8. Teratology.pptx

FETOLOGY

1. Teratology Themba Hospital FCOG(SA) Part 1 Tutorials By Dr N.E Manana

2. Intro Birth defects are common — 2 to 3 percent of all newborns have a major congenital abnormality detectable at birth By age 5, another 3 percent have been diagnosed with a malformation , and by age 18 , another 8 to 10 percent have one or more apparent functional or developmental abnormalities Importantly , nearly 70 percent of birth defects do not have an obvious etiology , and of those with an identified cause , it is far more likely to be genetic than teratogenic The Food and Drug Administration (FDA) (2005b) estimates that less than 1 percent of all birth defects are caused by medications .

3. TERATOLOGY The study of birth defects and their etiology is termed teratology . The word teratogen is derived from the Greek teratos , meaning monster Pragmatically , a teratogen may be defined as any agent that acts during embryonic or fetal development to produce a permanent alteration of form or function A Trophogen is an agent that alters growth A Hadegen —after the god Hades —is an agent that interferes with normal maturation and function of an organ

4. Studies in Pregnant Women The study of medication safety —or teratogenicity —in pregnant women is fraught with complications . Animal studies are considered necessary but insufficient , which is a lesson learned from the safety of thalidomide in several animal species Rarely are medications approved by the FDA with the specific indication for their use being pregnancy . Between 1996 and 2011 , for example, the only medication approved specifically for pregnancy was hydroxyprogesterone caproate for recurrent preterm birth prevention Pregnant women are generally considered a special population and excluded from trials

5. Table 12.1

6. CRITERIA FOR DETERMINING TERATOGENICITY Table 12.2

7. COUNSELING FOR TERATOGEN EXPOSURE Women who request counselling for prenatal drug exposure often have misinformation regarding their level of risk . Not uncommonly , they may underestimate the background risk for birth defects in the general population and exaggerate the potential risks associated with medication exposure Koren and colleagues (1989) reported that a fourth of women exposed to nonteratogenic drugs thought they had a 25-percent risk for fetal anomalies . Misinformation may be amplified by inaccurate reports in the lay press . Knowledgeable counseling may allay anxiety considerably and in some situations may even avoid pregnancy termination

8. The Food and Drug Administration Classification System Table 12.3

9. GENETIC AND PHYSIOLOGICAL SUSCEPTIBILITY TO TERATOGENS Teratogens act by disturbing specific physiological processes , which may in turn lead to abnormal cellular differentiation , altered tissue growth , or cell death But even the most potent teratogen induces birth defects in only a fraction of exposed embryos Despite the numerous factors that influence exposure , teratogens appear merely to have potential to cause birth defects . The reasons why some infants are affected and others are not remains largely unknown

10. Disruption of Folic Acid Metabolism Fetal neural-tube defects , cardiac defects , and oral clefts can be a result of folic acid metabolic pathway disturbances Folates are essential for methionine production , which is required for gene methylation and thus production of proteins , lipids , and myelin . Some anticonvulsants — phenytoin , carbamazepine , valproic acid , and phenobarbital —either impair folic acid absorption or act as folic acid antagonists Some congenital heart defects are related to interactions between folate-related genes and environmental or genetic factors

11. Paternal Exposures In some cases , paternal exposures to drugs or environmental influences may increase the risk of adverse fetal outcome Proposed mechanisms include induction of a gene mutation or chromosomal abnormality in sperm . Because of the 64 days in which male germ cells mature into functional spermatogonia , drug exposure during the 2 months before conception could cause gene mutations . It may be that epigenetic pathways suppress germ-cell apoptosis or interfere with imprinting Another possibility is that during intercourse the developing embryo is exposed to a teratogenic agent in seminal fluid .

12. KNOWN AND SUSPECTED TERATOGENS Alcohol Ethyl alcohol is a potent and prevalent teratogen . 8 percent of women report drinking alcohol during pregnancy , and the NBDPS identified a prevalence as high as 30 percent The spectrum of alcohol -related fetal defects known as fetal alcohol syndrome The Institute of Medicine (1996) has estimated that prevalence of the syndrome ranges from 0.6 to 3 per 1000 births . For every child with fetal alcohol syndrome , many more are born with neurobehavioral deficits from alcohol exposure (American College of Obstetricians and Gynecologist , 2013a).

13. Table 12.4

14. Figure 12.2

15. Anticonvulsant Medications Pragmatically , no anticonvulsant drugs are considered truly “ safe ” in pregnancy . This is because most medications used to treat epilepsy have been proven or suspected to confer an increased risk for fetal malformations Management of epilepsy in pregnancy , including risks associated with individual anticonvulsants Women treated with valproic acid are at significantly increased risk for malformations The most frequently reported anomalies are orofacial clefts , cardiac malformations , and neural-tube defects (Food and Drug Administration, 2009)

16. Figure 12.3

17. Angiotensin-Converting Enzyme Inhibitors and Angiotensin-Receptor Blocking Drugs Angiotensin-converting enzyme (ACE) inhibitors are considered fetotoxic and result in ACE-inhibitor fetopathy Normal renal development depends on the fetal renal-angiotensin system ACE-inhibit or medication causes fetal hypotension and renal hypoperfusion , with subsequent ischemia and anuria Reduced perfusion may cause fetal-growth restriction and calvarium maldevelopment, whereas oligohydramnios may result in pulmonary hypoplasia and limb contractures The possible embryotoxicity of these two drug classes is less certain

18. Antifungal Medications From this class of drugs , fluconazole has been associated with a pattern of congenital malformations resembling the autosomal recessive Antley-Bixler syndrome Abnormalities include oral clefts , abnormal facies , and cardiac , skull , long-bone , and joint abnormalities . Such findings have been reported only with chronic , high-dose treatment in the first trimester —at doses of 400 to 800 mg daily . The FDA (2011e) lists fluconazole as pregnancy category D, but it states that a single 150-mg dose to treat vulvovaginal candidiasis does not appear to be teratogenic

19. Anti-inflammatory Agents Nonsteroidal Antiinflammatory Drugs This drug class includes both aspirin and traditional “NSAIDs ” such as ibuprofen and indomethacin They exert their effects by inhibiting prostaglandin synthesis . At least 20 percent of pregnant women report use of these drugs in the first trimester . But, based on data from the NBDPS , such exposure does not appear to be a major risk factor for birth defects Importantly, NSAIDs may cause adverse fetal effects when taken in late pregnancy .

20. Leflunomide This is a pyrimidine-synthesis inhibitor used to treat rheumatoid arthritis It is considered contraindicated in pregnancy because when given at or below human-equivalent doses in several animal species , it is associated with multiple abnormalities . These include hydrocephalus , eye anomalies, skeletal abnormalities , and embryo death

21. Antimicrobial Drugs Medications used to treat infections are among those most commonly administered during pregnancy Aminoglycosides : Preterm infants treated with gentamicin or streptomycin have developed nephrotoxicity and ototoxicity Chloramphenicol: The gray baby syndrome was described in neonates who received the medication Nitrofurantoin : NBDPS found an association between first-trimester nitrofurantoin exposure and selected birth defects . The ACOG (2013b) has concluded that first-trimester nitrofurantoin use is appropriate if no suitable alternatives are available

22. Antimicrobial Drugs Sulfonamides : The NBDPS found associations between first-trimester exposure and a threefold increased risk for anencephaly and left ventricular outflow tract obstruction , an eightfold increased risk for choanal atresia , and a twofold increased risk for diaphragmatic hernia Tetracyclines : These drugs are no longer commonly used in pregnant women. They are associated with yellowish-brown discoloration of deciduous teeth when used after 25 weeks , although the risk for subsequent dental caries does not appear increased

23. Antineoplastic Agents Cancer management in pregnancy includes many chemotherapeutic agents generally considered to be at least potentially toxic to the embryo , fetus , or both Cyclophosphamide : Pregnancy loss is increased , and reported malformations include skeletal abnormalities , limb defects , cleft palate , and eye abnormalities Methotrexate : cause defects known collectively as the fetal methotrexate-aminopterin syndrome .

24. Antineoplastic Agents Tamoxifen : Although it has not been associated with fetal malformations , it is fetotoxic and carcinogenic in rodents, inducing malformations similar to those caused by diethylstilbestrol (DES) Trastuzumab: This drug has not been associated with fetal malformations , but cases of oligohydramnios , anhydramnios , and fetal renal failure have been described Use may result in fetal pulmonary hypoplasia , skeletal abnormalities , and neonatal death.

25. Antiviral Agents Ribavirin : This nucleoside analogue is a component of therapy for hepatitis C infection Reported malformations i nclude skull , palate , eye , skeleton , and gastrointestinal abnormalities . Efavirenz : This is a nonnucleoside reverse transcriptase inhibitor used to treat HIV infection Multiple case reports of central nervous system abnormalitie s following human exposure

26. Sex Hormones Testosterone and Anabolic Steroids : Exposure of a female fetus may cause varying degrees of virilization and may result in ambiguous genitalia similar to that encountered in cases of congenital adrenal hyperplasia Danazol : Brunskill (1992) reported that 40 percent of exposed female fetuses were virilized . There was a dose-related pattern of clitoromegaly , fused labia , and urogenital sinus malformation . Diethylstilbestrol : Herbst and associates (1971) reported a series of eight women exposed to DES in utero who developed an otherwise rare neoplasm , vaginal clear-cell adenocarcinoma

27. Immunosuppressant Medications Corticosteroids : Corticosteroids have been associated with clefts in animal studies A 10-year prospective cohort study by the same group, however, did not identify increased risks for major malformations. Radioiodine : Radioiodine is contraindicated during pregnancy because it readily crosses the placenta and is then concentrated in the fetal thyroid gland by 12 weeks . It causes irreversible fetal hypothyroidism and may increase the risk for childhood thyroid cancer Lead : Prenatal lead exposure is associated with fetal-growth abnormalities and with childhood developmental delay and behavioral abnormalities

28. Psychiatric Medications Lithium : This medication has been associated with Ebstein anomaly , a cardiac abnormality characterized by apical displacement of the tricuspid valve Selective Serotonin- and Norepinephrine Reuptake Inhibitors : these medications are not considered major teratogens The one exception is paroxetine , which has been associated with increased risk for cardiac anomalies , particularly atria l and ventricular septal defects .

29. Antipsychotic Medications There are no antipsychotic medications that are considered teratogenic . Exposed neonates have manifested abnormal extrapyramidal muscle movements and withdrawal symptoms , These findings are nonspecific and transient , similar to the neonatal behavioral syndrome that has been described following SSRI exposure An FDA (2011a) alert cited all medications in this class . These include older drugs such as haloperidol and chlorpromazine , as well as newer medications such as aripiprazole , olanzapine , quetiapine , and risperidone

30. Retinoids These vitamin A derivatives are among the most potent human teratogens. Three retinoids available are highly teratogenic when orally administered —isotretinoin, acitretin, and bexarotene By inhibiting neural-crest cell migration during embryogenesis , they result in a pattern of cranial neural-crest defects —termed retinoic acid embryopathy Specific anomalies may include ventriculomegaly , maldevelopment of the facial bones or cranium , microtia or anotia , micrognathia , cleft palate , conotruncal heart defects , and thymic aplasia or hypoplasia

31. Warfarin Like other coumarin derivatives , warfarin is a vitamin K antagonist and a potent anticoagulant It has a low molecular weight and readily crosses the placenta , causing embryotoxic and fetotoxic effects . Exposure between the 6th and 9th weeks may result in warfarin embryopath This is characterized by stippling of the vertebrae and femoral epiphyses and by nasal hypoplasia with depression of the nasal bridge Affected infants may also have choanal atresia , resulting in respiratory distress.

32. Figure 12.5

33. Recreational Drugs At least 10 percent of fetuses are exposed to one or more illicit drugs (American Academy of Pediatrics and the American College of Obstetricians and Gynecologists , 2012) Assessment of outcomes attributable to illicit drugs may be confounded by factors such as poor maternal health , malnutrition, infectious disease, and poly substance abuse Moreover, illegal substances may contain toxic contaminants such as lead, cyanide, herbicides, and pesticides.

34. Recreational Drugs Amphetamines : These sympathomimetic amines are not considered to be major teratogens Cocaine : Studies of congenital abnormalities in the setting of cocaine exposure have yielded conflicting results , but associations have been reported with cleft palate , cardiovascular abnormalities , and urinary tract abnormalities Opioids–Narcotics : As a class , opioids are not considered to be major teratogens NBDPS has identified a slightly increased risk for spina bifida , gastroschisis , and cardiac abnormalities In contrast , opioid use is strongly associated with adverse fetal and neonatal effects

35. Miscellaneous Drugs Marijuana use has not been associated with an increased risk for human fetal anomalies Phencyclidine (PCP) or angel dust is not associated with congenital anomalies . More than half of exposed newborns , however, experience withdrawal symptoms Toluene is a common solvent used in paints and glue. Occupational exposure is reported to have significant fetal risk When abused by women in early pregnancy , it is associated with toluene embryopathy

36. Tobacco Cigarette smoke contains a complex mixture of nicotine, cotinine, cyanide, thiocyanate, carbon monoxide, cadmium, lead, and various hydrocarbons In addition to being fetotoxic , many of these substances have vasoactive effects or reduce oxygen levels . Tobacco is not considered a major teratogen , although selected birth defects have been reported to occur with increased frequency among infants of women who smoke . It is plausible that the vasoactive properties of tobacco smoke could produce congenital defects related to vascular disturbances

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