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A. Major Organ Malformation navigator

  1. The embryo is most susceptible to teratogens in the 5-12 weeks LMP (first trimester)
  2. Causes of Major Organ Malformation
    1. Idiopathic 65%
    2. Congenital 25%
    3. Environmental 10%
  3. Of the environmental causes, ~10% (1% overall) are due to drugs
  4. Folate (0.4-1mg po qd) may help prevent spina bifida and other neural tube defects

B. Factors Enhancing Placental Transfer of Drugsnavigator

  1. Lipid Solubility High
  2. Unionized forms
  3. Molecular Size and Weight Low
  4. High placental blood flow
  5. Stage of Placental Development
  6. Placental metabolism
  7. Protein Binding Low

C. Drugs Compatible with Safe Pregnancynavigator

  1. Anti-Fungal Agents
    1. All topical preparations
    2. Oral fluconazole (Diflucan®) is the only systemic therapy allowed in pregnancy
  2. Specific Anti-H1-Histamines
    1. Chlorpheniramine (Chlor-Trimeton®)
    2. Azatadine (Optimine®)
    3. Loratidine (Claritin®)
    4. Not recommended: astemizol, terfanadine, brompheniramine, clemastine, hydroxazine [5]
  3. Decongestants
    1. Pseudephedrine
    2. Phenylpropanolamine
  4. Oral Contraceptives
  5. Anti-Hypertensives (Except ACE Inhibitors)
  6. Barbiturates and Diazepam (except near delivery date)
  7. Antidepressants [12]
    1. Selective Serotonin Reuptake Inhibitors (SSRI) are most commonly used
    2. SSRI's appear to be safe overall in pregnancy [12] but this is now been questioned
    3. Fluoxetine (Prozac®) associated with a slight increase in pregnancy complications when taken in 3rd trimester [8], but these effects were not seen in other studies [11,12]
    4. Tricyclic Antidepressants also appear to be safe throughout pregnancy [12]
  8. Digitalis
  9. Narcotic Analgesics - except for withdrawal syndromes
  10. ß2-Adrenergic Agonists - inhaled agents highly preferred over oral
  11. Caffeine
  12. Zidovudine (ZDV, AZT)
  13. Spermicides
  14. Lower doses of Salicylates
  15. Glucocorticoids - no association with cleft palate
  16. Mebandzole for hookworm safe in second and third trimesters

D. Teratogenic Effects [12]navigator

  1. Anticonvulsants [15]
    1. Overall risk of birth defects ~3X increased in women taking anticonvulsants
    2. Epilepsy itself confers no increased risk of birth defects
    3. Carbamazepine (Tegretol®) - neural tube defects
    4. Phenytoin (Dilantin®) - growth retardation, CNS deficits
    5. Primidone - neural tube defects
    6. Valproic Acid (Depokote®, Depokene®) - neural tube defects
    7. Benzodiazepines - neonatal withdrawal syndromes
  2. Folic Acid Antagonists [14]
    1. Trimethoprim (including TMP/SMX)
    2. Triampterene
    3. Anticonvulsants carbamazepine, phenytoin, phenobartital and primidone
    4. Methotrexate - CNS and limb malformations
    5. Neural tube, cardiovascular and urinary bladder defects and oral clefts
    6. Multivitamins containing folate reduced risks with DHFR antagonists (not anticonvulsants)
    7. Folate supplementation 400-4000µg per day during pregnancy is critical
  3. Anti-Thyroid agents
    1. Propylthiourea (PTU) and methimazole
    2. Fetal and neonatal goiter and hypothyroidism
    3. Aplasia cutis with methimazole
  4. Aminoglycosides (ototoxic)
  5. Anti-Tuberculosis Agents
  6. Lithium - Epstein's anomaly, other heart defects
  7. Vitamin A and Retinoids
    1. High doses of Vitamin A (over 10,000U per day) [6]
    2. Isotreinoin and Etretinate - CNS, craniofacial, cardiovascular and other defects
  8. Thalidomide - limb abnormalities, internal organ abnormalities
  9. Anti-Malarials - hydroxychloroquine, primaquine, mefloquine
  10. ACE Inhibitors [1,17]
    1. Unsafe when used at ANY time during pregnancy
    2. Prolonged neonatal renal insufficiency
    3. Renal tubule dysgenesis
    4. Decreased skull ossification
    5. Cardiovascular and CNS malformations when used in first trimester [17]
  11. Anticholinergic Drgus - high potency specific agents
  12. Tetracyclines - anomalies of teeth and bones
  13. Anabolic Steroids / Androgens / Danazol - masculinization of feminine fetus
  14. Warfarin - skeletal and CNS defects, midline defects, optic atrophy
  15. Cocaine
    1. Growth retartdation (weight, length, head circumference)
    2. Placental abruption
    3. Uterine rupture
  16. Fetal Alcohol Syndrome
    1. Prenatal and postnatal growth deficiency
    2. CNS anomalies - microcephaly, behvioral problems, mental retardation
    3. Short palpebral fissures, flattened maxilla
    4. Organ system malfunctions
  17. Diethyl Stilbestrol - vaginal carcinomas and other genitourinary defects in offspring
  18. Misoprostal (Prostaglandin E2) - Moebius sequence
  19. Nonsteroidal Antiinflammatory Drugs (NSAIDS)
    1. Constriction of ductus arteriosus
    2. Necrotizing enterocolitis
    3. Prevention of normal labor

E. Concerns with Drugs in Breast Feeding [13]navigator

  1. Drug used for >1 week
  2. Drug t1/2 >12 hours
  3. Drug in rapid equilibrium between plasma and milk
  4. Milk to plasma ratio >1% to >10%

F. Drugs to be Avoided in Lactating Mothers [13]navigator

  1. Anti-neoplastic agents
  2. Antibiotics
    1. Chloramphenicol
    2. Tetracyclines
    3. Sulfonamides (?)
  3. Antidepressants
    1. Fluoxetine (Prozac®)
    2. Doxepin
  4. Lithium
  5. Anxiolytics
    1. Diazepam (Valium®)
    2. Alprazolam (Xanax®)
  6. Antiinflammatory Agents
    1. Gold
    2. Methotrexate
    3. High dose aspirin
    4. Cyclosporine
    5. Azathioprine
  7. Endocrine Agents
    1. Estrogens
    2. Methimazole
    3. Bromocriptine
  8. Cardiovascular
    1. Acebutolol
    2. Amiodarone
    3. Reserpine
    4. Sotalol
    5. Nadolol
    6. Atenolol
  9. Analgesics
    1. Meperidine (Demerol®)
    2. Oxycodone
  10. Anticonvulsants
    1. Phenobarbital
    2. Ethosuximide
    3. Primidone
    4. Lamotrigine may be acceptable (~10% milk to plasma levels)
  11. Theophylline
  12. Radiopharmaceuticals - discontinue breast feeding for 1 half life
  13. Anti-helminthics
  14. Drugs of Abuse (all)
  15. Ergotamines (serotonin selective agonists are acceptable for migraines)
  16. Smoking - nicotine is secreted in breast milk
  17. Caffeine and ethanol in moderation are acceptable (see below)

G. Drugs of Choice in Breast Feeding Women [13]navigator

  1. Antibiotics
    1. Penicillins
    2. Cephalosporins
    3. Aminoglycosides
    4. Macrolides
  2. Sumatriptan (Imitrex®) - for migraine
  3. Antihistamine: Loratidine (Claritin®); older agents may cause sedation in infants
  4. Antidepressants
    1. Sertraline (Zoloft®)
    2. Tricyclic antidepressants
  5. Anticoagulants
    1. Warfarin (Coumadin®)
    2. Heparin - standard and low molecular weight
  6. Endocrine Agents
    1. Propylthiourea (PTU)
    2. Levothiroxine (Synthroid®)
    3. Insulin
  7. Glucocorticoids - inhaled, oral, injectable are all acceptable
  8. Analgesics
    1. NSAIDs of the profen class: ibuprofen, flurbiprofen
    2. Acetaminophen
    3. Morphine
  9. Anticonvulsants
    1. Carbamazepine (Tegretol®)
    2. Valproate
    3. Phenytoin (Dilantin®)
    4. Vigabatrin is probably acceptable
  10. ß-Blockers
    1. Labetolol
    2. Propranolol (Inderal®)
  11. Methadone or buprenorphine for opiate dependence
  12. Ethanol - 1 drink or less within 2 hours of breast feeding
  13. Caffeine - 6 cups of coffee per day or less

H. Helpful Agents in Pregnancynavigator

  1. Folic Acid [7,16]
    1. Correlation between erythrocyte folate levels and reduction in birth defects
    2. These defects are mainly in the neural tube
    3. Folic acid intake should be at least 0.4mg per day during pregnancy
    4. For women with a history of fetus with neural tube defects, 4mg/d folate recommended
    5. Only risk of high folate is masking vitamin B12 deficiency (uncommon before menopause)
    6. Folate supplements for ALL women attempting to become pregnant or who are pregnant
  2. Zinc [4]
    1. Daily supplementation with 25mg zinc may improve birthweight
    2. Effect is greatest in women with a low body mass index
    3. Study was done on African-American women
  3. Calcium Supplementation [3,9]
    1. Patients begin taking 2gm CaCO3 qd at 20 weeks gestation
    2. 37% decrease in HTN and also decrease risk of preeclampsia without side effects
    3. In another trial, there was no effect of CaCO3 on hypertension or preeclampsia [9]
    4. Calcium supplementation also does not reduce bone density loss during pregnancy [10]
  4. Low dose aspirin is not beneficial in pregnancy with hypertension or preeclampsia

References navigator

  1. Shotan A, Widerhorn J, Hurst A, Elkayam U. 1994. Am J Med. 96(5):451 abstract
  2. Koren G, Pastuszak A, Ito S. 1998. NEJM. 338(16):1128 abstract
  3. Belizan JM, Villar J, Gonzalez L, et al. 1991. NEJM. 325(20):1399 abstract
  4. Goldenberg RL, Tamura T, Neggers Y, et al. 1995. JAMA. 274(6):463 abstract
  5. Peggs JF, Shimp LA, Opdycke RA. 1995. Am Fam Phys. 52(2):593 abstract
  6. Rothman KJ, Moore LL, Singer MR, et al. 1995. NEJM. 333(21):1369 abstract
  7. Daly LE, Kirke PN, Molloy A, et al. 1995. JAMA. 274(21):1698 abstract
  8. Chambers CD, Johnson KA, Dick LM, et al. 1996. NEJM. 335(14):1010 abstract
  9. Levine RJ, Hauth JC, Curet LB, et al. 1997. NEJM. 337(2):69 abstract
  10. Kalkwarf HJ, Specker BL, Bianchi DC, et al. NEJM. 330(15):1062
  11. Kulin NA, Pastuszak A, Sage SR, et al. 1998. JAMA. 279(8):609 abstract
  12. Wisner KL, Gelenberg AJ, leonard H, et al. 1999. JAMA. 282(13):1264 abstract
  13. Ito S. 2000. NEJM. 343(2):118 abstract
  14. Hernandez-Diaz S, Werler MM, Walker AM, Mitchell AA. 2000. NEJM. 343(22):1608 abstract
  15. Holmes LB, Harvey EA, Coull BA, et al. 2001. NEJM. 344(15):1132 abstract
  16. Folic Acid Supplementation. 2004. Med Let. 46(1177):17 abstract
  17. Cooper WO, Hernandez-Diaz S, Arboast PG, et al. 2006. NEJM. 354(23):2443 abstract