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EFFECT OF MATERNAL DRUGS ON FETUS. Congenital Malformations 3-4% of all babies are born with a major birth defect Of these, 50% are of unknown cause.

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Presentation on theme: "EFFECT OF MATERNAL DRUGS ON FETUS. Congenital Malformations 3-4% of all babies are born with a major birth defect Of these, 50% are of unknown cause."— Presentation transcript:

1 EFFECT OF MATERNAL DRUGS ON FETUS

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3 Congenital Malformations 3-4% of all babies are born with a major birth defect Of these, 50% are of unknown cause Consider teratogen exposure and realize genetics plays a role

4 TERATOGENS A substance, organism, physical agents or deficiency state capable of inducing abnormal structure or function such as: Gross structural abnormalities Functional deficiencies Intrauterine growth restriction Behavioral aberrations

5 Teratogenic agents 1) Drugs and chemicals 2) Infectious agents 3) Radiation 4) Other

6 Teratogenic Factors Time of exposure Developmental stage during exposure Maternal dose and duration Maternal pharmacokinetics Genetic factors/phenotypes Interactions between agents

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8 TERATOGENIC EFFECT

9 Drug Transfer to the Fetus Placental transfer may occur by: Passive diffusion Facilitated diffusion Active transport Placental surface area Placental metabolism

10 Drug use in pregnancy Drugs can be harmful for the unborn fetus Across Placenta Molecular weight Lipid solubility Ionization Protein binding Chemical Structure

11 Fetal Drug Disposition 60 – 80% passes through liver, the rest travels through ductus venosus to heart and brain Hepatic drug metabolism Adrenal gland metabolism Recirculation through amniotic fluid

12 Drug use in pregnancy Effects of toxic drugs malformation growth retardation fetal death functional defects in newborn premature birth

13 Risk classifications Different risk classifications have been proposed. The FDA risk classification is widely used Risk classification of FDA drug risks to the fetus runs from: Category A (safest) → Category X (known danger--do not use!) Different risk classifications have been proposed. The FDA risk classification is widely used Risk classification of FDA drug risks to the fetus runs from: Category A (safest) → Category X (known danger--do not use!)

14 FDA Risk Categories A- Studies on humans; no risk B- Animal studies- no risk; No human studies C- Either animal studies show adverse effect and no human studies or no animal or human studies (benefit should outweigh risk) Drugs should be given only if the potential benefit justifies the potential risk to the fetus. Drugs should be given only if the potential benefit justifies the potential risk to the fetus.

15 FDA Categories (cont) D- Positive evidence of human risk(drug is needed in a life-threatening situation or for a serious disease for which safer drugs cannot be used or are ineffective). X- Positive evidence of human risk; risk outweighs benefit and drug is contraindicated outweighs benefit and drug is contraindicated Thalidomide, DES (diethylstilboestrol)., Thalidomide, DES (diethylstilboestrol).,

16 Anti-infectives PenicillinsCephalosporinsCarbapenemsFluoroquinolonesMacrolidesAminoglycosides Sulfonamides Antivirals Antiretrovirals Antifungals

17 Penicillins Category B in pregnancy Category B in pregnancy Cross the placenta easily and rapidly Concentrations increased in maternal levels

18 Cephalosporins Category B in pregnancy Cross the placenta during pregnancy Some reports of increased anomalies with specific cephalosporins (cefaclor, cephalexin, cephradrine) Primarily cardiac and oral cleft defects

19 Carbapenems (ertapenem, imipenem, meropenem) Category B/C/B in pregnancy Likely cross the placenta Very little human data

20 Fluoroquinolones (floxins) Pregnancy Category C Not recommended in pregnancy Cartilage damage

21 Macrolides (azithromycin, clarithromycin, erythromycin) Pregnancy Categories B/C/B Cross the placenta in low amounts Limited data with azithromycin and clarithromycin

22 Aminoglycosides (amikacin, gentamicin, tobramycin) Pregnancy Category C Rapidly cross placenta Enter amniotic fluid through fetal circulation

23 Sulfonamides Pregnancy Category C Readily cross the placenta Concerns of use at term

24 Antiepileptics Risk for syndrome 10% Dilantin- phenytoin syndrome Microcephaly Nail dysplasia Developmental delay Risk for some adverse effect (low IQ)- 30%

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26 Accutane X Vitamin A derivative Retinoic acid Timing is key- beyond 15 days postconception Dose specific

27 Accutane Risk of syndrome % Microcephaly/hydrocephaly CHD Microtia Cleft lip/palate Risk of spontaneous abortion- 25% Risk of stillborn

28 Anticoagulants Warfarin: D Exposure- 4-7 weeks Fetal warfarin syndrome: 10% Hemorrhage Depressed nasal bridge Spontaneous abortion / stillbirth- 25%

29 Heparin Not teratogenic

30 Angiotensin-converting enzyme inhibitor D Reduced fetal renal blood flow Fetal anuria IUGR Oligohydramnios

31 Tetracyclines Maternal- IV use in pregnancy: acute fatty liver, hepatotoxicity decidual bone/teeth: forms a complex calcium orthophospphate complications Minor anomalies?

32 Quinolone Animal studies Fetal death, neonatal death, preterm delivery, IUGR Anomalies: nonspecific 1000 exposed women: no increase in adverse effects Birth Registry: No increased risk Use alternatives:

33 Lithium 11% malformations rate- 1st trimester exposure Most were CV defects Risk of rare Ebstein’s anomaly Neonatal toxicity (1-2 weeks)

34 Antivirals (acyclovir, famciclovir, valacyclovir) Pregnancy Category B Acyclovir and valacyclovir readily cross the placenta Can be used for HIV treatment and suppression

35 Antiretrovirals zidovudine Pregnancy Category C Maternal benefit usually outweighs fetal risk Cross the placenta by simple diffusion Zidovudine is commonly used, but may cause neonatal anemia

36 Antiretrovirals( nevirapine) Pregnancy Category C Maternal risk usually outweighs fetal risk Likely cross into fetus Nevirapine can cause hepatotoxicity and rash Nevirapine can be used as a single dose in labor to prevent HIV transmission

37 Antifungals/Azoles (fluconazole, ketoconazole) Pregnancy Categories C/D Likely cross placenta Fluconazole > 400mg/day seems to be associated with cranio-facial abnormalities Ketoconazole can impair cortisol synthesis

38 Ergots (Dihydroergotamine, ergotamine) Pregnancy Category X Oxytocic properties could cause IUGR by vascular disruption or increased uterine tone Early exposure appears safe, not teratogens Chronic exposure is contraindicated

39 Frequently used teratogenic agents Alcohol Smoking orofacial clefts 1/500 – 1/183 lower birth weight premature birth

40 Alcohol 1-2% women of child-bearing age have an alcohol abuse problem Fetal alcohol syndrome- most common cause of mental retardation in the US Craniofacial skeletal abnormalities growth retardation mental disorders

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42 Nicotine is a Neuroteratogen Cell damage and deficits in cell number Impaired synaptic activity Receptor-Mediated, therefore low threshold Affects Cell Replication/Differentiation Switchover Initiates the Program for Cell Death Morphological changes subtle but detectable in adulthood

43 Maternal Cigarette Smoking Effects on Fetal Brain General Development Hypoxia/Ischemia CO, HCN Anorexia Maternal-Fetal Unit Nicotine in Fetus Perinatal Morbidity/Mortality Growth Retardation Behavioral Anomalies Risky Behaviors: Other drugs/alcohol Prenatal Care Socioeconomic

44 Frequently used teratogenic agents Coffee > 300 mg caffein/day (>3-6 cups of coffee) ↑ risk of fetal death advice: limit coffee to 3 cups/day Coffee > 300 mg caffein/day (>3-6 cups of coffee) ↑ risk of fetal death advice: limit coffee to 3 cups/day Vitamin A teratogenic in animal model, in human beings? avoid > 3 mg = IE liver contains large amounts of vitamin A Vitamin A teratogenic in animal model, in human beings? avoid > 3 mg = IE liver contains large amounts of vitamin A

45 Herbs use in pregnancy Herbs not recommended nettle root alkaloid-containing herbs coffee, mandrake (podophyllin) … essential oils rosemary … anthraquinone laxatives senna … herbs with potential hormonal action hops, ginseng, licorice …

46 Drug use in pregnancy Use of drugs in pregnancy is not always wrong Drugs should be used with caution during pregnancy

47 Thank you


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