title: Urinary paracetamol and time-to-pregnancy.
abstract: Is preconception urinary paracetamol (acetaminophen) associated with time-to-pregnancy (TTP)?
  
  
  
  Higher urinary paracetamol concentrations among male partners were associated with a longer TTP.
  
  
  
  Paracetamol is a commonly used analgesic among women and men of all ages. As metabolites of select chemicals used in the manufacturing of polyurethane foam, dyes and various industrial products, as well as a common medicinal product, paracetamol and its primary metabolite p-aminophenol, are ubiquitous in the environment. Studies investigating the relationship between adult urinary concentrations of paracetamol and TTP are lacking.
  
  
  
  This prospective cohort included 501 couples discontinuing contraception for the purposes of attempting conception during the years 2005-2009 and residing in Michigan or Texas, USA.
  
  
  
  Total urinary paracetamol, its metabolite para-aminophenol (p-aminophenol), and a summary measure of both urinary biomarkers were quantified by ultra-performance liquid chromatography coupled with an electrospray triple quadrupole mass spectrometry (UPLC-ESI-MS/MS). Female partners used the Clearblue® digital home test to confirm pregnancy. Cox's proportional odds models for discrete survival time were used to estimate fecundability odds ratios (FORs) and 95% confidence intervals (CIs), adjusting for age, body mass index (BMI), urinary creatinine, preconception smoking status, race/ethnicity and household income. Models were further adjusted for hypothyroidism and hypertension as an attempt to account for possible indications of paracetamol medication use. FOR estimates <1.0 denote a longer TTP (diminished fecundity). Models were performed to examine urinary concentrations of paracetamol as a continuous and variable or categorized into quartiles. In light of TTP being a couple-dependent outcome, models were first performed for females and males, modeled separately, and then modeled for couples with each partner's concentrations being adjusted for the other.
  
  
  
  Among the 501 enrolled couples, 347 (69%) had an human chorionic gonadotrophin confirmed pregnancy. Urinary concentrations of paracetamol were lowest among females and males who achieved pregnancy and p-aminophenol concentrations were lowest among those not achieving pregnancy. Urinary paracetamol concentrations were higher among female than male partners (Median = 26.6 and 13.2 ng/ml, respectively; P < 0.0001). After adjustment for age, BMI, urinary creatinine, preconception smoking status, race/ethnicity and household income, the highest quartile of male urinary paracetamol was associated with a longer TTP [FOR = 0.67; 95% CI = (0.47, 0.95)]. This association remained after adjustment for chronic health conditions, hypothyroidism and hypertension and female partner's urinary paracetamol concentration [FOR = 0.65; 95% CI = (0.45, 0.94)]. No associations were observed between female or male partners' urinary concentrations of paracetamol or of its metabolite p-aminophenol when urinary concentrations were modeled continuously.
  
  
  
  Only a single spot urine was available for analysis despite the short-lived nature of paracetamol. Additionally, participants were not asked to provide information on indication of use for paracetamol medications; any underlying conditions for the paracetamol use would have been potential confounders.
  
  
  
  If corroborated with more robust studies, findings from our exploratory analysis may have both clinical and public health relevance among reproductive aged individuals, including those trying for pregnancy, given the prevalent use of paracetamol/acetaminophen medications and the ubiquitous nature of paracetamol in the environment.
  
  
  
  This research was supported by the National Institutes of Health, Intramural Research Program, and Eunice Kennedy Shriver National Institute of Child Health and Human Development (contracts N01-HD-3-3355; N01-HD-3-3356; NOH-HD-3-3358; HHSN27500001/HHSN27500001). None of the authors have any conflicts to declare.
authors.affiliation: Division of Intramural Population Health Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, 6100 Executive Blvd., Room 7B05, Rockville, MD 20852, USA melissa.smarr@mail.nih.gov.
authors.forename: Melissa M
authors.initials: MM
authors.lastname: Smarr
authors.affiliation: Epidemiology Branch, Division of Intramural Population Health Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Rockville, MD 20852, USA.
authors.forename: Katherine L
authors.initials: KL
authors.lastname: Grantz
authors.affiliation: Biostatics and Bioinformatics Branch, Division of Intramural Population Health Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Rockville, MD 20852, USA.
authors.forename: Rajeshwari
authors.initials: R
authors.lastname: Sundaram
authors.affiliation: Glotech, Inc., Division of Intramural Population Health Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Rockville, MD 20852, USA.
authors.forename: José M
authors.initials: JM
authors.lastname: Maisog
authors.affiliation: Wadsworth Center, New York State Department of Health, and Department of Environmental Health Sciences, School of Public Health, State University of New York at Albany, Albany, NY 12201, USA.
authors.forename: Masato
authors.initials: M
authors.lastname: Honda
authors.affiliation: Wadsworth Center, New York State Department of Health, and Department of Environmental Health Sciences, School of Public Health, State University of New York at Albany, Albany, NY 12201, USA.
authors.forename: Kurunthachalam
authors.initials: K
authors.lastname: Kannan
authors.affiliation: Division of Intramural Population Health Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, 6100 Executive Blvd., Room 7B05, Rockville, MD 20852, USA.
authors.forename: Germaine M
authors.initials: GM
authors.lastname: Buck Louis
mesh_terms: D000082:Acetaminophen / Q000652:urine*; D000328:Adult; D018712:Analgesics, Non-Narcotic / Q000652:urine*; D005260:Female; D006801:Humans; D008297:Male; D008824:Michigan; D011247:Pregnancy; D011446:Prospective Studies; D013781:Texas; D061685:Time-to-Pregnancy; D055815:Young Adult
chemical_list: D018712:Analgesics, Non-Narcotic; D000082:Acetaminophen
keywords: TTP; acetaminophen; biomarkers; fecundity; p-aminophenol; paracetamol