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Developmental Toxicology Drugs, and Fetal Teratogenesis

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Developmental Toxicology Drugs, and Fetal Teratogenesis Brent, RL and Fawcett, LB: Developmental toxicology, drugs, and fetal teratogenesis. In Reece EA, Hobbins JC (eds.) Clinical Obstetrics: The Fetus and Mother, 3rd edition, Blackwell Publishing Inc., Malden, MA, Chapter 15, pp. 217-235, 2007. Developmental toxicology, drugs, and fetal teratogenesis Robert L. Brent and Lynda B. Fawcett Reproductive problems encompass a multiplicity of diseases example, environmental agents dispensed by healthcare including sterility, infertility, abortion (miscarriage), stillbirth, providers or utilized by emp10yers.l.~ congenital malformations (resulting from environmental or Reproductive problems alarm the public, the press, and sci- hereditary etiologies), fetal growth retardation, and prematu- entists to a greater degree than many other diseases. Severely rity. These clinical problems occur commonly in the general malformed children are disquieting to healthcare providers, population and, therefore, environmental causes are not especially if they are not experienced in dealing with such always easy to corroborate (Table 15.1). Severe congenital problems; no physician will be comfortable informing a family malformations occur in 3% of births; according to the Center that their child was born without arms and legs. The objec- for Disease Control, they include those birth defects that cause tive evaluation of the environmental causes of reproductive death, hospitalization, and mental retardation, and those that diseases is clouded by the emotional climate that surrounds necessitate significant or repeated surgical procedures, are dis- these diseases, resulting in the expression of partisan positions figuring, or interfere with physical performance. This means that either diminish or magnify the environmental risks. These that each year in the USA, 120000 babies are born with severe nonobjective opinions can be expressed by scientists, the laity, birth defects. Genetic disease occurs in approximately 11% of or the It is the responsibility of every physician to be births, and spontaneous mutations account for approximately aware of the emotionally charged situation when a family has 2-3% of genetic disease. This spontaneous mutation rate pres- a child with a birth defect; an inadvertent comment from ents difficulties when determining the proportion of mutations medical staff attending delivery can have grave consequences that are induced from preconception exposure to environ- for the physician and the family. Comments such as, "Oh, you mental mutagens. had a radiograph during your pregnancy," or "You did not There have been dramatic advances in our-understandingof tell me that you were prescribed tetracycline while you were the causes of human birth defects. In earlier times, supersti- pregnant," can direct the patient's family to an attorney rather tion, ignorance, and prejudice played a major role in explain- than to a teratology or genetic counselor. .ing why birth defects occurred. Reproductive problems have At present, the etiology of congenital malformations can be been viewed throughout history as diseases of affliction, along divided into three categories: unknown, genetic, and environ- with cancer, psychiatric illness, and hereditary diseases. The mental. Unfortunately, the largest group (65-7546) has an stigma associated with birth defects has primitive beginnings unknown etiology, whereas the most common known cause is and persists today; in the minds of many, even the most sophis- genetic (15-25%).7-9 Environmental factors account for 10% ticated, a birth defect is felt to be some form of punishment of congenital malformations. Over 50 teratogenic environ- for previous misdeeds.14 Ancient Babylonian writings recount mental drugs, chemicals, and physical agents have been tales of mothers being put to death because they delivered described9-l2 by clinical dysmorphologists using modern malformed infants. In the seventeenth century, one George epidemiological tool^.'^-'^ The basic science and clinical rules Spencer was slain by the Puritans in New Haven having been for evaluating teratogenic risks have been e~tablished.~'The convicted of fathering a cyclopean pig; the Puritans were purpose of this chapter is to inform clinicians about envi- unable to differentiate between George Spencer's cataract and ronmental drugs, chemicals, and physical agents that have the malformed pig's cloudy cornea.' More recently, the situa- been documented to produce congenital malformations and tion has been reversed and the responsibility for reproductive reproductive effects, and to indicate that the multdude of problems such as congenital malformations, infertility, abor- teratogenic agents accounts for only a small proportion %f tions, and hereditary diseases is often blamed on others, for malformations. CHAPTER 15 *.Table 15.1 Background reproductive risks in pregnancy. Reproductive risk , Frequency Immunologically and clinically diagnosed spontaneous abortions per million conceptions 350 000 Clinically recognized spontaneous abortions per million clinically recognized pregnancies 150000 Genetic diseases per million births: 110000 Multifactorial or polygenic genetic environmental interactions (i.e., neural tube defects, cleft lip, hypospadias, 90 000 hyperlipidemia, diabetes) Dominantly inherited disease (i.e., achondroplasia, Huntington's chorea, neurofibromatosis) 10000 Autosomal and sex-linked genetic disease (i.e., cystic fibrosis, hemophilia, sickle-cell disease, thalassemia) 1200 'Cytogenetic (chromosomal abnormalities) (i.e., Down syndrome (trisomy 21), trisomies 13 and 18, Turner syndrome, 5 000 22q deletion, etc.) New mutations* 3 000 Severe congenital malformationst per million births (resulting from all causes of birth defects: genetic, unknown, 30 000 environmental) Prematurity per million births 40 000 Fetal growth retardation per million births 30 000 Stillbirths (> 20 weeks) per million births 2000-20900 Infertility 7% of couples Modified from ref. 11. 'The mutation rate for many genetic diseases can be calculated; this can be readily performed with dominantly inherited diseases when offspring are born with a dominant genetic disease and neither parent has the disease. tcongenital malformations have multiple etiologies including a significant proportion that are genetic. the basic principles of teratology and developmental bi~logy;~ Basic principles of teratology these principles are outlined in Table 15.2.2s"2 To label an environmental agent as teratogenic it is necessary to characterize the dose, route of exposure, and stage of preg- The etiology of nancy when the exposure occurred. A SO-mg dose of thalido- congenital malformations mide administered on the 26th day post conception has a significant risk of maiforming the embryo. The same dose As mentioned earlier, the etiology of congenital malformations taken during the 10th week of gestation will not result in con- can be divided into three categories: unknown, genetic, and genital malformations, and I mg of thalidomide taken at any environmental (Table 15.3). A significant proportion of con- time during pregnancy will have no effect on the developing genital malformations of unknown etiology are likely to have embryo. X-ray irradiation can be teratogeni~;~'-~~however, if an important genetic component. Mhlformations with an the dose is too low or the X-ray does not directly expose the increased recurrent risk such as cleft lip and palate, anen- embryo, there is no increased risk of congenital malforma- cephaly, spina bifida, certain congenital heart diseases, pyloric tion~.~Therefore a list of teratogens indicates only teratogenic stenosis, hypospadias, inguinal hernia, talipes equinovarus, potential; evaluation of the dose and time of exposure may and congenital dislocation of the hip fit into the category of indicate that there is no teratogenic risk or that the risk is multifactorial disease as well as that of polygenic inherited significant. di~ease.~~,~~The multifactoriaVthreshold hypothesis postulates Physicians must be careful to carry out a thorough evalua- the modulation of a continuum of genetic characteristics by tion of the risks faced by a woman exposed to drugs and chem- intrinsic and extrinsic (environmental) factors. icals during pregnancy, and before alleging that a child's A significant percentage of spontaneous errors of develop- malformations result from exposure to an environmental ment can occur without apparent abnormalities of the genome agent. Clinical teratology and genetics is not emphasized in or environmental influences; these are due to the statistical medical schools and residency education programs. However, probability of errors in the developmental process, similar to clinicians have a multitude of educational aids to assist them the concept of spontaneous mutation, and mean that we may in their evaluations; these include consultations with clinical never achieve our goal of eliminating birth defects. It is esti- , teratologists and geneticists, the medical literature, and the mated that the majority of all miscarriages occur early in preg- Online Mendelian Inheritance of Man (OMIM) ~ebsite.'~ nancy, many within the first 3 weeks of deve!opment. The The analysis of human and animal studies on the repro- World Health Organization estimated that 15% of all clini- ductive effects of environmental agents should be guided by cally recognizable pregnancies end in spontaneous abortion, DEVELOPMENTAL TOXICOLOGY, DRUGS, AND FETAL TERATOGENESIS Table 15.2 Basic scientific principles of teratology. Principle
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