Mid-pregnancy cotinine and risks of orofacial clefts and neural tube defects

J Pediatr. 2009 Jan;154(1):17-9. doi: 10.1016/j.jpeds.2008.08.006. Epub 2008 Nov 5.


Objective: Past studies of cigarette smoking as a contributor to orofacial clefts and neural tube defects (NTDs) used self-reports of smoke exposures. We have correlated measurements of cotinine (a nicotine metabolite) in mid-pregnancy sera with clefts and NTDs.

Study design: From a repository of >180 000 mid-pregnancy serum specimens collected in California from 2003 to 2005 and linked to delivery outcome information, we identified 89 orofacial cleft-associated pregnancies, 80 NTD-affected pregnancies, and randomly selected 409 pregnancy specimens that corresponded to infants without malformations as control subjects. Cotinine was measured by liquid chromatography-mass spectrometry. No smoke exposure was defined as cotinine values <2 ng/mL, and any exposure was defined as >or=2 ng/mL.

Results: We observed odds ratios of 2.1 (95% CI, 1.0-4.4) for clefts and 0.4 (95% CI, 0.1-1.7) for NTDs associated with exposure. After adjusting for race/ethnicity, age, and serum folate levels, odds ratios were 2.4 (95% CI, 1.1-5.3) and 0.6 (95% CI, 0.1-2.5). We explored 2 cotinine levels, 2 to 10 ng/mL and >10 ng/mL for clefts (data were too sparse for NTDs). Odds ratios for these levels were 3.3 (95% CI, 0.9-11.9) and 1.7 (95% CI, 0.7-4.2), respectively.

Conclusion: Smoking exposures, as measured with cotinine levels during mid-pregnancy, were associated with increased risks of clefts and possibly reduced risks of NTDs.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adult
  • Cleft Lip / epidemiology*
  • Cleft Palate / epidemiology*
  • Cotinine / blood*
  • Female
  • Humans
  • Neural Tube Defects / epidemiology*
  • Odds Ratio
  • Pregnancy
  • Pregnancy Trimester, Second
  • Prenatal Exposure Delayed Effects / epidemiology*
  • Prospective Studies
  • Smoking / epidemiology*


  • Cotinine