*2.2.2 Alcohol*

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

(CNS) malformations, apart from embryonic loss and fetal demise [41].

embryo implantation resulting in miscarriage.

*2.2.1 Radiation*

are deafness, visual impairment, skeletal anomalies, and central nervous system

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

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

**Gestational period (weeks) Effects Estimated dose amount** Preimplantation (0–2) Miscarriage or is not affected 50–100 mSv

genital, or eye)

8–15 Severe mental retardation (high risk) 60–130 mSv 8–15 Intellectual influence Reduction of 25 intelligence

8–15 Microcephaly 200 mSv 16–25 Severe mental retardation (mild) 250–280 mSv

200 mSv

coefficients per Sv

Organogenesis (2–8) Congenital anomaly (skeletal system,

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

**20**

**Table 2.**

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 consumption [52].

As with other teratogenic agents, the effects of alcohol in the fetus vary according 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 periconceptional period [57].

### *2.2.3 Smoking and secondhand smoking*

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%

#### **Figure 3.**

*Fetal alcohol syndrome (© 2009 University of Washington. With permission, Susan Astley, PhD).*

1.Fetal alcohol syndrome (FAS) (all conditions will be met)

	- i. Short palpebral fissure (≤10th percentile)
	- ii. Thin upper lip (score 4 or 5 in the lip/philtrum guide)
	- iii. Straight philtrum (score 4 or 5 in the lip/philtrum guide)
	- i. Structural abnormalities in the brain
	- ii. Head circumference ≤ 10th percentile

#### **Table 3.**

*Fetal alcohol spectrum disorders.*

in the mother's blood. Nicotine acts on the brain by binding to nicotinic acetylcholine receptors (nAChRs) in autonomic ganglia and at neuromuscular junction. The binding results in the release of neurotransmitters and important neuromodulators, such as dopamine, adrenaline, acetylcholine, Seratonin (5- hydroxytryptamine), GABA, glutamate, and substance P [60].

Both nicotine and carbon monoxide induce degenerative changes and premature aging in the placenta. The degenerative changes are marked by an increased amount of collagen in the chorionic villi and the thickening of subtrophoblastic basement membrane [61]. Premature aging is suggested by the increase in the syncope buds and apoptosis in the placentas. Both premature aging and degenerative changes significantly reduce the placental functional capacity and lead to multiple adverse fetal effects. The incidence of premature births is significantly higher in mothers who

**23**

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

smoke [62]. The results of a recent meta-analysis by Hackshaw et al. demonstrated that maternal smoking increases the risks for a variety of system malformations, including those of cardiovascular (cardiac septal defects, malformations of pulmonary and tricuspid valves, and malformations of the great arteries), musculoskeletal (limb reduction, clubfoot), craniofacial (craniosynostosis, cleft lip and palate),

**2.3 Adverse maternal conditions: nutritional deficiencies, diseases, and** 

Nutrients taken during pregnancy can have significant and lasting effects on maternal and newborn health. Inadequate or excessive intake of nutrients if associated with consequent pathophysiological changes during pregnancy can bring about epigenetic changes in the fetus with adverse short- and long-term implications. Optimum intakes of energy and nutrients during pregnancy as well as during breastfeeding are essential for the initiation and maintenance of a healthy life during childhood. It may also protect against several adulthood

Zinc is essential for normal fetal growth and development. It is a component of

It has been shown that maternal zinc deficiency can affect embryonic protein and DNA synthesis and cause chromosomal damage characterized by terminal deletion [66]. Maternal zinc deficiency is associated with increased apoptosis in the embryonic cells. TUNEL analysis has shown that cell death is increased in the peri-implantation embryos if the cultured cells have low zinc levels [67]. The cell cycle may not be adversely affected if the maternal zinc deficiency is short term [68]. In zinc deficiency, the formation of free radicals is increased as they cannot bind to the membranes and intracellular regions of redox-active metals, such as copper and iron [69], which results in increased oxidative stress and teratogenicity. Zinc can prevent oxidation of numerous proteins, including zinc finger transcription factors of redox-sensitive cysteine and sulfhydryl groups. Zinc is a component of copper-zinc superoxide dismutase and is the regulator of metallothionein, a metal-binding protein which has important roles in the execution of various physiological processes and in the prevention of stress [70]. Metallothionein releases zinc, which plays a central role in the antioxidant defense system during oxidative stress. Inadequate zinc uptake of the mother leads to a decrease in the circulating zinc levels which may adversely affect the neural tube development of the fetus as demonstrated in both animals and humans. In humans, the risk of neural tube defects is found to be increased in women with acrodermatitis enteropathica, a rare genetic disorder of zinc metabolism. It is noted that the prevalence of neural tube defects is higher in Africa and the Middle East, where zinc intake is chronically low due to ecological reasons [70, 71]. The relationship between zinc deficiency and cleft palate and lip was demonstrated in a study which showed the zinc levels in the blood of such infants and their moth-

over 200 enzymes which take part in the formation and release of various proteins, hormones, and neuropeptides. The element is involved in the transcription process in which a gene's DNA sequence is copied to make an RNA molecule. Zinc is required for proper cell division, growth, and differentiation. Severe zinc deficiency is embryotoxic and teratogenous and may cause lethal fetal developmental

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

and gastrointestinal (gastroschisis) [63].

**infections**

diseases [9, 64].

and structural anomalies [65].

ers to be significantly low [72].

*2.3.1 Zinc*

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

smoke [62]. The results of a recent meta-analysis by Hackshaw et al. demonstrated that maternal smoking increases the risks for a variety of system malformations, including those of cardiovascular (cardiac septal defects, malformations of pulmonary and tricuspid valves, and malformations of the great arteries), musculoskeletal (limb reduction, clubfoot), craniofacial (craniosynostosis, cleft lip and palate), and gastrointestinal (gastroschisis) [63].

### **2.3 Adverse maternal conditions: nutritional deficiencies, diseases, and infections**

Nutrients taken during pregnancy can have significant and lasting effects on maternal and newborn health. Inadequate or excessive intake of nutrients if associated with consequent pathophysiological changes during pregnancy can bring about epigenetic changes in the fetus with adverse short- and long-term implications. Optimum intakes of energy and nutrients during pregnancy as well as during breastfeeding are essential for the initiation and maintenance of a healthy life during childhood. It may also protect against several adulthood diseases [9, 64].

#### *2.3.1 Zinc*

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

in the mother's blood. Nicotine acts on the brain by binding to nicotinic acetylcholine receptors (nAChRs) in autonomic ganglia and at neuromuscular junction. The binding results in the release of neurotransmitters and important neuromodulators, such as dopamine, adrenaline, acetylcholine, Seratonin (5- hydroxytryptamine),

Both nicotine and carbon monoxide induce degenerative changes and premature aging in the placenta. The degenerative changes are marked by an increased amount of collagen in the chorionic villi and the thickening of subtrophoblastic basement membrane [61]. Premature aging is suggested by the increase in the syncope buds and apoptosis in the placentas. Both premature aging and degenerative changes significantly reduce the placental functional capacity and lead to multiple adverse fetal effects. The incidence of premature births is significantly higher in mothers who

GABA, glutamate, and substance P [60].

1.Fetal alcohol syndrome (FAS) (all conditions will be met) A. Confirmation of alcohol use during pregnancy

ii. Thin upper lip (score 4 or 5 in the lip/philtrum guide) iii. Straight philtrum (score 4 or 5 in the lip/philtrum guide)

2.FAS in which alcohol use cannot be confirmed during pregnancy 3.Partial FAS in which alcohol use is confirmed during pregnancy 4.Partial FAS in which alcohol use cannot be confirmed during pregnancy

i. Short palpebral fissure (≤10th percentile)

C. Prenatal and/or postnatal growth retardation: i. Length or weight ≤ 10th percentile

i. Structural abnormalities in the brain ii. Head circumference ≤ 10th percentile

5.Alcohol-related congenital disorders 6.Alcohol-related neurodevelopmental disorders

*Fetal alcohol spectrum disorders.*

B. The presence of characteristic minor facial anomalies (at least two of the following):

*Fetal alcohol syndrome (© 2009 University of Washington. With permission, Susan Astley, PhD).*

D. Mental development disorder or abnormal morphogenesis (at least one of the following):

**22**

**Table 3.**

**Figure 3.**

Zinc is essential for normal fetal growth and development. It is a component of over 200 enzymes which take part in the formation and release of various proteins, hormones, and neuropeptides. The element is involved in the transcription process in which a gene's DNA sequence is copied to make an RNA molecule. Zinc is required for proper cell division, growth, and differentiation. Severe zinc deficiency is embryotoxic and teratogenous and may cause lethal fetal developmental and structural anomalies [65].

It has been shown that maternal zinc deficiency can affect embryonic protein and DNA synthesis and cause chromosomal damage characterized by terminal deletion [66]. Maternal zinc deficiency is associated with increased apoptosis in the embryonic cells. TUNEL analysis has shown that cell death is increased in the peri-implantation embryos if the cultured cells have low zinc levels [67]. The cell cycle may not be adversely affected if the maternal zinc deficiency is short term [68]. In zinc deficiency, the formation of free radicals is increased as they cannot bind to the membranes and intracellular regions of redox-active metals, such as copper and iron [69], which results in increased oxidative stress and teratogenicity. Zinc can prevent oxidation of numerous proteins, including zinc finger transcription factors of redox-sensitive cysteine and sulfhydryl groups. Zinc is a component of copper-zinc superoxide dismutase and is the regulator of metallothionein, a metal-binding protein which has important roles in the execution of various physiological processes and in the prevention of stress [70]. Metallothionein releases zinc, which plays a central role in the antioxidant defense system during oxidative stress. Inadequate zinc uptake of the mother leads to a decrease in the circulating zinc levels which may adversely affect the neural tube development of the fetus as demonstrated in both animals and humans. In humans, the risk of neural tube defects is found to be increased in women with acrodermatitis enteropathica, a rare genetic disorder of zinc metabolism. It is noted that the prevalence of neural tube defects is higher in Africa and the Middle East, where zinc intake is chronically low due to ecological reasons [70, 71]. The relationship between zinc deficiency and cleft palate and lip was demonstrated in a study which showed the zinc levels in the blood of such infants and their mothers to be significantly low [72].

#### *2.3.2 Folic acid (FA)*

Folic acid, a group B vitamin, plays an important role in the production of new cells by assisting in the production of DNA and RNA that control cell proliferation [73]. It also works with vitamin B12 to form hemoglobin in erythrocytes. It has a protective effect against heart diseases. It decreases the risk of birth of infants with neural tube defects (spina bifida), obstructive urinary tract anomalies, limb deficiencies, orofacial clefts, and congenital hypertrophic pyloric stenosis [74]. After absorption, folic acid is carried as a monoglutamate in the blood and is converted to various compounds in the cell, the most important being the reductase enzyme, tetrahydrofolate (THF). THF functions as the donor of single carbon units at various steps of DNA synthesis, which is required for the synthesis of purines, thymidylate and hence thymine [75, 76].

Research on the effect of folic acid on NTD began in the 1980s when studies showed that FA is effective in preventing both primary NTD and its recurrence [77]. In a multicenter randomized controlled study which included 1200 women with a history of NTD in their prior pregnancies, FA intake in the dose of 0.4 mg/ day started at least 1 month before conception and continued during the first 3 months of pregnancy reduced the risk of NTD by 3.6 times [78]. In a cohort study in China, which included approximately 250,000 women, it was demonstrated that maternal intake of 0.4 mg folic acid reduces the risk of NTD in the fetus by 85% in high-prevalence areas and by 40% in low-prevalence areas [79, 80]. Folic acid has been also reported to reduce the incidence of CHD if used during the preconceptional period [81]. The use of folic acid antagonist drugs, which cause the inhibition of dihydrofolate reductase enzyme, increases the frequency of CHD.

#### *2.3.3 Maternal diabetes mellitus*

The discovery of insulin in 1922 and advances in obstetrics and neonatal intensive care reduced perinatal mortality in pregnancies complicated by diabetes mellitus by approximately 30 times. By maintaining maternal euglycemia, such pregnancies were able to continue until term with a resultant decrease in prematurity-related complications including respiratory distress syndrome [82]. Still, perinatal mortality in diabetic women continues to be about twice that of nondiabetic women. Also spontaneous abortion rates are higher in diabetic women, especially if the glycemic control is suboptimal in the periconceptional period [83].

Hyperglycemia has been shown to induce oxidative stress in the developing embryonic and fetal cells and tissues in animal studies, with the release of reactive oxygen species (ROS). Increased concentrations of ROS induce organ malformation and birth defects via membrane changes, mitochondrial dysfunction, and the initiation of abnormally programmed cell death (apoptosis). In mice models injected streptozotocin (STZ) to induce type 1 diabetes hyperglycemia caused changes in the yolk sac, as well as abnormalities in the endoplasmic reticulum and premature aging. It induced oxidative phosphorylation in the mitochondria and increased the concentration of ROS [84]. If appropriate glycemic control is maintained during the third and sixth weeks of pregnancy, the periods when the embryo is most susceptible to teratogens, congenital anomaly rates are found to be the same as in the general population [85]. Vitamins E and C, which are antioxidants, have been shown to reduce hyperglycemia-related anomalies in animal models. Some prostaglandins may have the same effects.

The incidence of congenital anomalies, which is 1–2% in the general population, is 4–8 times higher in infants of mothers with pregestational diabetes. Congenital anomalies are the most important cause of perinatal death in pregnancies

**25**

**Table 4.**

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

complicated with diabetes mellitus [86]. Although anomalies can be seen in all organ systems in the neonates of diabetic mothers, the most important ones are those in the cardiac and central nervous systems (**Table 4**). Caudal regression syndrome is a rare congenital anomaly caused by maternal diabetes. No increase in the rate of congenital anomalies is seen in normoglycemic mothers or those with gestational diabetes occurring after the first trimester, which reiterates that glycemic control during embryogenesis plays a major role in the pathogenesis of fetal anomalies. Congenital anomalies are found to be more common in pregnant women with high HbA1c levels in the first trimester with a direct relationship with its level

Maternal phenylketonuria is one of the most common teratogenic syndromes of pregnancy. Phenylalanine crosses the placenta by active transport and increases the level of phenylalanine in fetal blood by 70–80% of maternal phenylalanine concentration [88]. Increased levels of phenylalanine are toxic and teratogenic to the developing fetus. Spontaneous abortions are observed in 24% of pregnancies with phenylketonuria, and in those who survive, microcephaly is found in 73%, mental retardation in 92%, congenital heart diseases in 12%, and intrauterine growth retardation in 40% of the offsprings [89]. If maternal phenylalanine levels are well controlled before conception and during pregnancy, the incidences of microcephaly and abnormal physical and neurological fetal development are significantly reduced. The prognosis is best in infants of mothers with a blood phenylalanine level of 120–360 μmol/L prior to pregnancy with no increase in the risks, while the prognosis is poor in those infants whose mothers had a phenylalanine level exceeding 360 μmol/L during pregnancy. Severe congenital heart diseases were reported in infants born to untreated pregnant women with high blood phenylalanine levels, especially if the diet restriction was not started until the 7th and 18th weeks of gestation. There is no increase in the risk in pregnant women with phenylalanine level 120–360 μmol/L during the first 8 weeks of pregnancy. Serious fluctuations in maternal phenylalanine levels in pregnancy also

In pregnant women with phenylketonuria, sapropterin dihydrochloride, an orally active synthetic form of (6R)-L-erythro-5,6,7,8-tetrahydrobiopterin, has been used in the doses of up to 20 mg/kg/day, in combination with a restricted diet for therapy, and the short-term results have been good. Large neutral amino acid

> • Atrial septal defect • Ventricular septal defect • Transposition of large vessels

• Aortic coarctation • Fallot tetralogy • Trunkus arteriosus • Dextrocardia/cardiomegaly • Caudal regression syndrome

• Sacral agenesis • Omphalocele

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

and the rate of anomalies [87].

*2.3.4 Maternal phenylketonuria (PKU)*

have a negative impact on prognosis [90].

*Congenital anomalies seen in children of diabetic mothers.*

• Cardiac anomalies

• Renal anomalies

• Neural tube defect • Anencephaly • Uretral duplication • Duodenal-anorectal atresia

• Central nervous system anomalies

• Gastrointestinal abnormalities

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

complicated with diabetes mellitus [86]. Although anomalies can be seen in all organ systems in the neonates of diabetic mothers, the most important ones are those in the cardiac and central nervous systems (**Table 4**). Caudal regression syndrome is a rare congenital anomaly caused by maternal diabetes. No increase in the rate of congenital anomalies is seen in normoglycemic mothers or those with gestational diabetes occurring after the first trimester, which reiterates that glycemic control during embryogenesis plays a major role in the pathogenesis of fetal anomalies. Congenital anomalies are found to be more common in pregnant women with high HbA1c levels in the first trimester with a direct relationship with its level and the rate of anomalies [87].
