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A Sharper Focus: Clarifying the PFAS–Preeclampsia Association by Analyzing Disease Subtypes

2022; National Institute of Environmental Health Sciences; Volume: 130; Issue: 1 Linguagem: Inglês

10.1289/ehp10524

1552-9924

Silke Schmidt,

Birth, Development, and Health

Vol. 130, No. 1 Science SelectionOpen AccessA Sharper Focus: Clarifying the PFAS–Preeclampsia Association by Analyzing Disease Subtypesis accompanied byMaternal Levels of Perfluoroalkyl Substances (PFAS) during Early Pregnancy in Relation to Preeclampsia Subtypes and Biomarkers of Preeclampsia Risk Silke Schmidt Silke Schmidt Search for more papers by this author Published:21 January 2022CID: 014002https://doi.org/10.1289/EHP10524AboutSectionsPDF ToolsDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InReddit AbstractPer- and polyfluoroalkyl substances (PFAS) are sometimes called “forever chemicals” owing to their slow decay in the environment and long half-lives in people,1 which for some PFAS exceeds a decade.2 The chemicals have been associated with multiple health risks,1 including adverse pregnancy outcomes, such as preterm birth, low birth weight, and preeclampsia.3,4,5,6,7 The clinical heterogeneity of preeclampsia has long been discussed8 but is rarely addressed in studies of environmental exposures.9 A study of PFAS recently published in Environmental Health Perspectives10 shows why future research should pay more attention to preeclampsia subtypes.The authors divided preeclampsia into early- and late-onset subtypes. They found that higher plasma concentrations of two PFAS in early pregnancy were associated with greater odds of late-onset preeclampsia but not the early-onset subtype. These results indicate that subtypes of preeclampsia should be considered in future studies of the disease. Image: © Rawpixel.com/stock.adobe.com.Preeclampsia, whose primary clinical feature is new-onset or worsening hypertension, affects 10–15% of worldwide pregnancies11,12 and is a major cause of maternal morbidity and mortality.13 “Preeclampsia is a syndrome with multiple independent or overlapping etiologies, and treating it as a single condition in analyses may miss associations with environmental factors,” says senior author David Cantonwine, an assistant professor of epidemiology at Boston’s Brigham and Women’s Hospital. “That is why we tested if PFAS associations differed for subtypes defined by gestational age at diagnosis.”The authors defined early-onset preeclampsia as receiving a diagnosis before 34 weeks of gestation and late-onset preeclampsia as diagnosed at 34 weeks or later.9 A clinical diagnosis of preeclampsia can be made after 20 weeks of gestation in women whose blood pressure was previously normal and who have protein in their urine.14 Early-onset preeclampsia is often associated with placental damage and fetal growth restriction, whereas these features are less common in the late-onset form.15,16,17The researchers analyzed 75 cases and 75 controls (mean age 32.2 years) randomly chosen from 1,648 participants in the LIFECODES cohort18 between 2006 and 2008. Plasma levels of two biomarkers—placental growth factor and soluble fms-like tyrosine kinase-1—had previously been measured four times during pregnancy (median 10, 18, 26, and 35 weeks).18 The two biomarkers are used to estimate the balance of pro- and anti-angiogenic activity within the placenta,19 which may be influenced by PFAS.20,21The researchers measured nine PFAS in plasma samples collected early in pregnancy (median 10 weeks). Early measurements are less likely to be confounded by preeclampsia-related changes in kidney function later in pregnancy10,22 and to have a greater potential to inform risk assessment and clinical care.23The authors reported that higher concentrations of two PFAS in early pregnancy were associated with greater odds of late-onset preeclampsia but did not change the odds of the early-onset subtype. On the other hand, early PFAS concentrations were not robustly associated with changes in the two angiogenic biomarkers during the course of pregnancy. Because these biomarkers may better predict early-onset preeclampsia,24,25 this finding supports the hypothesis that PFAS may influence the late-onset subtype via other mechanisms.“We think the different PFAS associations indicate that late-onset preeclampsia may be due to mechanisms other than disruptions in angiogenesis, such as dyslipidemia and altered thyroid hormone functioning,” says Cantonwine.Most early-onset preeclampsia cases, he adds, show consistent signs of early ischemic damage to the placenta. Less pronounced damage may develop later in some, but not all, women diagnosed after 34 weeks of gestation.For Tracey Woodruff, a professor of reproductive sciences at the University of California, San Francisco, these mechanistic differences between preeclampsia subtypes are a plausible explanation for the observed data and highlight the importance of accounting for gestational age at diagnosis. “Incorporating clinical biomarkers into an analysis of environmental chemicals is another strength of the study,” says Woodruff, who was not involved in the project. “Using these biomarkers to tease out potential etiologic differences between subtypes is valuable for future studies.”Tracy Manuck, an associate professor of obstetrics and gynecology at the University of North Carolina at Chapel Hill, who also was not involved in the project, agrees that the joint analysis of well-known biomarkers and PFAS levels is a unique contribution to the field. “Despite the small sample size, I think the findings are very interesting and show that precise phenotyping may help identify associations between environmental chemicals and adverse pregnancy outcomes,” she says.Silke Schmidt, Ph.D., writes about science, health, and the environment from Madison, Wisconsin.References1. Sunderland EM, Hu XC, Dassuncao C, Tokranov AK, Wagner CC, Allen JG. 2019. A review of the pathways of human exposure to poly- and perfluoroalkyl substances (PFASs) and present understanding of health effects. J Expo Sci Environ Epidemiol 29(2):131–147, PMID: 30470793, 10.1038/s41370-018-0094-1. Crossref, Medline, Google Scholar2. Agency for Toxic Substances and Disease Registry.2021. Toxicological Profile for Perfluoroalkyls. Atlanta, GA: U.S. Department of Health and Human Services, Public Health Service. https://wwwn.cdc.gov/TSP/ToxProfiles/ToxProfiles.aspx?id=1117&tid=237 [accessed 5 January 2022]. Google Scholar3. Savitz DA, Stein CR, Bartell SM, Elston B, Gong J, Shin HM, et al.2012. Perfluorooctanoic acid exposure and pregnancy outcome in a highly exposed community. Epidemiology 23(3):386–392, PMID: 22370857, 10.1097/EDE.0b013e31824cb93b. Crossref, Medline, Google Scholar4. Stein CR, Savitz DA, Dougan M. 2009. Serum levels of perfluorooctanoic acid and perfluorooctane sulfonate and pregnancy outcome. Am J Epidemiol 170(7):837–846, PMID: 19692329, 10.1093/aje/kwp212. Crossref, Medline, Google Scholar5. Erinc A, Davis MB, Padmanabhan V, Langen E, Goodrich JM. 2021. Considering environmental exposures to per- and polyfluoroalkyl substances (PFAS) as risk factors for hypertensive disorders of pregnancy. Environ Res 197:111113, PMID: 33823190, 10.1016/j.envres.2021.111113. Crossref, Medline, Google Scholar6. Stone J, Sutrave P, Gascoigne E, Givens MB, Fry RC, Manuck TA. 2021. Exposure to toxic metals and per- and polyfluoroalkyl substances and the risk of preeclampsia and preterm birth in the United States: a review. Am J Obstet Gynecol MFM 3(3):100308, PMID: 33444805, 10.1016/j.ajogmf.2021.100308. Crossref, Medline, Google Scholar7. Varshavsky JR, Robinson JF, Zhou Y, Puckett KA, Kwan E, Buarpung S, et al.2021. Organophosphate flame retardants, highly fluorinated chemicals, and biomarkers of placental development and disease during mid-gestation. Toxicol Sci 181(2):215–228, PMID: 33677611, 10.1093/toxsci/kfab028. Crossref, Medline, Google Scholar8. Roberts JM, Rich-Edwards JW, McElrath TF, Garmire L, Myatt L, Global Pregnancy Collaboration.2021. Subtypes of preeclampsia: recognition and determining clinical usefulness. Hypertension 77(5):1430–1441, PMID: 33775113, 10.1161/HYPERTENSIONAHA.120.14781. Crossref, Medline, Google Scholar9. von Dadelszen P, Magee LA, Roberts JM. 2003. Subclassification of preeclampsia. Hypertens Pregnancy 22(2):143–148, PMID: 12908998, 10.1081/PRG-120021060. Crossref, Medline, Google Scholar10. Bommarito PA, Ferguson KK, Meeker JD, McElrath TF, Cantonwine DE. 2021. Maternal levels of perfluoroalkyl substances (PFAS) during early pregnancy in relation to preeclampsia subtypes and biomarkers of preeclampsia risk. Environ Health Perspect 129(10):107004, PMID: 34637358, 10.1289/EHP9091. Link, Google Scholar11. Shah S, Gupta A. 2019. Hypertensive disorders of pregnancy. Cardiol Clin 37(3):345–354, PMID: 31279428, 10.1016/j.ccl.2019.04.008. Crossref, Medline, Google Scholar12. Wikström S, Lindh CH, Shu H, Bornehag CG. 2019. Early pregnancy serum levels of perfluoroalkyl substances and risk of preeclampsia in Swedish women. Sci Rep 9(1):9179, PMID: 31235847, 10.1038/s41598-019-45483-7. Crossref, Medline, Google Scholar13. Ananth CV, Keyes KM, Wapner RJ. 2013. Pre-eclampsia rates in the United States, 1980-2010: age-period-cohort analysis. BMJ 347:f6564, PMID: 24201165, 10.1136/bmj.f6564. Crossref, Medline, Google Scholar14. American College of Obstetricians and Gynecologists.2013. Report of the American College of Obstetricians and Gynecologists’ Task Force on Hypertension in Pregnancy. Obstet Gynecol 122(5):1122–1131, PMID: 24150027, 10.1097/01.AOG.0000437382.03963.88. Crossref, Medline, Google Scholar15. Roberts JM, Hubel CA. 2009. The two stage model of preeclampsia: variations on the theme. Placenta 30(suppl A):S32–S37, PMID: 19070896, 10.1016/j.placenta.2008.11.009. Crossref, Medline, Google Scholar16. Steegers EAP, von Dadelszen P, Duvekot JJ, Pijnenborg R. 2010. Pre-eclampsia. Lancet 376(9741):631–644, PMID: 20598363, 10.1016/S0140-6736(10)60279-6. Crossref, Medline, Google Scholar17. Raymond D, Peterson E. 2011. A critical review of early-onset and late-onset preeclampsia. Obstet Gynecol Surv 66(8):497–506, PMID: 22018452, 10.1097/OGX.0b013e3182331028. Crossref, Medline, Google Scholar18. McElrath TF, Lim KH, Pare E, Rich-Edwards J, Pucci D, Troisi R, et al.2012. Longitudinal evaluation of predictive value for preeclampsia of circulating angiogenic factors through pregnancy. Am J Obstet Gynecol 207(5):407.e1–e7, PMID: 22981320, 10.1016/j.ajog.2012.08.010. Crossref, Medline, Google Scholar19. Maynard SE, Min JY, Merchan J, Lim KH, Li J, Mondal S, et al.2003. Excess placental soluble fms-like tyrosine kinase 1 (sFlt1) may contribute to endothelial dysfunction, hypertension, and proteinuria in preeclampsia. J Clin Invest 111(5):649–658, PMID: 12618519, 10.1172/JCI17189. Crossref, Medline, Google Scholar20. Pham A, Zhang J, Feng L. 2020. Exposure to perfluorobutane sulfonate and perfluorooctanesulfonic acid disrupts the production of angiogenesis factors and stress responses in human placental syncytiotrophoblast. Reprod Toxicol 98:269–277, PMID: 33144174, 10.1016/j.reprotox.2020.10.013. Crossref, Medline, Google Scholar21. Poteser M, Hutter HP, Moshammer H, Weitensfelder L. 2020. Perfluoroctanoic acid (PFOA) enhances NOTCH-signaling in an angiogenesis model of placental trophoblast cells. Int J Hyg Environ Health 229:113566, PMID: 32485599, 10.1016/j.ijheh.2020.113566. Crossref, Medline, Google Scholar22. Sagiv SK, Rifas-Shiman SL, Webster TF, Mora AM, Harris MH, Calafat AM, Ye X, et al.2015. Sociodemographic and perinatal predictors of early pregnancy per- and polyfluoroalkyl substance (PFAS) concentrations. Environ Sci Technol 49(19):11849–11858, PMID: 26333069, 10.1021/acs.est.5b02489. Crossref, Medline, Google Scholar23. Dubon Garcia A, Devlieger R, Redekop K, Vandeweyer K, Verlohren S, Poon LC. 2021. Cost-utility of a first-trimester screening strategy versus the standard of care for nulliparous women to prevent pre-term pre-eclampsia in Belgium. Pregnancy Hypertens 25:219–224, PMID: 34271426, 10.1016/j.preghy.2021.06.012. Crossref, Medline, Google Scholar24. Levine RJ, Maynard SE, Qian C, Lim KH, England LJ, Yu KF, et al.2004. Circulating angiogenic factors and the risk of preeclampsia. N Engl J Med 350(7):672–683, PMID: 14764923, 10.1056/NEJMoa031884. Crossref, Medline, Google Scholar25. Pinheiro CC, Rayol P, Gozzani L, dos Reis LM, Zampieri G, Dias CB, et al.2014. The relationship of angiogenic factors to maternal and neonatal manifestations of early-onset and late-onset preeclampsia. Prenat Diagn 34(11):1084–1092, PMID: 24916790, 10.1002/pd.4432. Crossref, Medline, Google ScholarFiguresReferencesRelatedDetailsRelated articlesMaternal Levels of Perfluoroalkyl Substances (PFAS) during Early Pregnancy in Relation to Preeclampsia Subtypes and Biomarkers of Preeclampsia RiskOct 12, 2021, 12:00:00 AMEnvironmental Health Perspectives Vol. 130, No. 1 January 2022Metrics Downloaded 1,414 times About Article Metrics Publication History Manuscript received21 October 2021Manuscript accepted7 January 2022Originally published21 January 2022 Financial disclosuresPDF download License information EHP is an open-access journal published with support from the National Institute of Environmental Health Sciences, National Institutes of Health. All content is public domain unless otherwise noted. 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