Office of the DiPHR Director (OD) Research: Reproductive Endocrinology

Longitudinal Investigation of Fertility and the Environment (LIFE) Study

Longitudinal Investigation of Fertility and the Environment (LIFE) StudyThe 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., Environmental Health Perspectives, 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., Environmental Health Perspectives, 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., Fertilility and Sterility, 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., American Journal of Epidemiology, 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., Environmental Health Perspectives, 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., Human Reproduction, 2015; Buck Louis et al., Fertility and Sterility, 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., Journal of Nutrition, 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 Reproduction), 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., Fertility and Sterility 2016). 

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

Principal Investigator

Rajeshwari Sundaram, M.Stat., Ph.D.

Division Collaborator

Zhen Chen, Ph.D.

Selected Publications

  • Sapra, K. J., Buck Louis, G. M., Sundaram, R., Joseph, K. S., Bates, L. M., Galea, S., & Ananth, C. V. (2018). Time-varying effects of signs and symptoms on pregnancy loss <20 weeks: Findings from a preconception prospective cohort study. Paediatric and Perinatal Epidemiology, 32(1), 30–39. PMID: 29336062
  • Eisenberg, M. L., Sapra, K. J., Kim, S. D., Chen, Z., & Buck Louis, G. M. (2017). Semen quality and pregnancy loss in a contemporary cohort of couples recruited before conception: Data from the Longitudinal Investigation of Fertility and the Environment (LIFE) Study. Fertility and Sterility, 108(4), 613–619. PMID: 28863939
  • Smarr, M. M., Sapra, K. J., Gemmill, A., Kahn, L. G., Wise, L. A., Lynch, C. D., Factor-Litvak, P., Mumford, S. L., Skakkebaek, N. E., Slama, R., Lobdell, D. T., Stanford, J. B., Jensen, T. K., Boyle, E. H., Eisenberg, M. L., Turek, P. J., Sundaram, R., Thoma, M. E., & Buck Louis, G. M. (2017). Is human fecundity changing? A discussion of research and data gaps precluding us from having an answer. Human Reproduction (Oxford, England), 32(3), 499–504. PMID: 28137753
  • Smarr, M. M., Kannan, K., Chen, Z., Kim, S., & Buck Louis, G. M. (2017). Male urinary paracetamol and semen quality. Andrology, 5(6), 1082–1088. PMID: 28853221
  • Patel, C. J., Sundaram, R., & Buck Louis, G. M. (2017). A data-driven search for semen-related phenotypes in conception delay. Andrology, 5(1), 95–102. PMID: 27792860
  • Smarr, M. M., Sundaram, R., Honda, M., Kannan, K., & Louis, G. M. (2017). Urinary concentrations of parabens and other antimicrobial chemicals and their association with couples' fecundity. Environmental Health Perspectives, 125(4), 730–736. PMID: 27286252
  • Sapra, K. J., Joseph, K. S., Galea, S., Bates, L. M., Louis, G. M., & Ananth, C. V. (2017). Signs and symptoms of early pregnancy loss. Reproductive Sciences (Thousand Oaks, Calif.), 24(4), 502–513. PMID: 27342274
  • Palmsten, K., Flores, K. F., Chambers, C. D., Weiss, L. A., Sundaram, R., & Buck Louis, G. M. (2018). Most frequently reported prescription medications and supplements in couples planning pregnancy: The LIFE Study. Reproductive Sciences (Thousand Oaks, Calif.), 25(1), 94–101. PMID: 28401798
  • Buck Louis, G. M., Smarr, M. M., Sundaram, R., Steuerwald, A. J., Sapra, K. J., Lu, Z., & Parsons, P. J. (2017). Low-level environmental metals and metalloids and incident pregnancy loss. Reproductive toxicology (Elmsford, N.Y.), 69, 68–74. PMID: 28163209
  • Sundaram, R., Mumford, S. L., & Buck Louis, G. M. (2017). Couples' body composition and time-to-pregnancy. Human Reproduction (Oxford, England), 32(3), 662–668. PMID: 28158570
  • Bae, J., Lynch, C. D., Kim, S., Sundaram, R., Sapra, K. J., & Buck Louis, G. M. (2017). Preconception stress and the secondary sex ratio in a population-based preconception cohort. Fertility and Sterility, 107(3), 714–722. PMID: 28104242
  • Whitcomb, B. W., Bloom, M. S., Kim, S., Chen, Z., & Buck Louis, G. M. (2017). Male birthweight, semen quality and birth outcomes. Human Reproduction (Oxford, England), 32(3), 505–513. PMID: 28104697
  • Mumford, S. L., Weck, J., Kannan, K., & Buck Louis, G. M. (2017). Urinary phytoestrogen concentrations are not associated with incident endometriosis in premenopausal women. The Journal of Nutrition, 147(2), 227–234. PMID: 28031375
  • Lum, K. J., Sundaram, R., Barr, D. B., Louis, T. A., & Buck Louis, G. M. (2017). Perfluoroalkyl chemicals, menstrual cycle length, and fecundity: Findings from a prospective pregnancy study. Epidemiology (Cambridge, Mass.), 28(1), 90–98. PMID: 27541842
  • Mendola, P., Sundaram, R., Louis, G., Sun, L., Wallace, M. E., Smarr, M. M., Sherman, S., Zhu, Y., Ying, Q., & Liu, D. (2017). Proximity to major roadways and prospectively-measured time-to-pregnancy and infertility. The Science of the Total Environment, 576, 172–177. PMID: 27783935
  • Bae, J., Kim, S., Chen, Z., Eisenberg, M. L., & Buck Louis, G. M. (2017). Human semen quality and the secondary sex ratio. Asian Journal of Andrology, 19(3), 374–381. PMID: 26975484
  • Buck Louis, G. M., Barr, D. B., Kannan, K., Chen, Z., Kim, S., & Sundaram, R. (2016). Paternal exposures to environmental chemicals and time-to-pregnancy: overview of results from the LIFE study. Andrology, 4(4), 639–647. PMID: 27061873
  • Jaacks, L. M., Boyd Barr, D., Sundaram, R., Grewal, J., Zhang, C., & Buck Louis, G. M. (2016). Pre-pregnancy maternal exposure to persistent organic pollutants and gestational weight gain: A prospective cohort study. International Journal of Environmental Research and Public Health, 13(9), 905. PMID: 27626435
  • Smarr, M. M., Grantz, K. L., Sundaram, R., Maisog, J. M., Honda, M., Kannan, K., & Buck Louis, G. M. (2016). Urinary paracetamol and time-to-pregnancy. Human Reproduction (Oxford, England), 31(9), 2119–2127. PMID: 27412248
  • Louis, G. M., Sapra, K. J., Barr, D. B., Lu, Z., & Sundaram, R. (2016). Preconception perfluoroalkyl and polyfluoroalkyl substances and incident pregnancy loss, LIFE study. Reproductive Toxicology (Elmsford, N.Y.), 65, 11–17. PMID: 27319395
  • Smarr, M. M., Grantz, K. L., Zhang, C., Sundaram, R., Maisog, J. M., Barr, D. B., & Louis, G. M. (2016). Persistent organic pollutants and pregnancy complications. The Science of the Total Environment, 551-552, 285–291. PMID: 26878640
  • Eisenberg, M. L., Sundaram, R., Maisog, J., & Buck Louis, G. M. (2016). Diabetes, medical comorbidities and couple fecundity. Human Reproduction (Oxford, England), 31(10), 2369–2376. PMID: 27591240
  • Sapra, K. J., Barr, D. B., Maisog, J. M., Sundaram, R., & Buck Louis, G. M. (2016). Time-to-pregnancy associated with couples' use of tobacco products. Nicotine & Tobacco Research: Official Journal of the Society for Research on Nicotine and Tobacco, 18(11), 2154–2161. PMID: 27190399
  • Buck Louis, G. M., Sapra, K. J., Schisterman, E. F., Lynch, C. D., Maisog, J. M., Grantz, K. L., & Sundaram, R. (2016). Lifestyle and pregnancy loss in a contemporary cohort of women recruited before conception: The LIFE study. Fertility and Sterility, 106(1), 180–188. PMID: 27016456
  • Sapra, K. J., Buck Louis, G. M., Sundaram, R., Joseph, K. S., Bates, L. M., Galea, S., & Ananth, C. V. (2016). Signs and symptoms associated with early pregnancy loss: findings from a population-based preconception cohort. Human Reproduction (Oxford, England), 31(4), 887–896. PMID: 26936888
  • Sapra, K. J., Eisenberg, M. L., Kim, S., Chen, Z., & Buck Louis, G. M. (2016). Choice of underwear and male fecundity in a preconception cohort of couples. Andrology, 4(3), 500–508. PMID: 26939021
  • Jaacks, L. M., Barr, D. B., Sundaram, R., Maisog, J. M., Zhang, C., & Buck Louis, G. M. (2016). Pre-pregnancy maternal exposure to polybrominated and polychlorinated biphenyls and gestational diabetes: A prospective cohort study. Environmental Health: A Global Access Science Source, 15, 11. PMID: 26792546
  • Lum, K. J., Sundaram, R., Buck Louis, G. M., & Louis, T. A. (2016). A Bayesian joint model of menstrual cycle length and fecundity. Biometrics, 72(1), 193–203. PMID: 26295923
  • Bae, J., Kim, S., Kannan, K., & Buck Louis, G. M. (2016). Couples' urinary concentrations of benzophenone-type ultraviolet filters and the secondary sex ratio. The Science of the Total Environment, 543(Pt A), 28–36. PMID: 26575635
  • Eisenberg, M. L., Kim, S., Chen, Z., Sundaram, R., Schisterman, E. F., & Louis, G. M. (2015). The relationship between male BMI and waist circumference on semen quality: data from the LIFE study. Human Reproduction (Oxford, England), 30(2), 493–494. PMID: 25516559
  • Mumford, S. L., Kim, S., Chen, Z., Boyd Barr, D., & Buck Louis, G. M. (2015). Urinary phytoestrogens are associated with subtle indicators of semen quality among male partners of couples desiring pregnancy. The Journal of Nutrition, 145(11), 2535–2541. PMID: 26423741
  • Smarr, M. M., Grantz, K. L., Sundaram, R., Maisog, J. M., Kannan, K., & Louis, G. M. (2015). Parental urinary biomarkers of preconception exposure to bisphenol A and phthalates in relation to birth outcomes. Environmental Health: A Global Access Science Source, 14, 73. PMID: 26362861
  • Bloom, M. S., Whitcomb, B. W., Chen, Z., Ye, A., Kannan, K., & Buck Louis, G. M. (2015). Associations between urinary phthalate concentrations and semen quality parameters in a general population. Human Reproduction (Oxford, England), 30(11), 2645–2657. PMID: 26350610
  • Buck Louis, G. M., Chen, Z., Kim, S., Sapra, K. J., Bae, J., & Kannan, K. (2015). Urinary concentrations of benzophenone-type ultraviolet light filters and semen quality. Fertility and Sterility, 104(4), 989–996. PMID: 26253817
  • Sapra, K. J., McLain, A. C., Maisog, J. M., Sundaram, R., & Buck Louis, G. M. (2015). Clustering of retrospectively reported and prospectively observed time-to-pregnancy. Annals of Epidemiology, 25(12), 959–963. PMID: 26033375
  • McLain, A. C., Sundaram, R., & Buck Louis, G. M. (2015). 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, 64(2), 339–357. PMID: 27122641
  • Louis, G. M., Chen, Z., Schisterman, E. F., Kim, S., Sweeney, A. M., Sundaram, R., Lynch, C. D., Gore-Langton, R. E., & Barr, D. B. (2015). Perfluorochemicals and human semen quality: The LIFE study. Environmental Health Perspectives, 123(1), 57–63. PMID: 25127343
  • Robledo, C. A., Yeung, E., Mendola, P., Sundaram, R., Maisog, J., Sweeney, A. M., Barr, D. B., & Louis, G. M. (2015). Preconception maternal and paternal exposure to persistent organic pollutants and birth size: The LIFE study. Environmental Health Perspectives, 123(1), 88–94. PMID: 25095280
  • Bloom, M. S., Buck Louis, G. M., Sundaram, R., Maisog, J. M., Steuerwald, A. J., & Parsons, P. J. (2015). Birth outcomes and background exposures to select elements, the Longitudinal Investigation of Fertility and the Environment (LIFE). Environmental Research, 138, 118–129. PMID: 25707016
  • Bae, J., Kim, S., Schisterman, E. F., Boyd Barr, D., & Buck Louis, G. M. (2015). Maternal and paternal serum concentrations of perfluoroalkyl and polyfluoroalkyl substances and the secondary sex ratio. Chemosphere, 133, 31–40. PMID: 25863705
  • Eisenberg, M. L., Chen, Z., Ye, A., & Buck Louis, G. M. (2015). 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, 103(5), 1271–1277. PMID: 25765658
  • Bae, J., Kim, S., Kannan, K., & Buck Louis, G. M. (2015). Couples' urinary bisphenol A and phthalate metabolite concentrations and the secondary sex ratio. Environmental Research, 137, 450–457. PMID 25677702
  • Zhang, C., Sundaram, R., Maisog, J., Calafat, A. M., Barr, D. B., & Buck Louis, G. M. (2015). A prospective study of prepregnancy serum concentrations of perfluorochemicals and the risk of gestational diabetes. Fertility and Sterility, 103(1), 184–189. PMID: 25450302
  • Goldstone, A. E., Chen, Z., Perry, M. J., Kannan, K., & Louis, G. M. (2015). Urinary bisphenol A and semen quality, the LIFE study. Reproductive Toxicology (Elmsford, N.Y.), 51, 7–13. PMID: 25462789
  • Mumford, S. L., Kim, S., Chen, Z., Gore-Langton, R. E., Boyd Barr, D., & Buck Louis, G. M. (2015). Persistent organic pollutants and semen quality: The LIFE study. Chemosphere, 135, 427–435. PMID: 25441930
  • Buck Louis G. M. (2014). Persistent environmental pollutants and couple fecundity: an overview. Reproduction (Cambridge, England), 147(4), R97–R104. PMID: 24310101
  • Guo, Y., Weck, J., Sundaram, R., Goldstone, A. E., Louis, G. B., & Kannan, K. (2014). 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, 48(16), 9804–9811. PMID: 25068827
  • Buck Louis, G. M., Kannan, K., Sapra, K. J., Maisog, J., & Sundaram, R. (2014). Urinary concentrations of benzophenone-type ultraviolet radiation filters and couples' fecundity. American Journal of Epidemiology, 180(12), 1168–1175. PMID: 25395025
  • Sapra, K. J., McLain, A. C., Maisog, J. M., Sundaram, R., & Buck Louis, G. M. (2014). Successive time to pregnancy among women experiencing pregnancy loss. Human Reproduction (Oxford, England), 29(11), 2553–2559. PMID: 25164026
  • Mumford, S. L., Sundaram, R., Schisterman, E. F., Sweeney, A. M., Barr, D. B., Rybak, M. E., Maisog, J. M., Parker, D. L., Pfeiffer, C. M., & Louis, G. M. (2014). Higher urinary lignan concentrations in women but not men are positively associated with shorter time to pregnancy. The Journal of Nutrition, 144(3), 352–358. PMID: 24401816
  • Schisterman, E. F., Mumford, S. L., Browne, R. W., Barr, D. B., Chen, Z., & Louis, G. M. (2014). Lipid concentrations and couple fecundity: The LIFE study. The Journal of Clinical Endocrinology and Metabolism, 99(8), 2786–2794. PMID: 24846535
  • Lynch, C. D., Sundaram, R., Maisog, J. M., Sweeney, A. M., & Buck Louis, G. M. (2014). Preconception stress increases the risk of infertility: Results from a couple-based prospective cohort study--the LIFE study. Human Reproduction (Oxford, England), 29(5), 1067–1075. PMID: 24664130
  • Schisterman, E. F., Mumford, S. L., Chen, Z., Browne, R. W., Boyd Barr, D., Kim, S., & Buck Louis, G. M. (2014). Lipid concentrations and semen quality: the LIFE study. Andrology, 2(3), 408–415. PMID: 24596332
  • Buck Louis, G. M., Sundaram, R., Sweeney, A. M., Schisterman, E. F., Maisog, J., & Kannan, K. (2014). Urinary bisphenol A, phthalates, and couple fecundity: The Longitudinal Investigation of Fertility and the Environment (LIFE) study. Fertility and Sterility, 101(5), 1359–1366. PMID: 24534276
  • Eisenberg, M. L., Kim, S., Chen, Z., Sundaram, R., Schisterman, E. F., & Buck Louis, G. M. (2014). The relationship between male BMI and waist circumference on semen quality: Data from the LIFE study. Human Reproduction (Oxford, England), 29(2), 193–200. PMID: 24306102
  • Buck Louis, G. M., Sundaram, R., Schisterman, E. F., Sweeney, A., Lynch, C. D., Kim, S., Maisog, J. M., Gore-Langton, R., Eisenberg, M. L., & Chen, Z. (2014). Semen quality and time to pregnancy: The Longitudinal Investigation of Fertility and the Environment study. Fertility and Sterility, 101(2), 453–462. PMID: 24239161
  • Buck Louis, G. M., Sundaram, R., Schisterman, E. F., Sweeney, A. M., Lynch, C. D., Gore-Langton, R. E., Maisog, J., Kim, S., Chen, Z., & Barr, D. B. (2013). Persistent environmental pollutants and couple fecundity: The LIFE study. Environmental Health Perspectives, 121(2), 231–236. PMID: 23151773
  • Buck Louis, G. M., Sundaram, R., Schisterman, E. F., Sweeney, A. M., Lynch, C. D., Gore-Langton, R. E., Chen, Z., Kim, S., Caldwell, K. L., & Barr, D. B. (2012). Heavy metals and couple fecundity, the LIFE study. Chemosphere, 87(11), 1201–1207. PMID: 22309709
  • Buck Louis, G. M., Schisterman, E. F., Sweeney, A. M., Wilcosky, T. C., Gore-Langton, R. E., Lynch, C. D., Boyd Barr, D., Schrader, S. M., Kim, S., Chen, Z., & Sundaram, R. (2011). 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, 25(5), 413–424. PMID: 21819423
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