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-