There have been amazing advances in embryology, teratology, reproductive biology, genetics, and epidemiology in the past 50 years that have provided scientists and clinicians with a better perspective on the causes of congenital malformations. We still cannot provide the families of children with malformations a definitive diagnosis and cause in every instance. The purpose of this article is to inform pediatricians about environmental drugs, chemicals, and physical agents that have been documented to produce congenital malformations and reproductive effects and to indicate that the multitude of teratogenic agents account for only a small proportion of malformations. The most common known cause is genetic, but the largest group, unfortunately, is unknown. There are a number of important clinical rules that are important for clinicians to use when determining the cause of their patient’s congenital malformations:
No teratogenic agent should be described qualitatively as a teratogen, because a teratogenic exposure includes not only the agent but also the dose and the time in pregnancy when the exposure has to occur.
Even agents that have been demonstrated to result in malformations cannot produce every type of malformation. Known teratogens may be presumptively implicated by the spectrum of malformations that they produce. It is easier to exclude an agent as a cause of birth defects than to conclude definitively that it was responsible for birth defects, because of the existence of genocopies of some teratogenic syndromes.
When evaluating the risk of exposures, the dose is a crucial component in determining the risk. Teratogenic agents follow a toxicologic dose-response curve. This means that each teratogen has a threshold dose below which there is no risk of teratogenesis, no matter when in pregnancy the exposure occurred.
The evaluation of a child with congenital malformations cannot be performed adequately unless it is approached with the same scholarship and intensity as the evaluation of any other complicated medical problem.
Each physician must recognize the consequences of providing erroneous reproductive risks to pregnant women who are exposed to drugs and chemicals during pregnancy or alleging that a child’s malformations are attributable to an environmental agent without performing a complete and scholarly evaluation.
Unfortunately, clinical teratology and clinical genetics is not emphasized in medical school and residency education programs, but pediatricians have a multitude of educational aids to assist them in their evaluations, which includes consultations with clinical teratologists and geneticists, the medical literature, and the OMIM web site.
- etiology of congenital malformations
- birth defects
- threshold exposure
- teratogenic syndrome
- method of evaluation of etiology
- stochastic and deterministic effects
When I was a medical student at the University of Rochester, I was fortunate to have James G. Wilson, an embryologist, as one of my teachers in the anatomy course. He was working on the effects of radiation on the embryo, and that is how I became interested in congenital malformations. Many of the faculty members discouraged me from pursuing the study of the causes of birth defects as an academic goal, “Because we are never going to solve that problem.” In 1955, when I had completed medical school and graduate school, the scientific world did not even have the correct figure for the number of human chromosomes. Gregg1 had recently described the teratogenicity of rubella virus infection during pregnancy. The teratogenic risk of the folic acid antagonists was established,2,3 and there were experimental studies indicating that nutritional deficiencies could produce birth defects in animals.4
What have we learned and accomplished in the past 50 years? Thousands of previously unknown genetic diseases have been described and many of their genes have been identified since the 1950s.5,6 The fields of prenatal intrauterine diagnoses, intervention, and treatment have been created. Metabolic and biochemical screening have become standard care for pregnant women and newborns. More than 50 teratogenic environmental drugs, chemicals, and physical agents have been described7–10 using modern epidemiologic tools and the talents of clinical dysmorphologists.11–17 The basic science and clinical rules for evaluating teratogenic risks have been established18 (Table 1). The development of the rubella vaccine and the recognition of the importance of adequate folic acid intake in women of reproductive age are forerunners for the prevention of birth defects from teratogenic infectious agents and nutritional components that are important for normal development. The completion of the first stage of the Human Genome Project in 2000 offers the geneticist and the teratologist immense opportunities to evaluate the concepts of polygenic and multifactorial causes19,20 of congenital malformations.
EMOTIONAL IMPACT OF CONGENITAL MALFORMATIONS
Reproductive problems encompass a multiplicity of diseases, including sterility, infertility, abortion (miscarriage), stillbirth, congenital malformations (as a result of environmental or hereditary causes), fetal growth retardation, and prematurity. These clinical problems occur commonly in the general population, and therefore environmental causes are not always easy to corroborate (Table 2). Severe congenital malformations occur in 3% of births. According to the Centers for Disease Control and Prevention, severe congenital malformations include birth defects that cause death, hospitalization, mental retardation; necessitate significant or repeated surgical procedures; are disfiguring; or interfere with physical performance. That means that each year in the United States, 120 000 newborns are born with severe birth defects. Genetic diseases occur in approximately 11% of births. Spontaneous mutations account for <2% to 3% of genetic disease. Therefore, mutations induced from preconception exposures of environmental mutagens are difficult endpoints to document (Table 3).
Along with cancer, psychiatric illness, and hereditary diseases, reproductive problems have been viewed throughout history as diseases of affliction (Fig 1). Inherent in the reactions of most cultures is that these diseases have been viewed as punishments for misdeeds21–24 (Fig 1). Regardless of the irrationality of this viewpoint, these feelings do exist. Ancient Babylonian writings recount tales of mothers being put to death because they delivered malformed infants. George Spencer was slain by the Puritans in New Haven in the 17th century, having been convicted of fathering a cyclopean pig, because the Puritans were unable to differentiate between George Spencer’s cataract and the malformed pigs cloudy cornea.21 In modern times, some individuals with reproductive problems reverse the historical perspective and blame others for the occurrence of their congenital malformations, infertility, abortions, and hereditary diseases. They place the responsibility of their illness on environmental agents dispensed by their health care provider or used by their employer.21,22
Reproductive problems alarm the public, the press, and some scientists to a greater degree than most other diseases. In fact, severely malformed children are disquieting to health care providers, especially when they are not experienced in dealing with these problems. No physician will be comfortable informing a family that their child was born without arms and legs. The objective evaluation of environmental causes of reproductive diseases is clouded by the emotional climate that surrounds these diseases, resulting in the expression of partisan positions that either diminish or magnify the environmental risks. These nonobjective opinions can be expressed by scientists, the laity, or the press.25,26 It is the responsibility of every physician to be aware of the emotionally charged situation when a family has a child with a birth defect. The inadvertent comment by the physician, nurse, resident, or student in attendance at the time of the child’s delivery can have grave consequences for the physician and the family. Comments such as, “Oh, you had a radiograph during your pregnancy,” or, “You did not tell me that you were prescribed tetracycline while you were pregnant,” can direct the patient’s family to an attorney rather than a teratology or genetic counselor.
BASIC PRINCIPLES OF TERATOLOGY
Labeling an environmental exposure as teratogenic is inappropriate unless one characterizes the exposure with regard to the dose, route of exposure, and the stage of pregnancy when the exposure occurred. Labeling an agent as teratogenic only indicates that it may have the potential for producing congenital malformations. A 50-mg dose of thalidomide administered on the 26th day postconception has a significant risk of malforming the embryo. That same dose taken during the 10th week of gestation will not result in congenital malformations. One milligram of thalidomide taken at any time during pregnancy will have no effect on the developing embryo. We know that X-irradiation can be teratogenic,27–29 but if the dose is too low or the radiograph does not directly expose the embryo, then there is no risk of congenital malformations.23 So a list of teratogens only indicates teratogenic potential. Evaluation of the dose and the time of exposure could indicate that there is no teratogenic risk or that the risk is significant.
When evaluating studies that deal with the reproductive effects of any environmental agent, important principles should guide the analysis of human and animal reproductive studies. Paramount to this evaluation is the application of the basic science principles of teratology and developmental biology.23 These principles are as follows:
Exposure to teratogens follows a toxicologic dose-response curve. There is a threshold below which no teratogenic effect will be observed, and as the dose of the teratogen is increased, both the severity and the frequency of reproductive effects will increase (Fig 2).
The embryonic stage of exposure is critical in determining which deleterious effects will be produced and whether any of these effects can be produced by a known teratogen. Some teratogenic effects have a broad and others a very narrow period of sensitivity. The most sensitive stage for the induction of mental retardation from ionizing radiation is from the 8th to the 15th week of pregnancy, a lengthy period. Thalidomide’s period of sensitivity is approximately 2 weeks24 (Table 4).
Even the most potent teratogenic agent cannot produce every malformation.
Most teratogens have a confined group of congenital malformations that result after exposure during a critical period of embryonic development. This confined group of malformations is referred to as the syndrome that describes the agent’s teratogenic effects.
Although a group of malformations may suggest the possibility of certain teratogens, they cannot definitively confirm the causal agent because some teratogenic syndromes mimic genetic syndromes. However, the presence of certain malformations can eliminate the possibility that a particular teratogenic agent was responsible because those malformations have not been demonstrated to be part of the syndrome or because the production of that malformation is not biologically plausible for that particular alleged teratogen.30
CAUSE OF CONGENITAL MALFORMATIONS
The cause of congenital malformations can be divided into 3 categories: unknown, genetic, and environmental (Table 3). The cause of a majority of human malformations is unknown. A significant proportion of congenital malformations of unknown cause is likely to have an important genetic component. Malformations with an increased recurrent risk, such as cleft lip and palate, anencephaly, spina bifida, certain congenital heart diseases, pyloric stenosis, hypospadias, inguinal hernia, talipes equinovarus, and congenital dislocation of the hip, fit in the category of multifactorial disease as well as in the category of polygenic inherited disease.19,20 The multifactorial/threshold hypothesis postulates the modulation of a continuum of genetic characteristics by intrinsic and extrinsic (environmental) factors.
Spontaneous errors of development may account for some of the malformations that occur without apparent abnormalities of the genome or environmental influence. Spontaneous errors of development may indicate that we never achieve our goal of eliminating birth defects because a significant percentage of birth defects are attributable to the statistical probability of errors in the developmental process, similar to the concept of spontaneous mutation. It is estimated that the majority of all conceptions are lost before term, many within the first 3 weeks of development. The World Health Organization estimated that 15% of all clinically recognizable pregnancies end in a spontaneous abortion, 50% to 60% of which are attributable to chromosomal abnormalities.31–34 Finally, 3T to 6% of offspring are malformed, which represents the background risk for human maldevelopment (Table 2).
FACTORS THAT AFFECT THE SUSCEPTIBILITY TO DEVELOPMENTAL TOXICANTS
A basic tenet of environmentally produced malformations is that teratogens or a teratogenic milieu have certain characteristics in common and follow certain basic principles. These principles determine the quantitative and qualitative aspects of environmentally produced malformations.
The types and risk of malformations caused by teratogenic agents usually result in a spectrum of malformations that vary depending on the stage of exposure and the dose. The developmental period at which an exposure occurs will determine which structures are most susceptible to the deleterious effects of the drug or the chemical and to what extent the embryo can repair the damage. This period of sensitivity may be narrow or broad, depending on the environmental agent and the malformation in question. The period of susceptibility to thalidomide-induced limb defects is very narrow24 (Table 4), whereas the susceptibility period for radiation-induced microcephaly is very broad.23
Dose or Magnitude of the Exposure
The quantitative correlation of the magnitude of the embryopathic effects to the dose of a drug, chemical, or other agent is referred to as the dose-response relationship. This is extremely important when comparing effects among different species because the use of mg/kg doses are, at most, rough approximations. Dose equivalence among species for drugs and chemicals can be accomplished only by performing pharmacokinetic studies, metabolic studies, and dose-response investigations in the human and the species being studied, whereas ionizing radiation exposures in rads or Sieverts (Sv) are comparable in most mammalian species.23
The threshold dose is the dosage below which the incidence of death, malformation, growth retardation, or functional deficit is not statistically greater than that of controls (Fig 2). The threshold level of exposure is usually from <1 to 2 orders of magnitude below the teratogenic or embryopathic dose for drugs and chemicals that kill or malform half of the embryos. An exogenous teratogenic agent, therefore, has a no-effect dose as compared with mutagens or carcinogens, which have a stochastic dose-response curve (Table 5, Fig 2). The severity and the incidence of malformations produced by every exogenous teratogenic agent that has been studied appropriately have exhibited threshold phenomena during organogenesis.
Pharmacokinetics and Metabolism of the Drug or the Chemical
The physiologic alterations in pregnancy and the bioconversion of compounds can significantly influence the teratogenic effects of drugs and chemicals by affecting absorption, body distribution, active form(s), and excretion of the compound. Physiologic alterations in the mother during pregnancy affect the pharmacokinetics of drugs:
Decreased gastrointestinal motility and increased intestinal transit time resulting in delayed absorption of drugs absorbed in the small intestine as a result of increased stomach retention and enhanced absorption of slowly absorbed drugs
Decreased plasma albumin concentration, which alters the kinetics of compound normally bound to albumin
Increased plasma and extracellular fluid volumes that affect concentration-dependent transfer of compounds
Renal elimination, which is generally increased but is influenced by body position during late pregnancy
Inhibition of metabolic inactivation in the maternal liver
Variation in uterine blood flow, although little is known about how this affects transfer across the placenta
The fetus also undergoes physiologic alterations that affect the pharmacokinetics of drugs:
The amount and distribution of fat varies with development and affects the distribution of lipid-soluble drugs and chemicals
The fetal circulation contains a higher concentration of unbound drug largely because the plasma fetal protein concentrations are lower than in the adult
The functional development of pharmacologic receptors is likely to proceed at different rates in the various tissues
Drugs that are excreted by the fetal kidneys may be recycled via amniotic fluid swallowing by the fetus
The role that the placenta plays in drug pharmacokinetics has been reviewed by Juchau and Rettie35 and involves 1) transport, 2) the presence of receptor sites for a number of endogenous and xenobiotic compounds (β-adrenergic, glucocorticoid, epidermal growth factor, immunoglobulin G Fc, insulin, low-density lipoproteins, opiates, somatomedin, testosterone, transcobalamin II, transferrin, folate, and retinoid), and 3) the bioconversion of xenobiotics. Bioconversion of xenobiotics has been shown to be important in the teratogenic activity of several xenobiotics. There is strong evidence that reactive metabolites of cyclophosphamide, 2-acetylaminofluorene, and nitroheterocycles (niridazole) are the proximal teratogens. There is also experimental evidence that suggests that other chemicals undergo conversion to intermediates that have deleterious effects on embryonic development, including phenytoin, procarbazine, rifampicin, diethylstilbestrol, some benzhydrylpiperazine antihistamines, adriamycin, testosterone, benzo(a)pyrene, methoxyethanol, caffeine, and paraquat.
The major site of bioconversion of chemicals in vivo is likely to be the maternal liver. Placental P450-dependent mono-oxygenation of xenobiotics will occur at low rates unless induced by such compounds as those found in tobacco smoke. However, the rodent embryo and yolk sac have been shown to possess functional P450 oxidative isozymes capable of converting pro-teratogens to active metabolites during early organogenesis. In addition, P450-independent bioactivation has been suggested: for example, there is strong evidence that the rat embryo can reductively convert niridazole to an embryotoxic metabolite.
As defined by Juchau and Rettie,35 there are several experimental criteria that would suggest that a suspected metabolite is responsible for the in vivo teratogenic effects of a chemical or drug: 1) the chemical must be convertible to the intermediate, 2) the intermediate must be found in or have access to the tissue(s) affected, 3) the embryotoxic effect should increase with the concentration of the metabolite, 4) inhibiting the conversion should reduce the embryotoxic effect of the agent, 5) promoting the conversion should increase the embryotoxicity of the agent, 6) inhibiting or promoting the conversion should not alter the target tissues, and 7) inhibition of biochemical inactivation should increase the embryotoxicity of the agent. It is readily apparent why there may exist marked qualitative and quantitative differences in the species response to a teratogenic agent.
The exchange between the embryo and the maternal organism is controlled by the placenta. The placenta varies in structure and function among species and for each stage of gestation. Thus, differences in placental function and structure may affect our ability to apply teratogenic data developed in one species directly to other species, including the human, yet as pharmacokinetic techniques and the actual measurement of metabolic products in the embryo become more sophisticated, the appropriateness of using animal data to project human effects may improve.
Although it has been alleged that the placental barrier was protective and therefore harmful substances did not reach the embryo, it is now clear that there is no “placental barrier” per se, yet the package inserts on many drugs state that “this drug crosses the placental barrier.”26 The uninitiated may infer from this statement that this characteristic of a drug is both unusual and hazardous. The fact is that most drugs and chemicals cross the placenta. It will be a rare chemical that will cross the placental barrier in one species and be unable to reach the fetus in another. No such chemical exists except for selected proteins whose actions are species specific.
The genetic constitution of an organism is an important factor in the susceptibility of a species to a drug or a chemical. More than 30 disorders of increased sensitivity to drug toxicity or effects in the human are attributable to an inherited trait.
ENVIRONMENTAL AGENTS WHOSE EXPOSURE DURING PREGNANCY HAS BEEN DEMONSTRATED TO RESULT IN REPRODUCTIVE TOXICITY
Table 6 lists environmental agents that have resulted in reproductive toxicity and or congenital malformations in human populations. The list cannot be used in isolation because so many other parameters must be used in any analysis of the risks in individual patients. Many of these agents represent a very small risk, whereas others may represent substantial risks. The risks will vary with the magnitude, timing, and length of exposure. More information can be obtained from more extensive reviews or summary articles. You will also note that Table 7 includes agents that have had concerns raised about their reproductive risks, but after careful and complete evaluation, the agents were found not to represent an increased reproductive risk.36–41
ROLE OF THE PEDIATRICIAN IN COUNSELING FAMILIES CONCERNING THE CAUSE OF THEIR CHILD’S CONGENITAL MALFORMATIONS
The clinician must be cognizant that many patients believe that most congenital malformations are caused by a drug or medication taken during pregnancy. Counseling patients about reproductive risks requires a significant degree of both knowledge and skill. Physicians must also realize that erroneous counseling by inexperienced health professionals may be a stimulus to nonmeritorious litigation.22
Unfortunately, some individuals have assumed that if a drug or chemical causes birth defects in an animal model or in vitro system at a high dose, then it has the potential for producing birth defects at any dose.48,49 This may be reinforced by the fact that many teratology studies reported in the literature using several doses do not determine the no-effect dose.
Ignoring the basic tenets of teratology seems to occur most commonly in the evaluation of environmental toxic exposures in which the exposure was very low or unknown and the agent has been reported to be teratogenic at a very high dose or a maternally toxic dose. In most instances—but of course not all instances—the actual population exposure is revealed to be orders of magnitude below the threshold dose and the doses that were used in animal studies or toxic exposures in the population. This has occurred with 2,4,5-trichlorophenoxyacetic acid, polychlorinated biphenyls, lead, cadmium, arsenic, pesticides, herbicides, veterinary hormones, and industrial exposures.
Unfortunately, we do have examples in which environmental disasters have been responsible for birth defects or pregnancy loss in exposed populations (methyl mercury in Japan, polychlorinated biphenyls in Asia, organic mercury in the Middle East, lead poisoning in the 19th and early 20th centuries), and we do have many examples of the introduction of teratogenic drugs (Table 6). Therefore, we can never generalize as to whether a chemical or a drug is safe or hazardous unless we know the magnitude of the exposure.
Before their infant is born, parents may be concerned about the risks of various environmental exposures. If the child is born with congenital malformations, then they may question whether there was a causal relationship with an environmental exposure.
Has the environmental agent been proved to increase the risk of congenital malformations in exposed human populations? In other words, is the agent a proven human teratogen?
Should a woman of reproductive age or who is pregnant be concerned about increased risks of reproductive effects from exposure to a particular environmental agent?
If a child is born with congenital malformations and the mother was exposed during her pregnancy to a particular environmental agent, then was the agent responsible for the child’s birth defects?
Should a physician report or publish a case of a patient or cluster of patients who were born with congenital malformations and whose mother was exposed to an environmental agent?50
When a pediatrician responds to a parent’s inquiry, “What caused my child’s birth defect?” the pediatrician should respond in the same scholarly manner that would be used in performing a differential diagnosis for any clinical problem. Pediatricians have a protocol for evaluating complex clinical problems (eg, “fever of unknown origin,” “failure to thrive,” “congestive heart failure,” “respiratory distress”). If a mother of a malformed infant had some type of exposure during pregnancy, such as a diagnostic radiologic examination or medication, then the consulting physician should not support or suggest the possibility of a causal relationship before performing a complete evaluation. Likewise, if a pregnant woman who had not yet delivered had some type of exposure during pregnancy, then the consulting physician should not support or suggest the possibility that the fetus is at increased risk before performing a complete evaluation. As mentioned previously, only a small percentage of birth defects are attributable to prescribed drugs, chemicals, and physical agents9,36,51 (Table 3). Even when the drug is listed as a teratogen, it has to have been administered during the sensitive period of development for that drug and above the threshold dose for producing teratogenesis. Furthermore, the malformations in the child should be the malformations that are included in the teratogenic syndrome produced by that drug. It should be emphasized that in a recent analysis, it was pointed out that there are no drugs with measurable teratogenic potential in the list of the 200 most prescribed drugs in the United States.51
After a complete examination of the child and a review of the genetic and teratology medical literature, the clinician must decide whether the child’s malformations are attributable to a genetic cause or an environmental toxin or agent. He may not be able to conclude definitively or presumptively the cause of the child’s birth defects. This information must then be conveyed to the patient in an objective and compassionate manner. A similar situation exists if a pregnant woman has been exposed to a drug, chemical, or physical agent, because the mother will want to know the risk of that exposure to her unborn child. If one wishes to answer the generic question, “Is a particular environmental drug, chemical, or physical agent a reproductive toxicant?” then a formal approach that includes a 5-part evaluation is recommended as described in Table 118 and is summarized as follows:
Consistency of epidemiologic studies
Secular trend analysis
Animal reproductive studies
Dose-response relationships and pharmacokinetic studies comparing human and animal metabolism
Some typical analyses of the risks of reproductive effects for Bendectin, sex steroids, diagnostic ultrasound, and electromagnetic fields demonstrate the usefulness of an organized approach to determine whether an environmental agent has been demonstrated to be a reproductive toxin.36–41 There are resources that can assist the physician with the medical literature evaluation and the clinical evaluation of the patient.5,6,11,16,34,42–47
There are many articles and books that can assist the physician with the clinical evaluation, although general pediatric training programs do not usually prepare generalists to perform sophisticated genetic counseling or teratology counseling.11,16 Besides the usual history and physical evaluation, the physician has to obtain information about the nature, magnitude, and timing of the exposure. The physical examination should include descriptive and quantitative information about the physical characteristics of the child. Although some growth measurements are routine, many measurements used by these specialized counselors are not part of the usual physical examination (eg, palpebral fissure size, ear length, intercanthal distances, total height-to-trunk ratio). Important physical variations in facial, hand, and foot structure as well as other anatomic structures may be suggestive of known syndromes, either teratologic or genetic.
Evaluation of the Reproductive Risk of an Environmental Exposure That Occurred During Pregnancy or the Cause of a Child’s Malformation in Which an Exposure Occurred During the Pregnancy
The vast majority of consultations involving pregnancy exposures conclude that the exposure does not change the reproductive risks in that pregnancy. In many instances, the information that is available is so vague that the counselor cannot reach a definitive conclusion about the magnitude of the risk. Information that is necessary for this evaluation is as follows:
What was the nature of the exposure?
Is the exposure agent identifiable? If the agent is identifiable, then has it been identified definitively as a reproductive toxin with a recognized constellation of malformations or other reproductive effects?
When did the exposure occur during embryonic and fetal development?
If the agent is known to produce reproductive toxic effects, then was the exposure above or below the threshold for these effects?
Were there other significant environmental exposures or medical problems during the pregnancy?
Is this is a wanted pregnancy, or is the family ambivalent about carrying this infant to term?
What is the medical and reproductive history of this mother with regard to previous pregnancies and the reproductive history of the family lineage?
Evaluation of the Reproductive Risk of an Environmental Exposure That Occurred During Pregnancy
After obtaining all of this information, the counselor is in a position to provide the family with an estimate of the reproductive risks of the exposure. Here are some examples of consultations that have been referred to our clinical teratology service.
A 34-year-old pregnant laboratory worker dropped and broke a reaction vessel that contained a mixture of chemical reagents. She proceeded to clean the floor with paper towels. Later she became concerned about the potential harmful effects of the exposure. She was in the sixth week of her pregnancy, which means that the embryo was in the period of early organogenesis. The chemicals in the spill were tetrahydrofuran (70%), pyridine (20%), and iodine (1%). It was not possible to estimate quantitatively the exposure to these agents, but the laboratory worker experienced no symptoms from the exposure. This was a planned, wanted pregnancy. Although iodine can interfere with thyroid development, the exposure in this situation would be inconsequential, because the thyroid is not yet present. The other 2 compounds have not been studied in epidemiologic studies of pregnant women. No other exposure to reproductive toxins occurred in this pregnancy, and the family history for congenital malformations was negative. The woman was advised that it would be very unlikely that this exposure would increase her teratogenic risk because the exposures to the embryo would be extremely low. She was also told that she still was faced with the background risks for birth defects and miscarriage. Therefore, her reproductive risks should be the same as the risks for the general population (Table 2).
A 26-year-old pregnant woman was in an automobile accident in her 10th week of pregnancy and sustained a severe concussion. Although she did not convulse postinjury, the treating neurosurgeon prescribed 300 mg of diphenylhydantoin during her first 24 hours in the hospital. Fortunately, she recovered from the injury without any sequelae, but her primary physician was concerned that she had received an anticonvulsant associated with a teratogenic syndrome. No other exposure to reproductive toxins occurred in this pregnancy, and the family history for congenital malformations was negative, except for an uncle with neurofibromatosis. The primary physician requested a consultation with regard to the teratogenic risk. Although diphenylhydantoin administered chronically throughout pregnancy has been associated with a low incidence of characteristic facial dysmorphogenesis, reduced mentation, cleft palate, and digital hypoplasia, there are no data to indicate that 1 day of therapy would cause any of the features of this syndrome. Furthermore, the lip and palate have completed their development by the 10th week. This was a wanted pregnancy, and the mother chose to continue her pregnancy. She delivered a normal 3370-g boy at term.
A 25-year-old woman was seen in the emergency service of her local hospital with nausea, vomiting, and diarrhea. She had just returned from a cruise on which a number of the passengers became ill on the last day of the trip with similar symptoms. The emergency department physician ordered a pregnancy test followed by a flat plate of the abdomen because there was evidence of peritoneal irritation. Both of these studies were negative, but 1 week later she missed her menstrual period and a week later her pregnancy test was positive. Her obstetrician was concerned because she had been exposed to a radiologic procedure at a time when she was pregnant. The obstetrician referred the patient for counseling after obtaining an ultrasound that indicated that the embryo was approximately 7 days postconception at the time of the radiologic examination. The patient advised the counselor that she was ambivalent about the pregnancy because of the “dangers” of the radiographs to her embryo. The estimated exposure to the embryo was <500 mrad (0.005 Sv). This exposure is far below the exposure that is known to affect the developing embryo. Just as important is that the embryo was exposed during the first 2 weeks postconception, a time that is less likely to increase the risk of teratogenesis, even if the exposure was much higher.23,52 After evaluation of the family history and after she received counseling about the risks of the radiograph, the prospective mother decided to continue the pregnancy. She delivered a 3150-g normal infant.
Evaluation of Whether the Cause of Congenital Malformations Was an Environmental Exposure During Pregnancy, Is Genetic, or Cannot Be Determined
The mother of a 30-year-old man who was born in the Azores in 1960 with congenital absence of the right leg below the knee had pursued compensation for her son because she was certain that she must have received thalidomide during her pregnancy.24 The German manufacturer of thalidomide refused compensation claiming that thalidomide had never been distributed in the Azores. The mother fervently believed that thalidomide was responsible for her son’s malformations, and I received a letter from her asking for my opinion. I requested her son’s medical records, radiographs, and photographs of the malformations. She sent me the radiograph studies of his hips and legs and his complete evaluation performed at the local hospital in the Azores. He had none of the other stigmata of thalidomide embryopathy (preaxial limb defects, phocomelia, facial hemangioma, ear malformations, deafness, crocodile tears, ventricular septal defect, intestinal or gall bladder atresia, kidney malformations). Most important, his limb malformations were not of the thalidomide type. He had a unilateral congenital amputation, with no digital remnants at the end of the limb. His pelvic girdle was completely normal, which would be unusual in a thalidomide-malformed limb. Finally, his limb defect involved only 1 leg; the other leg was completely normal. This would be very unusual in a true thalidomide embryopathy. In this particular case, the young man had a congenital amputation, probably as a result of vascular disruption, cause unknown. Known causes of vascular disruptive malformations are cocaine, misoprostol, and chorionic villous sampling. It is difficult to determine whether any amount of appropriate counseling will put closure on this problem for this mother.
A family claimed that the antinausea medication Bendectin,36,37,53 taken by the mother of a malformed boy, was responsible for her son’s congenital limb reduction defects. Bendectin was taken during the mother’s pregnancy after the period of limb organogenesis, but some limb malformations can be produced by teratogens later in pregnancy. The malformation was unaccompanied by any other dysmorphogenetic effects. The boys malformations were the classical split-hand, split-foot syndrome, which is dominantly inherited. This malformation has a significant portion of cases that are attributable to a new mutation. Because neither parent manifested the malformation, the conclusion had to be that a new mutation had occurred in the sex cells of 1 of the parents. Therefore, the risk of this malformation’s occurring in the offspring of this boy would be 50%. Obviously, Bendectin was not responsible for this child’s malformations. Despite the obvious genetic cause of the malformed child’s birth defects, a legal suit was filed. A jury decided for the defendant; namely, that Bendectin was not responsible for the child’s birth defects.
A woman visited the emergency department of an excellent university hospital complaining of severe lower abdominal pain. An obstetric resident saw her because she informed the staff that she had a previous ectopic pregnancy that necessitated the removal of her ovary and tube. A pregnancy test was positive, and she was scheduled to return to the obstetric clinic in 1 week. At that time, her chorionic gonadotropin level was repeated and had not changed from its previous level. Without performing an ultrasound, a diagnosis of ectopic pregnancy was made. To preserve the patient’s reproductive potential, it was decided to treat the ectopic pregnancy with methotrexate rather than remove the remaining tube and ovary. After the administration of methotrexate, the patient was sent home, but a laboratory report indicated that the gonadotropin level had increased 5-fold. The laboratory report received earlier in the day was a copy of the original report performed a week earlier. The patient was called back to the hospital, and an ultrasound revealed a normally implanted embryo. The senior obstetric staff counseled the mother that the infant was at increased risk for having congenital malformations because of the exposure. The patient refused to abort the pregnancy. The obstetric department offered to provide care for the pregnancy and delivery that included a number of ultrasound examinations. At 28 weeks, the patient went into labor and delivered a live-born premature infant. During infancy, a diagnosis of hydrocephalus, developmental delay, and spastic cerebral symptoms was made. A lawsuit was filed by the family against the doctors and the university hospital. The attorney representing the child called me and asked me to evaluate the allegation that the abnormalities in the child were attributable to the administration of the methotrexate. Methotrexate has been reported to cause growth retardation, microcephaly, developmental delay, and hydrocephalus, but not prematurity. The clinical care provided by the resident doctor was unfortunate, but the offer of providing care by the senior obstetricians turned out to be fortunate for the defendants in this case. Review of the records revealed 2 important findings. First, an ultrasound examination taken 1 week before the premature delivery revealed that there was no evidence of hydrocephalus. Second, the birth weight was appropriate for the gestational stage. The exposure to methotrexate was not responsible for the serious problems in this infant, because the hydrocephalus and neurologic symptoms were attributable to a central nervous system bleed in the postnatal period as a complication of the prematurity.
It should be apparent that determining the reproductive risks of an exposure during pregnancy or the cause of a child’s congenital malformations is not a simple process. It involves a careful analyses of the medical and scientific literature pertaining to the reproductive toxic effects of exogenous agents in humans and animals, as well as an evaluation of the exposure and biological plausibility of an increased risk or a causal connection between the exposure and a child’s congenital malformation. It also involves a careful physical examination and a review of the scientific literature pertaining to genetic and environmental causes of the malformations in question. Abridged counseling on the basis of superficial and incomplete analyses is a disservice to the family.
- Received October 7, 2003.
- Accepted October 20, 2003.
- Reprint requests to (R.L.B.) Rm 308, R/A, Alfred I. duPont Hospital for Children, Box 269, Wilmington, DE 19899. E-mail
- 4.↵Warkany J, Schraffenberger E. Congenital malformations of the eyes induced in rats by maternal vitamin A deficiency. Proc Soc Exp Biol Med.1944;57 :49– 52
- 5.↵McKusick VA. Mendelian Inheritance in Man: Catalogs of Autosomal Dominant, Autosomal Recessive, and X-linked Phenotypes. 8th ed. Baltimore, MD: Johns Hopkins University Press; 1998
- 6.↵OMIM, Online Mendelian Inheritance of Man. Available at: www3./ncbi.nlm.nih.gov/omim
- 8.Beckman DA, Fawcett LB, Brent RL. Developmental toxicity. In: Massaro, EJ, ed. Handbook of Human Toxicology. New York, NY: CRC Press; 1997:1007–1084
- 9.↵Brent RL, Beckman DA. Prescribed drugs, therapeutic agents, and fetal teratogenesis. In: Reece EA, Hobbins JC, eds. Medicine of the Fetus and Mother. 2nd ed. Philadelphia, PA: Lippincott-Raven Publishers; 1999:289–313
- 10.↵Heinonen OP, Slone D, Shapiro S. Birth Defects and Drugs in Pregnancy, Littleton, MA: Publishing Sciences Group; 1977
- 11.↵Aase JM. Diagnostic Dysmorphology. New York, NY: Plenum Medical Book Co; 1990
- 12.Beckman DA, Brent RL. Fetal effects of prescribed and self-administered drugs during the second and third trimester. In: Avery GB, Fletcher MA, MacDonald MG, eds. Neonatology: Pathophysiology and Treatment. 4th ed. Philadelphia, PA: JB Lippincott Company; 1994:197–206
- 14.Brent RL, Beckman DA. Teratogens: an overview. In: Knobil E, Neill JD, eds. Encyclopedia of Reproduction. Vol 4. San Diego, CA: Academic Press; 1999:735–750
- 15.Graham JM Jr, Jones KL, Brent RL. Contribution of clinical teratologist and geneticists to the evaluation of the etiology of congenital malformations alleged to be caused by environmental agents, ionizing radiation, electromagnetic fields, microwaves, radionuclides, and ultrasound. Teratology.1999;59 :307– 313
- 16.↵Jones KL. Smith’s Recognizable Patterns of Human Malformations. 5th ed. Philadelphia, PA: WB Saunders Co; 1994
- 18.↵Brent RL. Methods of evaluating the alleged teratogenicity of environmental agents. In: Sever JL, Brent RL, eds. Teratogen Update: Environmentally Induced Birth Defect Risks. New York, NY: Alan R. Liss; 1986:199–201
- 19.↵Carter CO. Genetics of common single malformations. Br Med Bull.1976;32 :21– 26
- 25.↵Brent RL. The irresponsible expert witness: a failure of biomedical graduate education and professional accountability. Pediatrics.1982;70 :754– 762
- 26.↵Brent RL. Drugs and pregnancy: are the insert warnings too dire? Contemp Obstet Gynecol.1982;20 :42– 49
- 27.↵Brent RL. Effects and risks of medically administered isotopes to the developing embryo. In: Fabro S, Scialli AR, eds. Drug and Chemical Action in Pregnancy. New York, NY: Marcel Dekker; 1986:427–439
- 29.↵Brent RL, Beckman DA. Developmental effects following radiation of embryonic and fetal exposure to x-ray and isotopes: counseling the pregnant and nonpregnant patient about these risks. In: Hendee WK, Edwards FM, eds. Health Effects of Low Level Exposure to Ionizing Radiation. Bristol, UK: Institute of Physics Publishing; 1996:169–213
- 30.↵Brent RL. Ionizing radiation. In: Queenan JT, ed. Protocols High-Risk Pregnancy, Contemporary Ob/Gyn. 1999;44(1):13–14,16,21,25–26
- 32.Hertig AT. The overall problem in man. In: Benirschke K, ed. Comparative Aspects of Reproductive Failure. Berlin, Germany: Springer-Verlag; 1967:11–41
- 35.↵Juchau MR, Rettie AE. The metabolic role of the placenta. In: Fabro S, Scialli AR, eds. Drug and Chemical Action in Pregnancy: Pharmacologic and Toxicologic Principles. New York, NY: Marcel Dekker, 1986;153–169
- 37.↵Brent RL. Review of the scientific literature pertaining to the reproductive toxicity of Bendectin. In: Faigman DL, Kaye DH, Saks MJ, Sanders J eds. Modern Scientific Evidence: The Law and Science of Expert Testimony. Vol 2. St. Paul, MN: West Publishing Group; 1997:373–393
- 38.Brent RL. Microwaves and ultrasound. In: Queenan JT, Hobbins JC, eds. Protocols for High-Risk Pregnancies. 3rd ed. Cambridge, MA: Blackwell Scientific; 1995:37–43
- 42.↵Friedman JM, Polifka JE. TERIS. The Teratogen Information System. Seattle, WA: University of Washington; 1999
- 43.Scialli AR, Lione A, Padget GKB, eds. Reproductive Effects of Chemical, Physical and Biologic Agents; Reprotox. Baltimore, MD: The Johns Hopkins University Press; 1995
- 45.Sever JL, Brent RL, eds. Teratogen Update: Environmentally Induced Birth Defect Risks. New York, NY: Alan R. Liss; 1986
- 46.Shepard TH. Catalogue of Teratogenic Agents. 8th ed. Baltimore, MD: The Johns Hopkins University Press; 1995
- 47.↵Schardein JL. Chemically Induced Birth Defects. 3rd ed. New York, NY: Marcel Dekker; 2000
- 48.↵Briggs GG, Freeman RK, Yaffe SJ. Drugs in Pregnancy and Lactation. 3rd ed. Baltimore, MD: Williams and Wilkins; 1990:502–508
- 50.↵Brent RL. Predicting teratogenic and reproductive risks in humans from exposure to various environmental agents using in vitro techniques and in vivo animal studies. Cong Anom.1988;28(suppl) :S41– S55
- 53.↵Wilson JG, Brent RL, Jordan HC. Differentiation as a determinant of the reaction of rat embryos to x-irradiation. Proc Soc Exp Biol Med.1953;82 :67– 70
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