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drugs in pregnancy

drugs in pregnancy

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drugs in pregnancy

  1. 1. Drugs in pregnancy  SAMEERSALEH SAWAED  2016
  2. 2. Drug Epidemiology  More than 50% of pregnant women take prescribed or non- prescribed (OTC) drugs or use social drugs (such as tobacco and alcohol) or illicit drugs at some time during pregnancy.  In general, drugs should NOT be used during pregnancy unless absolutely necessary because many can harm the fetus.  About 2-3% of all birth defects result from drugs that are taken to treat a disorder or symptom.
  3. 3. Drug Disposition In The Maternal-fetal Unit
  4. 4. Maternal Pharmacokinetics  Changes in body fluid volume  Changes in CVS parameters  Changes in pulmonary function  Alterations in gastric activity  Changes in serum binding protein concentrations and occupancy  Alterations in kidney function
  5. 5. Fetal Pharmacokinetics  Plasma binding proteins differ from maternal.  Drugs transferred across placenta undergo 1st pass through the fetal liver.  Liver expresses metabolizing enzymes, but capacity less than mother.  Fetal kidney immature.
  6. 6. Placental Pharmacokinetics  Blood flow through the placenta (maternal side) increases during gestation  Transfer of flow-limited drugs affected by placental flow  Compounds that alter blood flow alter maternal drug disposition and placental transfer  Placental metabolism (dealkylation, hydroxylation, demethylation) affects drug transfer across the placenta  At term, the surface area of the placenta is at its maximum and nearly all substances can reach the fetus
  7. 7. Drug Transfer  Most drugs have a molecular weight below 1000 daltons (D)  Drugs  1000 D cross the placenta ( 500 D cross easily)  Main determinant of the drug concentration in the embryo/fetus is the mother's blood concentration  Other factors:- lipid solubility & protein binding degree of ionization at physiologic pH placental blood flow & surface area available for transfer
  8. 8. The Processes That Govern The Passage Of A Drug Into Milk Are Similar To The Placenta  Maternal serumconcentration is the main determinant  The milk pH is slightly acidic in comparison to serumpH; so weak bases couldbecome trappedin milk (ion trapping).
  9. 9. Fetal Age Affects The Type Of Drug Effect:  Before the 20thday after fertilization :  (all-or-nothing effect), Teratogenesis is unlikely during this stage.  During organogenesis (between 20 and 56 days after fertilization):  Teratogenesis is most likely at this stage, spontaneous abortion, gross anatomic defect (true teratogenic effect), or the drugs may have no measurable effect.  After organogenesis (in the2nd and 3rd trimesters):  Teratogenesis is unlikely, but drugs may alter growth and function of normally formed fetal organs and tissues
  10. 10. Timing Of The Development Of Major Body Structures In The Embryo And Fetus
  11. 11. Type Of Effects  Teratogenicity (e.g. thalidomide) - detected at, or shortly after, birth .  Long term latency (e.g. DES - increased risk of vaginal adenocarcinoma after puberty, or abnormalities in testicular function and semen production) .  Predisposition to metabolic diseases (e.g. Barker hypothesis - low birth weight associated with increased risk of diabetes, hypertension, heart disease in adulthood).  Impaired intellectual or social development(e.g. exposure to phenobarbitone- alters programming of brain)
  12. 12. Teratogenesis
  13. 13. Teratogenesis  It is defined as structural or functional dysgenesis of the fetal organs.  Typical manifestations include congenital malformations with varying severity intrauterine growth restriction carcinogenesis fetal demise  In humans, the critical time for drug-induced congenital malformations is in the first trimester
  14. 14. Malformations  The overall incidence of major congenital malformations is around 2-3% minor malformations is 9% 25% are due to genetic or chromosomal abnormalities 10% due to environmental causes including drugs 65% of unknown aetiology  The part played by drugs is probably small
  15. 15. Organogenesis  The critical time for drug-induced congenital malformations is usually the period of organogenesis about 20 to 55 days after conception about 34 to 69 days (5-10 weeks) after the first day of the LMP  If a drug is given after this time it will not produce a major anatomical defect, but more of a functional one
  16. 16. Pregnancy Risk Categories - FDA  Category |A| Safety has been established using human studies, no fetal risk.  Category |B| Presumed safety based on animal studies, but no well- controlled human studies.  Category |C|Uncertain safety. Animal studies show an adverse effect, no human studies.  Category |D| Evidence of fetal risk, but benefits outweigh risks.  Category |X| Highly unsafe. Risk outweighs any possible benefit.
  17. 17. Antibiotics Category |B| Penicillin | Cephalosporin | Macrolides | Nitrofurantoin | Metronidazole | Vancomycin (oral)
  18. 18. Antibiotics… Cont.  Penicillin one of the safest antibiotics that could be used in pregnancy  Cephalosporin one of the safest antibiotics in pregnancy  Macrolides; erythromycin& azithromycin can be used.  Nitrofurantoin;Commonly used in pregnancy to treat UTI should not be given to women in late pregnancy due to the potential risk of hemolytic anemia in the newborn.  Metronidazole; not recommended for lactation  Vancomycin (oral); possible fetal ototoxic effect
  19. 19. Antibiotics… Cont. Category |C| Aminoglycoside [neomycin – tobramycin]| Quinolones | Trimethoprim | Chloramphenicol Quinolones [ciprofloxacin – levofloxacin]; There are safety concerns of fluoroquinolone use during pregnancy and, as a result, are contraindicated except for when no other safe alternative antibiotic exists. Trimethoprim; can affect folate metabolism, so; relatively contraindicated during pregnancy, especially the 1st trimester. Chloramphenicol; Gray Baby Syndrome
  20. 20. Antibiotics… Cont. Category |D| Tetracycline | Aminoglycosides [streptomycin – gentamicin] Tetracycline; use during tooth development can cause permanent discoloration & enamel hypoplasia. Aminoglycosides [streptomycin – gentamicin]; hearing deficit & 8th cranial nerve damage
  21. 21. Antivirals Acyclovir |B| recommended for treatment of Varicella during pregnancy, especially during the 2nd and 3rd trimesters Amantadine|C| CHD; tetralogy of Fallot / single ventricle with pulmonary atresia Anti-retroviral agents|B| [Didanosine – Etravirine – Ritonavir – Enfuviritide – Maraviroc] Anti-retroviral agents|C| [Lamivudine – Delaviridine – Indinavir ]
  22. 22. Antifungals Category |B| Amphotericin b | remains the drug of choice for systemic fungal infections in pregnancy despite its serious side effects i.e. renal toxicity Terbinafine; approved for the treatment of onychomycosis
  23. 23. Antifungals… Cont. Category |C| Ketoconazole; inhibits placental microsomal aromatase & cytochrome P-450
  24. 24. Antifungals… Cont. Category |C/D| Fluconazole; depends on doses & duration of use
  25. 25. Antifungals… Cont. Category |X|  Griseofulvin; contraindicated during pregnancy & pregnancy should be avoided for 1 month after treatment
  26. 26. Antimalarial  Chloroquine**; drug of choice for the prophylaxis and treatment of sensitive malaria species during pregnancy.
  27. 27. Thalidomide*** Potent Teratogen |X| was used against nausea and to alleviate morning sickness in pregnant women.  Meromelia  CHD  Eye abnormalities  Facial Palsy Phocomelia
  28. 28. Cytotoxic Drugs  Methotrexate*** |X|; Potent teratogen that produces major congenital anomalies.  Cyclophosphamide*** – Chlorambucil ***|D|; Teratogenic: - growth restriction - ear and facial abnormalities - absence of digits - hypoplastic limbs
  29. 29. Cytotoxic Drugs… Cont.  Azathioprine** |D|; can cause birth defects  Cyclosporine***|C|; does not appear to be a major human teratogen; but could cause complications like: - Preeclampsia - Eclampsia - Oligohydramnios
  30. 30. Anti-inflammatory Drugs NSAIDs:  Aspirin*** |D| in 3rd trimester  Ibuprofen*** – diclofenac** - celecoxib* |D|; >30 weeks could cause premature closure of DA
  31. 31. Anticonvulsants Phenytoin** - Carbamazepine** |D|; Potent teratogen Fetal HydantoinSyndrome || 5-10% - IUGR - Craniofacial anomalies - Developmental delay - Mental retardation
  32. 32. Anticonvulsants… Cont.  Valproic Acid*|D| - neural tube defects - cognitive impairment - dysmorphic features - risk of autism
  33. 33. Diethylstilbestrol [Des] Human teratogen |X| - Vaginal adenosis - Cervical erosions - Transverse vaginal ridges - Vaginal adenocarcinoma
  34. 34. Vitamin A Analogues  Isotretinoin*** |X|; Potent teratogenic - Severe birth defects - Neuropsychological impairment - Spontaneous abortion - Premature birth - Fetal death - Internal abnormalities
  35. 35. ANTICOAGULANTS  WARFARIN • Adverse effects when given during the 1st trimester, fetal warfarin syndrome (e.G. Nasal hypoplasia, epiphyses stippling, bilateral optic atrophy, various degrees of intellectual disability) • Adverse effects when given during the 2nd or 3rd trimester, optic atrophy, cataracts, intellectual disability, microcephaly, microphthalmia, and fetal and maternal hemorrhage. • FDA Pregnancy category |X/D| for women with mechanical heart valves who are at high risk for thromboembolism.  HEPARIN • Heparins are used for the management of venous thromboembolism in pregnancy because they do not cross the placenta. • FDA Pregnancy category: Low molecular weight heparin: |B| Unfractionated heparin: |C|
  36. 36. Cardiovascular drugs  ACE inhibitors, ARBs  Contraindicated in pregnancy. FDA pregnancy category |C| for the 1st trimester of pregnancy and |D| during the 2nd and 3rd trimesters.  Prenatal exposure to an ACE inhibitor (e.g. enalapril) or to an angiotensin II receptor antagonist (e.g. losartan) during the 2nd or 3rd trimester of pregnancy is associated with an increased risk for fetal hypotension, renal failure, and oligohydramnios leading to fetal growth restriction, joint contractures, pulmonary hypoplasia, & stillbirth or neonatal death.  β-Blockers  FDA Pregnancy category |C|  Can cause Fetal bradycardia, hypoglycemia, & possibly fetal growth restriction
  37. 37.  Amiodarone  FDA pregnancy category |D|; should only be given during pregnancy when there are no alternatives and benefit outweighs risk.  Ca channel blockers  When given during the 1st trimester, possibly phalangeal deformities  When given during the 2nd or 3rd trimester, fetal growth restriction  FDA Pregnancy Category |C|  Methyldopa  FDA Pregnancy Category |B|
  38. 38.  Thiazide diuretics  Can cause neonatal hyponatremia, hypokalemia, & thrombocytopenia  FDA Pregnancy Category |D|  Statins  FDA pregnancy category |X|  statins should be avoided during pregnancy – congenital anomalies have been reported.
  39. 39. Insulin & Hypoglycemic Drugs  insulin is the treatment of choice for diabetes during pregnancy.  Neonates born to mothers with diabetes who are taking oral hypoglycaemics in pregnancy may have hypoglycaemia.  Metformin is FDA pregnancy category |B|.
  40. 40. Progesterone  Danazol, Synthetic progestin (but not the low doses used in oral contraceptives), when given during the first 14 wks., masculinization of a female fetus's genitals. FDA pregnancy category |X|  progestin exposure is associated with an increased prevalence of cardiovascular abnormalities.  Combined Oral contraceptive pills, when taken during the early stages of an unrecognized pregnancy, are believed to be teratogenic agents.
  41. 41. Antithyroid drugs  Carbimazole - Propylthiouracil (PTU)  Both drugs cross the placenta and may cause fetal hypothyroidism in high doses. PTU is preferred for new cases as there is less transfer across the placenta. Corticosteroids  When used during the 1st trimester, possibly orofacial clefts  FDA pregnancy category |B|  Hydrocortisone and prednisolone are largely (90%) metabolized by placental dehydrogenase, but fluorinated corticosteroids (e.g. betamethasone) and dexamethasone are not, thus making them the drugs of choice when treating the fetus is the aim of therapy, such as for fetal lung maturation.
  42. 42. GI drugs  Omeprazole does not seem to be teratogenic, but less is known about other PPIs during pregnancy.  Ranitidine crosses the placenta. Although the manufacturer advises use should be avoided during pregnancy, epidemiological study reveals no increased prevalence of adverse fetal outcomes. Rodent teratogenicity studies are reassuring.  Metoclopramide has been assigned to pregnancy category B by the FDA Dermatologic agents  Based on large population-based follow-up studies, topical corticosteroids are generally considered safe for use at any stage of pregnancy.
  43. 43. Benzodiazepines  FDA pregnancy category |D|  If benzodiazepines (especially those with a long half-life) are taken in late pregnancy, they can cause neonatal respiratory depression, poor temperature regulation, poor feeding and hypotonicity.  There is a risk of neonatal withdrawal symptoms and craniofacial anomalies.  Avoid regular use and use only if there is a clear indication such as seizure control. Lithium  FDA pregnancy category |D|  Neonatal lethargy, hypotonia, poor feeding, hypothyroidism, goiter, and nephrogenic diabetes insipidus  Increased risk of Ebstein’s anomaly when it is used in early pregnancy.
  44. 44. SSRI  Fluoxetine (category |C|) is the SSRI with lowest known risk in pregnancy.  Paroxetine is category |D|  SSRIs should not be used during pregnancy unless the potential benefit outweighs the risk.  There is a small increased risk of congenital heart defects when SSRIs are taken during early pregnancy.  If SSRIs are used during the third trimester there is a risk of neonatal withdrawal symptoms, and persistent pulmonary hypertension in the newborn has been reported.
  45. 45. Opioids  Codeine, Meperidine, Morphine  FDA pregnancy category |C|  In neonates of women addicted to opioids, withdrawal symptoms possibly occurring 6 h to 8 days after birth  With high doses given in the hour before delivery, possibly neonatal CNS depression and bradycardia Tricyclic antidepressants  Tricyclic antidepressants (amitriptyline, imipramine, & nortriptyline) have lower known risks than other newer antidepressants.
  46. 46.  There is no convincing evidence that any of the drugs commonly used to treat respiratory disorders cause particular problems during pregnancy.  Pseudoephedrine: possible risk of gastroschisis. FDA pregnancy category |C|  Loratadine; Possible risk of hypospadias. FDA pregnancy category |B|
  47. 47. Vaccines  Killed virus, toxoid, or recombinant vaccines may be given during pregnancy.  Live attenuated vaccines (varicella, measles, mumps, polio, and rubella) should be given 3 months before pregnancy or postpartum. Live virus vaccines are contra-indicated in pregnancy secondary to the potential risk of fetal infection.
  48. 48. Caffeine  Whether consuming caffeine in large amounts can increase perinatal risk is unclear. Consuming caffeine in small amounts(e.g. 1 cup of coffee/day) appears to pose little or no risk to the fetus.  Some data, which did not account for tobacco or alcohol use, suggest that consuming large amounts increases risk of stillbirths, preterm deliveries, low birth weight, and spontaneous abortions. Aspartame (artificial sweetener)  Use during pregnancy is often questioned.  The most common metabolite of aspartame, phenylalanine, is concentrated in the fetus by active placental transport; toxic levels may cause intellectual disability. However, when ingestion is within the usual range, fetal phenylalanine levels are far below toxic levels. Thus, moderate ingestion of aspartame (e.g. no more than 1 liter of diet soda per day) during pregnancy appears to pose little risk of fetal toxicity.
  49. 49. Smoking  Carbon monoxide and nicotine in cigarettes cause hypoxia and vasoconstriction, increasing risk of spontaneous abortion, fetal growth restriction, abruptio placentae, placenta previa, premature rupture of the membranes, preterm birth, chorioamnionitis, and stillbirth.  Neonates whose mothers smoke are also more likely to have anencephaly, congenital heart defects, orofacial clefts, sudden infant death syndrome, deficiencies in physical growth and intelligence, and behavioral problems.  Smoking during pregnancy is linked to childhood asthma.
  50. 50. Alcohol  Increases risk of spontaneous abortion.  Decreases birth weight by about 1 to 1.3 kg if regular drinking.  Binge drinking in particular can cause fetal alcohol syndrome. This syndrome may include fetal growth restriction, facial and cardiovascular defects, neurologic dysfunction, Vision or hearing problems, behavioral, and intellectual disabilities.  It can cause neonatal death due to failure to thrive (FTT)

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drugs in pregnancy


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