Which effect would the nurse identify as seen when the fetus is exposed to teratogen during the embryonic period?

Mechanisms of Teratogens in the Causation of Malformations

Teratogens affect morphogenesis, development and differentiation through cell death, failed cell interactions or alterations in the movement of cells. As these affect the basic processes of cells, not only may a teratogen have a general effect on several tissues, but different teratogens may produce common effects. Some teratogens do, however, produce a characteristic pattern of anomaly. For example carbimazole for the treatment of thyrotoxicosis causes choanal atresia, cutis aplasia with distinctive facial features.

All women should be asked about drug exposure both therapeutic and recreational, as well as over-the-counter medications whose availability vary considerably between countries.

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

36.1.5.3 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 her 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 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 (31,32). 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.

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).

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.

Teratogens and Mutagens

The word teratogen has its origins in the Greek terato, meaning “monster.” Teratogens are substances that cause structural abnormalities in the fetus. The drug thalidomide was a powerful example of a teratogen, and its legacy has left an imprint on those who prescribe medications to pregnant women. There is extremely limited knowledge about which herbs are teratogenic. Most of what is known is derived primarily from animal studies, observation of teratogenesis in grazing cattle, and suspected teratogenicity in humans from ingestion of suspected harmful herbal products. Known teratogens include those plants in the Lupinus, Veratrum, Conium, and Solanum genuses; and suspected teratogenic substances can be found in Astragalus, Nicotiana, Ferula, and Trachymene genuses. Plants in the Datura, Prunus, Sorghum, and Senecio genuses may also contain teratogenic substances.26 The primary means for identifying the propensity for this type of reaction is through general toxicologic screenings or through pharmacovigilance programs. Birth defects that occur between conception and birth are caused by teratogenic agents, whereas mutagens cause direct changes in the nucleus of cells.

The potential for mutagenicity is discerned through in vitro assays, most notably Salmonella microsome test (Ames assay) or rodent tests and then followed by animal studies. In both types of tests, isolated compounds rather than complete herbal products are most often investigated. Unfortunately, simple in vitro toxicity screenings do not reveal much useful data as they often can not be extrapolated to human use. The presence of a mutagen in a product does not automatically contraindicate the use of the substance in pregnancy. There are many commonly consumed substances such as basil, black pepper, coffee, tomatoes, and potatoes that contain toxic compounds, including those with mutagenic or teratogenic potential. However, consumption of these in pregnancy is not contraindicated when consumed as a normal part of the diet.

Methods for Teratogenicity Assessment

“Teratogens” refer to toxins that can lead to fetal death or developmental abnormality. The baseline birth defects rate is approximately 6% (Christianson et al., 2006); it is not known if this baseline rate is a normal frequency of errors in the highly complex developmental process or the consequence of any yet to be identified environmental or dietary factors. Major identified teratogenic mechanisms include folate antagonism, neural crest cell disruption, endocrine disruption, oxidative stress, vascular disruption, and specific receptor-mediated or enzyme-mediated teratogenesis (Van et al., 2010). Studies have shown that plant alkaloids like indolizidine (Lather et al., 2011), pyrrolizidine (Prakash et al., 1999), piperidine, triterpene (Gaffield and Keeler, 1994), cyclopamine, veratramine, veratrosine, and germine or their metabolites exert teratogenic effects in animals. Ginsenoside Rb1(triterpenic saponin), extracted from Ginseng (a commonly used botanical), exerts direct teratogenic effects on rat embryos (Chan et al., 2003). However, most dietary supplements including botanicals have never been assessed for their teratogenic potential.

The Organization for Economic Cooperation and Development (OECD, 2015) and the European Centre for the Validation of Alternative Methods (ECVAM, 2015) have largely investigated the validation of teratogenicity tests; the FP6 European project “Reprotect” has investigated possible strategies to cover the entire mammalian reproductive cycle and has published a series of articles (ReproTect, 2015).