Reproductive Hazard Myth vs Reality

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Reproductive HazardMyth vs Reality

• Fred Fung, M.D., M.S.
• SRSMG, UCSD, UCI

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Pre-test

• Female reproductive system
• ova produced in a womans life time?
• Male reproductive system
• days testes need to produce sperms?
• Placenta
• Why is heparin safer than coumadin?
• Fetus
• Time frame for organogenesis?

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Overview

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

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Workforce demographics

• A gradual shift of workforce demographics over
  the last 2-3 decades
• 50 women constitute todays workforce
• Many take up jobs traditionally held by men
• Most of them in reproductive age

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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?

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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

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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

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

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1991 Supreme Court-reverses lower courts decisions
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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

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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?

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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

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Sources of exposure

• Occupational 90,000 chemicals in use
• 45000 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

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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

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Severity and frequency

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

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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 lt10 good control, 5-35 poor control
• DBCP12 azoospermia,12 hypospermia
• Methyl Hg 10 Minamata Bay syndrome
• Dilantin/valproate 1 fetal hydantoin synd.
• Folate def 30 NTD

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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

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Occupational smellers-Whats in body odor?
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Placenta
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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

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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

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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

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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

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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

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Important historical events

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

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Rubella

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

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Rubella cases drop after vaccination starts
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First drug induced birth defect

• 1960s- infants with limb abnormalities (Hamburg
  U.)

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Phocomelia

• Amelia- absence of limbs
• Phokos- seal
• Phocomelia- seal limbs
• Taussig HB. A study of German outbreak of
  phocomelia (JAMA 1962, 1801106)
• First 2 cases presented 1960, no attention
• All physicians knew about it by 1962

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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

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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

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Thalidomide

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

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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

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Why didnt rodents show defects?

• Thalidomide poorly absorbed by rodents PO
• Human more sensitive to teratogenic effects of
  thalidomide

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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

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

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Other teratogens

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

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FAS

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

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Fetal alcohol syndrome

• First described by Lemoine 1968
• Landmark paper Lancet 1973

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Normal vs FAS brain
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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

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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

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Folic acid deficiency-neural tube
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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

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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

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Diagnostic strategies

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

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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?

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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

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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

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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

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Issues to keep in mind

• Innumeracy vs illiteracy
• Heuristics vs emotion
• Feeling about risk is more important to patient
  than evidence

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Innumeracy

• Numbers dont 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

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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)

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Remember the Donts

• Dont make extreme decisions
• Dont make decisions yourself-team
• Dont sell science/stats to employees
• Dont forget to collect some evidence
• Dont ignore examples
• Examples of good outcome (employee likely
  admires/accepts the person or gp)

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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

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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

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Closing remarks

• Complex and emotional issues
• Many chemicals and drug dont 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

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Main Resources

• Centers for Disease Control Division of
  Reproductive Health www.cdc.gov/reproductivehealt
  h/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

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