Preconception use of pain-relievers and time-to-pregnancy: a prospective cohort study.
To what extent is preconception use of pain-relieving medication associated with female fecundability?



Women who used naproxen or opioids had slightly lower fecundability than women who did not use any pain-relieving medications; use of acetaminophen, aspirin and ibuprofen was not appreciably associated with fecundability.



Over-the-counter pain-relieving medications are commonly used by women of reproductive age in the USA. Studies investigating the effects of pain-relieving medication use on ovulation, implantation and fecundability have shown conflicting results.



We analyzed data from an internet-based prospective cohort study of 2573 female pregnancy planners aged 21-45 years from the USA and Canada. Participants were enrolled and followed from June 2013 through September 2015. Participants completed a baseline questionnaire and bimonthly follow-up questionnaires until a reported pregnancy or for 12 months, whichever occurred first. Over 80% of participants completed at least one follow-up questionnaire.



Use of pain-relieving medication during the past month was assessed at baseline and on each follow-up questionnaire. Medications were categorized according to type (acetaminophen, aspirin, ibuprofen, naproxen and opioids) and total monthly dose. Self-reported pregnancy was assessed at each follow-up. Multivariable-adjusted fecundability ratios (FRs) and 95% CI were calculated using proportional probabilities regression. Models were adjusted for demographic, lifestyle and anthropometric factors; reproductive history; gynecologic morbidity; and indications for use of pain medications. Models were also run with and without adjustment for parity. After restricting to women with 6 or fewer months of attempt time at study entry, 1763 were included in the analyses.



At baseline, 1279 (73%) women reported using ≥1 pain-relieving medications in the previous month. When compared with non-use of pain-relieving medications, FRs for use of naproxen and opioids at baseline were 0.78 (95% CI: 0.64-0.97) and 0.81 (95% CI: 0.60-1.10), respectively. A dose-response relation was observed between naproxen use and fecundability; FRs for use of <1500 and ≥1500 mg of naproxen were 0.85 (95% CI: 0.68-1.07) and 0.58 (95% CI: 0.36-0.94), respectively. Small numbers (n = 74) precluded the examination of opioid use by dose. Overall, there was little evidence of an association between fecundability and acetaminophen (FR 1.04, 95% CI: 0.92-1.18), aspirin (FR 1.00, 95% CI: 0.80-1.25), or ibuprofen (FR 1.00, 95% CI: 0.89-1.11). Similar results were observed when exposure information was updated over time.



Numbers of opioid users were small. Information collected on reason for use of pain medications was not specific to each type of pain medication. Therefore, we cannot rule out confounding by indication as an explanation of these results.



Use of naproxen and opioids was associated with a small reduction in fecundability, but there was little association between other pain-relieving medications and fecundability.



This study was supported through funds provided by National Institute of Child Health and Human Development, National Institute of Health (R21 HD072326, T32 HD052458). The authors have no conflicts of interest to disclose.



Not applicable.
Department of Epidemiology, Boston University School of Public Health, 715 Albany Street, 3rd Floor, Boston, MA 02118, USA kamci@bu.edu.
Kathryn A
KA
McInerney
Department of Epidemiology, Boston University School of Public Health, 715 Albany Street, 3rd Floor, Boston, MA 02118, USA.
Elizabeth E
EE
Hatch
Department of Epidemiology, Boston University School of Public Health, 715 Albany Street, 3rd Floor, Boston, MA 02118, USA.
Amelia K
AK
Wesselink
Department of Epidemiology, Boston University School of Public Health, 715 Albany Street, 3rd Floor, Boston, MA 02118, USA.|RTI Health Solutions, PO Box 12194, Research Triangle Park, NC 27709, USA.
Kenneth J
KJ
Rothman
Department of Clinical Epidemiology, Aarhus University Hospital, Norrebrogade 44, DK-8000 Aarhus, Denmark.
Ellen M
EM
Mikkelsen
Department of Epidemiology, Boston University School of Public Health, 715 Albany Street, 3rd Floor, Boston, MA 02118, USA.
Lauren A
LA
Wise
D000082:Acetaminophen / Q000494:pharmacology / Q000627:therapeutic use; D000328:Adult; D000700:Analgesics / Q000494:pharmacology* / Q000627:therapeutic use; D000701:Analgesics, Opioid / Q000494:pharmacology / Q000627:therapeutic use; D001241:Aspirin / Q000494:pharmacology / Q000627:therapeutic use; D005260:Female; D006801:Humans; D007052:Ibuprofen / Q000494:pharmacology / Q000627:therapeutic use; D020407:Internet; D009288:Naproxen / Q000494:pharmacology / Q000627:therapeutic use; D010146:Pain / Q000188:drug therapy*; D011247:Pregnancy; D011446:Prospective Studies; D061685:Time-to-Pregnancy / Q000187:drug effects*
D000700:Analgesics; D000701:Analgesics, Opioid; D000082:Acetaminophen; D009288:Naproxen; D001241:Aspirin; D007052:Ibuprofen
acetaminophen; conception; fecundability; fertility; non-steroidal anti-inflammatory drugs; opioids; pain medications; time-to-pregnancy