Environmental Causes of Human Congenital Malformations: The Pediatrician’s Role in Dealing With These Complex Clinical Problems Caused by a Multiplicity of Environmental and Genetic Factors

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 misdeeds^21–24 (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

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Fig 1.

Through the ages these diseases have been interpreted or considered by multiple cultures to be stigmatizing; punishments for misdeeds or sins. In modern times, these are the diseases whose causation is thought to be due to environmental factors—thus converting the guilt of the past into anger that is projected onto others in our society and sometimes leads to litigation.

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:

1. 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).

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).

3. Even the most potent teratogenic agent cannot produce every malformation.

4. 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.

5. 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

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Fig 2.

The dose response curve of environmental toxicants (drugs, chemicals, and physical agents) can have deterministic (threshold) and/or stochastic effects. Mutagenic and carcinogenic events are stochastic phenomena and theoretically do not have a threshold exposure below which no risk exists. At low exposures the risk still exists, but it is usually below the spontaneous risk of cancer and mutations. Whether the curve is linear or curvilinear for stochastic phenomena can be debated, but from a theoretical point, it traverses zero. Toxicological phenomena, such as teratogenesis, that do not involve mutagenic and carcinogenic effects usually follow an S-shaped curve, with a threshold below which no effects are expected.

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.

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

References for the environmental agents can be found in review articles and texts that deal with teratogenesis.^{5,6,11,16,34,42–47}

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.

1. 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?

2. 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?

3. 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?

4. 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

Scholarly Evaluation

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 agents^9,36,51 (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:

1. Consistency of epidemiologic studies

2. Secular trend analysis

3. Animal reproductive studies

4. Dose-response relationships and pharmacokinetic studies comparing human and animal metabolism

5. Biological plausibility

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}

Clinical Evaluation

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:

1. What was the nature of the exposure?

2. 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?

3. When did the exposure occur during embryonic and fetal development?

4. If the agent is known to produce reproductive toxic effects, then was the exposure above or below the threshold for these effects?

5. Were there other significant environmental exposures or medical problems during the pregnancy?

6. Is this is a wanted pregnancy, or is the family ambivalent about carrying this infant to term?

7. 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.

Evaluation of Whether the Cause of Congenital Malformations Was an Environmental Exposure During Pregnancy, Is Genetic, or Cannot Be Determined