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Cited by 21Per- and polyfluoroalkyl substances researchEffects and risks of endocrine disrupting chemicalsSynthesis and properties of polymers

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Environmental Exposure to Per- and Polyfluorylalkyl Substances (PFASs) and Reproductive Outcomes in the General Population: A Systematic Review of Epidemiological Studies

Open access
Haimbaugh, Alex, Meyer, Danielle N., Connell, Mackenzie L., Blount-Pacheco, Jessica, Tolofari, Dienye, Gonzalez, Gabrielle, Banerjee, Dayita, Norton, John, Miller, Carol J., Baker, Tracie R.·2024·International Journal of Environmental Research and Public Health
DOI 10.3390/ijerph21121615PMC PMC11675763
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Abstract

This Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) systematic review synthesized effects of background levels of per- and polyfluorylalkyl substance (PFAS) levels on reproductive health outcomes in the general public: fertility, preterm birth, miscarriage, ovarian health, menstruation, menopause, sperm health, and in utero fetal growth. The inclusion criteria included original research (or primary) studies, human subjects, and investigation of outcomes of interest following non-occupational exposures. It drew from four databases (Web of Science, PubMed, Embase and Health and Environmental Research Online (HERO)) using a standardized search string for all studies published between 1 January 2017 and 13 April 2022. Risk of bias was assessed by two independent reviewers. Data were extracted and reviewed by multiple reviewers. Each study was summarized under its outcome in terms of methodology and results and placed in context, with recommendations for future research. Of 1712 records identified, 30 were eligible, with a total of 27,901 participants (33 datasets, as three studies included multiple outcomes). There was no effect of background levels of PFAS on fertility. There were weakly to moderately increased odds of preterm birth with higher perfluorooctane sulfonic acid (PFOS) levels; the same for miscarriage with perfluorooctanoic acid (PFOA) levels. There was limited yet suggestive evidence for a link between PFAS and early menopause and primary ovarian insufficiency; menstrual cycle characteristics were inconsistent. PFAS moderately increased odds of PCOS- and endometriosis-related infertility, respectively. Sperm motility and DNA health were moderately impaired by multiple PFAS. Fetal growth findings were inconsistent. This review may be used to inform forthcoming drinking water standards and policy initiatives regarding PFAS compounds and drinking water. Future reviews would benefit from more recent studies. Larger studies in these areas are warranted. Future studies should plan large cohorts and open access data availability to capture small effects and serve the public. Funding: Great Lakes Water Authority (Detroit, MI), the Erb Family Foundation through Healthy Urban Waters at Wayne State University (Detroit, MI), and Wayne State University CLEAR Superfund Research (NIH P42ES030991).

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Crossref · 10.3390/ijerph21121615

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Figures

Figure 1 PRISMA flow diagram.
Figure 1 PRISMA flow diagram.CC BY · PubMed Central
Figure 2 Pie charts depicting study characteristics. Percentages are rounded to nearest whole number and may not add up to 100%. (a) Number of studies included for each outcome. Some studies measured multiple outcomes. (b) Media type used in studies. Some studies used multiple media. (c) Study design type. (d) Open access status. (e) Region of studies. Scandinavia includes Sweden, Norway, Faroe Islands, and Denmark.
Figure 2 Pie charts depicting study characteristics. Percentages are rounded to nearest whole number and may not add up to 100%. (a) Number of studies included for each outcome. Some studies measured multiple outcomes. (b) Media type used in studies. Some studies used multiple media. (c) Study design type. (d) Open access status. (e) Region of studies. Scandinavia includes Sweden, Norway, Faroe Islands, and Denmark.CC BY · PubMed Central
Figure 3 (a) Participants in each outcome. (b) Average risk of bias scores in each outcome stratified by cohort or cross-sectional studies (left) or case–control (right). Minimum points to be included in the review for cohort/cross-sectional was 7; maximum achievable was 10. Minimum points to be included in the review for case–control was 10; maximum achievable was 14. (c) Median PFAS levels (ng/mL) in each study in maternal/paternal blood, serum, or plasma. Levels reported from controls only in case–control studies. Multi-region studies denoted with (S) for Sweden, (N) for Norway, (Y) for Yantai, and (B) for Beijing. Meng et al., 2018 [58]. Sagiv et al., 2017 [59]. Liew et al., 2020 [60]. Petersen et al., 2018 [61]. Ding et al., 2020 [62]. Lauritzen et al., 2017 [63]. Kalloo et al., 2020 [64]. Singer et al., 2018 [65]. Zhou et al., 2017 [66]. Song et al., 2018 [67]. Huo et al., 2020 [68]. Pan et al., 2019 [69]. Chu et al., 2020 [70]. Wang et al., 2021 [71]. Wang et al., 2017 [72]. Costa et al., 2019 [73]. Manzano-Salgado et al., 2017 [74]. Zhang et al., 2018 [75]. Wikström et al., 2021 [76]. Ouidir et al., 2020 [77]. Wang et al., 2021 [71]. Wise et al., 2022 [78]. Wang et al., 2019 [79]. Bjorvang et al., 2022 [80]. Heffernan et al., 2018 [81]. Bjorvang et al., 2021 [82]. Eick & Hom Thepaksorn et al., 2020 [83]. Liu et al., 2020 [84]. Asterisk denotes the concentration of controls in case-control studies, if overall median is not reported.
Figure 3 (a) Participants in each outcome. (b) Average risk of bias scores in each outcome stratified by cohort or cross-sectional studies (left) or case–control (right). Minimum points to be included in the review for cohort/cross-sectional was 7; maximum achievable was 10. Minimum points to be included in the review for case–control was 10; maximum achievable was 14. (c) Median PFAS levels (ng/mL) in each study in maternal/paternal blood, serum, or plasma. Levels reported from controls only in case–control studies. Multi-region studies denoted with (S) for Sweden, (N) for Norway, (Y) for Yantai, and (B) for Beijing. Meng et al., 2018 [58]. Sagiv et al., 2017 [59]. Liew et al., 2020 [60]. Petersen et al., 2018 [61]. Ding et al., 2020 [62]. Lauritzen et al., 2017 [63]. Kalloo et al., 2020 [64]. Singer et al., 2018 [65]. Zhou et al., 2017 [66]. Song et al., 2018 [67]. Huo et al., 2020 [68]. Pan et al., 2019 [69]. Chu et al., 2020 [70]. Wang et al., 2021 [71]. Wang et al., 2017 [72]. Costa et al., 2019 [73]. Manzano-Salgado et al., 2017 [74]. Zhang et al., 2018 [75]. Wikström et al., 2021 [76]. Ouidir et al., 2020 [77]. Wang et al., 2021 [71]. Wise et al., 2022 [78]. Wang et al., 2019 [79]. Bjorvang et al., 2022 [80]. Heffernan et al., 2018 [81]. Bjorvang et al., 2021 [82]. Eick & Hom Thepaksorn et al., 2020 [83]. Liu et al., 2020 [84]. Asterisk denotes the concentration of controls in case-control studies, if overall median is not reported.CC BY · PubMed Central
Figure 4 Forest plot of odds and risk ratios for preterm birth with increasing PFAS levels from four studies. LNE: line of no effect. PFNA: perfluorononanoic acid. PFHxS: perfluorohexane sulfonic acid. PFOS: perfluorooctane sulfonic acid. PFOA: perflurooctanoic acid. Yang et al., 2022 [108]. Sagiv et al., 2018 [59]. Manzano-Salgado et al., 2017 [74]. Eick & Hom Thepaksorn et al., 2020 [83]. Liu et al., 2020 [84]. Chu et al., 2020 [70].
Figure 4 Forest plot of odds and risk ratios for preterm birth with increasing PFAS levels from four studies. LNE: line of no effect. PFNA: perfluorononanoic acid. PFHxS: perfluorohexane sulfonic acid. PFOS: perfluorooctane sulfonic acid. PFOA: perflurooctanoic acid. Yang et al., 2022 [108]. Sagiv et al., 2018 [59]. Manzano-Salgado et al., 2017 [74]. Eick & Hom Thepaksorn et al., 2020 [83]. Liu et al., 2020 [84]. Chu et al., 2020 [70].CC BY · PubMed Central
Figure 5 Forest plot of miscarriage odds and risk ratios with increasing PFAS levels from three studies. LNE: line of no effect. PFOS: perfluorooctane sulfonic acid. PFOA: perflurooctanoic acid. PFNA: perfluorononanoic acid. PFHxS: perfluorohexane sulfonic acid. PFDA: perfluorodecanoic acid. Wang et al. (2021) results are from Beijing and Yantai sites combined. Wang et al., 2021 [71]. Wikström et al., 2021 [76]. Liew et al., 2020 [60].
Figure 5 Forest plot of miscarriage odds and risk ratios with increasing PFAS levels from three studies. LNE: line of no effect. PFOS: perfluorooctane sulfonic acid. PFOA: perflurooctanoic acid. PFNA: perfluorononanoic acid. PFHxS: perfluorohexane sulfonic acid. PFDA: perfluorodecanoic acid. Wang et al. (2021) results are from Beijing and Yantai sites combined. Wang et al., 2021 [71]. Wikström et al., 2021 [76]. Liew et al., 2020 [60].CC BY · PubMed Central
Figure 6 Forest plot of odds and risk ratios of ovarian health effects (top: endometriosis; bottom: PCOS-related infertility) with increasing PFAS levels from two studies. PFHpA: perfluoroheptanoic acid. PFBS: perfluorobutanesulfonic acid. PFDoA: perfluorododecanoic acid. PFHxS: perfluorohexane sulfonic acid. PFUA: perfluoroundecanoic acid. PFDA: perfluorodecanoic acid. PFNA: perfluorononanoic acid. PFOS: perfluorooctanesulfonic acid. PFOA: perfluorooctanoic acid. Wang et al., 2019 [184]. Wang et al., 2017 [72].
Figure 6 Forest plot of odds and risk ratios of ovarian health effects (top: endometriosis; bottom: PCOS-related infertility) with increasing PFAS levels from two studies. PFHpA: perfluoroheptanoic acid. PFBS: perfluorobutanesulfonic acid. PFDoA: perfluorododecanoic acid. PFHxS: perfluorohexane sulfonic acid. PFUA: perfluoroundecanoic acid. PFDA: perfluorodecanoic acid. PFNA: perfluorononanoic acid. PFOS: perfluorooctanesulfonic acid. PFOA: perfluorooctanoic acid. Wang et al., 2019 [184]. Wang et al., 2017 [72].CC BY · PubMed Central
Figure 7 Forest plot of beta coefficients for sperm health effects with increasing PFAS levels in semen from two studies. Top panel: DNA stability (decreasing); DNA fragmentation index. Bottom panel: sperm motility (% motile sperm). PFDA: perfluorodecanoic acid. PFUnDA: perfluoroundecanoic acid. 6:2 Cl-PFESA: 6:2 chlorinated polyfluorinated ether sulfonate. PFNA: perfluorononanoic acid. PFOS: perfluorooctanesulfonic acid. PFOA: perfluorooctanoic acid. Pan et al., 2019 [69]. Petersen et al., 2018 [61].
Figure 7 Forest plot of beta coefficients for sperm health effects with increasing PFAS levels in semen from two studies. Top panel: DNA stability (decreasing); DNA fragmentation index. Bottom panel: sperm motility (% motile sperm). PFDA: perfluorodecanoic acid. PFUnDA: perfluoroundecanoic acid. 6:2 Cl-PFESA: 6:2 chlorinated polyfluorinated ether sulfonate. PFNA: perfluorononanoic acid. PFOS: perfluorooctanesulfonic acid. PFOA: perfluorooctanoic acid. Pan et al., 2019 [69]. Petersen et al., 2018 [61].CC BY · PubMed Central
Figure 8 For each PFAS, median level (ng/mL) across ethnicities (concentrations are compared by column, not row). Color darkens with increasing median concentration. Me-FOSAA: N-methylperfluorooctane sulfonamidoacetic acid. PFDA: perfluorodecanoic acid. PFDoDA: perfluorododecanoic acid. PFHxS: perfluorohexane sulfonate. PFNA: perfluorononanoic acid. PFOA: perfluorooctanoic acid. PFOS: perfluorooctane sulfonate. PFUnDA: perfluoroundecanoic acid.
Figure 8 For each PFAS, median level (ng/mL) across ethnicities (concentrations are compared by column, not row). Color darkens with increasing median concentration. Me-FOSAA: N-methylperfluorooctane sulfonamidoacetic acid. PFDA: perfluorodecanoic acid. PFDoDA: perfluorododecanoic acid. PFHxS: perfluorohexane sulfonate. PFNA: perfluorononanoic acid. PFOA: perfluorooctanoic acid. PFOS: perfluorooctane sulfonate. PFUnDA: perfluoroundecanoic acid.CC BY · PubMed Central
Figure 9 Heatmap of beta-values at FDR < 0.05 for measures of fetal growth, broken down by group. Warmer colors (orange, red) indicate lower values, yellow indicates mid-range values, and green indicates higher values. AC: abdominal circumference, FL: femur length, EFW: estimated fetal weight, BD: biparietal diameter. Head circumference not included (not significant for any ethnicity). Me-FOSAA: N-methylperfluorooctane sulfonamidoacetic acid. PFDA: perfluorodecanoic acid. PFDoDA: perfluorododecanoic acid. PFHxS: perfluorohexane sulfonate. PFNA: perfluorononanoic acid. PFOA: perfluorooctanoic acid. PFOS: perfluorooctane sulfonate. PFUnDA: perfluoroundecanoic acid.
Figure 9 Heatmap of beta-values at FDR < 0.05 for measures of fetal growth, broken down by group. Warmer colors (orange, red) indicate lower values, yellow indicates mid-range values, and green indicates higher values. AC: abdominal circumference, FL: femur length, EFW: estimated fetal weight, BD: biparietal diameter. Head circumference not included (not significant for any ethnicity). Me-FOSAA: N-methylperfluorooctane sulfonamidoacetic acid. PFDA: perfluorodecanoic acid. PFDoDA: perfluorododecanoic acid. PFHxS: perfluorohexane sulfonate. PFNA: perfluorononanoic acid. PFOA: perfluorooctanoic acid. PFOS: perfluorooctane sulfonate. PFUnDA: perfluoroundecanoic acid.CC BY · PubMed Central

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  1. The BMJ (2024, September 14). Correlation and Regression. Available online: https://www.bmj.com/about-bmj/resources-readers/publications/statistics-square-one/11-correlation-and-regression.

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Metadata

Authors
Haimbaugh, A., Meyer, D. N., Connell, M. L., Blount-Pacheco, J., Tolofari, D., Gonzalez, G., Banerjee, D., Norton, J., Miller, C. J., & Baker, T. R.
Affiliations
  • Wayne State University (US)
  • University of Florida Health (US)
  • Great Lakes Water Authority (US)
Corresponding author
Baker, Tracie R.
ORCID
Venue
International Journal of Environmental Research and Public Health
Publisher
MDPI AG
Published
2024-12-02
Volume
21
Issue
12
Pages
1615
ISSN
1660-4601 (ISSN-L)
DOI
10.3390/ijerph21121615
PMC
PMC11675763
OpenAlex
W4404915882
Cited by
21
References
200
Citations by year
2026: 16 · 2025: 5
FWCI
0.67
Type
journal article
Language
en
Open access
Licence
Locations
  • International Journal of Environmental Research and Public Health (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
Funders
  • Great Lakes Water Authority (GLWA) (NIH P42ES030991)
  • Erb Family Foundation through Healthy Urban Waters at Wayne State University, and Wayne State University CLEAR Superfund Research (NIH P42ES030991)
  • NIH Superfund (NIH P42ES030991)
Topics
  • Physical Sciences › Environmental Science › Environmental Chemistry › Per- and polyfluoroalkyl substances research
  • Physical Sciences › Environmental Science › Health, Toxicology and Mutagenesis › Effects and risks of endocrine disrupting chemicals
  • Physical Sciences › Materials Science › Polymers and Plastics › Synthesis and properties of polymers
Keywords
per- and polyfluoroalkyl substances, PFAS exposure, reproductive outcomes, fertility, preterm birth, miscarriage, perfluorooctanoic acid, PFOS, early menopause, primary ovarian insufficiency, menstrual cycle, polycystic ovary syndrome, endometriosis, sperm motility, sperm DNA damage, fetal growth, drinking water standards, general population
MeSH terms
Environmental Exposure, Environmental Pollutants, Female, Fluorocarbons, Humans, Male, Pregnancy, Reproduction

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