1. Environmental Epidemiologic Studies of Reproductive Endpoints Gayle C. Windham CA Department of Health Services

2. Reasons for Studying Exposure Effects on Repro Endpoints Concern to exposed persons or communities Many endpoints are frequent (more power) Short latency period usually (pregnancy) Sensitive population (developing fetus) Some standardly collected data available

3. Issues Specific to Reproductive Endpoints Exposure of >1 person important (couple and fetus) “Disease” may not come to medical attention Continuum of possible effects, etiology may or may not vary Critical exposure periods may vary by endpoint Repeated opportunity for risk Account for prior history

4. Prevalence of Selected Adverse Reproductive Outcomes in the U.S. EventFrequency per 100 Infertility8-12Couples Recognized miscarriage10-20Pregnancies Birthweight <2500 g 4-7Live births Preterm (<37 wks) 8-12Live births Stillbirth 1-2SB + LB Infant death 1Live births Birth defects 2-5Live births Chromosomal anomalies 0.2Live births

5. Teratogenesis

6. Rates of Selected Birth Defects in CA DefectRate per 1,000 births Anencephaly0.26 Cleft Lip and/or Cleft Palate1.40 Chromosome Defects (all)1.30 Trisomy 21 (Downs)1.01 Heart Defects (combined)2.63 Hypospadias0.45 Limb Reduction Defects0.41 Neural Tube Defects0.5

7. Measures of Fetal Size (surrogate for Growth) Low Birth Weight (<2500gms) IUGR or SGA (<10 th % of Weight/Wk) Preterm Delivery (< 37 weeks)

8. Risk Factors for Low Birthweight * Demographic Factors Age ( 34) Race (Black, Asian) Low SES Unmarried Low education Maternal Factors Parity (0 or > 4) Low weight for height Selected diseases Poor obstetric history Maternal genetic factors Risks in Current Pregnancy Multiple pregnancy Poor weight gain (nutrition) Short interpregnancy interval Inadequate prenatal care Hypertension/pre-eclampsia Selected infections Placental problems Oligo- or polyhydramnios Tobacco, alcohol or drug use Fetal anomalies Prematurity (PROM)

9. Fetal Death and Infant Mortality 20 weeks   (500 gms)  28 weeks   Fetal Deaths  36 weeks or stillbirth     BIRTH  Perinatal   Death 7 daysNeonatal Death    28 days  Infant  Death  Postneonatal  1 year 

10. Continuum of Reproductive Loss— Probability of Loss of Conceptuses Time Interval% (Estimates) From Conception Lost After Start of Interval 0-6 days (preimplantation)75% 7-20 days (hCG detection)45% 3-5 weeks (recognized pregnancy)21% 6-13 weeks14% 14-29 weeks 4% 30-37 weeks 1%

11. Menstrual Cycle Hormone Patterns

12. Examples of Cycle Characteristics CharacteristicDefinition (in WRHS) Cycle LengthDiary or biomarkers Short cycle<24 days Long cycle>34 days DysmenorrheaDiary AnovulationInsufficient rise in Progesterone Questionable ovulationQuestionable P rise or few days Day of ovulationLH peak or E1C/PdG Long follicular phase>20 days Short luteal phase<10 days Abnormal bleeding>1 bleed/cycle or >8 days Other, continuous: Mean and variance of cycle and phase lengths Hormone levels—daily averages, area under curve

13. Covariates When Studying Menstrual Function Age Race or ethnicity Parity or reproductive history Weight/height Tobacco and alcohol use Stress Physical activity Participation rates (selection bias?)

14. Assessment of Semen Parameters MeasureNormal Values Sperm concentration20-250 (10 6 /ml) Sperm viability>50% Sperm motility Percent motile >50% Curvilinear velocity LinearityMeans Lateral head amplitude Beat cross frequency Sperm morphometry>60% normal forms Sperm head shape: (Strict 10-15% normal) (perimeter, length, area and roundness) Semen Volume 2-6 ml

15. Computer-Aided Sperm Analysis

16. Sperm Morphometry

17. Factors to Consider in Studying Male Reproductive Function by Semen Analysis Age Medical conditions and medications Heat exposure (occupation, sauna, exercise, etc.) Tobacco, alcohol and drug use Sexual and reproductive history Stress Exposures Length of abstinence Standardized collection procedures and lab methods Participation rates (selection bias?)

18. Selected Agents with Adverse Female Reproductive or Developmental Effects AgentHuman Outcomes Anesthetic gasesSub-fertility, Spontaneous abortion (SAB), Birth defects Anti-neoplastic drugsSAB, birth defects (BD) Carbon monoxideSAB, LBW DDT/DDESGA, preterm, menstrual disorders DioxinsMenstrual disorders, SAB, birth defects Electro-magnetic fieldsSAB, childhood cancer LeadInfertility, SAB, preterm, neurologic MercuryMenstrual, SAB, LBW, CNS, Cerebral palsy PCBsLBW, hyperpegmentation, menstrual disorders Radiation, ionizingInfertility, menstrual, SAB, BD, childhood cancer SolventsMenstrual, SAB, birth defects Tobacco smokeLBW, fetal loss, infertility, childhood growth

19. CDHS Studies of Drinking Water and Reproductive Outcomes Leak of Solvents into Drinking Water Well, 1981 Anecdotal Reports of SABs and Cardiac Defects  Vital Record Review -little evidence, but not appropo for SABs-  Household Interview SurveyHospital Record Review for (2 census tracts)Cardiac Malformations -SABS 2X (county-wide) -Anomalies 3X-Rates 2.5 x county, but distribution and timing don’t fit leak-

20. CDHS Studies of Drinking Water and Reproductive Outcomes, cont. Follow-up InterviewCase-Control StudyCase-Control Study of Study of SABof Solvents & SABCardiac Malformations (additional tract (countywide) (county-wide) and time) -exposure modelling -some increases in -still increased, but prior to did not show higher SAB w/occup. exp.- exposure, inconclusive- dose- -Increased risk in tap drinkers (1.5-6X) and Decreased risk in bottled water (0.5-0.7) Prospective Study ofStudy of EarlyRat Studies of SAB in 3 areas ofPregnancy Loss inDrinking Water CaliforniaSame County-Some confirmation-