The folly of believing positive findings from underpowered intervention studies
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Supplemental Table 1. Rating Level of EvidenceFirst Author
Year Article Type
Reproductive Endpoints Type of Bias Present (Biases marked no)
Number of Bias Questions Answered No
Total Number of Bias Questions
Percentage of Bias
Bias Ranking
Initial Confidence
Downgrade Factors
Upgrade Factors
Confidence of Evidence
Direction (effect/ no effect)
Level of Evidence
Bull 1999 crs fecundity ratio performance, attrition, detection
3 8 37.5 probably low
moderate imprecision (underpowered)
low no effect inadequate
spontaneous abortions low no effect inadequateDesrosiers 2012 coh glaucoma/anterior chamber
defectsdetection 2 8 25.0 definitely
lowmoderate imprecision (low
sample size)low effect low
colonic atresia/stenosis low effect lowlimb deficiency, intercalary low effect lowASD (atrial septal defect) secundum or NOS
low effect low
Johnson 1987 coh confounding bias, detection bias
2 7 28.6 probably low
Moderate imprecision (underpowered)
very low no effect N/A
Khalifa 1997 cas sperm concentration other, confounding, performance, detection
4 6 66.7 probably high
very low imprecision (case study), risk of bias
very low effect N/A
sperm motility very low effect N/Asperm morphology very low effect N/Atesticular tissue disruption very low effect N/A
Mandani et al
2013 hct sperm motility – phenol - hydroquinone
selection, performance
2 9 22.2 definitely low
high large magnitude of effect, dose response
high effect high
sperm motility – catechol high effect highsperm viability – phenol - hydroquinone
high effect high
sperm motility – catechol high effect highsperm nuclear DNA Integrity high effect high
Rosenberg 1985 crs sperm concentration selection, performance
3 8 37.5 probably low
moderate imprecision (underpowered), risk of bias
low no effect inadequate
sperm concentration with hours worked
low no effect inadequate
sperm morphology probably low
moderate risk of bias moderate no effect inadequate
sperm morphology with hours worked
moderate no effect inadequate
Wang 2001 crs sperm concentration detection 2 8 25.0 definitely low
moderate risk of bias moderate effect moderate
sperm count moderate effect moderatesperm motility moderate effect moderateseminal volume moderate no effect Inadequatesperm viability moderate no effect Inadequateyears of exposure and various semen parameters
moderate no effect Inadequate
sperm concentration vs. years smoked and years of exposure were combined
moderate effect low
R.T. Gun 2004 coh prostate cancer selection, detection 3 8 37.5 probably low
low residual confounding
moderate effect moderate
testicular cancer selection, detection 3 8 37.5 probably low low no effect inadequate
lowcervical cancer selection, detection 3 8 37.5 probably
lowlow imprecision very low no effect N/A
breast cancer selection, detection 3 8 37.5 probably low
low low no effect inadequate
R.T. Gun 2006 coh prostate cancer selection, detection 3 8 37.5 probably low
low residual confounding
moderate effect moderate
testicular cancer selection, detection 3 8 37.5 probably low
low low no effect inadequate
Benjamin A. Rybicki
2006 cas prostate cancer risk associated with lifetime occupational respiratory PAH exposure from petroleum
detection 1 8 12.5 definitely low
low low no effect inadequate
prostate cancer risk associated with lifetime occupational cutaneous PAH exposure from petroleum
detection 1 8 12.5 definitely low
low low no effect inadequate
John Kaldor
1984 coh prostate cancer other, detection, confounding, selective reporting
4 8 50.0 probably low
low dose response
moderate effect moderate
testicular cancer other, detection, confounding, selective reporting
4 8 50.0 probably low
low low no effect inadequate
breast cancer other, detection, confounding, selective reporting
4 8 50.0 probably low
low low no effect inadequate
cervical cancer other, detection, confounding, selective reporting
4 8 50.0 probably low
low low no effect inadequate
uterine cancer other, detection, confounding, selective reporting
4 8 50.0 probably low
low low no effect inadequate
Martin T. Schechter
1989 coh prostate cancer detection, confounding
3 8 37.5 probably low
low imprecision very low N/A N/A
breast cancer other, detection, confounding
4 8 50.0 probably low
low imprecision very low N/A N/A
gynecologic cancer other, detection, confounding
4 8 50.0 probably low
low imprecision very low N/A N/A
D. Christie 1991 coh prostate cancer selection, detection 4 8 50.0 probably low
low low no effect inadequate
testicular cancer selection, detection 4 8 50.0 probably low
low imprecision very low N/A N/A
R. J. Lewis 2003 coh prostate cancer selection, confounding, detection, selective reporting
4 8 50.0 probably low
low imprecision very low N/A N/A
testicular cancer selection, confounding, detection, selective reporting
4 8 50.0 probably low
low imprecision very low N/A N/A
breast cancer selection, confounding, detection, selective
4 8 50.0 probably low
low imprecision very low N/A N/A
reportingcervical cancer selection,
confounding, detection, selective reporting
4 8 50.0 probably low
low imprecision very low N/A N/A
uterine cancer selection, confounding, detection, selective reporting
4 8 50.0 probably low
low imprecision very low N/A N/A
ovarian, fallopian tube, and broad ligament cancers
selection, confounding, detection, selective reporting
4 8 50.0 probably low
low imprecision very low N/A N/A
Bengt Järvholm
1997 coh prostate cancer selection, confounding, performance, detection
5 8 62.5 probably high
low risk of bias Very low N/A N/A
Chun-Yuh Yang
2002a
coh preterm birth confounding bias, attrition bias, detection bias
3 8 37.5 probably low
moderate risk of bias moderate no effect inadequate
Shaina L. Stacy
2015 coh preterm birth attrition bias, detection bias
2 8 25.0 definitely low
moderate moderate no effect inadequate
Joan A. Casey
2016 coh preterm birth confounding bias, attrition bias, detection bias
3 8 37.5 probably low
moderate risk of bias dose response
high effect high
Meng-Chiao Lin
2001a
coh preterm birth confounding bias, attrition bias, detection bias
3 8 37.5 probably low
moderate risk of bias moderate effect moderate
Shang-Shyue Tsai
2003 coh preterm birth confounding bias, attrition bias, detection bias
3 8 37.5 probably low
moderate risk of bias moderate effect moderate
Chun-Yuh Yang
2002b
coh preterm birth confounding bias, attrition bias, detection bias
3 8 37.5 probably low
moderate risk of bias moderate effect moderate
Chun-Yuh Yang
2004 coh preterm birth confounding bias, attrition bias, detection bias
3 8 37.5 probably low
moderate risk of bias moderate effect moderate
Lisa M. McKenzie
2014 coh preterm birth confounding bias, attrition bias, detection bias
3 8 37.5 probably low
moderate risk of bias high effect (protective)
high
Gösta Axelsson
1988 crs miscarriage confounding bias, attrition bias, detection bias
3 8 37.5 probably low
moderate risk of bias moderate no effect inadequate
Miguel San Sebastián
2002 crs miscarriage attrition bias, detection bias, other bias
3 8 37.5 probably low
moderate risk of bias large magnitude of effect
high effect high
Xiping Xu 1998 crs miscarriage confounding bias, detection bias, other bias
3 8 37.5 probably low
moderate risk of bias large magnitude of effect
high effect high
Gösta Axelsson
1989 crs miscarriage selection bias, confounding bias, attrition bias
3 8 37.5 probably low
low risk of bias, imprecision (low sample size)
very low not rated N/A
Miguel San Sebastián
2002 crs Stillbirth confounding bias, attrition bias, detection bias, other bias
4 8 50.0 probably low
moderate risk of bias, imprecision (low sample size)
low no effect inadequate
Lenice 2002 cac Stillbirth confounding bias, 2 8 25.0 probably moderate risk of bias, low no effect inadequate
Minussi Oliveira
detection bias low imprecision (low sample size)
Chun-Yuh Yang
2002a
coh low birth weight (term) confounding bias, attrition bias, detection bias
3 8 37.5 probably low
moderate risk of bias moderate no effect inadequate
Lenice Minussi Oliveira
2002 cac low birth weight confounding bias, attrition bias, detection bias
3 8 37.5 probably low
moderate risk of bias moderate no effect inadequate
Joan A. Casey
2016 coh birth weight (term) confounding bias, attrition bias, detection bias
3 8 37.5 probably low
moderate risk of bias moderate no effect inadequate
Gösta Axelsson
1988 crs birth weight confounding bias, attrition bias, detection bias
3 8 37.5 probably low
moderate risk of bias moderate no effect inadequate
Meng-Chao Lin
2001b
coh low birth weight (term) confounding bias, detection bias
3 8 37.5 probably low
moderate risk of bias moderate effect moderate
Lisa M. McKenzie
2014 coh low birth weight (term) confounding bias, attrition bias, detection bias
3 8 37.5 probably low
moderate risk of bias moderate effect (protective)
moderate
Gösta Axelsson
1988 crs+coh
low birth weight confounding bias, detection bias
2 8 25.0 definitely low
moderate moderate effect (protective)
moderate
Shaina L. Stacy
2015 coh birth weight attrition bias, detection bias
2 8 25.0 definitely low
moderate moderate effect moderate
small for gestational age attrition bias, detection bias
2 8 25.0 definitely low
moderate moderate effect moderate
Gösta Axelsson
1989 crs+coh
birth weight selection bias, confounding bias, attrition bias
3 8 37.5 probably low
low risk of bias , imprecision (low sample size)
very low not rated N/A
Lenice Minussi Oliveira
2002 cac birth defects (not specified) confounding bias, attrition bias, detection bias
3 8 37.5 probably low
moderate risk of bias , imprecision (low sample size)
low no effect inadequate
Lisa M. McKenzie
2014 coh birth defects (oral clefts) confounding bias, attrition bias, detection bias
3 8 37.5 probably low
moderate risk of bias moderate no effect inadequate
birth defects (congenital heart defect)
confounding bias, attrition bias, detection bias
3 8 37.5 probably low
moderate risk of bias moderate effect moderate
birth defects (neural tube defects)
confounding bias, attrition bias, detection bias
3 8 37.5 probably low
moderate risk of bias moderate effect moderate
C. Chevrier 2006 cac birth defects (oral clefts) attrition bias 1 8 12.5 definitely low
moderate imprecision (low sample size)
large magnitude of effect
moderate effect moderate
Gösta Axelsson
1988 crs+coh
birth defects (not specified) selection bias, confounding bias, detection bias, other bias
4 8 50.0 probably low
low risk of bias , imprecision (low sample size)
very low not rated N/A
Chun-Yuh Yang
2000b
coh sex ratio selection bias, confounding bias, detection bias
2 8 25.0 definitely low
moderate moderate no effect inadequate
Chun-Yuh Yang
2000a
coh sex ratio selection bias, confounding bias, detection bias
2 8 25.0 definitely low
moderate moderate effect moderate
Supplemental Table 2. Detailed Endpoint Summaries
Reference Group Study Group
Endpoint Exposure Type
Publication Year
First Author
Study Location
n Description n Description Health Effect (Effect/No Effect)
Comparison Results Level of Confidence
Level of Evidence
Birth Outcomes Associated with Maternal Exposure
preterm birth residential exposure
2002a Yang Taiwan 19,673 Women who had singleton deliveries living in 16 municipalities where the number of workers in the petroleum and petrochemical industry comprised less than 2% of the municipality's total population
20,077 Women who had first-parity singleton deliveries living in 16 petrochemical industrial municipality where the number of workers in the petroleum and petrochemical industry comprised equal or greater than 2% of the municipality's total population
no effect Study group vs. Reference group
OR=1.03 (95% CI=0.94-1.13)
moderate inadequate
preterm birth residential exposure
2015 Stacy USA 3,604 (first quartile)
Women living in the area with an inverse distance weighted count of unconventional wells >0, but <0.87
3,905 (second quartile)
Women living in the area with an inverse distance weighted count of unconventional wells ≥0.87, but <2.60
no effect Second quartile vs. First quartile
OR=0.82 (95% CI=0.68-0.98) (actual number mentioned in text)
moderate inadequate
3,791 (third quartile)
Women living in the area with an inverse distance weighted count of unconventional wells ≥2.60, but <6.00
Third quartile vs. First quartile
OR≈1.1 (95% CI crossing 1) (data presented in figure, no actual number)
4,151 (fourth quartile)
Women living in the area with an inverse distance weighted count of unconventional wells ≥6.00
Fourth quartile vs. First quartile
OR≈1.0 (95% CI crossing 1) (data presented in figure, no actual number)
preterm birth residential exposure
2016 Casey USA 2,590 (first quartile)
Women living in the area within the first quartile of natural gas development activity calculated by an inverse-distance squared model and delivered babies during 2009 and 2013
2,648 (second quartile)
Women living in the area within the second quartile of natural gas development activity calculated by an inverse-distance squared model and delivered babies during 2009 and 2013
effect Second quartile vs. First quartile
OR=1.3 (95% CI=1.0-1.8)
high high
2,642 (third quartile)
Women living in the area within the third quartile of natural gas development activity calculated by an inverse-distance squared model and delivered babies during 2009 and 2013
Third quartile vs. First quartile
OR=1.6 (95% CI=1.1-2.4)
2,616 (fourth quartile)
Women living in the area within the fourth quartile of natural gas development activity calculated by an inverse-distance squared model and delivered babies
Fourth quartile vs. First quartile
OR=1.9 (95% CI=1.2-2.9)
during 2009 and 2013preterm birth residential
exposure2001a Lin Taiwan 49,673 A 10% random sample of all
women in Taiwan who had first-parity singleton between 1993 and 1996 and who did not live in the study region.
2,027 Women who had first-parity singleton deliveries and who lived in two petrochemical municipalities.
effect Study group vs Reference group
OR=1.41 (95% CI=1.08-1.82)
moderate moderate
preterm birth residential exposure
2003 Tsai Taiwan 49,670 A 10% random sample of all women in Taiwan who had first-parity singleton between 1994 and 1997 and who did not live in the study region.
14,545 Women who had first-parity singleton deliveries and who lived within a circle of 2km radius around the multiple sources of industrial complexes including petrochemical industries
effect Study group vs Reference group
OR=1.11 (95% CI=1.02-1.21)
moderate moderate
preterm birth residential exposure
2002b Yang Taiwan 51,789 A 10% random sample of all women in Taiwan who had first-parity singleton between 1993 and 1996 and who did not live in the study region.
5,338 Women who had first-parity singleton deliveries and who lived in area with petrochemical complexes.
effect Study group vs Reference group
OR=1.18 (95% CI=1.04-1.34)
moderate moderate
preterm birth residential exposure
2004 Yang Taiwan 50,388 A 10% random sample of all women in Taiwan who had first-parity singleton between 1994 and 1997 and who did not live in the study region.
7,095 Women who had first-parity singleton deliveries and who lived near three oil refinery plants.
effect Study group vs Reference group
OR=1.14 (95% CI=1.01-1.28)
moderate moderate
preterm birth residential exposure
2014 McKenzie USA 65,506 Women who delivered live babies during 1996 and 2009 and who lived an area with no natural gas wells within 10 miles
18,884 (low exposure)
Women who delivered live babies during 1996 and 2009 and who lived in an area within 10-mile radius of natural gas wells (first tertile calculated by an inverse distance weighted approach)
effect (protective)
Low exposure vs Reference group
OR=0.96 (95% CI=0.89-1.0)
high high
18,854 (medium exposure)
Women who delivered live babies during 1996 and 2009 and who lived in an area within 10-mile radius of natural gas wells falling into the second tertile calculated by an inverse distance weighted approach
Medium exposure vs Reference group
OR=0.93 (95% CI=0.87-1.0)
19,384 (high exposure)
Women who delivered live babies during 1996 and 2009 and who lived in an area within 10-mile radius of natural gas wells (third tertile calculated by an inverse distance weighted approach)
High exposure vs Reference group
OR=0.91 (95% CI=0.85-0.98)
miscarriage residential exposure
1988 Axelsson Sweden 705 Women who lived in an area without petrochemical industries and who have had pregnancies between
607 Women who lived near petrochemical industries and who have had pregnancies between
no effect Study group vs Reference group
OR=1.15 (95% CI=0.75-1.76)
moderate inadequate
1963 and 1981 1963 and 1981miscarriage residential
exposure2002 Sebastián Ecuador 586 Women living in 14
communities at least 30 km upstream from any oil field
791 Women living 9 communities within 5 km of an oil field, following a downstream direction
effect Study group vs Reference group
OR=2.47 (95% CI=1.61-3.79)
high high
miscarriage occupational exposure
1998 Xu China 1,621 (based on self-reported exposure); 1,233 based on employment history recorded exposure)
Women who worked in petrochemical plants, but did not occupationally expose to petrochemicals during the first trimester of pregnancy. Current and past exposure was assessed by self-report via questionnaire developed by professional industrial hygienist or employment record.
1,232(based on self-reported exposure); 1,620 (based on employment history recorded exposure)
Women working in petrochemical plants and occupationally exposed to petrochemicals during the first trimester of pregnancy. Current and past exposure was assessed by self-report via questionnaire developed by professional industrial hygienist or employment record.
effect Study group vs Reference group
OR=2.9 (95%CI=2.0-4.0) based on self-reported exposure; OR=2.7 (95% CI=1.8-3.9) based on employment history recorded exposure
high high
miscarriage occupational exposure
1989 Axelsson Sweden 47 Women who were not involved in laboratory work at the petrochemical plant
55 Women involved in laboratory work at a petrochemical plant during 1973 and 1987
effect Study group vs Reference group
observed/expected=3, p<0.05
very low N/A
stillbirth residential exposure
2002 Sebastián Ecuador 586 Women living in 14 communities at least 30 km upstream from any oil field
791 Women living in 9 communities within 5 km of an oil field, following a downstream direction
no effect Study group vs Reference group
OR=0.85 (95% CI=0.35-2.05)
low inadequate
stillbirth residential exposure
2002 Oliveira Brazil 230 The first newborns from the same hospital weighing ≥2,500g without malformations and of case-matching sex.
230 Stillborn (>500g) selected from 17,113 birth records in Brazil from 1983 to 1998.
no effect Geographic distance: Region close to petrochemical plant vs Reference region
OR=0.78 (95% CI=0.22-2.72) p=0.659
low inadequate
230 The first newborns from the same hospital weighing ≥2,500g without malformations and of case-matching sex.
230 Stillborn (>500g) selected from 17,113 birth records in Brazil from 1983 to 1998.
Wind direction: Region with preferential wind direction vs Reference region
OR=0.98 (95% CI=0.38-2.54) p=0.959
low birth weight (term)
residential exposure
2002a Yang Taiwan 19,673 Women who had singleton deliveries living in 16 municipalities where the number of workers in the petroleum and petrochemical industry comprised less than 2% of the municipality's total population
20,077 Women who had first-parity singleton deliveries living in 16 petrochemical industrial municipality where the number of workers in the petroleum and petrochemical industry comprised equal or greater than 2% of the municipality's total population
no effect Study group vs Reference group
OR=1.07 (95% CI=0.95-1.22)
moderate inadequate
low birth weight
residential exposure
2002 Oliveira Brazil 986 The first newborns from the same hospital weighing ≥2,500g without malformations and of case-matching sex.
987 Newborns with low birth weight selected from 17,113 birth records in Brazil from 1983 to 1998.
no effect Geographic distance: Region close to petrochemical plant vs Reference region
OR=1.50 (95% CI=0.90–2.50) p=0.117
moderate inadequate
986 The first newborns from the 987 Newborns with low birth Wind direction: OR=1.42 (95%
same hospital weighing ≥2,500g without malformations and of case-matching sex.
weight selected from 17,113 birth records in Brazil from 1983 to 1998.
Region with preferential wind direction vs Reference region C
CI=0.87–2.31) p=0.158
birth weight (term)
residential exposure
2016 Casey USA 2341 (first quartile)
Women living in the area within the first quartile of natural gas development activity calculated by an inverse-distance squared model and delivered babies during 2009 and 2013
2384 (second quartile)
Women living in the area within the second quartile of natural gas development activity calculated by an inverse-distance squared model and delivered babies during 2009 and 2013
no effect Second quartile vs. First quartile
Difference in mean: -16 g (95% CI= -44 to 11)
moderate inadequate
2336 (third quartile)
Women living in the area within the third quartile of natural gas development activity calculated by an inverse-distance squared model and delivered babies during 2009 and 2013
Third quartile vs. First quartile
Difference in mean: 1 g (95% CI=-34 to 36)
2332 (fourth quartile)
Women living in the area within the fourth quartile of natural gas development activity calculated by an inverse-distance squared model and delivered babies during 2009 and 2013
Fourth quartile vs. First quartile
Difference in mean: -20 g (95% CI=-56 to 16)
birth weight residential exposure
1988 Axelsson Sweden 221 (first baby)
Women who lived in an area without petrochemical industries and who have had pregnancies between 1963 and 1981
185 Women who lived near petrochemical industries and who have had pregnancies between 1963 and 1981
no effect first baby (Study group vs Reference group)
Mean±SD: 3464 ± 507 vs 3405 ± 581; difference in mean: 59 g, p>0.05
moderate inadequate
198 (second baby)
Women who lived in an area without petrochemical industries and who have had pregnancies between 1963 and 1981
186 Women who lived near petrochemical industries and who have had pregnancies between 1963 and 1981
Second baby (Study group vs Reference group)
Mean±SD: 3621 ± 529 vs 3557 ± 509; difference in mean: 64 g, p>0.05
112 (third baby)
Women who lived in an area without petrochemical industries and who have had pregnancies between 1963 and 1981
99 Women who lived near petrochemical industries and who have had pregnancies between 1963 and 1981
Third baby (Study group vs Reference group)
Mean±SD: 3667 ± 546 vs 3607 ± 553; difference in mean: 60 g, p>0.05
low birth weight (term)
residential exposure
2001b Lin Taiwan 868 Women who had first-parity singleton deliveries and who lived in a control area without petrochemical air pollution between 1993 and 1996
1,677 Women who had first-parity singleton deliveries and who lived in a petrochemical area between 1993 and 1996
effect Study group vs Reference group
OR=1.77 (95% CI=1.0-3.1)
moderate moderate
low birth weight (term)
residential exposure
2014 McKenzie USA 60,653 Women who delivered live babies during 1996 and 2009 and who lived an area with no natural gas wells within 10 miles
17,525 (low exposure)
Women who delivered live babies during 1996 and 2009 and who lived in an area within 10-mile radius of natural gas wells (first tertile calculated by an inverse distance weighted
effect (protective)
Low exposure vs Reference group
OR=1.0 (95% CI=0.9-1.1)
moderate moderate
approach)17,565 (medium exposure)
Women who delivered live babies during 1996 and 2009 and who lived in an area within 10-mile radius of natural gas wells (second tertile calculated by an inverse distance weighted approach)
Medium exposure vs Reference group
OR=0.86 (95% CI=0.77-0.95)
18,104 (high exposure)
Women who delivered live babies during 1996 and 2009 and who lived in an area within 10-mile radius of natural gas wells (third tertile calculated by an inverse distance weighted approach)
High exposure vs Reference group
OR=0.9 (95% CI=0.8-1.0)
low birth weight
residential exposure
1988 Axelsson Sweden 1,527 Women who lived in an area without petrochemical industries and who have had pregnancies between 1963 and 1981
1,255 Women who lived near petrochemical industries and who have had pregnancies between 1963 and 1981
effect (protective)
Study group vs Reference group
exposed area: observed/expected=0.66 (95% CI=0.44, 0.94)
moderate moderate
birth weight residential exposure
2015 Stacy USA 3,604 (first quartile)
Women living in the area with an inverse distance weighted count of unconventional wells >0, but <0.87
3,905 (second quartile)
Women living in the area with an inverse distance weighted count of unconventional wells ≥0.87, but <2.60
effect Second quartile vs. First quartile
3370.4±540.5 vs 3343.9±543.9 (difference in mean: 26.5 g) p>0.05
moderate moderate
3,791 (third quartile)
Women living in the area with an inverse distance weighted count of unconventional wells ≥2.60, but <6.00
Third quartile vs. First quartile
3345.4±553.5 vs 3343.9±543.9 (difference in mean: 1.5 g) p>0.05
4,151 (fourth quartile)
Women living in the area with an inverse distance weighted count of unconventional wells ≥6.00
Fourth quartile vs. First quartile
3323.1±558.2 vs 3343.9±543.9 (difference in mean: -20.8 g ) p=0.02
birth weight (small for gestational age)
3,604 (first quartile)
Women living in the area with an inverse distance weighted count of unconventional wells >0, but <0.87
3,905 (second quartile)
Women living in the area with an inverse distance weighted count of unconventional wells ≥0.87, but <2.60
effect Second quartile vs. First quartile
OR≈1.1 (95% CI crossing 1) (data presented in figure, no actual number)
moderate moderate
3,791 (third quartile)
Women living in the area with an inverse distance weighted count of unconventional wells ≥2.60, but <6.00
Third quartile vs. First quartile
OR≈1.2 (95% CI crossing 1) (data presented in figure, no actual number)
4,151 (fourth quartile)
Women living in the area with an inverse distance weighted count of unconventional wells ≥6.00
Fourth quartile vs. First quartile
OR=1.34 (95% CI=1.10-1.63) (actual number mentioned in text)
birth weight occupational exposure
1989 Axelsson Sweden 1,238 (general population)
All singleton infants born in the same city during 1973-1981
40 Women involved in laboratory work at a petrochemical plant during 1973 and 1987
effect (protective)
Study group vs Reference group
no statistical conclusion
very low N/A
birth defects (not specified)
residential exposure
2002 Oliveira Brazil 158 The first newborns from the same hospital weighing ≥2,500g without birth defects and of case-matching sex.
159 Newborns with birth defects selected from 17,113 birth records in Brazil from 1983 to 1998.
no effect Geographic distance: Region close to petrochemical plant vs Reference region
OR=0.30 (95% CI=0.70–1.27) p=0.103
low inadequate
birth defects (not specified)
158 The first newborns from the same hospital weighing ≥2,500g without birth defects and of case-matching sex.
159 Newborns with birth defects selected from 17,113 birth records in Brazil from 1983 to 1998.
Wind direction: Region with preferential wind direction vs Reference region
OR =1.08 (95% CI=0.30–3.88) p=0.907
birth defects (oral clefts)
residential exposure
2014 McKenzie USA 66,626 Women who delivered live babies during 1996 and 2009 and who lived an area with no natural gas wells within 10 miles
19,214 (low exposure)
Women who delivered live babies during 1996 and 2009 and who lived in an area within 10-mile radius of natural gas wells falling into the first tertile calculated by an inverse distance weighted approach
no effect Low exposure vs Reference group
OR=0.65 (95% CI=0.43-0.98)
moderate inadequate
19,209 (medium exposure)
Women who delivered live babies during 1996 and 2009 and who lived in an area within 10-mile radius of natural gas wells falling into the second tertile calculated by an inverse distance weighted approach
Medium exposure vs Reference group
OR=0.89 (95% CI=0.61-1.3)
19,793 (high exposure)
Women who delivered live babies during 1996 and 2009 and who lived in an area within 10-mile radius of natural gas wells falling into the third tertile calculated by an inverse distance weighted approach
High exposure vs Reference group
OR=0.82 (95% CI=0.55-1.2)
birth defects (congenital heart defect)
66,626 Women who delivered live babies during 1996 and 2009 and who lived an area with no natural gas wells within 10 miles
19,214 (low exposure)
Women who delivered live babies during 1996 and 2009 and who lived in an area within 10-mile radius of natural gas wells falling into the first tertile calculated by an inverse distance weighted approach
effect Low exposure vs Reference group
OR=1.1 (95% CI=0.93-1.3)
moderate moderate
19,209 (medium exposure)
Women who delivered live babies during 1996 and 2009 and who lived in an area within 10-mile radius of natural gas wells falling into the second tertile calculated by an inverse distance weighted approach
Medium exposure vs Reference group
OR=1.2 (95% CI=1.0-1.3)
19,793 (high exposure)
Women who delivered live babies during 1996 and 2009 and who lived in an area within 10-mile radius of natural gas wells falling into third tertile calculated by an inverse distance weighted approach
High exposure vs Reference group
OR=1.3 (95% CI=1.2-1.5)
birth defects (neural tube defects)
66,626 Women who delivered live babies during 1996 and 2009 and who lived an area with no natural gas wells within 10 miles
19,214 (low exposure)
Women who delivered live babies during 1996 and 2009 and who lived in an area within 10-mile radius of natural gas wells falling into the first tertile calculated by an inverse distance weighted approach
effect Low exposure vs Reference group
OR=0.65 (95% CI=0.25-1.7)
moderate moderate
19,209 (medium exposure)
Women who delivered live babies during 1996 and 2009 and who lived in an area within 10-mile radius of natural gas wells falling into the second tertile calculated by an inverse distance weighted approach
Medium exposure vs Reference group
OR=0.80 (95% CI=0.34-1.9)
19,793 (high exposure)
Women who delivered live babies during 1996 and 2009 and who lived in an area within 10-mile radius of natural gas wells falling into the third tertile calculated by an inverse distance weighted approach
High exposure vs Reference group
OR=2.0 (95% CI=1.0-3.9)
birth defects (oral clefts)
occupational exposure
2006 Chevrier France 10 Children hospitalized for treatment of some other disorders without any birth defects, cancer or genetic disease and matched with cases by sex, age, maternal geographic origin, and residence
17 Child diagnosed with cleft lip and/or cleft palate requiring surgery during 1998 and 2001 at seven hospitals.
effect Study group vs Reference group
OR=3.64 (95% CI=1.5-8.8)
moderate moderate
birth defects (not specified)
residential exposure
1988 Axelsson Sweden 1,527 Women who lived in an area without petrochemical industries and who have had pregnancies between 1963 and 1981
1,255 Women who lived near petrochemical industries and who have had pregnancies between 1963 and 1981
effect Study group vs Reference group
observed/expected=0.68 based on registry of birth defects. observed/expected=0.79 based on Medical Birth Registry.
very low N/A
sex ratio residential exposure
2000a Yang Taiwan no data Did not have a reference group.
92,601 All babies born by mothers living near a petroleum refinery plant during 1971 and 1996
no effect Study group vs Reference group
Not significant (Z-scores for individual year of a total of 26 years were listed in table)
low inadequate
sex ratio residential exposure
2000b Yang Taiwan no data Did not have a reference group.
208,501 All babies born by mothers living in petrochemical industrial municipalities during 1987 and 1996
effect Study group vs Reference group
M/F=109.3 (Z=2.96, p=0.003)
low moderate
Semen quality, Fertility and Birth Outcomes Associated with Adult Male Exposures
Sperm and Fertilitysperm concentration
occupational 1985 Rosenberg unknown 74 other petroleum refinery workers
42 petroleum refinery's waste water facility workers
no effect reference group vs study group
unexposed=80.8mill/ML; exposed=66.9mill/mL: p=0.16
low inadequate
sperm concentration
occupational 1997 Khalifa Saudi Arabia
1 Petroleum field worker 0 none effect during exposure vs. after employment
During employment = 0.025 mill/ml-3.2 mill/ml; after employment=12 mill/ml-20.6 mill/ml
very low N/A
sperm concentration
occupational 2001 Wang China 49 Non-exposed/non-smoker 23 Exposed/Non-smoker effect Non-smokers: Exposed vs. unexposed
control=60.07 mill/mL, exposed=52.52 mill/ml
moderate moderate
81 Non-exposed/smoker 45 Exposed/smoker Smokers: Exposed vs. unexposed
control=55.32 mill/ml, exposed=41.49 mill/ml
49 Non-exposed/non-smoker 45 Exposed/smoker Exposed/smoker vs. unexposed/non-smoker
control=60.07 mill/mL, exposed=41.49 mill/ml (p<0.01)
81 Non-exposed/smoker 23 Exposed/Non-smoker Exposed/non-smoker vs. unexposed/smoker
control=55.32 mill/ml, exposed=52.52 mill/ml
sperm count occupational 2001 Wang China 49 Non-exposed/non-smoker 23 Exposed/Non-smoker effect Non-smokers: Exposed vs. unexposed
Control=152 mill/ejac, Exposed=127.02 mill/ejac
moderate moderate
81 Non-exposed/smoker 45 Exposed/smoker Smokers: Exposed vs. unexposed
control=141.86 mill/ejac, exposed=108.48 mill/ejac (p<0.05)
49 Non-exposed/non-smoker 45 Exposed/smoker Exposed/smoker vs. unexposed/non-smoker
control=152 mill/ejac, exposed=108.48 mill/ejac (p<0.05)
sperm motility
occupational 1997 Khalifa Saudi Arabia
1 Petroleum field worker 0 none effect during exposure vs. after employment
During employment: Rapid=0-15, Sluggish=0-15%; after employment: Rapid=30-40,
very low N/A
sluggish=5-15%sperm motility
experimental 2013 Mandani 12 Healthy human semen samples (sperm count 75-110 mill/mL) exposed to Benzene metabolite phenol-hydroquinone
10 Healthy human semen samples (sperm count 75-110 mill/mL)
effect control vs. 0.05 ppm
Control=76%, 0.05ppm=30.2% (p<0.001)
high high
control vs. 0.1 ppm
Control=76%, 0.1ppm=27% (p<0.001)
control vs. 0.2 ppm
Control=76%, 0.2ppm=12% (p<0.001)
control vs. 0.3 ppm
Control=76%, 0.3ppm=2.2% (p<0.001)
sperm motility
experimental 2013 Mandani 12 Healthy human semen samples (sperm count 75-110 mill/mL) exposed to Benzene metabolite catechol
10 Healthy human semen samples (sperm count 75-110 mill/mL)
effect control vs. 0.05 ppm
Control=76%, 0.05ppm=52% (p<0.01)
high high
control vs. 0.1 ppm
Control=76%, 0.1ppm=44% (p<0.01)
control vs. 0.2 ppm
Control=76%, 0.2ppm=30% (p<0.01)
control vs. 0.3 ppm
Control=76%, 0.3ppm=24% (p<0.01)
sperm motility
occupational 2001 Wang China 49 Non-exposed/non-smoker 23 Exposed/Non-smoker effect Non-smokers: Exposed vs. unexposed
Control=2.41, scale, exposed=2.02 (p<0.05)
moderate moderate
81 Non-exposed/smoker 45 Exposed/smoker Smokers: Exposed vs. unexposed
Control=2.45, scale, Exposed=2.01 (p<0.01)
49 Non-exposed/non-smoker 45 Exposed/smoker Exposed/smoker vs. unexposed/non-smoker
Control=2.41, scale, exposed=2.01 (p<0.01)
81 Non-exposed/smoker 23 Exposed/Non-smoker Exposed/non-smoker vs. unexposed/smoker
Control=2.45, scale, exposed =2.02 (p<0.01)
sperm viability
occupational 2001 Wang China 49 Non-exposed/non-smoker 23 Exposed/Non-smoker no effect Non-smokers: Exposed vs. unexposed
Control=61.44%, Exposed=63.41% (p>0.05)
moderate inadequate
81 Non-exposed/smoker 45 Exposed/smoker Smokers: Exposed vs. unexposed
control=60.28%, exposed=60.78% (p>0.05)
49 Non-exposed/non-smoker 45 Exposed/smoker Exposed/smoker vs. unexposed/non-smoker
Control=61.44%, exposed=60.78% (p>0.05)
81 Non-exposed/smoker 23 Exposed/Non-smoker Exposed/non-smoker vs. unexposed/smoker
control=60.28%, exposed=63.4% (p>0.05)
sperm viability
occupational 2013 Mandani 12 Healthy human semen samples (sperm count 75-110 mill/mL) exposed to Benzene metabolite phenol-hydroquinone
10 Healthy human semen samples (sperm count 75-110 mill/mL)
effect control vs. 0.05 ppm
Control=59%, 0.05ppm=49%
high high
control vs. 0.1 ppm
Control=59%, 0.1ppm=41%
control vs. 0.2 ppm
Control=59%, 0.2ppm=32%(p<0.01)
control vs. 0.3 ppm
Control=59%, 0.3ppm=13%(p<0.001)
sperm viability
occupational 2013 Mandani 12 Healthy human semen samples (sperm count 75-110 mill/mL) exposed to Benzene metabolite catechol
10 Healthy human semen samples (sperm count 75-110 mill/mL)
effect control vs. 0.05 ppm
Control=60%, 0.05ppm=52%(p<0.01)
high high
control vs. 0.1 ppm
Control=60%, 0.1ppm=44%(p<0.01)
control vs. 0.2 ppm
Control=60%, 0.2ppm=30%(p<0.001)
control vs. 0.3 ppm
Control=60%, 0.3ppm=24%(p<0.001)
DNA Damage - Intact DNA
occupational 2013 Mandani 12 Healthy human semen samples (sperm count 75-110 mill/mL) exposed to Benzene metabolite phenol-hydroquinone
10 Healthy human semen samples (sperm count 75-110 mill/mL)
effect reference group vs study group
Control=86.5%, phenol-hydroquinone=47.9%(p<0.001)
high high
DNA Damage - Denatured SS DNA
reference group vs study group
Control=14.5%, phenol-hydroquinone=63.3%(p<0.001)
DNA Damage - Effective DNA
reference group vs study group
Control=73.5%, phenol-hydroquinone=40.5%(p<0.001)
DNA Damage - Intact DNA
occupational 2013 Mandani 12 Healthy human semen samples (sperm count 75-110 mill/mL) exposed to Benzene metabolite catechol
10 Healthy human semen samples (sperm count 75-110 mill/mL)
effect reference group vs study group
Control=86.5%, catechol=55.3%(p<0.001)
high high
DNA Damage - Denatured SS DNA
reference group vs study group
Control=14.5%, catechol=44.7%(p<0.001)
DNA Damage - Effective DNA
reference group vs study group
Control=73.5%, catechol=47%(p<0.001)
sperm concentration
occupational 1985 Rosenberg unknown 74 other petroleum refinery workers
39 petroleum refinery's waste water facility workers
no effect reference group vs study group
unexposed=49.1%; exposed=44.5%
low inadequate
(p=.94)sperm motility
occupational 1997 Khalifa Saudi Arabia
1 Petroleum field worker 0 none effect during exposure vs. after employment
During employment = 10-90%; after employment=10-35%
very low N/A
fertility occupational 1999 Bull unknown 51 offshore operators (Non-exposed)
30 offshore mechanics (exposed)
no effect Offshore operators vs. offshore mechanics
Fecundity Ratio=0.8 (95% CI=0.49-1.32)
low inadequate
51 offshore operators (Non-exposed)
95 offshore drilling personnel (exposed)
Offshore operators vs. offshore drilling
Fecundity Ratio=0.89 (95% CI=0.61-1.29)
Birth Outcomes Arising from Paternal Exposurefetal Loss occupational 1999 Bull unknown 86 pregnancies - offshore
operators (Non-exposed)59 pregnancies - offshore
mechanics (exposed)no effect Offshore
operators vs. offshore mechanics
OR= 1.1 (95% CI=0.4-3.1)
low inadequate
86 pregnancies - offshore operators (Non-exposed)
172 pregnancies - offshore drilling personnel (exposed)
Offshore operators vs. offshore drilling
OR = 1.4 (95% CI=0.6-3.2)
birth defects occupational 2012 Desrosiers USA 4066 fathers of children without major birth defects (20 worked in petroleum and gas)
9998 fathers of children with birth defects (71 worked in petroleum and gas)
effect reference group vs study group
OR=2 (95% CI=0.8-5.1)
low low
birth defects occupational 2012 Desrosiers USA 4066 fathers of children without major birth defects (20 worked in petroleum and gas)
9998 fathers of children with birth defects (71 worked in petroleum and gas)
effect reference group vs study group
OR=2.8 (95% CI=0.9-9.1)
low low
birth defects occupational 2012 Desrosiers USA 4066 fathers of children without major birth defects (20 worked in petroleum and gas)
9998 fathers of children with birth defects (71 worked in petroleum and gas)
effect reference group vs study group
OR=2.6 (95% CI=1.1-6.5)
low low
birth defects occupational 2012 Desrosiers USA 4066 fathers of children without major birth defects (20 worked in petroleum and gas)
9998 fathers of children with birth defects (71 worked in petroleum and gas)
effect reference group vs study group
OR=1.6 (95% CI=1.0-2.4)
low low
childhood cancer
occupational 1987 Johnson USA 30 Unaffected children of Chemical, petroleum and rubber industries workers
20 Affected children of Chemical, petroleum and rubber industries workers
no effect reference group vs study group
OR=1.3 (95% CI= 0.8-2.4)
very low N/A
6 Unaffected children of Petroleum refining industry workers
8 Affected children of Petroleum refining industry workers
OR=2.7 (95% CI= 0.9-7.8)
6 Unaffected children of Petroleum refinery workers
6 Affected children of Petroleum refinery workers
OR=2.0 (95% CI=0.6-6.2)
Reproductive Cancer
prostate cancer
occupational 2006 Rybicki USA 244 men without cancer with occupational respiratory exposure to petroleum
637 men with prostate cancer with respiratory exposure to petroleum
no effect reference group vs study group
OR 1.12 (95% CI 0.73-1.73); p=0.61
low inadequate
prostate occupational 2006 Rybicki USA 244 men without cancer with 637 men with prostate no effect reference group OR 0.74 (95% CI low inadequate
cancer cutaneous exposure to petroleum
cancer with cutaneous exposure to petroleum
vs study group 0.48-1.13); p=0.16
prostate cancer incidence
occupational 1991 Christie Australia not reported
incidence rates of general population
15,000 Australian Institute of Petroleum employees
no effect reference group vs study group
SIR of 1.0 (95% CI 0.4-1.9)
low inadequate
prostate cancer incidence
occupational 2004 Gun Australia not reported
incidence rates of general population
15,956 Australian Institute of Petroleum employees
effect reference group vs study group
SIR of 1.19 (95% CI 1.00 to 1.40)
moderate moderate
prostate cancer incidence
occupational 2006 Gun Australia not reported
incidence rates of general population
16,547 Australian Institute of Petroleum employees
effect reference group vs study group
SIR of 1.18 (95% CI 1.04 to 1.34)
moderate moderate
prostate cancer incidence
residential 1984 Kaldor USA 411,180 low exposure area (Area 2) 300,494 (Area 3); 486,691 (Area 4)
Area 3: "medium" exposure level group Area 4: "high" exposure level group
effect reference group vs two study groups
trend (p=0.002) for increasing prostate cancer incidence rates with areas of increasing exposure
moderate moderate
prostate cancer incidence
residential 1989 Schechter Canada not reported
expected cancer rates of three rural areas in Southern Alberta selected that were socio-demographically similar to cohort area
1,126 rural residents of Southern Alberta, Canada living near natural gas refineries
no effect reference group vs study group
SIR 1.76 (95% CI 0.84-4.38)
very low N/A
prostate cancer incidence
occupational 1997 Järvholm Sweden not reported
incidence rates of general population
4,128 Swedish petroleum industry workers
no effect reference group vs study group
SIR 1.1 (90% CI 0.78-1.5)
very low N/A
prostate cancer incidence
occupational 2003 Lewis Canada not reported
incidence rates of general population
17,230 Canadian petroleum industry workers
no effect reference group vs study group
SIR of 0.67 (95% CI 0.41-1.03)
very low N/A
testicular cancer incidence
occupational 2004 Gun Australia not reported
incidence rates of general population
15,956 Australian Institute of Petroleum employees
no effect reference group vs study group
SIR of 1.24 (95% CI 0.68 to 2.08)
low inadequate
testicular cancer incidence
occupational 2006 Gun Australia not reported
incidence rates of general population
16,547 Australian Institute of Petroleum employees
no effect reference group vs study group
SIR of 1.33 (95% CI 0.80 to 2.08)
low inadequate
testicular cancer incidence
residential 1984 Kaldor USA 411,180 low exposure area (Area 2) 300,494 (Area 3); 486,691 (Area 4)
Area 3: "medium" exposure level group Area 4: "high" exposure level group
no effect reference group vs two study groups
no trend (p>0.1) low inadequate
testicular cancer incidence
occupational 1991 Christie Australia not reported
incidence rates of general population
15,000 Australian Institute of Petroleum employees
no effect reference group vs study group
SIR of 1.0 (95% CI 0.2-2.8)
very low N/A
testicular cancer incidence
occupational 2003 Lewis Canada not reported
incidence rates of general population
17,230 Canadian petroleum industry workers
no effect reference group vs study group
SIR of 0.82 (95% CI 0.45-1.37)
very low N/A
cervical cancer incidence
residential 1984 Kaldor USA 421,995 low exposure area (Area 2) 303,397 (Area 3); 506,191 (Area 4)
Area 3: "medium" exposure level group Area 4: "high" exposure level group
no effect reference group vs two study groups
no trend (p>0.1) low inadequate
uterine cancer incidence
residential 1984 Kaldor USA 421,995 low exposure area (Area 2) 303,397 (Area 3); 506,191 (Area 4)
Area 3: "medium" exposure level group Area 4: "high" exposure level group
no effect reference group vs two study groups
no trend (p>0.1) low inadequate
cervical cancer incidence
occupational 2004 Gun Australia not reported
incidence rates of general population
867 Australian Institute of Petroleum employees
no effect reference group vs study group
SIR of 1.61 (95% CI 0.33 to 4.71)
very low N/A
cervical cancer incidence
occupational 2003 Lewis Canada not reported
incidence rates of general population
8,062 Canadian petroleum industry workers
effect reference group vs study group
SIR of 0.42 (95% CI 0.17-0.86)
very low N/A
uterine cancer incidence
occupational 2003 Lewis Canada not reported
incidence rates of general population
8,062 Canadian petroleum industry workers
effect reference group vs study group
SIR of 0.31 (95% CI 0.06-0.89)
very low N/A
ovarian, fallopian tube, and broad ligament cancer incidence
occupational 2003 Lewis Canada not reported
incidence rates of general population
8,062 Canadian petroleum industry workers
no effect reference group vs study group
SIR of 1.40 (95% CI 0.78-2.30)
very low N/A
gynecologic cancer incidence
residential 1989 Schechter Canada not reported
expected cancer rates of three rural areas in Southern Alberta selected that were socio-demographically similar to cohort area
1,038 rural residents of Southern Alberta, Canada living near natural gas refineries
no effect reference group vs study group
1 case out of 1038 residents (no statistical analysis)
very low N/A
breast cancer incidence
residential 1984 Kaldor USA 421,995 low exposure area (Area 2) 303,397 (Area 3); 506,191 (Area 4)
Area 3: "medium" exposure level group Area 4: "high" exposure level group
no effect reference group vs two study groups
no trend (p>0.1) low inadequate
breast cancer incidence
occupational 2004 Gun Australia not reported
incidence rates of general population
867 Australian Institute of Petroleum employees
no effect reference group vs study group
SIR of 1.02 (95% CI 0.53 to 1.79)
low inadequate
breast cancer incidence
occupational 2003 Lewis Canada not reported
incidence rates of general population
8,062 Canadian petroleum industry workers
no effect reference group vs study group
SIR of 1.02 (95% CI 0.80-1.28)
very low N/A
breast cancer incidence
residential 1989 Schechter Canada not reported
expected cancer rates of three rural areas in Southern Alberta selected that were socio-demographically similar to cohort area
1,038 rural residents of Southern Alberta, Canada living near natural gas refineries
no effect reference group vs study group
9 cases out of 1038 residents (no statistical analysis)
very low N/A