Standards for a permissible exposure limit PEL for toluene have been set by the U. Toluene embryopathy includes prenatal and postnatal growth deficiency, microcephaly, anencephaly, developmental delay, cardiac and limb defects, and craniofacial anomalies similar to fetal alcohol syndrome FAS [ 57 , 59 — 67 ]. Phenotypic facial abnormalities similar to those of FAS suggest a common mechanism of craniofacial teratogenesis for toluene and alcohol attributed to deficiency of craniofacial neuropeithelium and mesodermal components due to increased embryonic cell death [ 67 ].
During pregnancy, obesity is associated with adverse outcomes that include macrosomia, hypertension, pre-eclampsia, gestational diabetes mellitus GDM , and fetal death [ 68 — 72 ]. In addition, many investigators have reported an increased risk of birth defects. Although hyperglycemia may be key in the pathogenesis of diabetic embryopathy, other factors contained in diabetic serum may also contribute to the embryopathy [ 73 ]. Hyperglycemia leads to inhibition of the myoinositol uptake that is essential for embryonic development during gastrulation and neurulation stages of embryogenesis [ 74 , 75 ].
Deficiency of myoinositol appears to cause perturbations in the phosphoinositide system that lead to abnormalities in the arachidonic acid-prostaglandin pathway. The gastrulation and neurulation stages of development are particularly sensitive to hypoglycemia and result in growth retardation as well as cranial and caudal neural tube defects NTDs. Obesity that occurs with a number of metabolic abnormalities, including abnormal glucose metabolism, is associated with a higher risk of malformations.
A possible role of free oxygen radicals in diabetic teratogenicity has been suggested. The pathogenesis of diabetic embryopathy is heterogeneous [ 73 , 74 ]; maintenance of glucose homeostasis is important for the prevention of diabetic embryopathy. There is a correlation between elevated hemoglobin A1c HbA1c levels and the incidence of major congenital anomalies in infants of diabetic mothers IDMs [ 76 — 80 ]. HbA1c is a normal, minor hemoglobin that differs from HbA by the addition of a glucose moiety to the amino-terminal valine of the beta chain.
Glycosylation of hemoglobin A occurs during circulation of the red cell and depends on the average concentration of glucose to which the red cell is exposed during its life cycle [ 81 ].
Anatomy & Physiology
Measurement of HbA1c provides an index of chronic glucose elevation, and therefore of diabetes control [ 82 ]. HbA1c levels during pregnancy that exceed Defects of the heart, central nervous system CNS , kidneys, and skeleton predominate. Transposition of the great vessels, ventricular septal defect VSD , and dextrocardia occur with greatest frequency.
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Anencephaly, spina bifida, and hydrocephaly are the major CNS malformations. Rare malformations include situs inversus and caudal dysplasia, vertebral and renal anomalies, imperforate anus, radius aplasia, renal abnormalities including agenesis and dysplasia, and other defects. Minor physical abnormalities include anteverted nares, flattened nasal bridge, excess skin folds on the neck, and tapered fingers with hyperconvex nails. Other complications include hyperbilirubinemia, hypocalcemia, vascular thromboses eg, renal vein thrombosis , and respiratory distress syndrome.
Hypothyroidism in infants occurs when the fetal thyroid gland has been suppressed by antithyroid drugs propylthiouracil, carbimazole, iodides , radioactive iodine [ 86 ] or possibly maternal antibodies [ 87 ].
Issues and Reviews in Teratology
Transfer of maternal thyroxin to the fetus is negligible during early pregnancy. During the final weeks of pregnancy, thyroid-binding globulin TBG may compete for thyroxin. Triiodothyronine is less bound by TBG and can more freely cross the placenta.
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Hyperthyroidism during pregnancy is usually due to Graves disease. The presence of thyroid-stimulating globulins may result in thyrotoxicity in the fetus and newborn regardless of the treatment of maternal disease. Neonatal thyrotoxicosis is usually a transient phenomenon lasting several months.
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Affected infants have goiter, exophthalmos, restlessness, tachycardia, periorbital edema, ravenous appetite, hyperthermia, cardiomegaly, cardiac failure, and hepatosplenomegaly [ 88 ]. Infants of mothers with untreated hypoparathyroidism may have transient hyperparathyroidism during the fetal and neonatal periods [ 89 ]. The fetal parathyroid hyperplasia that occurs in response to low maternal and fetal serum calcium concentration is mediated by the maternal parathyroid dysfunction. Bone demineralization and subperiosteal reabsorption occurs in the long bones. Iodine deficiency is the cause of endemic goiter and cretinism due to deficiency or of insufficient availability of thyroxine at the fetoplacental level.
There is a role of maternal T 4 in neurological embryogenesis, before the onset of fetal thyroid function and, therefore, its protective role in fetal thyroid failure. Congenital hypothryoidism associated with deafness and mental retardation is found in the offspring of hypothyroid mothers. Deafness persists in spite of thyroid replacement therapy. Developmental changes in the brain and cerebellum have been described [ 90 ].
Fetal iodine deficiency results in cretinism characterized by mental retardation, spastic diplegia, deafness, and strabismus [ 91 , 92 ]. The myotonic dystrophy gene contains a segment of CTG repeats that tends to amplify in each generation [ 87 — 89 ]. Infants born of women with myotonic dystrophy may show fetal hypokinesia and generalized weakness, and may experience difficulty in respiration and feeding. The facies characteristically shows tenting of the upper lip, ptosis, absence of movement, and anterior cupping of the pinnas.
Clubfoot is often present and postnatal growth is slow. Maternal phenylketonuria PKU leads to defects that include intrauterine and postnatal growth retardation, cardiovascular defects, dislocated hips, and other anomalies [ 93 — 95 ]. Infants of mothers with PKU are heterozygous, and because phenylketonuric heterozygotes are generally normal, the defect in the fetus must be attributed to the maternal metabolic disturbance. These effects are directly related to the maternal phenylalalnine level.
One-fourth of pregnancies abort spontaneously. The full picture of FAS usually occurs in babies born to alcoholic mothers, or those who drink regularly or binge-drink. However, no amount of alcohol is safe. Even light or moderate drinking can affect the developing fetus. Acetaldehyde is implicated as the cause of FAS through its inhibiting effects on DNA synthesis, placental amino acid transport, and development of the fetal brain [ 96 — 98 ].
The biologic basis for FAS is related to genetic polymorphisms identified for alcohol dehydrogenase ADH , which converts alcohol to acetaldehyde, and acetaldehyde dehydrogenase ALDH2 , which converts acetaldehyde to acetate. Genetic differences in ADH alleles make some infants exposed to the same level of alcohol in utero more likely to have longer or higher levels of exposure to acetaldehyde.
This may explain the greater frequency in American blacks and Native Americans. Characteristics of the fetal alcohol syndrome [ ]. Structural and functional impairments occur in up to one half of infants born to alcoholic women who drink heavily. Functional and growth disturbances without other morphologic changes can occur in infants whose mothers drink moderately 1 to 2 oz of absolute ethanol daily. However, the risk of spontaneous abortion is twice the normal rate in women who drink 1 oz of ethanol twice a week [ 99 ]. Binge drinking in the first trimester may be a cause of fetotoxicity [ ].
In view of the limited understanding of the effects of prenatal exposure to alcohol, abstinence from alcohol during pregnancy is a wise precaution. Minimal knowledge is available of the effects of chloroquine malarial prophylaxis used during pregnancy.
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Malformations in three half-siblings included up-slanting palpebral fissures, flat philtrum, thin upper lip, and brachydactyly of the fifth finger. Maternal chloroquine use during pregnancy may be associated with auditory, vestibular, retinal, and other neurologic dysfunction in children. Nicotine is a vasoconstrictor that results in uterine vascular constriction and intrauterine growth retardation IUGR through decreased perfusion of fetal tissues [ ]. It is a cholinergic agonist and a constituent of tobacco. Cigarette smoking during pregnancy raises the risk of perinatal mortality and morbidity [ ].
The increased mortality is attributed to abruptio placentae, placenta previa, spontaneous abortion, prematurity, and IUGR [ ]. Carbon monoxide from cigarette smoke also crosses the placenta and produces an increase in blood carboxyhemoglobin HbCO levels; there is a longer half-life of HbCO in fetal blood than in maternal blood [ — ].
The active ingredient of marijuana is 8,9-tetrahydrocannabinol, which is fat soluble, crosses the placenta easily, and may persist in the fetus for as long as 30 days [ — ]. Growth retardation and malformations are reported after marijuana use during pregnancy, especially in the first trimester. However, other potentially teratogenic drugs are often used by women who smoke marijuana. Increased risk of nonlymphoblastic leukemia has been reported [ ].
Children born to mothers who used LSD before or during pregnancy have had a variety of anomalies. Defects of the limbs, eyes, CNS, and arthrogryposis may be present [ ]. There is no indication that the risk of congenital anomalies is great [ ]. LSD-induced chromosomal damage may last up to 2 years but is sometimes transient [ , ]. There is no evidence that paternal exposure to LSD in small doses before conception is associated with increased rates of spontaneous abortion, premature birth, or birth defects [ , ].
Increased frequencies of cleft lip, cleft palate, and congenital heart disease have been reported after maternal phenobarbital exposure [ ]. Benzodiazepine-containing drugs, taken in large amounts, may produce IUGR, cleft lip, and facial features that resemble the findings of FAS [ 2 , ], although studies have shown little or no increase in congenital anomalies.
Manifestations in isotretinoin embryopathy [ ]. The critical period of exposure is 4 to 10 wk of gestation.