Teratogens



Teratogens


Scott A. Sullivan

Barbara B. Head



Introduction

Congenital malformations or birth defects may be found in up to 3% of neonates.1 An additional 2% to 3% of infants may be found subsequently to have an anomaly that was not previously diagnosed. Approximately 10% of human malformations are due to environmental causes and less than 3% are related to prescription drug exposure, chemicals, or radiation. These anomalies may range from clinically insignificant to fatal. Birth defects are a leading cause of infant mortality, along with premature birth.2 Birth defects also are responsible for significant morbidity, acute and long-term costs, significant anxiety, and developmental delays. Malformations caused by medications and other therapeutic agents are important because these exposures may be preventable. Advances in animal research and epidemiology have enabled scientists to gain a better understanding of the mechanisms and patterns of teratogenesis.

Virtually every organ system has the potential to be affected during fetal development. Given the associated potential morbidity and mortality, there is great interest in the prevention, detection, and treatment of congenital anomalies. This requires an understanding of the mechanisms and underlying pathogenesis of the anomalies; however, this is often lacking. It is generally understood that there are a number of potential causes for anomalies, including genetics (single gene, polygenic, aneuploidy), congenital infections, radiation, medications, environmental toxins, physical force, illicit drugs, maternal conditions, and frequently combinations of the same. Some exposures even require “two-hit” scenario, with a genetic predisposition followed by an exposure in the development window to result in an anomaly.

A teratogen, strictly speaking, is any agent that can contribute or cause a congenital anomaly. Under most circumstances, the term applies to medications, although there are certainly nonmedication teratogens (eg, radiation). It is estimated that up to half of pregnant women are exposed to a medication during pregnancy.3 This does not include exposures to over-the-counter or herbal medications. There are very limited data about the risks of many of these products, despite the public perception that “natural” supplements are somehow inherently safer than prescribed medications. Malformations caused by medications and other therapeutic agents are important because these exposures may be preventable.

For the purposes of this chapter, we will consider a teratogen to be any nongenetic cause of a malformation. Our discussion includes the most common teratogenic medications and rubella and cytomegalovirus (CMV). Chapter 8 Substance and alcohol use and Chapter 9 Radiation Exposure discuss those major teratogens in more detail.

A number of important factors contribute to the potential risk for an exposure to be a teratogen. These may include:



  • the amount or dose of an exposure


  • the length and route of the exposure


  • the timing in gestation


  • pharmacological characteristics, including placental permeability, clearance patterns, solubility, half-life, interactions, and mechanism of action

Expectant parents are often understandably anxious about the risks for birth defects and seek guidance for how to prevent or reduce their risk. Clinicians should review all medications taken before pregnancy and those prescribed during pregnancy and provide advice about relative risks and benefits. The impulse to “stop all medications” at the discovery of a pregnancy should generally be avoided, as many untreated conditions may present
a graver risk to the mother or the pregnancy than the medication exposure. Ideally, a discussion regarding pregnancy should occur well in advance of conception. Preconception is an ideal time to consider alternate agents, adjust doses, and balance potential risks. Unfortunately, in many instances, these discussions occur well after the period of organogenesis.

The foundation for sound patient counseling is quality outcome data. However, limited data are sometimes available on the safety of medications used during pregnancy: a review of prescription medications approved by the U.S. Food and Drug Administration (FDA) from 2000 to 2010 showed that the teratogenic risk was undetermined in 97.7%.4 Obviously new drugs in development are not given purposefully to cohorts of pregnant women. Instead, the desired data are obtained indirectly from animal studies, registries, and case series of women exposed either inadvertently or out of necessity. Unfortunately, this process takes a prolonged period of time to accumulate actionable information, often many years.

For women to receive optimal care during pregnancy, we need to better define what data are needed to determine whether a medication or exposure is “safe” for use during pregnancy. In addition, in the absence of adequate, well-controlled data, it is important to determine how best to weigh the benefits of medications with potential, but often unknown, risks to the embryo or fetus. Another essential concern is to understand how we can communicate these effectively to patients.5


Basic Principles of Teratology

To determine if an agent is teratogenic, it is necessary to characterize the dose, route of exposure, and gestational age of pregnancy when exposure occurred. For example, a 50-mg dose of thalidomide administered on the fourth week post conception has a significant risk of causing malformations in the embryo.6 The same dose taken during the 10th week of gestation is unlikely to result in congenital malformations, and 1 mg of thalidomide taken at any time during pregnancy will have no effect on the developing fetus. Radiation exposure can be teratogenic7; however, if the dose is too low or the radiation does not directly expose the uterus, there is significantly decreased risk of congenital malformations (see Chapter 9). Lisinopril has been associated with a risk for renal agenesis, but only if the exposure occurs during the gestational age when the kidneys are developing.8 An accidental exposure prior to this would have no expected effect.

Therefore, a list of teratogens indicates only teratogenic potential; evaluation of the dose and time of exposure is critical in determining the extent of potential risk. This may not always be precisely known, as patient recall or documentation may at times be incomplete. It is also critically important to determine an accurate gestational age, if possible, by comparing the menstrual history to the earliest possible ultrasound.9

Despite these limitations, physicians and clinicians must be careful to carry out a thorough evaluation of the risks faced by a woman exposed to drugs and chemicals during pregnancy. Clinical teratology and genetics is sometimes not emphasized in medical schools and residency education programs. However, clinicians have a multitude of educational aids to assist them in their evaluations; these include consultations with maternal-fetal medicine subspecialists, geneticists, pharmacists, the medical literature, texts, government and manufacturer websites, and searchable online databases.


The Etiology of Congenital Malformations

As mentioned earlier, the etiology of congenital malformations may be divided into three general categories: unknown, genetic, and environmental (Table 7.1). A significant proportion of congenital malformations of unknown etiology may have an important underlying genetic component. Malformations with an increased recurrence risk, such as cleft lip and palate, anencephaly, spina bifida, certain congenital heart diseases, pyloric stenosis, hypospadias, inguinal hernia, gastroschisis, and congenital dislocation of the hip, are examples of multifactorial disease as well as that of probable polygenic inherited disease.10 The multifactorial/threshold hypothesis postulates the modulation of a continuum of genetic characteristics by intrinsic and extrinsic (environmental) factors.

The expansion of knowledge and technology for detecting genetic abnormalities has moved some cases of congenital anomalies from “unknown” to a genetic diagnosis. Widespread use of microarray testing and increased understanding of variants of unknown significance have improved the diagnostic yield over conventional karyotype.11 Advances
in technology likely will continue to provide new insights and new testing capabilities into the relationship between genetics and birth defects.








A significant percentage of congenital anomalies can occur without apparent abnormalities of the genome or environmental influences. These are due to the statistical probability of errors in the developmental process, which is incredibly complex and similar to the concept of spontaneous genetic mutations. Given the multitude of developmental steps that must occur in proper sequence and timing makes it likely that we may never achieve our goal of completely eliminating birth defects.


Factors That Affect Susceptibility to Potential Teratogens

A basic tenet of environmentally produced malformations is that teratogens have certain characteristics in common and follow certain basic principles. These principles determine the quantitative and qualitative aspects of environmental exposures.


Timing of Exposure

The embryo is most sensitive to the lethal effects of drugs and chemicals during the period of embryonic development, from fertilization through the early postimplantation stage (Figure 7.1).1 Surviving embryos have malformation rates that are similar to those of control subjects because significant cell loss or chromosome abnormalities at these stages have a high likelihood of resulting in embryonic death, not because malformations cannot be produced at this stage. Because of the totipotentiality of early embryonic cells, surviving embryos have a high probability of having malformation rates that are similar to embryos that have not been exposed.

The period of organogenesis (from day 18 through about day 40 post conception in the human) is the period of greatest sensitivity to teratogenic insults and when most anatomic malformations can be induced.12 Most environmentally produced major malformations occur before the 36th day post conception in humans (Table 7.2). The exceptions are malformations of the genitourinary system, the palate, and the brain, or deformations due to problems of fetal growth. Unfortunately, some patients are unaware of their pregnancy at this early stage, or do not seek or have access to timely medical care. These represent missed opportunities to stop, modify, or counsel patients about their individual risks.

The fetal period is characterized by histogenesis involving cell growth, differentiation, maturation, and migration. Agents that result in cell depletion, vascular disruption, necrosis, specific tissue or organ pathology, physiological decompensation, or severe growth restriction have the potential to cause deleterious effects throughout gestation. The fetus is most sensitive to the induction of developmental delays and microcephaly at the end of the first and the beginning of the second trimester.12 Developmental delays or other neurological effects

can be induced in the second and third trimesters.13 Effects such as cell damage or functional abnormalities, not readily apparent at birth, may give rise to changes in behavior or fertility, which are only apparent later in life. Given that fetal effects on growth or development can occur late in pregnancy, prenatal ultrasounds that appear normal at 19 to 20 weeks may become abnormal if obtained in the third trimester.














Dose of the Exposure

The quantitative correlation between the magnitude of the teratogenic effects and the dose of a drug, chemical, or other agent is referred to as the dose-response relationship (Table 7.3). This is extremely important when comparing effects among different species because the use of mg/kg doses are, at best, rough approximations. Dose equivalence for drugs and chemicals between humans and other species can be accomplished only by performing pharmacokinetic studies, metabolic studies, and dose-response investigations. For example, a substance given in large enough amounts to cause maternal toxicity is also likely to have deleterious effects on the embryo such as death, growth restriction, or disrupted development. Doses administered in some animal trials are supratherapeutic, testing for the possibility of any teratogenic potential. These doses may not have a human equivalent or even be realistic. In addition, animal physiology is not identical to human physiology and there are several examples of malformations reported in animals that do not seem to occur in humans. The reverse can also be true. Several considerations affect the interpretation of dose-response relationships and must be carefully reviewed.










Threshold Dose

The threshold dose is the dose below which the incidence of death, malformation, growth restriction, or functional deficit is not statistically greater than that of control subjects. The threshold level of exposure usually varies between less than one and up to two orders of magnitude below the teratogenic or embryopathic dose for drugs and chemicals that kill or malform one-half of the embryos. An exogenous teratogenic agent, therefore, has a no-effect dose compared with mutagens or carcinogens, which have a stochastic dose-response curve (Table 7.4). The incidence and severity of malformations produced by most exogenous teratogenic agents that have been appropriately studied have exhibited threshold phenomena during organogenesis.1,16 The threshold concept stems from the principle that manifestations of developmental toxicity occur because the processes of repair and regeneration have been overwhelmed by a particular exposure to a developmental toxicant. It does not predicate that no effect occurs at lower dose exposures, just that there is no deleterious or irreversible effect.


Genetic Susceptibilities

The genetic constitution of an organism is an important factor in the susceptibility of a species to a drug or chemical. Many disorders of increased sensitivity to drug toxicity or effects in the human may result from an inherited gene or trait.17 Maternal and fetal genotypes determine the types of bioconversion route, the rate at which clearance occurs, and the extent to which a compound is metabolized. Some of these associations are known but many remain mysterious or unknown to the patient. The era of personalized or genetic medicine may someday provide earlier warning to individuals with particular susceptibilities.









Environmental Agents Resulting in Toxicity

Table 7.5 lists examples of environmental agents that have resulted in reproductive toxicity and/or congenital malformations in humans. The list should not be used in isolation because many other parameters must be considered when analyzing reproductive risks in individual patients. Many of these agents represent a very small risk while others may represent substantial risks; the risks will vary with the magnitude, timing, and length of exposure. Further information can be obtained from more extensive reviews or summary articles. Table 7.6 lists agents that have had concerns raised about their reproductive effects but, after a careful and complete evaluation, have not been found to represent an increased reproductive risk.18,19,20 References for various environmental agents can be found in review articles, registries, databases, and texts on teratogenesis.21,22

Some agents remain highly controversial despite years of study. Methimazole provides one example. The literature provides conflicting information,



with some studies indicating risk for aplasia cutis and gastrointestinal anomalies, while other studies have contradictory results.23,24 It becomes even more confusing when studies point to different patterns of anomalies. The rarity of the anomaly, the population studied, the type of study, and dosing differences can make comparisons difficult. This makes the clinician’s job difficult when trying to advise a patient about her risks.









Interpretation of Animal Study Data

Whole animal teratology studies are helpful in raising concerns about the reproductive effects of drugs and chemicals; however, negative animal studies do not guarantee that these agents are free from reproductive effects in humans. There are examples in which drug testing was negative in animal models but was teratogenic in humans (ie, thalidomide).6 Similarly, there are examples in which a drug was teratogenic in an animal model but not in humans (diflunisal).25 Therefore, while chemicals and drugs can be evaluated for their toxic potential by utilizing in vivo animal studies and in vitro systems, it should be recognized that these testing procedures are only one component in the process of evaluating the potential toxic risk of drugs and chemicals.

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Jun 19, 2022 | Posted by in OBSTETRICS | Comments Off on Teratogens
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