*2.1.1 Phenytoin*

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


#### **Table 1.**

*Some teratogenic drugs and their effects.*

carnitine deficiency in the fetus which may lead to cardiomyopathies and ventricular septum defects [21]. Infants born to women with mutations in the methylenetetrahydrofolate reductase (MTHFR) gene are at an increased risk for fetal hydantoin syndrome as its protein products compromise the metabolism of phenytoin and/ or its metabolites. Free radicals released as intermediate metabolites of phenytoin bind to deoxyribonucleic acid (DNA), proteins, and lipids and adversely affect the neurodevelopment. The wide variation in the presentation of anomalies related to PTN may be due to the genetic differences in the formation of free radicals, drug clearance, and repair mechanism. Fetal hydantoin syndrome can be seen in approximately 5–10% of infants with in utero exposure to phenytoin, whereas incomplete clinical syndrome can be seen in about one third of them [22]. The characteristic features of fetal hydantoin syndrome include microcephaly, craniofacial anomalies, hypertelorism, flattened nasal root, ptosis, wide mouth, cleft palate-lip, cardiac defects, urogenital malformations, and hypoplastic distal phalanx and nails. There is also an increased risk of neural tube defects (NTD) as this antiepileptic reduces fetal serum folate levels [23].

#### *2.1.2 Valproic acid*

Depending upon the dose and duration, the in utero exposure to VPA may increase the incidence of congenital malformations in neonates by 2–16 times [24]. The teratogenic effects of VPA on the fetus are typically caused by maternal ingestion of drug in doses over 1000 mg/day. However, adverse effects can be seen at lower doses of 500 mg/day as well. In one study, the rate of major congenital malformations with fetal exposure to VPA via maternal medication in the doses of <700 mg/day for 1 year was 6%, which increased to 10% when the doses were between 700 and 1500 mg and to 24% when over 1500 mg [25].

Like PTN the exact mechanism of action of VPA is unknown and various theories have been forwarded. Crudup et al. showed that VPA can increase γ-aminobutyric acid (GABA) levels in the brain via the inhibition of its catabolism [26]. VPA can directly inhibit voltage-gated sodium channels or bind to the proteins by acting as a histone deacetylase inhibitor (HDACi). HDACi can disrupt cell cycle, stop growth, and induce apoptosis [27, 28]. Furthermore, VPA induces chromatin changes and reduces the transcription of mRNA by converting chromatin segments to heterochromatin. The high affinity of valproic acid to folate receptors causes their competitive inhibition and increases the frequency of neural tube defects by as much as 20 times [29].

Valproic acid may cause multi-organ system anomalies, including those of craniofacies (epicanthal fold, small wide nose, anteverted nostril, long philtrum, thin upper-thick lower lip, retroverted ears), extremities (polydactyly, arachnodactyly, rudimentary fingers), and spinal column (neural tube defects, spina bifida). Other important defects include those of cardiovascular (ventricular septal defect (VSD), patent ductus arteriosus (PDA), aortic coarctation), respiratory (tracheomalacia), and urogenital systems (inguinal hernia, hypospadias, cryptorchidism, incomplete fusion of the Müllerian duct). The incidence of meningomyelocele, especially lumbar or lumbosacral, is reported to be 1–2% with in utero fetal exposure during the first trimester [30, 31]. Developmental anomalies and autism are other teratogenic effects of VPA described in the literature.

#### *2.1.3 Thalidomide*

Thalidomide (TD), which is currently being used for the treatment of multiple myeloma and leprosy, was initially prescribed for pregnancy-associated nausea and

**19**

**Figure 2.**

*Phocomelia and amelia.*

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

emesis in Europe, Asia, and America, without any preceding drug phase studies in the 1950s. Its teratogenic effects were first noticed in Europe in the early 1960s [32] when several case reports of phocomelia in babies born to mothers treated with TD during pregnancy were published. This revelation became a turning point in the history of pharmacovigilance. In November 1961, Lenz presented the specific features including limb anomalies in 52 in utero exposed infants to TD at a Pediatric Congress. This was followed by a publication documenting an association between the drug and congenital malformations in 1962 [33] (**Figure 2**). Subsequently, 115 case reports of similarly affected infants in Germany, Belgium, Sweden, and the UK were published, and the drug was withdrawn from the market [34]. Thalidomide affected about 10,000–15,000 infants and caused death in more than half of them

The incidence of congenital malformations is 50% if 50 mg of TD is ingested during the postfertilization days of 20–36 [35]. If given earlier it may cause miscarriages as demonstrated in rats. More than 30 scientific theories for thalidomide embryopathy have been forwarded over the past 50 years [36]. DNA mutagenesis, chondrogenesis, nerve/neural crest toxicity, and inhibition of cell adhesion molecules have been proposed as the potential mechanisms of thalidomide embryopathy. However, the most widely accepted theory is that of the antiangiogenic action of the drug on fetus [37]. D'Amato et al. showed that thalidomide inhibits angiogenic vascularization of the rodent cornea induced by a fibroblast growth factor protein. It is believed that thalidomide exerts its teratogenic effects by adversely affecting the embryonic blood vessels, which results in the disruption of vascularization during organogenesis leading to abnormal fetal growth and congenital malformations [38, 39]. The congenital anomalies caused by thalidomide are phocomelia, dementia, dysosmia, bone hypoplasia, cardiac malformations, ear malformations, splenic agenesis, gallbladder agenesis, and esophageal, duodenal, and anal atresia as

There has been a rapid progress in the awareness of adverse effects of a wide variety of environmental, medical, infectious, and nutritional toxins on the developing fetus since the end of the twentieth century. With the expanding scientific knowledge and clinical experience about the association of these toxins with significant, at times crippling, congenital anomalies, the avoidance of exposure to pregnant mothers has become the most important part of their prevention and management. The congenital malformations associated with exposure to the current known toxins

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

during this period.

well as stenosis [40].

**2.2 Toxins**

#### *The Pathogenesis of Congenital Anomalies: Roles of Teratogens and Infections DOI: http://dx.doi.org/10.5772/intechopen.92580*

emesis in Europe, Asia, and America, without any preceding drug phase studies in the 1950s. Its teratogenic effects were first noticed in Europe in the early 1960s [32] when several case reports of phocomelia in babies born to mothers treated with TD during pregnancy were published. This revelation became a turning point in the history of pharmacovigilance. In November 1961, Lenz presented the specific features including limb anomalies in 52 in utero exposed infants to TD at a Pediatric Congress. This was followed by a publication documenting an association between the drug and congenital malformations in 1962 [33] (**Figure 2**). Subsequently, 115 case reports of similarly affected infants in Germany, Belgium, Sweden, and the UK were published, and the drug was withdrawn from the market [34]. Thalidomide affected about 10,000–15,000 infants and caused death in more than half of them during this period.

The incidence of congenital malformations is 50% if 50 mg of TD is ingested during the postfertilization days of 20–36 [35]. If given earlier it may cause miscarriages as demonstrated in rats. More than 30 scientific theories for thalidomide embryopathy have been forwarded over the past 50 years [36]. DNA mutagenesis, chondrogenesis, nerve/neural crest toxicity, and inhibition of cell adhesion molecules have been proposed as the potential mechanisms of thalidomide embryopathy. However, the most widely accepted theory is that of the antiangiogenic action of the drug on fetus [37]. D'Amato et al. showed that thalidomide inhibits angiogenic vascularization of the rodent cornea induced by a fibroblast growth factor protein. It is believed that thalidomide exerts its teratogenic effects by adversely affecting the embryonic blood vessels, which results in the disruption of vascularization during organogenesis leading to abnormal fetal growth and congenital malformations [38, 39]. The congenital anomalies caused by thalidomide are phocomelia, dementia, dysosmia, bone hypoplasia, cardiac malformations, ear malformations, splenic agenesis, gallbladder agenesis, and esophageal, duodenal, and anal atresia as well as stenosis [40].

## **2.2 Toxins**

*Congenital Anomalies in Newborn Infants - Clinical and Etiopathological Perspectives*

fetal serum folate levels [23].

*2.1.2 Valproic acid*

much as 20 times [29].

*2.1.3 Thalidomide*

effects of VPA described in the literature.

carnitine deficiency in the fetus which may lead to cardiomyopathies and ventricular septum defects [21]. Infants born to women with mutations in the methylenetetrahydrofolate reductase (MTHFR) gene are at an increased risk for fetal hydantoin syndrome as its protein products compromise the metabolism of phenytoin and/ or its metabolites. Free radicals released as intermediate metabolites of phenytoin bind to deoxyribonucleic acid (DNA), proteins, and lipids and adversely affect the neurodevelopment. The wide variation in the presentation of anomalies related to PTN may be due to the genetic differences in the formation of free radicals, drug clearance, and repair mechanism. Fetal hydantoin syndrome can be seen in approximately 5–10% of infants with in utero exposure to phenytoin, whereas incomplete clinical syndrome can be seen in about one third of them [22]. The characteristic features of fetal hydantoin syndrome include microcephaly, craniofacial anomalies, hypertelorism, flattened nasal root, ptosis, wide mouth, cleft palate-lip, cardiac defects, urogenital malformations, and hypoplastic distal phalanx and nails. There is also an increased risk of neural tube defects (NTD) as this antiepileptic reduces

Depending upon the dose and duration, the in utero exposure to VPA may increase the incidence of congenital malformations in neonates by 2–16 times [24]. The teratogenic effects of VPA on the fetus are typically caused by maternal ingestion of drug in doses over 1000 mg/day. However, adverse effects can be seen at lower doses of 500 mg/day as well. In one study, the rate of major congenital malformations with fetal exposure to VPA via maternal medication in the doses of <700 mg/day for 1 year was 6%, which increased to 10% when the doses were

Like PTN the exact mechanism of action of VPA is unknown and various theories have been forwarded. Crudup et al. showed that VPA can increase

γ-aminobutyric acid (GABA) levels in the brain via the inhibition of its catabolism [26]. VPA can directly inhibit voltage-gated sodium channels or bind to the proteins by acting as a histone deacetylase inhibitor (HDACi). HDACi can disrupt cell cycle, stop growth, and induce apoptosis [27, 28]. Furthermore, VPA induces chromatin changes and reduces the transcription of mRNA by converting chromatin segments to heterochromatin. The high affinity of valproic acid to folate receptors causes their competitive inhibition and increases the frequency of neural tube defects by as

Valproic acid may cause multi-organ system anomalies, including those of craniofacies (epicanthal fold, small wide nose, anteverted nostril, long philtrum, thin upper-thick lower lip, retroverted ears), extremities (polydactyly, arachnodactyly, rudimentary fingers), and spinal column (neural tube defects, spina bifida). Other important defects include those of cardiovascular (ventricular septal defect (VSD), patent ductus arteriosus (PDA), aortic coarctation), respiratory (tracheomalacia), and urogenital systems (inguinal hernia, hypospadias, cryptorchidism, incomplete fusion of the Müllerian duct). The incidence of meningomyelocele, especially lumbar or lumbosacral, is reported to be 1–2% with in utero fetal exposure during the first trimester [30, 31]. Developmental anomalies and autism are other teratogenic

Thalidomide (TD), which is currently being used for the treatment of multiple myeloma and leprosy, was initially prescribed for pregnancy-associated nausea and

between 700 and 1500 mg and to 24% when over 1500 mg [25].

**18**

There has been a rapid progress in the awareness of adverse effects of a wide variety of environmental, medical, infectious, and nutritional toxins on the developing fetus since the end of the twentieth century. With the expanding scientific knowledge and clinical experience about the association of these toxins with significant, at times crippling, congenital anomalies, the avoidance of exposure to pregnant mothers has become the most important part of their prevention and management. The congenital malformations associated with exposure to the current known toxins

**Figure 2.** *Phocomelia and amelia.*

are deafness, visual impairment, skeletal anomalies, and central nervous system (CNS) malformations, apart from embryonic loss and fetal demise [41].

#### *2.2.1 Radiation*

Radiation is a highly teratogenic toxic agent which exerts its adverse effects at cellular, subcellular, and molecular levels. It disrupts the molecular structure by both direct and indirect actions. No cell is known to be completely resistant to the toxicity of radiation. The risks are highest during the organogenesis phase [42], and the most vulnerable part of the cells to radiation injury is the highly active nucleus. The radiation-induced damage to the DNA may result in cell death, genetic mutations, and malformations, the severity and extent depending on the radiation dose and the stage of cell development at the time of exposure. Chromosomal anomalies are observed in cells when they are exposed to radiation during mitosis and DNA molecule formation [43, 44]. Cellular interruption and suppression of cell growth are the most common manifestations of radiation exposure during mitosis. Bergonie and Tribondeau (1906) documented that the most sensitive cells to radiation are the ones that are un- or underdifferentiated with undetermined function and morphology and are undergoing the highest mitotic activity [45]. The effects of radiation exposure during the first 14 days after fertilization are abnormal or failed embryo implantation resulting in miscarriage.

The dose is an important determinant of the radiation toxicity, and, accordingly, all pregnancies may not suffer from adverse effects [46]. As per the International Commission on Radiation Protection (ICRP), the chances of adverse or lethal effects in the preimplantation period of embryonic development are very low if the dose is less than 100 milliSieverts (mSv), and the actual threshold dose for the production of malformations is around 100 mSv [47]. The embryo is most susceptible to radiation-induced congenital malformations during the postconceptional ninth day and sixth weeks, the phase of organogenesis. Cerebral structural and functional anomalies such as microcephaly and mental retardation occur following exposure to doses over 100 mSv during the 8–16 weeks of intrauterine life, whereas ocular and skeletal abnormalities result with doses exceeding 200 mSv. After the sixth week of pregnancy and when the major part of organogenesis is competed, radiation causes neurodevelopmental delays. It is stated that the therapeutic risks of radiation are minimal in doses less than 50 mSv (**Table 2**) [48]. These dose-effect relationships were demonstrated in animal experiments. In humans, microcephaly and mental retardation were the most common anomalies identified in children exposed to radiation during early conception in Hiroshima and Nagasaki survivors


**21**

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

after World War II. Other anomalies noted were low birth weight, cataract, genital and skeletal malformations, and microphthalmos [49]. Streffer et al. suggested that after organogenesis, the effects of exposure may be similar to the postnatal effects with no major congenital anomalies encountered. They reiterated that the mammalian embryo and fetus are highly radiosensitive and the nature and sensitivity of induced biological effects depend upon the dose and developmental stage at

Alcohol is an important teratogen with multisystemic adverse effects. No amount of consumption is safe during pregnancy. In the USA, one "standard" drink contains approximately 14 g of pure alcohol. This translates to 12 ounces of regular beer (5% alcohol), 5 ounces of wine (12% alcohol), and about 1.5 ounces of distilled spirits (40% alcohol). The 2016 National Institute on Alcohol Abuse and Alcoholism has defined prenatal alcohol exposure as follows: ≥6 drinks per week for ≥2 weeks or ≥3 drinks per occasion on ≥2 occasions, started at 3 months before pregnancy, or at diagnosis, and continued until delivery [51]. The fetus eliminates alcohol poorly at a rate of only 3–4% of the maternal rate. Moreover, part of the alcohol excreted via the fetal urine into the amniotic fluid is swallowed back, thus recirculating it into the system, and a small volume of amniotic fluid alcohol is absorbed into fetal compartments via a transmembranous route. These factors make fetus specifically more vulnerable to the adverse effects of maternal alcohol

As with other teratogenic agents, the effects of alcohol in the fetus vary accord-

ing to the gestational age and the duration and dose of exposure [53]. Alcohol damages the structure, neuronal migration, and synaptogenesis in the developing CNS of the fetus. The consumption of two glasses of alcohol per day during pregnancy, especially the first 3 months, leads to the typical fetal alcohol spectrum disorder (FASD), which is characterized by structural, behavioral, emotional, and neurological problems in the offsprings [54]. The typical features of this syndrome are the minor facial anomalies, including short palpebral fissure, thinner upper lip, and flat philtrum. Significant pre- and postnatal growth retardation is a common feature, along with variable mental retardation which may manifest as a decrease in intelligence quotient, difficulties in perception, and delays in certain skillsseeking tasks (**Figure 3** and **Table 3**) [55, 56]. FASD may present with congenital cardiac defects as well, the most common being ventricular septal defect, atrial septal defect, conotruncal anomaly, and tetralogy of Fallot. The risk of conotruncal anomaly increases as per the amount of alcohol consumed during the periconcep-

Cigarette smoking during pregnancy remains a major worldwide problem despite a significant decrease in incidence as a result of an increasing awareness of its adverse fetal effects. It is estimated that around 10–24% of women smoke while pregnant [58]. Fetal exposure to nicotine negatively affects its growth and increases the risk of neonatal and infant mortality and morbidity [59]. Nicotine and carbon monoxide (CO) decrease the placental blood flow via the vasoconstrictive effects of catecholamines, which are released from adrenals by nicotine activation. Nicotine promptly crosses the placental barrier and reaches its maximum activity in the fetus within 30 min of exposure. The concentration of nicotine in the amniotic fluid is demonstrated to be six times higher at 88% compared to 15%

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

irradiation [50].

consumption [52].

tional period [57].

*2.2.3 Smoking and secondhand smoking*

*2.2.2 Alcohol*

**Table 2.**

*Effects of radiation doses according to the gestational age.*

after World War II. Other anomalies noted were low birth weight, cataract, genital and skeletal malformations, and microphthalmos [49]. Streffer et al. suggested that after organogenesis, the effects of exposure may be similar to the postnatal effects with no major congenital anomalies encountered. They reiterated that the mammalian embryo and fetus are highly radiosensitive and the nature and sensitivity of induced biological effects depend upon the dose and developmental stage at irradiation [50].
