

Concept Description Example

Active Metabolites may be the proximate The metabolite phosphoramide metabolites teratogen rather than the mustard and acrolein may

administered drug or chemical produce abnormal development resulting from the metabolism of cyclophosphamide

Duration of A chronic exposure to a prescribed Anticonvulsant therapy; in exposure drug can contribute to an contrast an acute exposure to

increased teratogenic risk the same drug may present little or no teratogenic risk

Fat solubility Fat-soluble substances can produce Polychlorinated biphenyls (PCBs). fetal malformations for an Etretinate may present a extended period after the last similar risk but the data are ingestion or exposure because they not conclusivehave an unusually long half-life

78

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79

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Figure 13.1 Dose–response relationship of reproductive toxins comparing preconceptionand postconception risks.

Table 13.6 Pregnancy-related physiological alterations in the mother that affect thepharmacokinetics of drugs.

Alteration Effect on drug pharmacokinetics

Decreased gastrointestinal motility; Results in delayed absorption of drugs in the small increased intestinal transit time intestine owing to increased stomach retention

and enhanced absorption of slowly absorbed drugs

Decreased plasma albumin Alters the kinetics of compounds normally bound to albumin

Renal elimination Generally increased but is influenced by body position later in pregnancy

Increased plasma and extracellular Affects concentration-dependent transfer of fluid volumes compounds

Inhibition of metabolic inactivation Increases half-life of drug in plasmain the maternal liver

Variation in uterine blood flow May affect transfer across the placenta (although little is known concerning this)

Based on concepts from: (1) Jackson M. Drug absorption. In: Fabro S, Scialli A, eds. Drugand chemical action in pregnancy: pharmacological and toxicological principles. New York:Marcel Dekker; 1986:15; (2) Mattison D. Physiological variations in pharmacokineticsduring pregnancy. In: Fabro S, Scialli A, eds. Drug and chemical action in pregnancy:pharmacological and toxicological principles. New York: Marcel Dekker; 1986:37–102; and(3) Sonawane B, Yaffe S. Physiologic disposition of drugs in the fetus and newborn. In:Fabro S, Scialli A, eds. Drug and chemical action in pregnancy: pharmacologic andtoxicologic principles. New York: Marcel Dekker; 1986:103.

79

embryo include molecular weight, lipid solubility, polarity or degree of ionization,protein binding, and receptor mediation. Compounds with a low molecular weightand lipid affinity, nonpolarity, and without protein-binding properties will easilycross the placenta. In general, compounds with molecular weights of 1000 daltonsor more do not readily cross the placenta, whereas those less than 600 daltonsusually do; most drugs are 250–400 daltons and therefore cross the placenta.

Environmental agents resulting in reproductive toxicity followingexposure during pregnancy

Table 13.8 lists environmental agents that have resulted in reproductive toxicityand/or congenital malformations in human populations. The list should not be usedin isolation as many other parameters must be considered when analyzing exposurerisks in individual patients. Many of these agents represent a very small risk whileothers may represent substantial risks; the risks will vary with the magnitude,timing, and length of exposure. Some environmental agents that were thought toshow reproductive toxicity have been found, after a careful and complete evalua-tion, to represent no increased risk; these are listed in Table 13.9.

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Table 13.7 Pregnancy-related physiological alterations in the fetus that may affect thepharmacokinetics of drugs.

Alteration Effect on drug pharmacokinetics

Amount and distribution of fat Affects distribution of lipid-soluble drugs and chemicals

Lower plasma protein concentrations Results in a higher concentration of unbound drug in the fetal circulation

Functional development of Likely to proceed at different rates in the various pharmacological receptors tissues of the developing fetus

Extent of amniotic fluid swallowing Drugs that are excreted by the fetal kidneys may be recycled through the fetus via swallowing of amniotic fluid

Based on concepts from: (1) Jackson M. Drug absorption. In: Fabro S, Scialli A, eds. Drugand chemical action in pregnancy: pharmacological and toxicological principles. New York:Marcel Dekker; 1986:15; (2) Mattison D. Physiological variations in pharmacokineticsduring pregnancy. In: Fabro S, Scialli A, eds. Drug and chemical action in pregnancy:pharmacological and toxicological principles. New York: Marcel Dekker; 1986:37–102; and(3) Sonawane B, Yaffe S. Physiologic disposition of drugs in the fetus and newborn. In:Fabro S, Scialli A, eds. Drug and chemical action in pregnancy: pharmacologic andtoxicologic principles. New York: Marcel Dekker; 1986:103.


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Table 13.8 Proven human teratogens or embryotoxins: drugs, chemicals, milieu, andphysical agents that have resulted in human congenital malformations.

Reproductive toxin Alleged effects

Aminopterin, methotrexate Growth retardation, microcephaly, meningomyelocele mental retardation, hydrocephalus, and cleft palate

Androgens Along with high doses of some male-derived progestins, can cause masculinization of the developing fetus

Angiotensin-converting Fetal hypotension syndrome in second and third trimester enzyme (ACE) inhibitors resulting in fetal kidney hypoperfusion and anuria,

oligohydramnios, pulmonary hypoplasia, and cranial bone hypoplasia. No effect in the first trimester

Antituberculous therapy The drugs isoniazid (INH) and paraaminosalicylic acid (PAS) have an increased risk for some CNS abnormalities

Caffeine Moderate exposure not associated with birth defects; high exposures associated with an increased risk of abortion but data are inconsistent

Chorionic villus sampling Vascular disruptive malformations, i.e., limb reduction (CVS) defects

Cobalt in hematemic Fetal goitermultivitamins

Cocaine Very low incidence of vascular disruptive malformations, pregnancy loss

Corticosteroids High exposures administered systemically have a low risk for cleft palate in some epidemiological studies; however,this is not a consistent finding

Coumarin derivative Exposure during early pregnancy can result in nasal hypoplasia, stippling of secondary epiphysis, and intrauterine growth retardation. Exposure in late pregnancy can result in CNS malformations as a result of bleeding

Cyclophosphamide and Many chemotherapeutic agents used to treat cancer have a other chemotherapeutic theoretical risk of producing fetal malformations, as and immunosuppressive most of these drugs are teratogenic in animals; however, agents, e.g., cyclosporine, the clinical data are not consistent. Many have not been leflunomide shown to be teratogenic but the numbers of cases in the

studies are small; caution is the bywordDiethylstilbestrol Genital abnormalities, adenosis, and clear cell

adenocarcinoma of the vagina in adolescents. The risk of adenosis can be quite high; the risk of adenocarcinoma is 1 :1000 to 1 :10000

Ethyl alcohol Fetal alcohol syndrome (microcephaly, mental retardation, growth retardation, typical facial dysmorphogenesis, abnormal ears, and small palpebral fissures)

(Continued)

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Table 13.8 Continued


Ionizing radiation A threshold greater than 20 rad (0.2Gy) can increase the risk of some fetal effects such as micocephaly or growth retardation. The threshold for mental retardation is higher

Insulin shock therapy Microcephaly and mental retardationLithium therapy Chronic use for the treatment of manic depressive illness

has an increased risk for Ebstein’s anomaly and other malformations, but the risk appears to be very low

Minoxidil Hirsutism in newborns (led to the discovery of the hair growth-promoting properties of minoxidil)

Methimazole Aplasia cutis has been reported*Methylene blue Fetal intestinal atresia, hemolytic anemia, and jaundice in

intraamniotic instillation the neonatal period. This procedure is no longer utilized to identify one twin

Misoprostol Low incidence of vascular disruptive phenomenon, such as limb reduction defects and Mobius syndrome, has been reported in pregnancies in which this drug was used to induce an abortion

Penicillamine This drug results in the physical effects referred to as (d-penicillamine) lathyrism, the results of poisoning by the seeds of the

genus Lathyrus. It causes collagen disruption, cutis laxa, and hyperflexibility of joints. The condition appears to be reversible and the risk is low

Progestin therapy Very high doses of androgen hormone-derived progestins can produce masculinization. Many drugs with progestational activity do not have masculinizing potential. None of these drugs has the potential for producing congenital malformations

Propylthiouracil Along with other antithyroid medications can result in an infant born with a goiter

Radioactive isotopes Tissue- and organ-specific damage is dependent on the radioisotope element and distribution, i.e., high doses of 131I administered to a pregnant woman can cause fetal thyroid hypoplasia after the 8th week of development

Retinoids, systemic Systemic retinoic acid, isotretinoin, and etretinate can result in an increased risk of CNS, cardio-aortic, ear, and clefting defects, microtia, anotia, thymic aplasia and other branchial arch and aortic arch abnormalities, and certain congenital heart malformations

Retinoids, topical This is very unlikely to have teratogenic potential because teratogenic serum levels are not achieved from topical exposure


83



Streptomycin Streptomycin and a group of ototoxic drugs can affect the eighth nerve and interfere with hearing; it is a relatively low-risk phenomenon. Children are even less sensitive to the ototoxic effects of these drugs than adults

Sulfa drug and vitamin K Hemolysis in some subpopulations of fetusesTetracycline Bone and teeth stainingThalidomide Increased incidence of deafness, anotia, preaxial limb

reduction defects, phocomelia, ventricular septal defects, and GI atresias during susceptible period from the 22nd to the 36th day post conception

Trimethoprim This drug was frequently used to treat urinary tract infections and has been linked to an increased incidence of neural tube defects. The risk is not high, but it is biologically plausible because of the drug’s lowering effect on folic acid levels. This has also resulted in neurological symptoms in adults taking this drug

Vitamin A (retinol) Very high doses of vitamin A have been reported to produce the same malformations as reported for the retinoids. Dosages sufficient to produce birth defects would have to be in excess of 25000 to 50000 units per day

Vitamin D* Large doses given in vitamin D prophylaxis are possibly involved in the etiology of supravalvular aortic stenosis, elfin facies, and mental retardation

Warfarin (coumarin) Exposure during early pregnancy can result in nasal hypoplasia, stippling of secondary epiphysis, and intrauterine growth retardation. Exposure in late pregnancy can result in CNS malformations as a result of bleeding

AnticonvulsantsCarbamazepine Used in the reatment of convulsive disorders; increases the

risk of facial dysmorphologyDiphenylhydantoin Used in the treatment of convulsive disorders; increases the

risk of fetal hydantoin syndrome, consisting of facial dysmorphology, cleft palate, ventricular septal defect (VSD), and growth and mental retardation

Trimethadione and Used in the treatment of convulsive disorders; increases the paramethadione risk of characteristic facial dysmorphology, mental

retardation, V-shaped eyebrows, low-set ears with anteriorly folded helix, high-arched palate, irregular teeth, CNS anomalies, and severe developmental delay

Valproic acid Used in the treatment of convulsive disorders; increases the risk of spina bifida, facial dysmorphology, and autism

(Continued)

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ChemicalsCarbon monoxide poisoning* CNS damage has been reported with very high exposures,

but the risk appears to be lowGasoline addiction Facial dysmorphology, mental retardation

embryopathyLead Very high exposures can cause pregnancy loss; intrauterine

teratogenesis is not established Methyl mercury Causes Minamata disease consisting of cerebral palsy,

microcephaly, mental retardation, blindness, and cerebellum hypoplasia. Endemics have occurred from adulteration of wheat with mercury-containing chemicals that are used to prevent grain spoilage. Present environmental levels of mercury are unlikely to represent a teratogenic risk, but reducing or limiting the consumption of carnivorous fish has been suggested in order not to exceed the Environmental Protection Agency’s (EPA’s) maximum permissible exposure (MPE), which is far below the toxic effects of mercury

Polychlorinated biphenyls Poisoning has occurred from adulteration of food products (cola-colored babies, CNS effects, pigmentation of gums, nails, teeth and groin, hypoplastic deformed nails, intrauterine growth retardation, abnormal skull calcification). The threshold exposure has not been determined, but it is unlikely to be teratogenic at the present environmental exposures

Toluene addiction Facial dysmorphology, mental retardationembryopathy

Embryonic and fetal infectionsCytomegalovirus Retinopathy, CNS calcification, microcephaly, mental

retardationHerpes simplex virus Fetal infection, liver disease, deathHuman immunodeficiency Perinatal HIV infection

virus (HIV)Parvovirus B19 infection Stillbirth, hydropsRubella virus Deafness, congenital heart disease, microcephaly, cataracts,

mental retardationSyphilis Maculopapular rash, hepatosplenomegaly, deformed nails,

osteochondritis at joints of extremities, congenital neurosyphilis, abnormal epiphyses, chorioretinitis

Toxoplasmosis Hydrocephaly, microphthalmia, chorioretinitis, mental retardation

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Varicella zoster virus Skin and muscle defects, intrauterine growth retardation, limb reduction defects, CNS damage (very low increased risk)

Venezuelan equine Hydranencephaly, microphthalmia, CNS destructive encephalitis lesions, luxation of hip

Maternal disease statesCorticosteroid-secreting Mothers with Cushing’s disease can have infants with

endocrinopathy hyperadrenocortism, but anatomical malformations do not appear to be increased

Iodine deficiency Iodine deficiency can result in embryonic goiter and mental retardation

Intrauterine problems of Defects such as club feet, limb reduction, aplasia cutis,constraint and vascular cranial asymmetry, external ear malformations, midline disruption closure defects, cleft palate and muscle aplasia, cleft lip,

omphalocele, and encephalocele. More common in multiple-birth pregnancies, pregnancies with anatomical defects of the uterus, placental emboli, and amniotic bands

Maternal androgen Masculinizationendocrinopathy (adrenal tumors)

Maternal diabetes Caudal and femoral hypoplasia, transposition of great vessels

Folic acid insufficiency in Increased incidence of neural tube defects (NTDs)the mother

Maternal phenylketonuria Abortion, microcephaly, and mental retardation. Very high risk in untreated patients

Maternal starvation Intrauterine growth retardation, abortion, NTDsTobacco smoking Abortion, intrauterine growth retardation, and stillbirthZinc deficiency* NTDs

*Controversial.

Table 13.9 Agents erroneously alleged to have caused human malformations.

Agent Alleged effect

Bendectin Alleged to cause numerous types of birth defects including limb reduction defects and heart malformations

Diagnostic ultrasonography No significant hyperthermia, therefore, no reproductive effects

Electromagnetic fields (EMF) Alleged to cause abortion, cancer, and birth defectsProgestational drugs Alleged to cause numerous types of nongenital birth defects,

including limb reduction defects and heart malformationsTrichloroethylene (TCE) Alleged to cause cardiac defects

Interpretation of animal study data for assessment of reproductiverisks in humans

When a new drug is marketed or a new environmental toxicant is discovered, theonly information that is frequently available are the animal data. When using thesedata to assess the potential risk of adverse effects of human exposure to a drug orchemical, it is important to critically evaluate the studies using the basic principlesof teratology guidelines (Table 13.2). As discussed previously, one of the most crit-ical factors for consideration is the dose or magnitude of the exposure and theconcept of the threshold dose. A major shortcoming in many studies is the use ofweight (mg/kg) as a measure of dose rather than the serum levels of the drug ortoxic metabolite that result from such a dose.

The role of the physician in counseling families regarding the etiology of their child’s congenital malformations

The clinician must be cognizant of the fact that many patients believe that mostcongenital malformations are caused by a drug or medication taken during preg-nancy. Physicians must also realize that erroneous counseling by inexperiencedhealth professionals may result in nonmeritorious litigation. Unfortunately, it issometimes assumed that if a drug or chemical has caused birth defects in an animalmodel or in vitro system at a high dose, then it has the potential to produce birthdefects at any dose. In fact, the vast majority of consultations involving exposuresduring pregnancy conclude that the exposure does not change the reproductive risksin that pregnancy.

Before deciding whether a child’s malformations are due to a genetic cause or an environmental toxicant or agent, the physician must first carry out a completeexamination of the child and a review of the genetic and teratology medical litera-ture. The information that is required for this evaluation is presented in Table 13.10.As well as the usual history and physical evaluation, including descriptive and quan-titative information about the physical characteristics of the child, the physicianmust obtain information about the nature, magnitude, and timing of the exposure. A formal evaluation of the data obtained is then recommended, as described in Table 13.11.

Summary

Approximately 10% of human malformations are due to environmental factors andfewer than 1% of all human malformations are related to chemical agents or pre-scribed drugs. However, malformations caused by prescription drugs and other ther-apeutic agents are important because these exposures are preventable. A betterunderstanding of the mechanisms of teratogenesis from all etiologies may improveour ability to predict and test for teratogenicity.

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Table 13.10 Information required to analyse the possibility that an environmental agent hasaltered the risk of congenital malformations in a pregnancy.

What was the nature of the exposure?Is the exposure agent identifiable? If the agent is identifiable, has it been definitively

identified as a reproductive toxin with a recognized constellation of malformations orother reproductive effects?

At what stage did the exposure occur during embryonic and fetal development?If the agent is known to produce reproductive toxic effects, was the exposure above or

below the threshold for these effects?Were there any other significant environmental exposures or medical problems during the

pregnancy?Is this is a wanted pregnancy or is the family ambivalent about carrying this baby to term?What is the medical and reproductive history of this mother with regard to prior

pregnancies, and the reproductive history of the family lineage?

Table 13.11 Proof of developmental toxicity in humans.

Epidemiological studiesControlled epidemiological studies consistently demonstrate an increased incidence of aparticular spectrum of embryonic and/or fetal effects in exposed human populations

Secular trend dataSecular trends demonstrate a positive relationship between the changing exposures to acommon environmental agent in human populations and the incidence of a particularembryonic and/or fetal effect

Animal developmental toxicity studiesAn animal model that mimics the human developmental effect at clinically comparableexposures can be developed. Because mimicry may not occur in all animal species, animalmodels are more likely to be developed once there is good evidence for the embryotoxiceffects reported in the human. Developmental toxicity studies in animals are indicative of apotential hazard in general rather than the potential for a specific adverse effect on the fetuswhen there are no human data on which to base the animal experiments

Dose–response relationship (pharmacokinetics and toxicokinetics)Developmental toxicity in the human increases with dose (exposure), and the developmentaltoxicity in animals occurs at a dose that is pharmacokinetically (quantitatively) equivalentto the human exposure

Biological plausibilityThe mechanisms of developmental toxicity are understood, and the effects are biologicallyplausible

Modified from: (1) Brent R. Methods of evaluating the alleged teratogenicity ofenvironmental agents. In: Sever J, Brent RL, eds. Teratogen update: environmentallyinduced birth defect risks. New York: Alan R Liss; 1986:199–201; and (2) Brent, R.Method of evaluating alleged human teratogens. Teratology 1978;17:83.

Further reading

Brent RL. Bendectin: review of the medical literature of a comprehensively studied humannonteratogen and the most prevalent tortigen-litigen. Reprod Toxicol 1995;9:337–349.

Brent RL. Environmental causes of human congenital malformations: the pediatrician’s rolein dealing with these complex clinical problems caused by a multiplicity of environmentaland genetic factors. Pediatrics 2004;113:957–968.

Brent RL. Utilization of developmental basic science principles in the evaluation of reproduc-tive risks from pre- and postconception environmental radiation exposures. Teratology1999;59:182–204.

Friedman JM, Polifka JE. TERIS: The teratogen information system. Seattle, WA: Universityof Washington Press, 1999.

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Schardein JL. Chemically induced birth defects. New York: Marcel Dekker; 2002:1109.Scialli AR, Lione A, Padget GKB. Reproductive effects of chemical, physical and biologic

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Hopkins University Press, 2004.

CHAPTER 14

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14 Drugs, alcohol abuse, and effects in pregnancyStephen R. Carr and Donald R. Coustan

It is daunting to attempt to study the effect of drugs, medications, or substances ondeveloping fetuses. It requires an understanding of embryology, pharmacology, andmaternal physiology during pregnancy as well as fetal physiology. Studies of illicitsubstance use or abuse of licit substances are hampered by inaccurate reporting aswell as the problem of multiple substance use. Teasing out the individual effects ofa given substance may be challenging indeed. There are numerous compendia avail-able to clinicians describing the effects of marketed pharmaceutical agents.

Alcohol abuse during pregnancy continues to impose a staggering burden onsociety – upwards of US$40 billion per year (in 1998 dollars) in total, or US$2million as a lifetime cost per individual affected with fetal alcohol syndrome (FAS).1

While efforts at establishing a dose–response curve have been stymied by under-reporting and multiple substance use, even low and sporadic alcohol ingestionduring pregnancy increases the risk of congenital anomalies.2 The effects of alcoholon the development of the human fetus may result from increased c-myc proteinand decreased growth-associated protein 43 levels and their effects on normal neu-

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