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OD Research - Reproductive Epidemiology

Longitudinal Investigation of Fertility and the Environment (LIFE) Study

The research aims of the LIFE Study are to identify environmental influences on human fecundity and fertility, particularly the role of endocrine-disrupting chemicals (EDCs) and lifestyle. During the past few decades, evidence from mechanistic, wildlife, and human research suggests that EDCs may interfere with any aspect of hormone action and, thereby, affect reproduction and development. The LIFE Study was specifically designed to fill critical data gaps regarding EDCs and human fecundity (biologic capacity for reproduction irrespective of pregnancy intention) and fertility (demonstrated fecundity as evident by having or fathering a live birth).

The LIFE Study recruited 501 couples between 2005 and 2009 who completed standardized baseline interviews and anthropometric assessments, provided blood and urine samples, and were instructed in the completion of daily journals to capture lifestyle; women’s journals also captured pregnancy test results. Women were trained in the use of the Clearblue Fertility® monitor to help time intercourse relative to ovulation. Women provided 2 saliva samples, and men provided 2 semen samples. Pregnant women completed daily journals through 7 post-conception weeks then monthly until delivery. The LIFE Study’s complete methodology is published (Buck Louis et al. 2011).

The LIFE Study assessed 66 persistent EDCs, which included 3 heavy metals; 9 organochlorine pesticides (OCPs); 7 perfluoroalkyl and polyfluoroalkyl substances (PFASs), 1 polybrominated biphenyls (PBB), 10 polybrominated diphenyl ethers (PBDEs), and 36 polychlorinated biphenyls (PCBs). In addition, the Study assessed non-persistent EDCs, including 5 benzophenone ultraviolet light-type filters, bisphenol A (BPA), 14 phthalates, 5 parabens, and 21 trace elements.

The LIFE Study has had many important discoveries. For example, we found that blood lead concentration in male partners was associated with an adjusted fecundity odds ratio (FOR) <1.0, which denotes diminished fecundity or a longer Time-to-Pregnancy (TTP), even after adjusting for female partners concentrations (FOR 0.83; 95% CI 0.70, 0.98; Buck Louis et al., Chemosphere 2012). We also individually assessed 63 persistent organic pollutants (OCPs, PBB, PBDEs, PCBs and PFAAs), as quantified in each partner in relation to couple fecundity. Eleven significant FORs were observed and all but one (PCB congener #101) was associated with FORs <1.0 indicative of diminished fecundity (Buck Louis et al., EHP 2013). Of further interest was the unique pattern of findings depending upon partner, with 3 PCB congeners (#118, 167, 209) and 1 PFAA (PFOSA) associated with diminished fecundity when assessing females, and 9 EDCs (8 PCB congeners and p,p’-DDE) for male partners (Buck Louis et al., EHP 2013). Only PCB congeners #167 (dioxin-like) and #209 (non-dioxin like) were consistently associated with FORs <1.0 in both partners. To summarize our adjusted results for POPs, fecundity was diminished 17% for p,p’-DDE and 17% to 29% for PCBs when assessing males, with similar ranges for PFOSA (18%) and PCBs (18% to 21%) when assessing females.

With regard to non-persistent chemicals, we did not find any such EDCs to be significantly associated with improved fecundity (FORs >1.0) meaning a shorter TTP.  In fact, all FORs were <1.0 irrespective of chemical class suggesting reduced fecundity or a longer TTP (Buck Louis et al., Fertil Steril 2014). Notably, male partners’ concentrations were associated with diminished fecundity. Our findings for BP-type UV filters (sunscreens) are the first reported human evidence for these commonly used compounds (Buck Louis et al., AJE 2014). Also of note was the absence of any association between urinary BPA concentrations and fecundity (females FOR=0.98; 95% CI 0.86, 1.13; males FOR=1.04; 95% CI 0.91, 1.18). Our most recent work focusing on other environmental phenols found that female partners in the highest versus lowest quartile of urinary methyl paraben concentrations had diminished fecundity (FOR=0.63; 95% CI 0.41, 0.96) even when accounting for male partners’ concentrations (Smarr et al., 2016).

The LIFE Study also assessed EDCs and semen endpoints. We found evidence that persistent EDCs such as specific PBDE and PCB congeners and PFASs were associated with a higher percentage of morphometric changes in sperm head or tail (Buck Louis et al., EHP 2015; Mumford et al., Chemosphere 2015). With regard to non-persistent EDCs, we found specific phthalates and BP-filter 2 (sunscreen) to be associated with not only lower sperm counts and concentrations, but also decreased motility and an increase in sperm head or tail abnormalities (Bloom et al., Hum Reprod 2015; Buck Louis et al., Fertil Steril 2015). We also assessed urinary phytoestrogens and semen quality and reported genistein and daidzein to be associated with fewer normal sperm and increased morphologic abnormalities (Mumford et al., J Nutr 2015). In terms of lifestyle factors, we found that overweight and obesity were associated with lower ejaculate volume, sperm count, and concentration (Eisenberg et al., Hum Reprod), and that serum total and free cholesterol and phospholipids were inversely associated with the percentage of sperm with intact acrosome, and sperm head area and perimeter (Schisterman et al., Andrology 2014). 

In the LIFE Study, the incidence of pregnancy loss was 28%. Moreover, being female but not male age ≥35 years was a significant risk factor for pregnancy loss, as was female and male consumption of >2 daily caffeinated beverages while trying for pregnancy. Women’s daily use of multivitamins reduced the risk of pregnancy loss (Buck Louis et al., Fertil Steril 2016). 

Collectively, the Study’s findings demonstrate that lifestyle and environmental exposures to EDCs may affect human fecundity and fertility.

Principal Investigator

Germaine Louis, Ph.D., M.S.

DIPHR Collaborators

Selected Publications

  • Buck Louis GM, Schisterman EF, Sweeney AM, Wilcosky TC, Gore-Langton RE, Lynch CD, Boyd Barr D, Schrader SM, Kim S, Chen Z, Sundaram R. Designing prospective cohort studies for assessing reproductive and developmental toxicity during sensitive windows of human reproduction and development--the LIFE Study. Paediatric and Perinatal Epidemiology.2011; 25(5):413-424. PMID: 21819423. PMCID: PMC4118054.
  • Buck Louis GM, Sundaram R, Schisterman EF, Sweeney AM, Lynch CD, Gore-Langton RE, Chen Z, Kim S, Caldwell KL, Barr DB. Heavy metals and couple fecundity, the LIFE Study. Chemosphere.2012; 87(11):1201-1207. PMID: 22309709. PMCID: PMC3327819.
  • Buck Louis GM, Sundaram R, Schisterman EF, Sweeney AM, Lynch CD, Gore-Langton RE, Maisog J, Kim S, Chen Z, Barr DB. Persistent environmental pollutants and couple fecundity: the LIFE Study. Environmental Health Perspectives.2013; 121(2):231-236. PMID: 23151773. PMCID: PMC3569685.
  • Buck Louis GM, Sundaram R, Schisterman EF, Sweeney A, Lynch CD, Kim S, Maisog JM, Gore-Langton R, Eisenberg ML, Chen Z. Semen quality and time to pregnancy: the Longitudinal Investigation of Fertility and the Environment Study. Fertility and Sterility.2014; 101(2):453-62. PMID: 24239161. PMCID: PMC3946620
  • Eisenberg ML, Kim S, Chen Z, Sundaram R, Schisterman EF, Buck Louis GM. The relationship between male BMI and waist circumference on semen quality: data from the LIFE study. Human Reproduction.2014; 29(2):193-200. PMID: 24306102. PMCID: PMC3896223.
  • Buck Louis GM, Sundaram R, Sweeney AM, Schisterman EF, Maisog J, Kannan K. Urinary bisphenol A, phthalates, and couple fecundity: the Longitudinal Investigation of Fertility and the Environment (LIFE) Study. Fertility and Sterility.2014; 101(5):1359-1366. PMID: 24534276. PMCID: PMC4008721.
  • Schisterman EF, Mumford SL, Chen Z, Browne RW, Boyd Barr D, Kim S, Buck Louis GM. Lipid concentrations and semen quality: The LIFE Study. Andrology.2014; 2(3):408-415. PMID: 24596332. PMCID: PMC3999259.
  • Lynch CD, Sundaram R, Maisog JM, Sweeney AM, Buck Louis GM. Preconception stress increases the risk of infertility: results from a couple-based prospective cohort study--the LIFE Study. Human Reproduction.2014; 29(5):1067-1075. PMID: 24664130. PMCID: PMC3984126.
  • Schisterman EF, Mumford SL, Browne RW, Barr DB, Chen Z, Louis GM. Lipid concentrations and couple fecundity: the LIFE study. The Journal of Clinical Endocrinology and Metabolism.2014; 99(8):2786-2794. PMID: 24846535. PMCID: PMC4121020.
  • Mumford SL, Sundaram R, Schisterman EF, Sweeney AM, Barr DB, Rybak ME, Maisog JM, Parker DL, Pfeiffer CM, Louis GM. Higher urinary lignan concentrations in women but not men are positively associated with shorter time to pregnancy. The Journal of Nutrition.2014; 144(3):352-358. PMID: 24401816. PMCID: PMC3927547.
  • Sapra KJ, McLain AC, Maisog JM, Sundaram R, Buck Louis GM. Successive time to pregnancy among women experiencing pregnancy loss. Human Reproduction.2014; 29(11):2553-2559. PMID: 25164026. PMCID: PMC4191452.
  • Buck Louis GM, Kannan K, Sapra KJ, Maisog J, Sundaram R. Urinary concentrations of benzophenone-type ultraviolet radiation filters and couples' fecundity. American Journal of Epidemiology.2014; 180(12):1168-1175. PMID: 25395025. PMCID: PMC4262441.
  • Guo Y, Weck J, Sundaram R, Goldstone AE, Louis GB, Kannan K. Urinary concentrations of phthalates in couples planning pregnancy and its association with 8-hydroxy-2'-deoxyguanosine, a biomarker of oxidative stress: longitudinal investigation of fertility and the environment study. Environmental Science & Technology. 2014; 48(16):9804-9811. PMID: 25068827. PMCID: PMC4140531.
  • Buck Louis GM. Persistent environmental pollutants and couple fecundity:  an overview. Reproduction. 2014; 147(4):R97-R104. PMID: 24310101. PMCID: PMC3943622.
  • Mumford SL, Kim S, Chen Z, Gore-Langton RE, Boyd Barr D, Buck Louis GM. Persistent organic pollutants and semen quality: the LIFE Study. Chemosphere. 2015; 135:427-435. PMID: 25441930. PMCID: PMC4447619.
  • Louis GM, Chen Z, Schisterman EF, Kim S, Sweeney AM, Sundaram R, Lynch CD, Gore-Langton RE, Barr DB. Perfluorochemicals and Human Semen Quality: the LIFE Study. Environmental Health Perspectives. 2015; 123(1):57-63. PMID: 25127343. PMCID: PMC4286271.
  • Goldstone AE, Chen Z, Perry MJ, Kannan K, Louis GM. Urinary bisphenol A and semen quality, the LIFE Study. Reproductive Toxicology. 2015; 51:7-13. PMID: 25462789. PMCID: PMC4426021.
  • Zhang C, Sundaram R, Maisog J, Calafat AM, Barr DB, Buck Louis GM. A prospective study of prepregnancy serum concentrations of perfluorochemicals and the risk of gestational diabetes. Fertility and Sterility. 2015; 103(1):184-189. PMID: 25450302. PMCID: PMC4282598.
  • Bae J, Kim S, Kannan K, Buck Louis GM. Couples’ urinary bisphenol A and phthalate metabolite concentrations and the secondary sex ratio. Reproductive Toxicology. 2015; 137:450-457. PMID 25677702. PMCID: PMC4355045.
  • Eisenberg ML, Chen Z, Ye A, Buck Louis GM. Relationship between physical occupational exposures and health on semen quality: data from the Longitudinal Investigation of Fertility and the Environment (LIFE) Study. Fertility and Sterility. 2015; 103(5):1271-1277. PMID: 25765658. PMCID: PMC4417418.
  • Bae J, Kim S, Schisterman EF, Boyd Barr D, Buck Louis GM. Maternal and paternal serum concentrations of perfluoroalkyl and polyfluoroalkyl substances and the secondary sex ratio. Chemosphere.2015; 133:31-40. PMID: 25863705.
  • Bloom MS, Buck Louis GM, Sundaram R, Maisog JM, Steuerwald AJ, Parson PJ. Birth outcomes and background exposures to select elements, the Longitudinal Investigation of Fertility and the Environment (LIFE). Environmental Research. 2015; 138:118-129. PMID: 25707016. PMCID: PMC4385418.
  • Robledo CA, Yeung E, Mendola P, Sundaram R, Maisog J, Sweeney AM, Barr DB, Louis GM. Preconception maternal and paternal exposure to persistent organic pollutants and birth size: the LIFE study. Environmental Health Perspectives. 2015; 123(1):88-94. PMID: 25095280. PMCID: PMC4286275.
  • Louis GM, Chen Z, Schisterman EF, Kim S, Sweeney AM, Sundaram R, Lynch CD, Gore-Langton RE, Barr DB. Perfluorochemicals and Human Semen Quality: the LIFE Study. Environmental Health Perspectives. 2015; 123(1):57-63. PMID: 25127343. PMCID: PMC4286271.
  • McLain AC, Sundaram R, Buck Louis GM. Joint analysis of longitudinal and survival data measured on nested timescales by using shared parameter models: an application to fecundity data. Journal of the Royal Statistical Society – Series C, Applied Statistics. 2015; 64(2):339-357. PMID: 27122641. PMCID: PMC4844229.
  • Sapra KJ, McLain AC, Maisog JM, Sundaram R, Buck Louis GM. Clustering of retrospectively reported and prospectively observed time-to-pregnancy. Annals of Epidemiology.2015; 25(12):959-963. PMID: 26033375. PMCID: PMC4636974.
  • Louis GM, Chen Z, Kim S, Sapra KJ, Bae J, Kannan K. Urinary concentrations of benzophenone-type ultraviolet light filters and semen quality. Fertility and Sterility. 2015; 104(4):989-996. PMID: 26253817. PMCID: PMC4592813.
  • Bloom MS, Whitcomb BW, Chen Z, Ye A, Kannan K, Buck Louis GM. Associations between urinary phthalate concentrations and semen quality parameters in a general population. Human Reproduction. 2015; 30(11):2645-2657. PMID: 26350610. PMCID: PMC4605371.
  • Smarr MM, Grantz KL, Sundaram R, Maisog JM, Kannan K, Louis GM. Parental urinary biomarkers of preconception exposure to bisphenol A and phthalates in relation to birth outcomes. Environmental Health. 2015; 14:73. PMID: 26362861. PMCID: PMC4567813.
  • Mumford SL, Kim S, Chen Z, Boyd Barr D, Buck Louis GM. Urinary Phytoestrogens Are Associated with Subtle Indicators of Semen Quality among Male Partners of Couples Desiring Pregnancy. The Journal of Nutrition. 2015; 145(11):2535-2541. PMID: 26423741. PMCID: PMC4620723.
  • Eisenberg ML, Kim S, Chen Z, Sundaram R, Schisterman EF, Louis GM. The relationship between male BMI and waist circumference on semen quality: data from the LIFE study. Human Reproduction. 2015; 330(2):493-494. PMID: 25516559. PMCID: PMC4303771.
  • Bae J, Kim S, Kannan K, Buck Louis GM. Couples' urinary concentrations of benzophenone-type ultraviolet filters and the secondary sex ratio. Reproductive Toxicology.2016; 543(Pt A):28-36. PMID: 26575635. PMCID: PMC4688162.
  • Lum KJ, Sundaram R, Buck Louis GM, Louis TA. A Bayesian joint model of menstrual cycle length and fecundity. Biometrics. 2016; 72(1):193-203. PMID: 26295923. PMCID: PMC4761533.
  • Jaacks LM, Barr DB, Sundaram R, Maisog JM, Zhang C, Buck Louis GM. Pre-pregnancy maternal exposure to polybrominated and polychlorinated biphenyls and gestational diabetes: a prospective cohort study. Environmental Health. 2016; 15:11. PMID: 26792546. PMCID: PMC4721055.
  • Sapra KJ, Eisenberg ML, Kim S, Chen Z, Buck Louis GM. Choice of underwear and male fecundity in a preconception cohort of couples. Andrology. 2016; 4(3):500-508. PMID: 26939021.
  • Sapra KJ, Buck Louis GM, Sundaram R, Joseph KS, Bates LM, Galea S, Ananth CV.  Signs and symptoms associated with early pregnancy loss: findings from a population-based preconception cohort.  Human Reproduction. 2016; 31(4):887-896. PMID: 26936888. PMCID: PMC4791918.
  • Buck Louis GM, Sapra KJ, Schisterman EF, Lynch CD, Maisog JM, Grantz KL, Sundaram R. Lifestyle and pregnancy loss in a contemporary cohort of women recruited prior to conception: the Life Study. Fertility and Sterility. 2016; 106(1):180-188. PMID: 27016456. PMCID: PMC4930884.
  • Sapra KJ, Barr DB, Maisog JM, Sundaram R, Buck Louis GM. Time-to-pregnancy associated with couples’ use of tobacco products. Nicotine and Tobacco Research. 2016; 18(11):2154-2161. PMID: 27190399. PMCID: PMC5055740 [Available on 2017-11-01].
  • Eisenberg ML, Sundaram R, Maisog J, Buck Louis GM. Diabetes, medical comorbidities and couple fecundity. Human Reproduction. 2016; 31(10):2369-2376. PMID: 27591240. PMCID: PMC5027928 [Available on 2017-10-01].
  • Smarr MM, Grantz KL, Zhang C, Sundaram R, Maisog JM, Barr DB, Louis GM. Persistent organic pollutants and gravid conditions. Science of the Total Environment. 2016; 551-552:285-291. PMID: 26878640.
  • Louis GM, Sapra KJ, Barr DB, Lu Z, Sundaram R. Preconception perfluoroalkyl and polyfluoroalkyl substances and incident pregnancy loss, LIFE Study. Reproductive Toxicology. 2016; 65:11-17. PMID: 27319395. PMCID: PMC5067185 [Available on 2017-10-01].
  • Smarr MM, Grantz KL, Sundaram R, Maisog JM, Honda M, Kannan K, Buck Louis GM. Urinary paracetamol and time-to-pregnancy. Human Reproduction. 2016; 31(9):2119-2127. PMID: 27412248. PMCID: PMC4991660 [Available on 2017-09-01].  
  • Jaacks LM, Boyd Barr D, Sundaram R, Grewal J, Zhang C, Buck Louis GM. Pre-pregnancy maternal exposure to persistent organic pollutants and gestational weight gain: A prospective cohort study. International Journal of Environmental Research and Public Health. 2016; 13(9). PMID: 27626435. PMCID: PMC5036738.
  • Buck Louis GM, Barr DB, Kannan K, Chen Z, Kim S, Sundaram R. Paternal exposures to environmental chemicals and time-to-pregnancy: overview of results from the LIFE Study. Andrology.2016; 4(4):639-647. PMID: 27061873. PMCID: PMC4961554.
  • Bae J, Kim S, Chen Z, Eisenberg ML, Buck Louis GM. Human Semen Quality and the Secondary Sex Ratio. Asian Journal of Andrology. 2017; 19(3):374-381. PMID: 26975484. PMCID: PMC5427797.
  • Mendola P, Sundaram R, Louis GMB, Sun L, Wallace ME, Smarr MM, Sherman S, Zhu Y, Ying Q, Liu D. Proximity to major roadways and prospectively-measured time-to-pregnancy and infertility. Science of the Total Environment. 2017; 576:172-177. PMID: 27783935. PMCID: PMC5164942 [Available on 2018-01-15].
  • Lum KJ, Sundaram R, Barr DB, Louis TA, Louis GM. Perfluoroalkyl chemicals, menstrual cycle length, and fecundity: findings from a prospective pregnancy study. Epidemiology. 2017; 28(1):90-98. PMID: 27541842. PMCID: PMC5131715 [Available on 2018-01-01].
  • Mumford SL, Weck J, Kannan K, Buck Louis GM. Urinary phytoestrogen concentrations are not associated with incident endometriosis in premenopausal women. The Journal of Nutrition. 2017; 147(2):227-234. PMID: 28031375. PMCID: PMC5265693 [Available on 2018-02-01].  
  • Whitcomb BW, Bloom MS, Kim S, Chen Z, Buck Louis GM. Male birthweight, semen quality and birth outcomes. Human Reproduction. 2017; 32(3):505-513. PMID: 28104697. PMCID: PMC5400075 [Available on 2018-03-01].
  • Bae J, Lynch CD, Kim S, Sundaram R, Sapra KJ, Buck Louis GM. Preconception stress and the secondary sex ratio in a population-based preconception cohort. Fertility and Sterility. 2017; 107(3):714-722. PMID: 28104242. PMCID: PMC5337443 [Available on 2018-03-01].
  • Sundaram R, Mumford SL, Buck Louis GM. Couples’ body composition and time-to-pregnancy. Human Reproduction. 2017; 32(3):662-668. PMID: 28158570. PMCID: PMC5400044 [Available on 2018-03-01]..  
  • Buck Louis GM, Smarr MM, Sundaram R, Steuerwald AJ, Sapra KJ, Lu Z, Parsons PJ. Low-level environmental metals and metalloids and incident pregnancy loss. Reproductive Toxicology. 2017; 69:68-74. PMID: 28163209. PMCID: PMC5406243 [Available on 2018-04-01].
  • Palmsten K, Flores KF, Chambers CD, Weiss LA, Sundaram, Buck Louis GM. Most frequently reported prescription medications and supplements in couples planning pregnancy: the LIFE Study. Reproductive Sciences. 2017:1933719117702249. PMID: 28401798.
  • Sapra KJ, Joseph KS, Galea S, Bates LM, Louis GM, Ananth CV. Signs and symptoms of early pregnancy loss. Paediatric and Perinatal Epidemiology. 2017; 24(4):502-513. PMID: 27342274.
  • Smarr MM, Sundaram R, Honda M, Kannan K, Buck Louis GM. Urinary concentrations of parabens and other antimicrobial chemicals and their association with couples' fecundity. Environmental Health Perspectives. 2017; 125(4):730-736. PMID: 27286252. PMCID: PMC5381974.
  • Patel CJ, Sundaram R, Buck Louis GM. A data-driven search for semen-related phenotypes in conception delay. Andrology. 2017; 5(1):95-102. PMID: 27792860. PMCID: PMC5164952.

Contact Information

Name: Constantine A. Stratakis, M.D., D(Med)Sc
Acting Director
Division of Intramural Population Health Research
Phone: 301-594-5984
E-mail: stratakc@mail.nih.gov

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