environmental epidemiologic studies of reproductive endpoints gayle c. windham ca department of...
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Environmental Epidemiologic Studies of Reproductive Endpoints
Environmental Epidemiologic Studies of Reproductive Endpoints
Gayle C. Windham
CA Department of Health Services
Reasons for Studying Exposure Effects on Repro Endpoints
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
Issues Specific to Reproductive Endpoints
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
Prevalence of Selected Adverse Reproductive Outcomes in the U.S.
Prevalence of Selected Adverse Reproductive Outcomes in the U.S.
Event Frequency per 100
Infertility 8-12 Couples Recognized miscarriage 10-20 Pregnancies
Birthweight <2500 g 4-7 Live births Preterm (<37 wks) 8-12 Live births Stillbirth 1-2 SB + LB
Infant death 1 Live births Birth defects 2-5 Live births Chromosomal anomalies 0.2 Live births
TeratogenesisTeratogenesis
Rates of Selected Birth Defects in CARates of Selected Birth Defects in CA
Defect Rate per 1,000 births Anencephaly 0.26 Cleft Lip and/or Cleft Palate 1.40 Chromosome Defects (all) 1.30 Trisomy 21 (Downs) 1.01 Heart Defects (combined) 2.63 Hypospadias 0.45 Limb Reduction Defects 0.41 Neural Tube Defects 0.5
Measures of Fetal Size (surrogate for Growth)
Measures of Fetal Size (surrogate for Growth)
Low Birth Weight (<2500gms)
IUGR or SGA(<10th % of Weight/Wk)
Preterm Delivery(< 37 weeks)
Risk Factors for Low BirthweightRisk Factors for Low Birthweight*Demographic Factors
Age (< 17; > 34)Race (Black, Asian)Low SESUnmarried
Low education Maternal Factors
Parity (0 or > 4)Low weight for heightSelected diseases
Poor obstetric historyMaternal 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)
Fetal Death and Infant MortalityFetal Death and Infant Mortality20 weeks (500 gms) 28 weeks Fetal Deaths 36 weeks or stillbirth BIRTH Perinatal Death7 days Neonatal Death 28 days Infant Death Postneonatal 1 year
Continuum of Reproductive Loss—Probability of Loss of Conceptuses
Continuum of Reproductive Loss—Probability of Loss of Conceptuses
Time Interval % (Estimates)From Conception Lost After Start
of Interval0-6 days (preimplantation) 75%
7-20 days (hCG detection) 45%
3-5 weeks (recognized pregnancy) 21%
6-13 weeks 14%
14-29 weeks 4%
30-37 weeks 1%
-16 -14 -12 -10 -8 -6 -4 -2 0 2 4 6 8 10 12 14 16
Cycle Day
OvulationFollicular Phase Luteal Phase
EstrogensLH
Progesterone
Menstrual Cycle Hormone PatternsMenstrual Cycle Hormone Patterns
Examples of Cycle CharacteristicsExamples of Cycle CharacteristicsCharacteristic Definition (in WRHS)• Cycle Length Diary or biomarkers Short cycle <24 days Long cycle >34 days• Dysmenorrhea Diary• Anovulation Insufficient rise in Progesterone• Questionable ovulation Questionable P rise or few days• Day of ovulation LH 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
Covariates When Studying Menstrual Function
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?)
Assessment of Semen ParametersAssessment of Semen Parameters
Measure Normal ValuesSperm concentration 20-250 (106/ml)Sperm viability >50%Sperm motility
Percent motile >50%Curvilinear velocityLinearity MeansLateral head amplitude Beat cross frequency
Sperm morphometry >60% normal formsSperm head shape: (Strict 10-15% normal)
(perimeter, length, area and roundness)Semen Volume 2-6 ml
Computer-Aided Sperm AnalysisComputer-Aided Sperm Analysis
Sperm MorphometrySperm Morphometry
Factors to Consider in Studying Male Reproductive Function by Semen Analysis
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?)
Selected Agents with Adverse Female Reproductive or Developmental EffectsSelected Agents with Adverse Female
Reproductive or Developmental EffectsAgent Human Outcomes
Anesthetic gases Sub-fertility, Spontaneous abortion (SAB), Birth defects
Anti-neoplastic drugs SAB, birth defects (BD)
Carbon monoxide SAB, LBW
DDT/DDE SGA, preterm, menstrual disorders
Dioxins Menstrual disorders, SAB, birth defects
Electro-magnetic fields SAB, childhood cancer
Lead Infertility, SAB, preterm, neurologic
Mercury Menstrual, SAB, LBW, CNS, Cerebral palsy
PCBs LBW, hyperpegmentation, menstrual disorders
Radiation, ionizing Infertility, menstrual, SAB, BD, childhood cancer
Solvents Menstrual, SAB, birth defects
Tobacco smoke LBW, fetal loss, infertility, childhood growth
CDHS Studies of Drinking Water and Reproductive Outcomes
CDHS Studies of Drinking Water and Reproductive Outcomes
Leak of Solvents into Drinking Water Well, 1981Anecdotal Reports of SABs and Cardiac Defects
Vital Record Review-little evidence, but not
appropo for SABs-
Household Interview Survey Hospital 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-
CDHS Studies of Drinking Water and Reproductive Outcomes, cont.CDHS Studies of Drinking Water and Reproductive Outcomes, cont.
Follow-up Interview Case-Control Study Case-Control Study ofStudy of SAB of Solvents & SAB Cardiac 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 of Study of Early Rat Studies ofSAB in 3 areas of Pregnancy Loss in Drinking WaterCalifornia Same County -Some confirmation-