**1. Introduction**

In utero exposure to teratogenic agents and infection are the two most important causes of nongenetic, acquired anomalies presenting at birth. The fetal response and susceptibility to such agents are variable, and the effects depend on the type, timing, and duration of intrauterine exposure [1, 2] (**Figure 1**). The end results of such exposures may be organ system malformations; aberrations in organ growth, function, and development; and even death. The developmental stage of organogenesis, which is characterized by rapid cellular differentiation and migration, is the most vulnerable period, as the actively dividing cells are highly sensitive to the adverse effects of noxious agents [3]. The effects of teratogens during the preimplantation embryonic phase of the first two postconceptional weeks might present as all or none, as the uterine implantation of a defective embryo may fail and the pregnancy end with undetected abortion, thus nullifying the possibility of congenital malformations [4, 5] (**Figure 1**).

**Figure 1.** *Sensitivity to teratogens during pregnancy.*

Congenital anomalies are health problems that are difficult to rehabilitate. They generate high treatment costs and might bring on huge financial and moral burdens to the family and society. According to the congenital anomalies survey conducted by the World Health Organization (WHO) in 193 countries in 2010, 270,000 of the 3.1 million newborn deaths were caused by congenital anomalies [6]. In the United States, 2–3% cases of the 3–5% of children born with birth defects are attributed to environmental or iatrogenic teratogen exposure during the intrauterine (IU) life [7]. Most of the teratogen-induced anomalies are preventable.

#### **2. Teratogenic agents**

Teratogens may cause significant congenital anomalies if encountered during the organogenesis period of 3–8 weeks of fetal life, which is the stage of tissue and organ formations (**Figure 1**). Minor morphological and functional disorders may occur with exposure during the fetal period of the first 2 weeks [8]. Multiple factors come into play for the teratogens to impart their effects. These are the genetic specifications of the conceptus, the dose and duration of exposure, and the mechanism of action of the offending agent. Teratogens effectuate primarily by disrupting cell-specific biochemical metabolism and by compromising blood circulation which lead to cell death. They can destroy and deplete essential nutrients, block enzyme activities, disrupt mitosis, interfere with nucleic acid functions, and derange membrane functions, osmolar balance, and energy production [9, 10]. Genetic differences in response to teratogens have been documented and may be due to the presence of genetic polymorphisms in the activities of enzymes involved in the excretion of toxic substances [11]. Animal studies have shown differences in the susceptibility to teratogen-induced damage within the same as well as between different species. Fetal hydantoin syndrome is detected in 5% of embryos exposed to phenytoin (PTN), and about 30% of them show some congenital anomalies, while more than half display no teratogenic effects [12]. Aspirin, corticosteroids,

**17**

**Table 1.**

*The Pathogenesis of Congenital Anomalies: Roles of Teratogens and Infections*

and some vitamins are teratogenic in mice and rats, but not in humans. Cleft palate

Drugs can directly affect the product of conception and cause malformation and/or embryo-fetal demise. They can impair the fetal development by compromising the transplacental transfer of nutrients and oxygen from the mother. They may diminish fetal blood supply and initiate premature myometrial contractions resulting in premature birth [14]. Drugs can play roles in the intrauterine development of gene-encoding proteins, thereby altering transcription regulation signals which adversely affect embryogenesis [15]. Drugs can exert their effects at different stages of cell development, namely, replication, proliferation, gene expression, signal transduction, programmed cell death, and cell migration (**Table 1**) [16, 17].

Although the exact pathogenesis of phenytoin (PTN) embryo toxicity is unclear, some possible mechanisms have been proposed [18]. Phenytoin acts as a membrane stabilizer by inhibiting sodium (Na) and calcium (Ca) channels, as a result of which free radicals are released and cause endothelial damage, myocardial depression, bradycardia, and consequently fetal hypoxia. Phenytoin induces cytochrome P450 activation which results in the release of teratogenic free radicals, sourced via the metabolism of epoxides, folate, and vitamin K in the liver [19, 20]. Phenytoin, like other antiepileptic agents, namely, valproic acid (VPA) and vigabatrin, induces

Fetal hydantoin syndrome, facial cleft,

Nasal hypoplasia, limb hypoplasia, optic atrophy, bone abnormalities, neurological

and structural brain abnormalities

Neural tube defect, cleft palate, atrial septal defect, hypospadias, polydactyly,

Skeletal and ocular defects, cleft palate

Craniofacial abnormalities, neonatal renal

CNS, limb, and skeletal defects

failure, pulmonary hypoplasia

Cleft lift and palate abnormalities

cognitive impairment

Ebstein's anomaly

impairment

craniosynostosis

**Drug Most susceptible period Effects**

(18–60 days)

(18–60 days)

(18–60 days)

(18–60 days)

(18–60 days)

(18–60 days)

(13th week term)

Lithium First trimester Ebstein's anomaly

trimester (6–9 weeks)

Amphetamines All trimester Cleft palate, heart defects, intestinal atresias,

Phenytoin Organogenesis

Lithium Organogenesis

Sodium valproate Organogenesis

Cyclophosphamide Organogenesis

Aminopterin Organogenesis

Benzodiazepines Organogenesis

*Some teratogenic drugs and their effects.*

ACE inhibitors Second. or third trimester

Warfarin Second part of the first

and cleft lip are more common in mice with consanguineous matings [13].

*DOI: http://dx.doi.org/10.5772/intechopen.92580*

**2.1 Drugs**

*2.1.1 Phenytoin*

and some vitamins are teratogenic in mice and rats, but not in humans. Cleft palate and cleft lip are more common in mice with consanguineous matings [13].
