fung

Reproductive HazardMyth vs Reality: 

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

Pre-test: 

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?

Overview: 

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

Workforce demographics : 

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

Common questions: 

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?

A medical-legal issue : 

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

Legal battles: 

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

Slide 10: 

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

What is the core issue?: 

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

Slide 12: 

1991 Supreme Court-reverses lower courts decisions

The final decision: 

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

Scope of problem: 

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?

Definitions: 

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

Sources of exposure: 

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

Human teratogens: 

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

Severity and frequency: 

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

Importance of severity and frequency: 

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

FDA classification of drugs: 

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

Slide 22: 

Occupational smellers-What’s in body odor?

Placenta: 

Placenta

Basic concept: 

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

How does teratogenesis occur?: 

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

Toxicology principles: 

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

Pharmacokinetic changes: 

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

Brief history: 

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

Important historical events: 

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

Rubella: 

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

Slide 33: 

Rubella cases drop after vaccination starts

First drug induced birth defect: 

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

Phocomelia: 

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

Thalidomide: 

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

Astonishing discovery: 

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

Thalidomide: 

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

More about Thalidomide: 

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

Why didn’t rodents show defects?: 

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

Acne and teenager: 

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

Slide 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.

Slide 44: 

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

Slide 45: 

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

Retinoic acid: 

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

Other teratogens: 

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

FAS: 

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

Fetal alcohol syndrome: 

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

Normal vs FAS brain: 

Normal vs FAS brain

FAS: 

FAS Zinc theory- maternal Zn def, impaired zinc metalloenzymes (aldehyde dehydrogenase), impaired fetal growth (protein synthesis) Other factors: timing, nutrition, genetics… Not 100% heavy pregnant drinkers beget FAS babies

Minamata Bay: 

Minamata Bay Inorganic mercury from plastics factory discharge into downstream bay, converted by bacteria into methyl mercury Cats ate fish had unsteady gait Mothers had no obvious symptoms Babies had congenital abnormalities CP, mental retardation, microcephaly

Folic acid deficiency-neural tube: 

Folic acid deficiency-neural tube

Warfarin: 

Warfarin 1st described in 1980 case series Nasal hypoplasia, short fingers, stippled epiphyses. No effect on clotting factors. Crosses placenta, embryo Vit K deficient Inh Vit K  inhibits GLA proteins (osteocalcins) in bone/cartilage Abn cartilage growth/calcification similar to Chondrodysplasia punctata genetic defect

Antiepileptics/anticonvulsants: 

Antiepileptics/anticonvulsants Maternal seizure in 1st trimester-risk per se Fetal hydantoin syndrome- hypoplasia of nails/fingers, digitized thumb, hirsutism Orofacial defects-low nasal bridge, bowed upper lip, cleft lip/palate Epoxides bind with fetal nucleic acids Epoxide hydrolase activities differ Inh K channel-bradycardia, fetal hypoxia

Diagnostic strategies: 

Diagnostic strategies Medical history Symptoms and signs Hobby, family and genetic history Partner history Physical exam Tests Prenatal tests Work place surveillance

What caused my baby to have a birth defect?: 

What caused my baby to have a birth defect? Scientific causation analysis What exact birth defect is it “X”? Can this substance “Y” cause birth defect? Did Y cause X?

Reproductive hazard management: 

Reproductive hazard management Hazard elimination and exposure control Exposure control monitoring Risk: no absolute risk free Risk Communication: put in perspective Require notification of pregnancy Temporary reassignment

Practical Approach : 

Practical Approach Approach issues scientifically, allows operational manager to make risk management decisions If work is risk, then re-assignment Avoid unneeded drugs and unnecessary chemical, radiological and viral exposures When in doubt/outrage, spend time on risk communication Early referral to high risk OB doctor if exposure significant

Set reasonable Policy & Procedures: 

Set reasonable Policy & Procedures Legal review- to ensure compliance of Fed/State laws Employee to notify- HR/OHS of any medical condition including pregnancy so safe duty placement can be made Employee may be offered- other available duties for which she is qualified Counseling- EAP to alleviate unnecessary fears

Issues to keep in mind : 

Issues to keep in mind Innumeracy vs illiteracy Heuristics vs emotion “Feeling” about risk is more important to patient than “evidence”

Innumeracy: 

Innumeracy Numbers don’t mean anything to people having reproductive concerns Risk between 0-1% is over-estimated Not all frequencies are equal: 1/10 is less impressive than 100/1000 Baseline or background rates irrelevant Most people believe 80/1000 carries a higher chance than 1/10

Heuristics-looking for guidance : 

Heuristics-looking for guidance Information availability-media (one case = all cases) Similarity of case (my friend had it!) Initial diagnosis by primary care physician (fixation on first impression) Persuasion not scientific content (messenger credibility, multiple weak arguments, audio-visual appeal)

Remember the Don’ts: 

Remember the Don’ts Don’t make extreme decisions Don’t make decisions yourself-team Don’t sell science/stats to employees Don’t forget to collect some evidence Don’t ignore examples* *Examples of good outcome (employee likely admires/accepts the person or gp)

Emotion is everything at first: 

Emotion is everything at first Beware of anxiety and depression-almost always negative and pessimistic view Happiness and anger-good predictors Rationality veneer-compromise represents reasoned decision Recall bias-impact on judgment, belief Social comparison-”how do I compare with…” (RR or AR not pertinent) Share bad news early-no surprises

Bottom line: 

Bottom line Avoid drugs and unnecessary chemical, radiological and viral exposures Try “how do you feel about our discussion” “I feel good for you that risk is negligible” When in doubt, offer alternative job duties

Closing remarks: 

Closing remarks Complex and emotional issues Many chemicals and drug don’t have complete toxicological data Suspicions justified but not as facts unless specific data available Specific about dangers but not to condemn all drugs/chemicals as fetotoxic Examples are more persuasive

Main Resources: 

Main Resources Centers for Disease Control Division of Reproductive Health: www.cdc.gov/reproductivehealth/index.htm Organization of Teratology Information Services (OTIS): www.otispregnancy.org Reprotox: www.reprotox.org TETRIS (Teratogen Information System): http://depts.washington.edu/~terisweb FDA: www.fda.gov/womens