Teratology

Introduction

A teratogenic exposure is one that has the ability to interfere with normal development of the fetus. Some exposures increase the risk for structural anomalies, others may interfere with fetal organ development, and others may increase the risk for other adverse pregnancy outcomes, including intrauterine growth restriction, preterm birth and intrauterine fetal demise.

This chapter discusses some of the exposures that might increase the risk for abnormal development in human pregnancy. At baseline, each pregnancy has a 2% to 4% probability of a structural anomaly diagnosed at birth. Chemically induced anomalies, including those caused by medication exposure, are thought to occur in fewer than 1% of these cases.

Historical Perspective

In the 19th century, experimental teratology focused on frogs and birds in which, for example, hypoxia could cause developmental aberrations. However, the mammalian uterus was thought to be impervious to external hazards, and genetic abnormalities were blamed for the occurrence of malformations. The notion that human embryos might be harmed by environmental factors was a revolutionary concept until Norman Gregg, an Australian physician, noted in his practice an increase in children with congenital cataracts after a rubella epidemic. He identified what came to be called the ‘congenital rubella syndrome’ with a combination of additional findings, including heart defects, hearing loss, thrombocytopenia and poor growth.

In response to the increased interest in studying birth defects, the Teratology Society was formed in 1960. Shortly thereafter, the field was changed by the unexpected tragedy of thalidomide. Thalidomide, a sedative–hypnotic, given in the usual (medicinal) doses caused fetal malformations in the absence of toxicity to the mother. Since this discovery of what is now called selective embryotoxicity, drug testing regulations have changed. For example, in 1962, the Food, Drug and Cosmetic Act was expanded to include the Kefauver-Harris Amendment, which requires drug manufacturers to provide proof of effectiveness and safety before approval as well as provide information regarding side effects. By 1966, the US Food and Drug Administration (FDA) instituted standard test protocols for drug testing in pregnant laboratory animals.

Mechanisms of Teratogenicity

Experience in experimental teratology led to the development of potential mechanisms for abnormal development, articulated by James Wilson ( Table 4.1 ). Wilson’s mechanisms included the idea that impairment of survival and function in differentiated cells in key locations in an embryo could perturb development. This concept gave rise to the ‘all-or-nothing’ principle in which it was believed that before gastrulation (approximately postconception day 14), cells in the embryo were largely undifferentiated and could substitute for one another, decreasing the ability of an exposure to cause selective malformations without destroying the entire embryo. This all-or-nothing principle has not proved invariable in experimental teratology, but it remains true that it is more difficult to produce malformations with experimental damage to undifferentiated compared with differentiated embryonic tissues.

Mechanisms of congenital malformations more recently have been understood in terms of developmental pathways that might be inhibited by a specific exposure. For example, DiGeorge syndrome, which is often associated with a deletion in the long arm of chromosome 22, includes disruption of Tbx1 , a gene that plays a role in development of cells in the secondary heart field. As a consequence, conotruncal heart defects can be seen in affected children. It has not been identified, however, whether isotretinoin therapy, which also has been associated with conotruncal heart defects, works by way of interference with Tbx1 .

There are basic cell behaviours during embryo development that may serve as targets for exposures. Cell populations in the embryo migrate to targeted locations, and interference with migration may cause abnormal development. Neural crest cells migrate into the branchial arches, for example, and interference results in a group of disorders of the jaw, ears, and zygomatic arch, among other defects. Neurons migrate from their birthplace in the centre of the brain towards the periphery, and inhibition of migration can cause microcephaly. Cells also can induce behaviours in neighbouring cells. The tips of the ureteric buds induce the mesenchyme of the developing kidney to form functioning nephrons. Cells produce substances that act at a distance to modify cell differentiation. For example, cells in the medial (postaxial) limb bud secrete Sonic Hedgehog protein, which diffuses across the limb paddle to help determine the identity of the individual digits.

The greater understanding of cellular and molecular events during embryo development has given rise to an opportunity for understanding mechanisms of abnormal development in more detail. Although the mechanistic details of malformations in human beings associated with exposures are incompletely understood, we expect that developments in the genetic basis of malformations and in cell biology will lead to our improved understanding of exposure-associated malformations.

Underlying Principles

The mechanisms of abnormal development were the basis of one of James Wilson’s principles. The full set of principles is listed in Table 4.2 as developed in the 1950s and 1960s. Of note is Wilson’s fourth principle, which tells us that malformations are not the only kind of developmental toxicity of importance. An exposure that causes an organ, say the brain, not to function correctly can be devastating even if there are no recognisable structural malformations in the child. We commonly call these adverse effects developmental toxicity , which is a more helpful term than teratogenicity in not requiring a definition of what exactly counts as a malformation. An exposure producing nonmalforming developmental effects does not necessarily also produce malformations. Indeed, an exposure that produces one kind of malformation does not of necessity produce any other kind of malformation. Thalidomide, for example, produces only certain kinds of limb defects, not all kinds of limb defects. Effects of developmentally toxic exposures are specific, producing a finite grouping of adverse effects. Dr Wilson captured this idea of specificity in his third principle, and the Public Affairs Committee of the Teratology Society made it explicit in 2005.

Wilson’s sixth principle is among the most important for practitioners because it reminds us that for all medications, other chemicals, and physical agents, there are an exposure level that produces no harm, an exposure level that produces death and a range of exposures in between that produces a gradation of effects. It is not useful to talk about agents (drugs, chemicals, radiations) as teratogenic or nonteratogenic. It is preferable to talk about teratogenic exposures , an exposure including the identity of the agent and the dose level at which it is encountered. X-irradiation during pregnancy was associated with microcephaly and mental retardation when exposure levels were about 50 cGy from the atomic bombings of Japan. Flying across the United States is associated with estimated radiation exposures about 8000 times lower and would not be expected to have the same effects. We do not, therefore, characterise x-ray as teratogenic or nonteratogenic. It depends, among other things, on dose.

How much evidence is needed before it is worthwhile warning patients and health care providers about possible adverse effects of exposures in reproducing men and women? There is some controversy in this area because there are potential adverse effects of excessive warning, namely anxiety, the interruption of otherwise wanted pregnancies, and the discontinuation of important, even essential, medical therapy.

It has been fashionable from time to time to claim that most human teratogenic exposures were first identified by ‘astute clinicians.’ Thalidomide is often cited as evidence of this claim because the first publications on thalidomide birth defects came from one paediatrician in Germany and another in Australia who described clusters of children with phocomelia and wondered whether there was a pregnancy exposure as the cause. The astute clinician model has been described in mathematical terms, but the astute clinician model produces only a hypothesis that must be confirmed by other evidence. The association between rubella and congenital cataracts and between thalidomide and phocomelia were, in fact, doubted by some teratologists until additional evidence was forthcoming. Perhaps clinicians whose hypotheses are confirmed may be as lucky as they are astute.

For a determination of causation in teratology, methods have been advanced that are based on the Hill criteria. These criteria ( Table 4.3 ) were most famously applied in the consideration by the US Surgeon General of the evidence for a causal relationship between cigarette smoking and lung cancer. To entertain a conclusion of causation, you need not satisfy each of the Hill criteria, but the more you satisfy, the more confident you can be that an association is causal.

In this chapter, we discuss some exposures that have been associated with developmental toxicity in human pregnancy. In some instances, there is evidence that the association is causal, but in other cases, a causal association cannot be concluded. We recognise, however, that giving patients advice about exposures during pregnancy does not require conviction that causation criteria have been satisfied. For example, we recommend that women who have taken lithium during pregnancy consider fetal echocardiography, even though causation criteria are not satisfied that lithium causes Ebstein anomaly or any other heart defect. In the end, counselling about exposures relies on the same kinds of judgments about adverse outcomes that we use every day as clinicians considering possible risks and benefits of medication therapy.

Personalised Risk Assessment and Resources

Several excellent books are available as resources. However, soon after publication, books in this ever-changing field have the potential to be outdated. Online databases offer summaries of pregnancy exposures written and frequently updated by teratology experts include TERIS ( http://depts.washington.edu/terisdb/terisweb/index.html ), REPROTOX ( Reprotox.org ), and Briggs (available through http://wolterskluwer.com ). Lactmed ( https://toxnet.nlm.nih.gov/newtoxnet/lactmed.htm ) is a free online resource for medication exposure and lactation.

There are two networks of teratology information services, one in North America called the Organization of Teratology Information Specialists (OTIS; http://www.mothertobaby.org ) and one serving Europe, the European Network of Teratology Information Services (ENTIS; http://www.entis-org.eu ). Both networks are staffed with physicians, genetic counsellors and teratology experts who offer individualised risk assessments and up-to-date information for any drug or environmental exposure during pregnancy and lactation. These complimentary services are available to both health care providers and patients. These networks also conduct prospective studies and patient follow-up after pregnancy exposures.

Pregnancy registries open to enrolment may be located from the FDA’s Office of Women’s Health ( www.fda.gov/ScienceResearch/SpecialTopics/WomensHealthResearch/ucm251314.htm ).

Selected Human Exposures