Teratology Define the term Teratology

Teratology refers to the study of abnormal fetal growth. Teratogenic prenatal exposures arise from: infectious agents, chemical and drug agents, metabolic or maternal causes (such as phenylketonuria and diabetes), and physical agents (such as heat, ionizing radiation, and mechanical factors) (Jelinek, 2005). Inbred abnormalities occur commonly, with 2-3% babies, both live and stillborn, as well as aborted fetuses having structural abnormalities. Furthermore, about 10% of infants have internal functional deficits or anomalies which might not be perceptible at birth, and may only surface later on in life. Congenital abnormalities can be categorized into: (1) Malformations, which denote changes in normal growth transpiring from an inherent development-process abnormality; (2) Deformations, which arise due to an irregular mechanical force upon a fetus which is otherwise normal (e.g., clubfoot in an environment of oligohydramnios); and (3) Disruptions, occurring because of disturbance in normal process of growth (for instance, gastroschisis, considered to be caused by vascular disturbance in the frontal abdominal wall of the fetus) (Adam, Polifka & Friedman, 2011).

1. Describe the Effects of various teratogens during different periods of development

Agent/Drug/Chemical

Risk category

Fetal effects

Fetal risks

Maternal risks

Prescribed or illegal drugs

Ethanol6,8,18-20

D/X

Fetal Alcohol Effects (FAEs): microcephaly, intrauterine growth retardation (IUGR), mental retardation (MR), characteristic facies, dermal, skeletal, joint, Congenital heart disease (CHD)

40% risk

Six drinks per day

Cocaine6,8,18

C/X

IUGR, bowel atresia, cerebral infarction, vascular, heart, facial, limb, genitourinary tract disruption

Death of fetus

Abruption placentae

Toluene6

X

Toluene embryopathy, which is similar to Fetal Alcohol Syndrome

10-100 times inhalation by mother Occupational exposure

Antimicrobial

Tetracycline6,8,18

D

Deciduous teeth discoloration, enamel hypoplasia

Risk during second and third trimesters

Streptomycin

Dm

Rare hearing loss with Protracted exposure in high doses

Risk mainly during second and third trimesters

Fluconazole6,8,21

Cm

Cleft palate, Brachycephaly,

CHD, arthrogryposis

Risk during first trimester

Cocecidiodomycosis treatment, high dose

Trimethoprim-sulam ethoxazole8

Impaired conjugation of bilirubin

Third trimester

Anticancer

Folic Acid

Antagonist6,7,18

Xm

Increased sudden abortion, stillbirth, ectrodactyly, skeletal abnormalities, craniofacial abnormalities, limb reduction deformities, neonatal death, IUGR,

30% risk if exposure is in first trimester (methotrexate) possible increased risk when exposed during first trimester

Methotrexate

X

Aminopterin

Dm

Alkylating agents6,8

Dm

IUGR, cleft palate, microphthalmia, genitourinary anomalies, limb reduction deformities

Busulfan

Dm

Anticonvulsants

Phenytoin

(hydantoin)6,8,18,22

D

MR, microcephaly, IUGR, heart, facial, hypoplastic distalphalanges / nails, increased risk of neuroblastoma

30% exposure effect 10% syndrome

Genetic makeup impacts metabolism.

Carbamazepine6,8,18,22

Dm

Lumbosacral neural tube defect (1%), microcephaly, facial, nail hypoplasia, developmental delay, IUGR,

First trimester exposure

Valproic acid6,8,18,22

Dm

Lumbosacral neural tube defect (1%), likely fetal valproate syndrome

First trimester exposure

Mother's drug metabolismalters risk

Trimethadione6,8,18

D

IUGR, cleft lip plus/minus cleft palate, mental retardation, microcephaly, facial, limb, ophthalmologic, genitourinary

60% to 80% risk by exposure during first trimester

Paramethadione

Dm

Antihypertensive

ACE inhibitors6,8,18,23

(enalapril, captopril, lisinopril)

Cm/Dm

IUGR, oligohydramnios, pulmonary hypoplasia, renal tubular dysplasia, joint contractures (30%), fetal morbidity,

Increased risk by exposure during second and third trimesters

Heavy metals/

Environmental

Lead6,8,18,33

Reduced growth of fetus

Increased risk of spontaneous abortion

Organic

mercury6,8,18

MR, Cerebral atrophy, spasticity, microcephaly, blindness, seizures,

Exposure during any trimester

PCB6

Intrauterine development restriction, retarded development, dermal pigmentation,

Neurotoxicity in mother with grain and fish contamination

Psychiatric

Lithium6,8,18,25

D

Neonatal CHD (Ebstein anomaly), increased neuromuscular and central nervous system (CNS) complications no linked birth defects reported (Paxil: 2% cardiac malformations), small, variable fetal effects, no risk proven

SSRI6,8,18,26-31

Cm

Benefit/Risk with admonitory recommendation

(Paroxetine)

D

Tricyclic

antidepressants8,32

D

Bupropion8,22

Bm

Miscellaneous

Methyl blue6

Cm/D

Intraamniotic exposure linked to probable bowel atresia

Depends on dose

Warfarin6,8,18,37,38

(Coumadin)

D/X

Microtia, cardiac, microphthalmia, nasal hypoplasia, craniofacial, cleft lip plus/minus cleft palate, IUGR, stippledepiphyses, CNS, ophthalmologic, growth retardation

5% to 25% risk by exposure in first trimester

Bacteria6,18,39

Syphilis

Severe: fetal death, hydrops mild: bone, skin, or teeth abnormalities neonatal: rash, rhinitis, pneumonia, thrombocytopenia, liver dysfunction

Early penicillin therapyaverts congenital infection complex diagnosis / therapy

Viral

Rubella6,18,45-47

Deafness, Microcephaly, CHD, MR, cataracts,

Some deficits might not be clear in...

(Adopted from Wilson, 2007)
Figure 1. Schematic Illustration of critical periods in human prenatal development (Adopted from Jelinek, 2005).

3. Describe Principles of teratology

Principle 1: Teratogenesis susceptibility is dependent on conceptus genotype and its environmental interaction. Taking into account known facts regarding the impact of established teratogen exposure, it is evident that two among the most significant teratogen characteristics are: variable phenotype production in infants who are exposed and impacted by them; and variable susceptibility, exposure does not necessarily mean the infant will be affected (Finnell, 1999).

Principle 2: Teratogen susceptibility depends upon the fetal development stage where exposure takes place. A fundamental biological principle is that organisms in the development state are more susceptible to change compared to full-grown, mature organisms. That is, heightened susceptibility continues all through the embryo's development, though the extent of susceptibility may vary (Finnell, 1999; Sadler, 2012).

Principle 3: Teratogens act through specific means on growing tissues and cells, which gives rise to pathogenesis or abnormal embryogenesis. They usually denote the foremost event among a succession of intermediate events transpiring from cause to effect. This first event is probably the most crucial in the series, as it links cause with subsequent physiologic changes as well as (probably) impact these changes' nature (Finnell, 1999).

Principle 4: Abnormal growth eventually manifests in functional disorder, growth delay, death, and malformation. The above likely outcomes of irregular fetal development do not have equal likelihood of occurrence and most likely be linked to exposure timing in relation to embryonic development. Though one or all these results may transpire through exposure to sufficient levels of fetotoxic agents during high sensitivity periods, there is greater likelihood of occurrence of certain manifestations at certain stages of development (Finnell, 1999; Sadler, 2012).

Principle 5: A harmful environmental agent's access to embryonic tissues is dependent on the agent's nature: Every teratogen does not reach the fetus in a similar fashion. Ultrasound, microwaves, x-rays and other such physical agents move unchanged into the mother's uterus and directly access the embryo. On the other hand, ingested agents (like drugs) are first exposed to the mother's metabolism; their fetal access is secondary. Consequently, drugs or chemicals normally reach the developing fetus in smaller concentrations than their original concentration in the mother's body. Whether their concentration in the fetus is sufficient to give rise to problems hinges on several factors (Finnell, 1999)

Principle 6: Abnormal developmental manifestations increase in their level with increase in dosage, from no-effect level to fatal level: Concerning teratogens and their activity, there is a link between dosage and response, just like for medications and curative effect. Considering this principle is imperative, since it ascertains the thresholds for different toxicologic outcomes (Finnell, 1999; Sadler, 2012).

4. Describe hereditary causes of congenital malformations

Hereditary sources of congenital deformities take place through genes; genetics' role in congenital deformities' etiology are; Chromosomal aberrations, Monogenic inheritance, Multifactorial / Polygenic inheritance, and Epigenetics, among others (Jelinek, 2005; Adam et al., 2011).

Monogenic inheritance: There are some congenital deformities acquired as monogenic characteristics. Numerous genes' mutations are linked with particular congenital abnormalities. MIM or Mendelian Inheritance in Man offers references in this regard. It is easier to diagnose and manage genetic counseling in the prenatal stage (Adam et al., 2011).

Polygenic inheritance implies that two or more genes affect the given phenotypic characteristic (anomaly, disease, etc.), whereas multifactorial inheritance implies that genetic as well as environmental agents influence the given trait. In practice, differentiating between the two kinds of inheritance is sometimes hard; the word 'multifactorial' is, thus, often utilized (Adam et al., 2011).

Abnormal gene-clusters carried over generations cause inherited genetic problems such as muscular dystrophy, cystic fibrosis and phenylketonuria. Spontaneous mutations in genes result from DNA replication errors, causing base replacement or base pair deletion/insertion from DNA. The cause of somatic genetic illness is the unexpected appearance of a gene in deviant form somewhere in the body (such as cancer). Finally, chromosomal aberrations bring about chromosomal structure anomalies (e.g., Down's syndrome) (Adam et al., 2011).

5. Describe the Prenatal diagnostic procedures used in identifying congenital anomalies

Prenatal diagnosis can be done through two key types of methods, invasive (Fetoscopy, Amniocentesis, Cordocentesis, Fetal biopsy, Chorionic villus sampling (CVS)), and noninvasive (Magnetic resonance, Biochemical screening (with use of blood sample of the mother), Ultrasound) (Adam et al., 2011; Sadler, 2012).

A common invasive technique is Amniocentesis, capable of obtaining an amniotic fluid sample, including amniocytes. These cells may be grown for cytogenetic examination. QF-PCR can be used for acquiring primary outcomes (for the most common of trisomies) in a span of two days (instead of two weeks, as is required for karyotype and cultivation). It is possible to perform early amniocentesis (i.e., earlier than usual, in the 14th, instead of 16th, week). But sufficient amount of amniotic fluid will not be obtained (Jones, 2005; Sadler, 2012).

CVS may be used quite soon (i.e., after 11 gestational weeks), enabling timely diagnosis. There is, however, confined placental mosaicism (CPM) risk, making the decision harder (Jelinek, 2005).

Often, cordocentesis is used after completion of 20 weeks. The blood sample permits hematologic testing and cultivation. Fetal biopsy and fetoscopy are rarely employed nowadays (Jelinek, 2005; Jones, 2005).

Fetoscopy may be employed for confirming certain dermatologic abnormalities, like Ichtyosis vulgaris. Fetal biopsy may be carried out for obtaining a fetal skin sample (or that of any other tissue), to carry out histopathological investigation (Jelinek, 2005).

Biochemical screenings: Combined 1st trimester screening - combines biochemical maternal serum test (using free beta human chorionic gonadotrophin (hCG) and pregnancy-associated plasma protein A (PAPP-A)) and ultrasound diagnostics (tricuspidal regurgitation, Nuchal Translucency scan, and nasal bone absence / presence). There are some other markers which may be tested during the first trimester. Second trimester biochemical screening --Mother's blood sample is normally taken following completion of 16 weeks. hCG, alfa-fetoprotein (AFP), and unconjugated estriol (uE3) are tested (Shenoy, 2004; Jelinek,…