*2.3.4 Maternal phenylketonuria (PKU)*

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

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

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.

the glycemic control is suboptimal in the periconceptional period [83].

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

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 prosta-

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

*2.3.2 Folic acid (FA)*

and hence thymine [75, 76].

*2.3.3 Maternal diabetes mellitus*

glandins may have the same effects.

**24**

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 have a negative impact on prognosis [90].

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



#### **Table 4.**

*Congenital anomalies seen in children of diabetic mothers.*

(LNAA) treatment, which is one of the other dietary alternatives used in patients with phenylketonuria, is contraindicated in pregnancy because it does not reduce blood phenylalanine levels to safe levels [91].
