Teratogens Flashcards
HUMAN TERATOGENS: A CRITICAL EVALUATION Orna Diav-Citrin, MD, Gideon Koren, MD, FACCT, FRCPC The Motherisk Program, the Hospital for Sick Children, Toronto, Ontario, Canada https://www.nvp-volumes.org/p2_4.htm
“all or none” period
The time from conception until implantation.
When insults to the embryo are likely to result in death of the conceptus and miscarriage (or resorption), or in intact survival. At this stage, the embryo is undifferentiated and repair and recovery are possible through multiplication of the still totipotential cells to replace those which have been lost. Exposure of embryos to teratogens during the preimplantation stage usually does not cause congenital malformations, unless the agent persists in the body beyond this period.
embryonic period
from 18 to 54-60 days after conception
the period when the basic steps in organogenesis occur. This is the period of maximum sensitivity to teratogenicity since not only are tissues differentiating rapidly but damage to them becomes irreparable. Exposure to teratogenic agents during this period has the greatest likelihood of causing a structural anomaly. Since teratogens are capable of affecting many organ systems, the pattern of anomalies produced depends upon which systems are differentiating at the time of teratogenic exposure.
foetal phase
end of the embryonic stage to term
when growth and functional maturation of organs and systems already formed occurs. Teratogen exposure in this period will affect foetal growth (e.g., intrauterine growth retardation), the size of a specific organ, or the function of the organ, rather than cause gross structural anomalies. The term foetal toxicity is commonly used to describe such an effect. Of particular interest is the potential effect of psychoactive agents (e.g., antidepressants, antiepileptics, alcohol and other drugs of abuse) on the developing central nervous system, which has led to a new field of behavioural teratology.
Teratogen - alchol
The foetal alcohol syndrome is a clinical pattern of anomalies characterized by intrauterine growth retardation which commonly continues postnatally. These include: microcephaly, developmental delay, and dysmorphic facies consisting of low nasal bridge, midface hypoplasia, long featureless philtrum, small palpebral fissures and thin upper lip. Cleft palate and cardiac anomalies may also occur. Full expression of this syndrome occurs with chronic daily ingestion of at least 2 grams alcohol per kilogram (eight drinks per day). The full syndrome is present in about one third of these mothers and partial effects occur in approximately three quarters of offspring.
Teratogen - Angiotensin converting enzyme inhibitors (ACEI) (captopril, enalapril, lisinopril)
ACEI are potent anti-hypertensive drugs. Their use in late pregnancy has been associated with foetal toxicity including intrauterine renal insufficiency. Reports of neonatal hypotension, oliguria with renal failure, and hyperkalemia have been reported with ACEI use in pregnancy. Complications of oligohydramnios (i.e., foetal limb contractures, lung hypoplasia, and craniofacial anomalies), prematurity, intrauterine growth retardation, and foetal death have also been reported with the use of these agents late in pregnancy. The adverse effects are related to the haemodynamic effects of ACEI on the foetus, teratogenic risk with first trimester exposure to these agents appears to be low.
Teratogen - Carbamazepine
Exposure to carbamazepine in utero carries a 1% risk of neural tube defects (10 times their baseline risk). A pattern of malformations similar to those described with the foetal hydantoin syndrome has also been associated with carbamazepine exposure in pregnancy.
Teratogen - Cocaine
Cocaine use during pregnancy has been associated with abruptio placentae, prematurity, foetal loss, decreased birth weight, microcephaly, limb defects, urinary tract malformations, and poorer neurodevelopmental performance. The contribution of cocaine to the incidence of congenital malformations is difficult to assess because of methodological problems, which make the results difficult to interpret. Cocaine abuse is often associated with poly-drug abuse, alcohol consumption, smoking, malnutrition, and poor prenatal care. Experimental animal studies and human epidemiology indicate that the risk of major malformation from cocaine is probably low, but the anomalies may be severe.
Teratogen - Coumarin anticoagulants
First trimester exposure to coumarin derivatives is associated with a characteristic pattern of malformations termed the foetal warfarin syndrome. Clinical features consist of nasal hypoplasia and calcific stippling of the epiphyses. Intrauterine growth retardation and developmental delay due to central nervous system damage, eye defects, and hearing loss have also been described. The critical period of exposure for the foetal warfarin syndrome appears to be between 6 and 9 weeks of gestation. A prospective study found evidence of warfarin embryopathy in about one third of the cases where a coumarin derivative was given throughout pregnancy. Oral anticoagulants are also associated with a high rate of miscarriage. Exposure to oral anticoagulants after the first trimester presents a risk of central nervous system damage due to haemorrhage. Unlike heparin, oral anticoagulants readily cross the placental barrier.
Teratogen - Diethylstilbestrol
Diethylstilbestrol was used in the 1950s and 1960s for the diagnosis of recurrent miscarriage. Clear cell adenocarcinoma of the vagina was found to be associated with diethylstilbestrol treatment of the patient’s mother during the first trimester of pregnancy. Over 90% of the cancers occurred after 14 years of age. Clear cell carcinoma has not occurred in women exposed in utero after the 18th week of gestation. A high incidence of benign adenosis of the vagina was found in women prenatally exposed to this nonsteroidal estrogen analogue. In a prospective study, exposure starting at 4 weeks was associated with adenosis in 56% of the offspring, decreasing later to 30% at 16 weeks and 10% at 20 weeks. Miscarriage rate and preterm delivery were significantly more common in women exposed in utero to diethylstilbestrol compared to matched controls. In 134 males exposed in utero to the agent no signs of malignancy were found but 27% had genital lesions (epididymal cysts, hypotrophic testes, or capsular induration of the testes). In 29%, pathologic changes were found in spermatozoa.
Teratogen - Folic acid antagonists: Aminopterin and methotrexate
Aminopterin has been known since 1950 to result in foetal death, which led to its use as a human abortifacient. The foetal aminopterin syndrome was described based on anomalies observed in aborted foetuses and infants born following unsuccessful abortions. Malformations include central nervous system defects (hydrocephalus, meningomyelocele), facial anomalies (cleft palate, high arched palate, micrognathia, ocular hypertelorism, external ear anomalies), abnormal cranial ossification, abnormalities in first branchial arch derivatives, intrauterine growth retardation and mental retardation. Infants have been born with features of the aminopterin syndrome after pregnancy exposure to methotrexate (methylaminopterin). It was suggested that the maternal dose necessary to induce defects is above 10 mg per week with a critical period of 6 to 8 weeks post conception being postulated.
Teratogen - Hydantoins (phenytoin and trimethadione)
Hydantoins have been associated with a recognizable pattern of malformation termed the foetal hydantoin syndrome. The clinical features include craniofacial dysmorphology (wide anterior fontanelle, ocular hypertelorism, metopic ridge, broad depressed nasal bridge, short anteverted nose, bowed upper lip, cleft lip, cleft palate), as well as variable degrees of hypoplasia of the distal phalanges, nail hypoplasia and low arch dermal ridge patterning. Growth retardation, mental deficiency and cardiac defects are additional features of the syndrome.
Teratogen - Isotretinoin (13-cis-retinoic acid)
Isotretinoin is a synthetic vitamin A derivative, prescribed for severe cystic acne, that has been proven to be a potent human teratogen as well as a behavioural teratogen when given systemically. A pattern of anomalies termed retinoic acid embryopathy has been associated with isotretinoin (and other retinoic acid derivatives such as etretinate and megadoses of vitamin A) exposure in pregnancy. The clinical features include craniofacial anomalies (microtia or anotia, accessory parietal sutures, narrow sloping forehead, micrognathia, flat nasal bridge, cleft lip and palate, and ocular hypertelorism), cardiac defects (primarily conotruncal malformations), abnormalities in thymic development, and alterations in central nervous system development. The risk for associated miscarriage was 40%.
Teratogen - Lithium
By 1983, the International Registry of Lithium Babies had collected retrospective information on 225 babies exposed to lithium during the first trimester. Despite the lack of a control group and the likely over-reporting of abnormal outcome, the data suggested a higher risk for major anomalies than in the general population and a specific risk for cardiac teratogenesis in early gestation. The number of cases of Ebstein’s anomaly, a rare malformation of the tricuspid valve, by far exceeded its spontaneous rate of occurrence. In a prospective study of 148 women who took lithium during the first trimester of pregnancy, three infants were born with major malformations, a rate comparable to that found in the control group. One pregnancy was terminated following prenatal diagnosis of Ebstein’s anomaly. Foetal echocardiography is recommended in the management of pregnancies exposed to lithium in the first trimester.
Teratogen - Misoprostol
Misoprostol is a synthetic prostaglandin E1 analogue, prescribed for duodenal and gastric ulceration, also used as an abortifacient by women in Brazil. A Brazilian case-series suggested an association between first trimester exposure to misoprostol and limb defects with or without Moebius’ sequence. The association was further supported by a case-control study comparing the frequency of misoprostol use during the first trimester by mothers of 96 infants with Moebius’ syndrome and mothers of infants with neural tube defects. Among the mothers of infants with Moebius’ syndrome, 49% had used misoprostol, as compared with 3% of the mothers of infants with neural tube defects (odds ratio, 29.7; 95% confidence interval 11.6 to 76.0). Despite the strong association between misoprostol exposure during the first trimester and Moebius’ syndrome, its absolute teratogenic risk is probably not high.
Teratogen - Tetracyclines
Yellow-brown discolouration of teeth may occur due to deposition of the antibiotic in calcifying teeth with tetracycline use in late pregnancy. The risk is apparent only after 17 weeks of gestation when the deciduous teeth begin to calcify. Generally, only the deciduous teeth are involved, although with administration of the drug close to term the crowns of the permanent teeth may be stained. Oxytetracycline and doxycycline are associated with a lower incidence of enamel staining.
