Teratogenesis

1. Teratogenesis • A “teratogen”, from the Greek root teras, meaning monster or marvel, is any environmental factor that causes a structural or functional abnormality in the developing fetus or embryo. These environmental agents include • infections, medications, drugs, chemicals, maternal metabolites, such as phenylalanine or mechanical forces.(1-2)

2. Effects of drugs on the fetus (2) • the first week after fertilization is the “period of the zygote”. During this time the most common adverse effect of drugs is the termination of pregnancy , which may occur before the woman even knows that she is pregnant. • The second to the eighth week of gestation is “period of the embryo”. It is mainly during this period of organogenesis that drugs produce dramatic and catastrophic structural malformations.

3. terminology Malformation(3) A primary structural defect arising from a localized error in morphogenesis. (cardiac septal defects) Deformation An alteration in shape or structure of a part that has differentiated normally. (mostly involving musculoskeletal system and are probably caused by intrauterine molding, like various forms of clubfoot and congenital hip dislocation) Disruption A structural defect resulting from destruction of a previously normally formed part. two mechanisms are involved: 1-entanglement followed by tearing apart or amputation (like amniotic bands) 2-interruptioin of blood supply to a developing part, leading to infarction, necrosis or resorption of structure distal to the insult. (like jejunoileal atresia and gastroschisis) Dysplasia An abnormal organization of cells and the structural consequences. ( localized like hemangioma, generalized like connective tissue disorders)

5. MATERNAL MEDICATION AND TOXIN EXPOSUREAND THE FETUS(3) The effects of drugs taken bythe mother vary considerably, especially in relation to the time inpregnancy when they are taken and the fetal genotype for drugmetabolizingenzymes. Miscarriage or congenital malformationsresult from the maternal ingestion of teratogenic drugs during theperiod of organogenesis. Maternal medications taken later, particularly during the last few weeks of gestation or during labor,tend to affect the function of specific organs or enzyme systems,and they adversely affect the neonate rather than the fetus .

6. Diagnosis time The effects of drugs may be evident immediately in the deliveryroom or later in the neonatal period, or they may be delayedeven longer. The administration of diethylstilbestrol during pregnancyhas resulted in vaginal adenosis and vaginal adenocarcinomain females in the 2nd or 3rd decade. In addition to in uterocarcinogenesis, various reproductive problems have been reportedin these women, including cervical anomalies and prematurebirths, ectopic pregnancies, and spontaneous pregnancy loss.

7. Impact of genetic Evidence has confirmed an interaction between genetic factorsand susceptibility to certain drugs or environmental toxins. Phenytoin teratogenesis may be mediated by genetic differencesin the enzymatic production of epoxide metabolites; specific genesmay influence the adverse effects of benzene exposure during pregnancy. Growth-restricting effects of smoking on the fetus is influenced by polymorphisms of genes encoding enzymes that metabolizethe polycyclic aromatic hydrocarbons in cigarette smoke .

8. Drug use in pregnancy Often the risk of controlling maternal disease must be balancedwith the risk of possible complications in the fetus. The majorityof women with epilepsy have normal fetuses. Nonetheless, severalcommonly used antiepileptic drugs (AEDs) are associated withcongenital malformations. Infants exposed to valproic acid mayhave multiple anomalies including neural tube defects, hypospadias,facial anomalies, cardiac anomalies, and limb defects. Inaddition, they have lower developmental index scores comparedto those unexposed infants or those exposed to other commonly used AED.

9. Radiation(3) Accidental exposure of pregnant women to radiation is acommon cause for anxiety about whether the fetus will have birthdefects or genetic abnormalities. It is unlikely that exposure todiagnostic radiation will cause gene mutations; no increase ingenetic abnormalities has been identified in the offspring exposedas unborn fetuses to the atomic bomb explosions in Japan in1945.

10. Maximum safe dose of radiation in pregnancy Therecommended occupational limit of maternal exposure to radiationfrom all sources is 500 mrad for the entire 40 wk of a pregnancy. The limiteddata on human fetuses show that large doses of radiation(20,000-50,000 mrad) are harmful to the central nervous system,as evidenced by microcephaly, mental retardation, and IUGR.Leukemia is another risk. Therapeutic abortion is often recommended when exposureexceeds 10,000 mrad. It is more likely that a human fetus will beexposed to 1,000-3,000 mrad, an amount not shown to causemalformations. Whether this level of fetal exposure is associatedwith an increased risk for childhood cancer or leukemia iscontroversial.

11. Maternal PKU Mental retardation, hypertonia, low birth weight, microcephaly, cardiac defects, spontaneous abortion.

12. Multiple malformation vs sequence The pattern ofmultiple anomalies that occurs when a single primary defect inearly morphogenesis produces multiple abnormalities through a cascading process of secondary and tertiary errors in morphogenesis is called a sequence. When evaluating a child withmultiple anomalies, the physician must differentiate multiple anomalies secondary to a single localized error in morphogenesis(a sequence) from a multiple malformation syndrome. Intheformer, recurrence risk counseling for the multiple anomaliesdepends entirely on the risk of recurrence for the single localizedmalformation. The Robin malformation sequence is a pattern ofmultiple anomalies produced by mandibular hypoplasia. Becausethe tongue is relatively large for the oral cavity, it drops back(glossoptosis), blocks closure of the posterior palatal shelves, andcauses a V-shaped cleft palate. There are numerous causes ofmandibular hypoplasia, all of which result in characteristic featuresof Robin sequence.

13. Fetal alcohol syndrome • Prenatal onset and persistence of growth deficiency for weight, length, and head circumference. • Facial abnormalities including short palpebral fissure, epicanthal folds, maxillary hypoplasia, micrognathia, and thin upper lips. • Cardiac defects, primarily septal defects. • Minor joint and limb abnormalities including some restriction in movements and altered palmar crease pattern. • Delayed development and mental deficiency varying from borderline to severe.

18. References Avery 2005 Fanarof 2006 Nelson 2004