Reproductive HazardReproductive HazardMyth vs RealityMyth vs Reality

Fred Fung, M.D., M.S.Fred Fung, M.D., M.S.

SRSMG, UCSD, UCISRSMG, UCSD, UCI

Pre-testPre-test

Female reproductive systemFemale reproductive system# ova produced in a woman’s life time?# ova produced in a woman’s life time?

Male reproductive systemMale reproductive system# days testes need to produce sperms?# days testes need to produce sperms?

PlacentaPlacentaWhy is heparin safer than coumadin?Why is heparin safer than coumadin?

FetusFetusTime frame for organogenesis?Time frame for organogenesis?

OverviewOverview

Medical-legal context* Medical-legal context*

DefinitionsDefinitions

Toxicology principlesToxicology principles

Lessons from the past*Lessons from the past*

Evaluation strategies and Practice Evaluation strategies and Practice guidelines*guidelines*

ResourcesResources

Workforce demographicsWorkforce demographics

A gradual shift of workforce demographics A gradual shift of workforce demographics over the last 2-3 decadesover the last 2-3 decades

50% women constitute today’s workforce50% women constitute today’s workforce

Many take up jobs traditionally held by Many take up jobs traditionally held by men men

Most of them in reproductive ageMost of them in reproductive age

Common questionsCommon questions

From employee: From employee:

Doctor, am I safe to work here?Doctor, am I safe to work here?

Is my baby going to be ok if I work with…?Is my baby going to be ok if I work with…?

From employer:From employer:

Is it safe for her to work with…?Is it safe for her to work with…?

How soon can she return to work?How soon can she return to work?

A medical-legal issueA medical-legal issue

1978 Pregnancy Protection Act and Title 1978 Pregnancy Protection Act and Title VII Civil Rights Act of 1964VII Civil Rights Act of 1964

1982 Johnson Controls: Fetal protection 1982 Johnson Controls: Fetal protection policy (shifts from warning to exclusion)policy (shifts from warning to exclusion)

1984: UAW v Johnson Controls over 1984: UAW v Johnson Controls over prohibiting female workers from working prohibiting female workers from working with leadwith lead

Legal battlesLegal battles

Is it lawful to exclude female employees Is it lawful to exclude female employees from jobs for hazard concerns over fetus?from jobs for hazard concerns over fetus?

Lead exposure and potential adverse fetal Lead exposure and potential adverse fetal outcome at issue outcome at issue

First round: Federal District CourtFirst round: Federal District Court

Second round: Appeals CourtSecond round: Appeals Court

Final round: US Supreme CourtFinal round: US Supreme Court

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

What is the core issue?What is the core issue?

Plaintiff: direct violation of PDAPlaintiff: direct violation of PDA

Defense: Business necessity (safety Defense: Business necessity (safety argument) and BFOQargument) and BFOQ

A 3-step decision. Substantial risk to A 3-step decision. Substantial risk to fetus? Transmission of hazard via fetus? Transmission of hazard via women? Availability of less discriminatory women? Availability of less discriminatory alternative? alternative?

BFOQ: condition of employment-sterilityBFOQ: condition of employment-sterility

1991 Supreme Court-reverses lower courts decisions1991 Supreme Court-reverses lower courts decisions

The final decisionThe final decision

US Supreme Court unanimous decision: US Supreme Court unanimous decision: beneficence of policy still violates PDA, beneficence of policy still violates PDA, fetal welfare/safety a parental decision, fetal welfare/safety a parental decision, tort remote if employer abides by all regstort remote if employer abides by all regs

Johnson Controls fetal protection policy is Johnson Controls fetal protection policy is a a prima facieprima facie sex discrimination, thus sex discrimination, thus illegal illegal

Scope of problemScope of problem

4 million live births/y US 20024 million live births/y US 2002

120,000 babies with BD each year120,000 babies with BD each year

Baseline 3/100 live births have birth defectBaseline 3/100 live births have birth defect

Why focus on birth defects?Why focus on birth defects?

Reproductive injury/fetal loss is generally Reproductive injury/fetal loss is generally not covered under work comp-why?not covered under work comp-why?

DefinitionsDefinitions

A teratogen is defined as a substance, A teratogen is defined as a substance, organism, or physical agent to which an embryo organism, or physical agent to which an embryo or fetus is exposed that produces a permanent or fetus is exposed that produces a permanent abnormality in structure or function, causes abnormality in structure or function, causes growth retardation, or causes death. growth retardation, or causes death. There are no absolute teratogensThere are no absolute teratogensToxicity: inherent ability to induce injuryToxicity: inherent ability to induce injuryHazard: potential of toxicityHazard: potential of toxicity

Risk: probability of damage to life/health Risk: probability of damage to life/health will occur for a given hazard. May include will occur for a given hazard. May include outrageoutrage

Sources of exposureSources of exposure

Occupational: 90,000 chemicals in useOccupational: 90,000 chemicals in use4~5000 tested for teratogenicity4~5000 tested for teratogenicity2/3 negative, 1/3 positive or equivocal2/3 negative, 1/3 positive or equivocalOnly 30 agents documented teratogensOnly 30 agents documented teratogensHabits and meds: 30-70% pregnant Habits and meds: 30-70% pregnant women use caffeine, alcohol and women use caffeine, alcohol and cigarettescigarettesIllicit drugs: 15-25% pregnant women use Illicit drugs: 15-25% pregnant women use sometime during pregnancy- cocaine, MJ sometime during pregnancy- cocaine, MJ

Human teratogensHuman teratogens

Infection: TORCH, syphilisInfection: TORCH, syphilis

Metabolic: folate deficiency, DMMetabolic: folate deficiency, DM

Medication/drug: alcohol, anticonvulsants, Medication/drug: alcohol, anticonvulsants, retinoids, DES, thalidomide, alkylating retinoids, DES, thalidomide, alkylating agents, cocaine, cigarette smokingagents, cocaine, cigarette smoking

Metals/chemicals: Pb, Hg, Cd, DCBP, Metals/chemicals: Pb, Hg, Cd, DCBP, OCl, EtO, anesthetic gases, dioxins, PCBOCl, EtO, anesthetic gases, dioxins, PCB

Radiation: therapeutic, diagnostic, fallout Radiation: therapeutic, diagnostic, fallout

Severity and frequencySeverity and frequency

Quality- severity, nature of hazard, clinical Quality- severity, nature of hazard, clinical significancesignificance

Quantity-number at risk, frequency of Quantity-number at risk, frequency of occurrence, statistical significanceoccurrence, statistical significance

Importance of severity and frequencyImportance of severity and frequency

Rubella: 40-60% birth defectRubella: 40-60% birth defectToxo: 10% major birth defectToxo: 10% major birth defectCMV: 1-2% major birth defectCMV: 1-2% major birth defectAlcohol: 4-40% FASAlcohol: 4-40% FASDM: <10% good control, 5-35% poor controlDM: <10% good control, 5-35% poor controlDBCP:12% azoospermia,12% hypospermia;DBCP:12% azoospermia,12% hypospermia;Methyl Hg: 10% Minamata Bay syndromeMethyl Hg: 10% Minamata Bay syndromeDilantin/valproate 1% fetal hydantoin synd.Dilantin/valproate 1% fetal hydantoin synd.Folate def: 30% NTD Folate def: 30% NTD

FDA classification of drugsFDA classification of drugs

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

Occupational smellers-What’s in body odor?

PlacentaPlacenta

Basic conceptBasic concept

Almost all agents can be teratogenic under Almost all agents can be teratogenic under certain circumstances. The certain circumstances. The dosedose and and timetime of the exposure to a particular agent often of the exposure to a particular agent often determines the severity of the damage and determines the severity of the damage and the type of damage that occurs. the type of damage that occurs. Types of teratogens: radiation, infections, Types of teratogens: radiation, infections, drugs, metabolic disorders and drugs, metabolic disorders and environmental chemicalsenvironmental chemicals

Semin Reprod Med 18(4):407-424, 2000Semin Reprod Med 18(4):407-424, 2000

How does teratogenesis occur?How does teratogenesis occur?

DNA replication may result in incorporation DNA replication may result in incorporation of the wrong bases (baseline)of the wrong bases (baseline)

DNA exposed to mutagens/teratogens:DNA exposed to mutagens/teratogens:

High energy radiation: UV, X-rays, High energy radiation: UV, X-rays, radioactivityradioactivityChemicals that react or bind to DNAChemicals that react or bind to DNAChemicals which when metabolized Chemicals which when metabolized generate reactive oxygen compounds that generate reactive oxygen compounds that damage DNAdamage DNA

Toxicology principlesToxicology principles

Basic principles still apply: exposure, Basic principles still apply: exposure, absorption, distribution, metabolism, absorption, distribution, metabolism, eliminationelimination

Dose-response still holds, i.e. threshold Dose-response still holds, i.e. threshold concept is goodconcept is good

Multi-multi-compartment modelMulti-multi-compartment model

Embryo remarkable restorative ability-DNA Embryo remarkable restorative ability-DNA repair and proof-readingrepair and proof-reading

Pharmacokinetic changesPharmacokinetic changes

Increase in: gastric pH, GI transit time, Vd, Increase in: gastric pH, GI transit time, Vd, GFRGFR

Decrease in: P450 CYP1A2, Protein Decrease in: P450 CYP1A2, Protein bindingbinding

Toxin Toxin maternal exposure maternal exposure maternal maternal factors factors placental factors placental factors fetal factors fetal factors

CYP1A2 drugs: caffeine, diazepam, CYP1A2 drugs: caffeine, diazepam, warfarin, TCAwarfarin, TCA

Brief historyBrief history

Teratology-relatively new scienceTeratology-relatively new science

Teras- Gk Teras- Gk for monsterfor monster

Mythology- cyclops, sirensMythology- cyclops, sirens

Maternal impression- listening to Mozart or Maternal impression- listening to Mozart or looking at beautiful thingslooking at beautiful things

Late 1800s, 1900s- geneticsLate 1800s, 1900s- genetics

1930s- induced birth defects animal study1930s- induced birth defects animal study

Important historical eventsImportant historical events

1941- 11941- 1stst human epidemic of birth defects human epidemic of birth defects from a natural environmental/infectious from a natural environmental/infectious agentagent

RubellaRubella

11stst, 2, 2ndnd month gestation infection- heart month gestation infection- heart and eyeand eye

33rdrd month- hearing and speech month- hearing and speech

Rubella cases drop after vaccination starts

First drug induced birth defectFirst drug induced birth defect

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

YearYear CasesCases

1940-581940-58 00

19591959 11

19601960 3030

19611961 154154

PhocomeliaPhocomelia

Amelia- absence of limbsAmelia- absence of limbs

Phokos- sealPhokos- seal

Phocomelia- seal limbsPhocomelia- seal limbs

Taussig HB. A study of German outbreak Taussig HB. A study of German outbreak of phocomelia (JAMA 1962, 180:1106)of phocomelia (JAMA 1962, 180:1106)

First 2 cases presented 1960, no attentionFirst 2 cases presented 1960, no attention

All physicians knew about it by 1962All physicians knew about it by 1962

ThalidomideThalidomide

Ciba developed it as anticonvulsant, Ciba developed it as anticonvulsant, worthless but caused sedationworthless but caused sedation

Found no fetal effects on animals Found no fetal effects on animals (rodents)(rodents)

Marketed as sedative for mental patientsMarketed as sedative for mental patients

Sold as OTC, 3Sold as OTC, 3rdrd best selling drug in best selling drug in EuropeEurope

Used illegally as sleeper in US Used illegally as sleeper in US

Astonishing discoveryAstonishing discovery

Dr. Francis Kelsey, new physician scientist Dr. Francis Kelsey, new physician scientist given drug application on Thalidomide as given drug application on Thalidomide as her first assignment 9/12/1960her first assignment 9/12/1960

Told an easy project, not to be so!Told an easy project, not to be so!

Found side effects of peripheral neuritis, Found side effects of peripheral neuritis, concerned about fetal effects- no dataconcerned about fetal effects- no data

Never approved for pregnancy useNever approved for pregnancy use

ThalidomideThalidomide

Gestational time criticalGestational time critical

40-44 days most sensitive time40-44 days most sensitive time

Hypothesis- Hypothesis- inhibits angiogenesisinhibits angiogenesis

down regulates adhesion receptorsdown regulates adhesion receptors

reduces phagocytosis of PMNs reduces phagocytosis of PMNs

More about ThalidomideMore about Thalidomide

Approved by FDA July 16, 1998Approved by FDA July 16, 1998

Current indications: Current indications: erythema nodosum erythema nodosum leprosumleprosum with disfiguring lesions with disfiguring lesions

Also for aphthous stomatitis, graft v host, Also for aphthous stomatitis, graft v host, multiple myelomamultiple myeloma

Must be in STEPS (System for Must be in STEPS (System for Thalidomide Education, Prescription Thalidomide Education, Prescription Safety) programSafety) program

Why didn’t rodents show defects?Why didn’t rodents show defects?

Thalidomide poorly absorbed by rodents Thalidomide poorly absorbed by rodents PO PO

Human more sensitive to teratogenic Human more sensitive to teratogenic effects of thalidomide effects of thalidomide

Acne and teenagerAcne and teenager

Tragic combination if Accutane used in Tragic combination if Accutane used in early pregnancyearly pregnancy

11stst reported 1954, offsprings from female reported 1954, offsprings from female rats fed with high Vit A had birth defectsrats fed with high Vit A had birth defects

Similar cells affected as in FASSimilar cells affected as in FAS

Cardiovascular- tetralogy of Fallot, VSDCardiovascular- tetralogy of Fallot, VSD

Most sensitive: 3-5 weeks gestation Most sensitive: 3-5 weeks gestation

Chemical Structures of Chemical Structures of (a) Vitamin A (b) Isotretinoin(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.

Isotretinoin MalformationIsotretinoin Malformation

Source: Jones KL. Smith’s Recognizable Patterns of Human Malformation, Source: Jones KL. Smith’s Recognizable Patterns of Human Malformation, 5th Ed. London: W.B. Saunders, 1996.5th Ed. London: W.B. Saunders, 1996.

Isotretinoin DeformityIsotretinoin Deformity

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

Retinoic acidRetinoic acid

FDA: 12/31/2005FDA: 12/31/2005

iPLEDGE programiPLEDGE program

Prescriber and user must register Prescriber and user must register

2 neg preg tests prior to filling Rx2 neg preg tests prior to filling Rx

Each month must enter by internet or Each month must enter by internet or phone 2 types of BC while on Rx and one phone 2 types of BC while on Rx and one month aftermonth after

Other teratogensOther teratogens

Infectious agents: TORCH Infectious agents: TORCH

Metabolic: DM, alcoholism Metabolic: DM, alcoholism

Drugs: warfarin, antiepileptics, cocaineDrugs: warfarin, antiepileptics, cocaine

Heavy metals: Pb, Cd, HgHeavy metals: Pb, Cd, Hg

RadiationRadiation

FASFAS

Growth retardationGrowth retardation

CNS degenerationCNS degeneration

Simian crease on palmsSimian crease on palms

Facial dysmorphologyFacial dysmorphology

Microcephaly, broad nasal bridge, Microcephaly, broad nasal bridge, epicanthal folds, thin upper lipepicanthal folds, thin upper lip

Fetal alcohol syndromeFetal alcohol syndrome

First described by Lemoine 1968First described by Lemoine 1968

Landmark paper Lancet 1973Landmark paper Lancet 1973

Normal vs FAS brainNormal vs FAS brain

FASFAS

Zinc theory- maternal Zn def, impaired Zinc theory- maternal Zn def, impaired zinc metalloenzymes (aldehyde zinc metalloenzymes (aldehyde dehydrogenase), impaired fetal growth dehydrogenase), impaired fetal growth (protein synthesis)(protein synthesis)

Other factors: timing, nutrition, genetics… Other factors: timing, nutrition, genetics… Not 100% heavy pregnant drinkers beget Not 100% heavy pregnant drinkers beget FAS babies FAS babies

Minamata BayMinamata Bay

Inorganic mercury from plastics factory Inorganic mercury from plastics factory discharge into downstream bay, converted discharge into downstream bay, converted by bacteria into methyl mercuryby bacteria into methyl mercury

Cats ate fish had unsteady gaitCats ate fish had unsteady gait

Mothers had no obvious symptomsMothers had no obvious symptoms

Babies had congenital abnormalitiesBabies had congenital abnormalities

CP, mental retardation, microcephalyCP, mental retardation, microcephaly

Folic acid deficiency-neural tubeFolic acid deficiency-neural tube

WarfarinWarfarin

11stst described in 1980 case series described in 1980 case series

Nasal hypoplasia, short fingers, stippled Nasal hypoplasia, short fingers, stippled epiphyses. No effect on clotting factors.epiphyses. No effect on clotting factors.

Crosses placenta, embryo Vit K deficientCrosses placenta, embryo Vit K deficient

Inh Vit K Inh Vit K inhibits GLA proteins inhibits GLA proteins (osteocalcins) in bone/cartilage(osteocalcins) in bone/cartilage

Abn cartilage growth/calcification similar to Abn cartilage growth/calcification similar to Chondrodysplasia punctata Chondrodysplasia punctata genetic defectgenetic defect

Antiepileptics/anticonvulsantsAntiepileptics/anticonvulsants

Maternal seizure in 1Maternal seizure in 1stst trimester-risk per se trimester-risk per se

Fetal hydantoin syndrome- hypoplasia of Fetal hydantoin syndrome- hypoplasia of nails/fingers, digitized thumb, hirsutismnails/fingers, digitized thumb, hirsutism

Orofacial defects-low nasal bridge, bowed Orofacial defects-low nasal bridge, bowed upper lip, cleft lip/palateupper lip, cleft lip/palate

Epoxides bind with fetal nucleic acidsEpoxides bind with fetal nucleic acids

Epoxide hydrolase activities differEpoxide hydrolase activities differ

Inh K channel-bradycardia, fetal hypoxiaInh K channel-bradycardia, fetal hypoxia

Diagnostic strategiesDiagnostic strategiesMedical historyMedical historySymptoms and signsSymptoms and signsHobby, family and genetic historyHobby, family and genetic historyPartner historyPartner historyPhysical examPhysical examTestsTestsPrenatal testsPrenatal testsWork place surveillanceWork place surveillance

What caused my baby to have a What caused my baby to have a birth defect?birth defect?

Scientific causation analysisScientific causation analysis

What exact birth defect is it “X”?What exact birth defect is it “X”?

Can this substance “Y” cause birth defect?Can this substance “Y” cause birth defect?

Did Y cause X?Did Y cause X?

Reproductive hazard managementReproductive hazard management

Hazard elimination and exposure controlHazard elimination and exposure control

Exposure control monitoringExposure control monitoring

Risk: no absolute risk free Risk: no absolute risk free

Risk Communication: put in perspective Risk Communication: put in perspective

Require notification of pregnancyRequire notification of pregnancy

Temporary reassignment Temporary reassignment

Practical ApproachPractical Approach

Approach issues scientifically, allows operational Approach issues scientifically, allows operational manager to make manager to make risk managementrisk management decisions decisions

If work is risk, then re-assignment If work is risk, then re-assignment

Avoid unneeded drugs and unnecessary Avoid unneeded drugs and unnecessary chemical, radiological and viral exposureschemical, radiological and viral exposures

When in doubt/outrage, spend When in doubt/outrage, spend timetime on on risk risk communicationcommunication

Early referral to high risk OB doctor if exposure Early referral to high risk OB doctor if exposure significant significant

Set reasonable Policy & Set reasonable Policy & ProceduresProcedures

Legal review- to ensure compliance of Legal review- to ensure compliance of Fed/State lawsFed/State lawsEmployee to notify- HR/OHS of any Employee to notify- HR/OHS of any medical condition including pregnancy so medical condition including pregnancy so safe duty placement can be made safe duty placement can be made Employee may be offered- other available Employee may be offered- other available duties for which she is qualifiedduties for which she is qualifiedCounseling- EAP to alleviate unnecessary Counseling- EAP to alleviate unnecessary fearsfears

Issues to keep in mindIssues to keep in mind

Innumeracy vs illiteracyInnumeracy vs illiteracy

Heuristics vs emotionHeuristics vs emotion

““Feeling” about risk is more important to Feeling” about risk is more important to patient than “evidence”patient than “evidence”

InnumeracyInnumeracy

Numbers don’t mean anything to people Numbers don’t mean anything to people having reproductive concernshaving reproductive concerns

Risk between 0-1% is over-estimatedRisk between 0-1% is over-estimated

Not all frequencies are equal: 1/10 is less Not all frequencies are equal: 1/10 is less impressive than 100/1000impressive than 100/1000

Baseline or background rates irrelevantBaseline or background rates irrelevant

Most people believe 80/1000 carries a Most people believe 80/1000 carries a higher chance than 1/10higher chance than 1/10

Heuristics-looking for guidanceHeuristics-looking for guidance

Information availability-media (one case = Information availability-media (one case = all cases)all cases)

Similarity of case (my friend had it!)Similarity of case (my friend had it!)

Initial diagnosis by primary care physician Initial diagnosis by primary care physician (fixation on first impression)(fixation on first impression)

Persuasion not scientific content Persuasion not scientific content (messenger credibility, multiple weak (messenger credibility, multiple weak arguments, audio-visual appeal) arguments, audio-visual appeal)

Remember the Don’tsRemember the Don’ts

Don’t make extreme decisionsDon’t make extreme decisions

Don’t make decisions yourself-teamDon’t make decisions yourself-team

Don’t sell science/stats to employeesDon’t sell science/stats to employees

Don’t forget to collect some evidenceDon’t forget to collect some evidence

Don’t ignore examples*Don’t ignore examples*

*Examples of good outcome (employee *Examples of good outcome (employee likely admires/accepts the person or gp)likely admires/accepts the person or gp)

Emotion is everything at firstEmotion is everything at first

Beware of anxiety and depression-almost Beware of anxiety and depression-almost always negative and pessimistic viewalways negative and pessimistic view

Happiness and anger-good predictorsHappiness and anger-good predictors

Rationality veneer-compromise represents Rationality veneer-compromise represents reasoned decision reasoned decision

Recall bias-impact on judgment, belief Recall bias-impact on judgment, belief

Social comparison-”how do I compare Social comparison-”how do I compare with…” (RR or AR not pertinent)with…” (RR or AR not pertinent)

Share bad news early-no surprises Share bad news early-no surprises

Bottom lineBottom line

Avoid drugs and unnecessary chemical, Avoid drugs and unnecessary chemical, radiological and viral exposuresradiological and viral exposures

Try “how do you Try “how do you feelfeel about our discussion” about our discussion”

““I I feelfeel good for you that risk is negligible” good for you that risk is negligible”

When in doubt, offer alternative job duties When in doubt, offer alternative job duties

Closing remarksClosing remarks

Complex and emotional issuesComplex and emotional issues

Many chemicals and drug don’t have Many chemicals and drug don’t have complete toxicological datacomplete toxicological data

Suspicions justified but not as facts unless Suspicions justified but not as facts unless specific data availablespecific data available

Specific about dangers but not to Specific about dangers but not to condemn all drugs/chemicals as fetotoxiccondemn all drugs/chemicals as fetotoxic

Examples are more persuasiveExamples are more persuasive

Main ResourcesMain ResourcesCenters for Disease Control Division of Centers for Disease Control Division of Reproductive Health: Reproductive Health: www.cdc.gov/reproductivehealth/index.htmwww.cdc.gov/reproductivehealth/index.htmOrganization of Teratology Information Organization of Teratology Information Services (OTIS): Services (OTIS): www.otispregnancy.orgwww.otispregnancy.orgReprotox: Reprotox: www.reprotox.orgwww.reprotox.orgTETRIS (Teratogen Information System): TETRIS (Teratogen Information System): http://depts.washington.edu/~teriswebhttp://depts.washington.edu/~teriswebFDA: FDA: www.fda.gov/womenswww.fda.gov/womens