Which period of development is the period during which the unborn baby most at risk of developing a structural defect due to a teratogen?

Teratogens

Teratogens are compounds and environmental conditions which interfere with normal in utero development [161]. There is a long list of known human teratogens (Table 23.3). There is an increasing understanding that stress, nutrition, infections, and the microbiome can also play a role in altering gene programming and expression during embryonic and fetal growth. The exact mechanisms and modes of interference with normal development have rarely been worked out, but because of the importance of avoiding teratogens during pregnancy there is some urgency to try to define the pathways and mechanisms. Methylation changes and differences in many different tissues are being observed when they are looked for. One common finding among teratogens is that they cause intrauterine growth restriction. Teratogens are likely to lead to alterations in normal control of gene expression and reprogramming during embryonic and/or fetal development in disorders like fetal alcohol syndrome [162]. There is no doubt that the pathway changes seen in teratogenic effects will be complex and will involve gene regulation.

Table 23.3. Recognized Human Teratogens After Hall [161]

1.

Drugs

ACE inhibitors (angiotensin converting enzyme)

Alcohol

Anticonvulsants

Carbamazepine (carbimazole)

Dilanten, Phenytoin

Phenobarbital

Tegretol

Trimethadione/paramethadione

Valproic acid

Cocaine

Cigarette smoking

Cyclosporin

Efarvirenz

Etretinate

Fluconazole

Heroin/methodone

Isotretinoin (13-cis-retinoic acid)

Lamotrigine

Lithium

LSD (lysergic acid diethylamide)

Methotrexate (aminopterin)

Misoprostol (prostaglandin E1)

Mycophenolate mofetil

Tetracycline

Thalidomide

Warfarin

Metals

Iodine

Lead

Mercury

Radiation

Cancer therapy

Industrial/terrorism exposure

Isotopes—131 Iodine

Maternal Illness Associated With Congenital Anomalies

Alcoholism

Cushing syndrome

Hyperparathyroidism

Hypoparathyroidism

Hyperthyroidism

Hypothyroidism

Iodine deficiency

Insulin-dependent diabetes mellitus

Myasthenia gravis

Obesity, severe

Smoking cigarettes/marijuana

Systemic lupus erythematosus

Uncontrolled maternal phenylketonuria

Intrauterine Infections

Cat litter

Toxoplasmosis

Blood Products

HIV (human immunodeficiency virus)

Hepatitis virus

Malaria

Respiratory

Coxsackievirus

Parvovirus B19

Rubella

Varicella

Venezuelan equine encephalitis

West Nile Virus

Uncooked food products

Listeria

Toxoplasmosis

Venereal

Cytomegalovirus

Herpes virus

HIV (human immunodeficiency virus)

Syphilis

Procedures Related

Assisted reproductive technologies (ARTs)

Chorionic villus sampling (CVS)

Dilation and cutterage (D&C)

Early amniocentesis

Intracytoplasmic sperm injection (ICSI)

Other Exposures/Deficiencies

Deficiencies

Calcium

Folic Acid

Iodine

Iron

Oxygen

Vitamin A

Vitamin D

Vitamin K

Hormones related

Androgens

Carbimazole

Corticosteroids

Diethylstilbestrol (DES)

Endocrine disruptors (plastics, insecticides, etc.)

Iodides

Progestins

Propylthiouracil

Thioureas

Vitamin D

Immunologic

ABO incompatibility (hemolytic disease of the newborn)

Antibodies against fetal neurotransmitters

Engraftment of maternal or twin's cells

Lupus erythematosus

Myasthenia gravis

Pemphigus vulgaris

Platelet alloimmunizaton

Rhesus (Rh) isoimmunisation

Thyroid antibodies

Mechanical forces Percentage of pregnancies

Amnion rupture < 1%

Fibroids 1%

Malformation of uterus 2–4%

Trauma (MVA, domestic, other) 6–7%

Twins 1/32

Vascular compromise which may be related to the uterus, placenta, and/or fetus

Other Potentially Harmful Maternal Exposures

Carbon monoxide poisoning

Gasoline fumes (excessive)

Heat

Hypothermia

Hypoxia

Magnesium sulphate (high levels, third trimester)

Methyl isocyanate

Methylene blue

Phthalates

Polychlorinated biphenyls

Toulene (excessive glue sniffing)

After Hall JG [69].

Environmental Factors and Birth Defects

A teratogen is an environmental agent that can cause abnormalities in an exposed fetus. The effects depend on the nature of the teratogen, the timing at which the exposure occurs and, most likely, the genetic susceptibility of the mother and/or the fetus. Teratogenic agents can be environmental chemicals, maternal metabolic factors, drugs, or infections.

A number of environmental chemicals have been linked with birth defects in exposed fetuses including lead, methyl mercury, and polychlorinated biphenyls. Maternal metabolic factors associated with a significant risk of birth defects are maternal diabetes and maternal phenylketonuria. Excessive alcohol intake in pregnancy has been linked with fetal growth retardation, microcephaly, and cardiac and other malformations. Many prescribed drugs can act as teratogens including some anticonvulsant agents, lithium, androgens, retinoids, and misoprostol.

Introduction

Teratogenic agents may affect development of the embryo and fetus and upon exposure by a pregnant woman can cause birth defects, fetal loss or abnormal growth and development. A teratogenic agent can be a medicinal product or other chemical agent (i.e., alcohol, nicotine), an infectious agent (i.e., rubella, cytomegalovirus), a medical condition (i.e., diabetes), an environmental toxin or genetic disorder. Teratogens cause about 10% of all birth defects (Box 8.1).1 This chapter will primarily focus on drug exposure in pregnancy and assessing risk of congenital malformations; however, other adverse pregnancy outcomes that are of interest to physicians include spontaneous abortions, stillbirths, preterm births, and small for gestational age (SGA) births.

The majority of prescription medications available have not been adequately evaluated to determine risks during pregnancy in humans.2 Preclinical developmental and reproductive toxicity studies in animal species are conducted; however, the results from these studies may not always be predictive of human risk. Thus, upon marketing approval of a medicinal product, human data is often lacking in respect to in utero drug exposure during pregnancy. Upon approval of a new drug, companies may be required to perform enhanced postmarketing surveillance, a pregnancy registry or another well-designed study to assess teratogenic drug effects and other adverse pregnancy outcomes.

ERRORS OF MORPHOGENESIS

Teratogens

Teratogens may be chemical, as in ingested drugs, or environmental, as in infection or irradiation.4 The impact of the insult will depend on gestational age of the pregnancy at the time of the insult and on the mechanism of action of the drug. In general terms, any organ is most vulnerable at the time of highest cell division. For the human fetus, the most vulnerable period is between 5 and 11 weeks’ menstrual age, but different organ systems have their own critical period. For the human brain, this is between 5 and 18 weeks, although it remains sensitive to insult throughout pregnancy. Major structural abnormality is likely to result from an insult prior to 10 weeks, and a functional or minor structural abnormality from later insults.

Environmental teratogens are infection and irradiation. For an infectious agent to cause problems, the mother has to be infected and the fetus affected via the transplacental route. Infection, most commonly viral, can cause microcephaly, eye abnormality (microphthalmia, retinal dysplasia, glaucoma, cataracts), calcification and mental retardation. High-level irradiation causes microcephaly and mental retardation.

Ingested drugs that cause developmental and structural abnormalities of the brain may be prescribed or connected with drug abuse and misuse. The most common drugs with known teratogenetic properties are listed in Table 6.1. These agents can cause multisystem abnormality, but only those relating to the central nervous system are listed. The reader is directed to other more comprehensive texts for more detailed information.

2.1.5.3 Teratogen Risk Counseling

Providing teratogen risk counseling involves more than just identifying and estimating the magnitude of risk. The information must be communicated to the patient in a way that allows the patient to make informed decisions about the management of her pregnancy. The approach varies from patient to patient and depends on many factors, including the patient’s cultural and social background, her understanding of the counselor’s language, her level of general and scientific knowledge, and her commitment to the pregnancy. The uncertainty about possible effects that usually exists complicates teratogen counseling and requires that information be provided as risks, which are difficult for many people to understand. Counselors need to be aware of the information and misinformation patients bring with them to the counseling session and how it affects their perception of risk [29,30]. Finally, the importance most women place on having healthy children and the emotional circumstances that often surround teratogen risk counseling require that the counselor have considerable skill as well as a thorough knowledge of clinical teratology.

B. Teratogens

Teratogens and congenital heart disease require intensive research. The thalidomide effects are well-known, however, there are several drugs that have teratogenic effects and are used occasionally worldwide during the first 16 weeks of pregnancy. Many drugs including alcohol and other unknown substances are used within the first three weeks of pregnancy often before the mother is aware that pregnancy has occurred. Electrical impulses in the developing embryo produce a heart impulse as early as the 22nd day. During the first 28 days the developing fetus may be exposed to alcohol, antidepressants, caffeine, nicotine, and other products that may alter the development of the unique human heart. The study of the embryo heart at weeks 2 through 8 is crucial and more research is needed in this area (see the chapter Embryology).

More than strict animal testing of new and old drugs that may be teratogenic must be done. It is necessary to determine which animals are the best representation of the human fetus. Development of the chick embryo is similar to that of the human embryo and much of our understanding of the heart's early development comes from studies of chick embryo. Perhaps a different model is required to test the effect substances on developmental injury in the human embryo.

Cardiovascular anomalies associated with prenatal exposure to teratogens are given in Table 1. Cardiovascular drugs that are contraindicated particularly during the first 16 weeks of pregnancy include angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers. These agents may adversely affect fetal and neonatal blood pressure control and renal function. They may cause defects and oligohydramnios. These agents are teratogenic in animals and are associated with a high incidence of intrauterine death. They are used in the management of hypertension and are contraindicated in women of childbearing age. Calcium antagonists such as diltiazem, verapamil, nifedipine, amlodipine, and similar dihydropyridines must also be avoided.

TABLE 1. Cardiovascular Defects Associated with Prenatal Exposure to Teratogens

CHD = congenital heart defect(s); VSD = ventricular septal defect; TOF = tetralogy of Fallot; ASD = atrial septal defect; ECD = endocardial cushion defect; PS = valvular pulmonic stenosis; TGA = transposition of great arteries; IAA = interrupted aortic arch; PPS = peripheral pulmonic stenosis; PDA = patent ductus arteriosus; AS = aortic stenosis; CoA = coarctation of aorta; HLH = hypoplastic left heart.

Critical or Sensitive Periods of Cell Growth

Teratogens, infections, and nutrient deficiency have different effects on the growth and function of organs, depending on growth speed. That is, during the growth process there are critical or sensitive periods which are characterized by an increase of vulnerability to a specific stimulus. This phenomenon occurs along periods of maximum cell proliferation (cell hyperplasia), mainly in the fetal period and the first year of life, and in puberty, to a lesser extent.

In line with this is the ‘programming phenomenon.’ Poor nutrition and other adverse biological and environmental influences in the critical periods of fetal development and the first year of life may cause permanent changes in gene expression, cell replication, organic function and structure, hormone action and secretion, and growth factors. These factors, apart from affecting growth and body composition, will also favor the development of degenerative diseases such as cardiovascular disorders, high blood pressure, diabetes or hyperlipidemia (X-syndrome) during adulthood, and these diseases are nowadays the main cause of morbid mortality. Fetal growth is a significant predicting factor for postnatal growth and adult size (Figure 2).

Case Reports

Many known teratogens and reproductive toxicants were identified initially through case reports of an unusual number of cases or a constellation of abnormalities. These have often come from astute clinicians who observed something out of the ordinary. Although the importance of astute observations of abnormal aggregations of cases or patterns of malformations must be recognized, we cannot rely on such methods for identifying health hazards. Furthermore, etiologic speculations based on case reports or case series usually do not lead to a causal agent and are often false-positive speculations. Whereas case reports may identify a new teratogen, they can never provide an estimate of the risk of disease after exposure.

Teratogens

A teratogen is an agent that may cause embryonic or fetal malformations. While identification of maternal teratogen exposure before or during pregnancy would be ideal, this is not always possible and infant testing is necessary. Currently, there are no federally mandated guidelines on infant teratogen and drug-exposure testing. The decision rests with the doctor and hospital. Teratogen levels are easily detected in the newborn period by blood, urine, meconium, or hair testing.

The use of illicit drugs (marijuana, cocaine, amphetamines, heroin, methadone, lysergic acid diethylamide (LSD), opioids, among others) and licit drugs (nicotine, alcohol, caffeine) during pregnancy may influence maternal and infant outcomes. Prenatal drug exposure has been associated with placental abruption, premature labor, microcephaly, congenital anomalies including cardiac and genito-urinary abnormalities, necrotizing enterocolitis, cognitive disabilities, and central nervous system stroke and hemorrhage. Withdrawal symptoms, such as sweating, irritability, hypertonia, jitteriness, diarrhea, and seizures are often seen in infants after in utero exposure to drugs. The 2004 National Survey on Drug Use and Health, based solely on self-report of randomly sampled pregnant American women, estimated that 4.6% used illicit drugs during pregnancy. When a child is found to have been exposed to drugs in utero, healthcare providers are often required to notify social services for a discharge placement decision and family court determination of custody. However separation of mother and child in the newborn period has lasting implications for the mother–infant relationship and long-term development.

Lead exposure is an additional potent neurotoxin with primary effects on the nervous, hematopoietic, and renal systems. Lead inhibits enzymes in many biochemical pathways; high levels of lead exposure are associated with poor attention, aggression, lowered cognitive abilities, somatic complaints, antisocial behaviors, seizures, coma, and death. Adverse neurodevelopmental sequelae associated with even mildly elevated levels include reduction in auditory threshold, abnormal balance, poor eye-hand coordination, slowed reaction times, sleep disturbances, and impaired cognition.

Lead is readily transmitted through the placenta from the mother to the fetus. Maternal exposure to high environmental lead levels may be associated with spontaneous abortion, premature rupture of membranes (PROM), and preterm delivery. Children absorb lead more readily than adults; children’s developing nervous systems are more susceptible to the toxic effects of lead. Even with treatment, it remains unclear to what extent the effects of lead exposure are reversible.

Currently, the primary sources of lead exposure are deteriorated lead paint, and the soil and dust it contaminates. The AAP recommends blood lead screening as part of routine health supervision for children between 9 to 12 months of age and re-screening at 24 months. It also recommends that children, pregnant women, and families be screened routinely by healthcare providers with community-specific risk-assessment questionnaires, which evaluate chances for lead exposure.

An estimated 890 000 children aged 1–5 years, or 4.4% of the US population in that age range, have elevated blood lead levels. Successful prenatal identification of lead-exposed women would allow for removal of lead, and a lead-free environment for newborns. Once exposed, treatment includes nutritional interventions (iron and calcium supplementation), a reduced-fat diet, and frequent meals. Use of chelating agents, which competitively bind lead and remove it from the body, may be necessary. Timely intervention prevents progression and improves outcome.