Reproductive Hazard Myth vs Reality

1. Reproductive HazardMyth vs Reality Fred Fung, M.D., M.S. SRSMG, UCSD, UCI

2. Pre-test • Female reproductive system # ova produced in a woman’s life time? • Male reproductive system # days testes need to produce sperms? • Placenta Why is heparin safer than coumadin? • Fetus Time frame for organogenesis?

3. Overview • Medical-legal context* • Definitions • Toxicology principles • Lessons from the past* • Evaluation strategies and Practice guidelines* • Resources

4. Workforce demographics • A gradual shift of workforce demographics over the last 2-3 decades • 50% women constitute today’s workforce • Many take up jobs traditionally held by men • Most of them in reproductive age

5. Common questions From employee: • Doctor, am I safe to work here? • Is my baby going to be ok if I work with…? From employer: • Is it safe for her to work with…? • How soon can she return to work?

6. A medical-legal issue • 1978 Pregnancy Protection Act and Title VII Civil Rights Act of 1964 • 1982 Johnson Controls: Fetal protection policy (shifts from warning to exclusion) • 1984: UAW v Johnson Controls over prohibiting female workers from working with lead

9. Legal battles • Is it lawful to exclude female employees from jobs for hazard concerns over fetus? • Lead exposure and potential adverse fetal outcome at issue • First round: Federal District Court • Second round: Appeals Court • Final round: US Supreme Court

10. US District Court, 7th Circuit Court-Summary J.

11. What is the core issue? • Plaintiff: direct violation of PDA • Defense: Business necessity (safety argument) and BFOQ • A 3-step decision. Substantial risk to fetus? Transmission of hazard via women? Availability of less discriminatory alternative? • BFOQ: condition of employment-sterility

12. 1991 Supreme Court-reverses lower courts decisions

13. The final decision • US Supreme Court unanimous decision: beneficence of policy still violates PDA, fetal welfare/safety a parental decision, tort remote if employer abides by all regs • Johnson Controls fetal protection policy is a prima facie sex discrimination, thus illegal

14. Scope of problem • 4 million live births/y US 2002 • 120,000 babies with BD each year • Baseline 3/100 live births have birth defect • Why focus on birth defects? • Reproductive injury/fetal loss is generally not covered under work comp-why?

16. Definitions • A teratogen is defined as a substance, organism, or physical agent to which an embryo or fetus is exposed that produces a permanent abnormality in structure or function, causes growth retardation, or causes death. • There are no absolute teratogens • Toxicity: inherent ability to induce injury • Hazard: potential of toxicity • Risk: probability of damage to life/health will occur for a given hazard. May include outrage

17. Sources of exposure • Occupational: 90,000 chemicals in use • 4~5000 tested for teratogenicity • 2/3 negative, 1/3 positive or equivocal • Only 30 agents documented teratogens • Habits and meds: 30-70% pregnant women use caffeine, alcohol and cigarettes • Illicit drugs: 15-25% pregnant women use sometime during pregnancy- cocaine, MJ

18. Human teratogens • Infection: TORCH, syphilis • Metabolic: folate deficiency, DM • Medication/drug: alcohol, anticonvulsants, retinoids, DES, thalidomide, alkylating agents, cocaine, cigarette smoking • Metals/chemicals: Pb, Hg, Cd, DCBP, OCl, EtO, anesthetic gases, dioxins, PCB • Radiation: therapeutic, diagnostic, fallout

19. Severity and frequency • Quality- severity, nature of hazard, clinical significance • Quantity-number at risk, frequency of occurrence, statistical significance

20. Importance of severity and frequency Rubella: 40-60% birth defect Toxo: 10% major birth defect CMV: 1-2% major birth defect Alcohol: 4-40% FAS DM: <10% good control, 5-35% poor control DBCP:12% azoospermia,12% hypospermia; Methyl Hg: 10% Minamata Bay syndrome Dilantin/valproate 1% fetal hydantoin synd. Folate def: 30% NTD

21. FDA classification of drugs • A- safety established in human studies, only thyroid hormone, folic acid, prenatal vitamins (Tylenol under Australian ADEC) • B-presumed safety based on animal studies (Amoxicillin) • C- safety uncertain, no studies (most drugs) Celebrex other NSAIDs • D- Unsafe, risk benefit analysis needed (Tetracycline) • X- highly unsafe e.g. Accutane, BCP

22. Occupational smellers-What’s in body odor?

23. Placenta

24. Basic concept • Almost all agents can be teratogenic under certain circumstances. The dose and time of the exposure to a particular agent often determines the severity of the damage and the type of damage that occurs. • Types of teratogens: radiation, infections, drugs, metabolic disorders and environmental chemicals Semin Reprod Med 18(4):407-424, 2000

26. How does teratogenesis occur? • DNA replication may result in incorporation of the wrong bases (baseline) • DNA exposed to mutagens/teratogens: • High energy radiation: UV, X-rays, radioactivity • Chemicals that react or bind to DNA • Chemicals which when metabolized generate reactive oxygen compounds that damage DNA

27. Toxicology principles • Basic principles still apply: exposure, absorption, distribution, metabolism, elimination • Dose-response still holds, i.e. threshold concept is good • Multi-multi-compartment model • Embryo remarkable restorative ability-DNA repair and proof-reading

29. Pharmacokinetic changes • Increase in: gastric pH, GI transit time, Vd, GFR • Decrease in: P450 CYP1A2, Protein binding • Toxin  maternal exposure  maternal factors placental factors  fetal factors • CYP1A2 drugs: caffeine, diazepam, warfarin, TCA

30. Brief history • Teratology-relatively new science • Teras- Gk for monster • Mythology- cyclops, sirens • Maternal impression- listening to Mozart or looking at beautiful things • Late 1800s, 1900s- genetics • 1930s- induced birth defects animal study

31. Important historical events • 1941- 1st human epidemic of birth defects from a natural environmental/infectious agent

32. Rubella • 1st, 2nd month gestation infection- heart and eye • 3rd month- hearing and speech

33. Rubella cases drop after vaccination starts

34. First drug induced birth defect • 1960s- infants with limb abnormalities (Hamburg U.)

35. Phocomelia • Amelia- absence of limbs • Phokos- seal • Phocomelia- seal limbs • Taussig HB. A study of German outbreak of phocomelia (JAMA 1962, 180:1106) • First 2 cases presented 1960, no attention • All physicians knew about it by 1962

37. Thalidomide • Ciba developed it as anticonvulsant, worthless but caused sedation • Found no fetal effects on animals (rodents) • Marketed as sedative for mental patients • Sold as OTC, 3rd best selling drug in Europe • Used illegally as sleeper in US

38. Astonishing discovery • Dr. Francis Kelsey, new physician scientist given drug application on Thalidomide as her first assignment 9/12/1960 • Told an easy project, not to be so! • Found side effects of peripheral neuritis, concerned about fetal effects- no data • Never approved for pregnancy use

39. Thalidomide • Gestational time critical • 40-44 days most sensitive time • Hypothesis- inhibits angiogenesis down regulates adhesion receptors reduces phagocytosis of PMNs

40. More about Thalidomide • Approved by FDA July 16, 1998 • Current indications: erythema nodosum leprosum with disfiguring lesions • Also for aphthous stomatitis, graft v host, multiple myeloma • Must be in STEPS (System for Thalidomide Education, Prescription Safety) program

41. Why didn’t rodents show defects? • Thalidomide poorly absorbed by rodents PO • Human more sensitive to teratogenic effects of thalidomide

42. Acne and teenager • Tragic combination if Accutane used in early pregnancy • 1st reported 1954, offsprings from female rats fed with high Vit A had birth defects • Similar cells affected as in FAS • Cardiovascular- tetralogy of Fallot, VSD • Most sensitive: 3-5 weeks gestation

43. Chemical Structures of (a) Vitamin A (b) Isotretinoin a) Vitamin A is formed by carboxylation of the aldehyde group (OH). b) Isotretinoin is also called 13-cis retinoic acid.

44. Isotretinoin Malformation Source: Jones KL. Smith’s Recognizable Patterns of Human Malformation, 5th Ed. London: W.B. Saunders, 1996.

45. Isotretinoin Deformity Source: Jones KL. Smith’s Recognizable Patterns of Human Malformation, 5th Ed. London: W.B. Saunders, 1996.

46. Retinoic acid • FDA: 12/31/2005 • iPLEDGE program • Prescriber and user must register • 2 neg preg tests prior to filling Rx • Each month must enter by internet or phone 2 types of BC while on Rx and one month after

47. Other teratogens • Infectious agents: TORCH • Metabolic: DM, alcoholism • Drugs: warfarin, antiepileptics, cocaine • Heavy metals: Pb, Cd, Hg • Radiation

48. FAS • Growth retardation • CNS degeneration • Simian crease on palms • Facial dysmorphology Microcephaly, broad nasal bridge, epicanthal folds, thin upper lip

49. Fetal alcohol syndrome • First described by Lemoine 1968 • Landmark paper Lancet 1973

50. Normal vs FAS brain