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Three alternative methods to resolve paradoxical associations of exposures before term

  • PERINATAL EPIDEMIOLOGY
  • Published:
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Abstract

To propose three methods to estimate associations between pregnancy exposures and outcomes before term, including the association between preeclampsia and preterm fetal-infant mortality, while avoiding the selection bias found in conventional analytic designs. Population-level analysis of 1,099,839 women who delivered live or stillborn infants in Quebec hospitals from 1989 to 2012, covering nearly a quarter of Canadian births. The exposure of interest was preeclampsia at 20–29, 30–33, 34–36, and ≥37 weeks of gestation. We compared preeclamptic with non-preeclamptic pregnancies in parametric survival models with a Weibull distribution using three analytic designs: (1) fetuses-at-risk; (2) bias correction factors; and (3) analysis of pregnancies at high risk of preterm delivery. Main outcome measures were occurrence of fetal or postnatal infant death before discharge. In models affected by bias due to selection of preterm births, women with preeclampsia early in gestation had paradoxically lower risks of fetal and infant mortality than women without preeclampsia. All three analytic approaches reversed the associations, showing a harmful effect of preeclampsia before term. At 20–29 weeks, for example, preeclampsia was associated with 1.35 times the risk of infant mortality (95 % confidence interval 1.14–1.60) and 1.40 times the risk of stillbirth (95 % confidence interval 1.18–1.67) with the fetuses-at-risk approach. Paradoxically protective benefits of exposures such as preeclampsia before term are artifacts of inappropriate analytic design. Outcomes before term should be analyzed with care, using methods that address bias due to selection of preterm deliveries.

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Acknowledgments

This study was supported by the Canadian Institutes of Health Research (MOP-130452). NA was supported by a career award from the Fonds de recherche du Québec-Santé. The authors thank Robert W Platt for helpful comments on the manuscript.

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Authors and Affiliations

  1. Institut national de santé publique du Québec, 190 Cremazie E. Blvd., Montreal, QC, H2P 1E2, Canada

    Nathalie Auger & Jessica Healy-Profitós

  2. University of Montreal Hospital Research Centre, Montreal, QC, Canada

    Nathalie Auger & Jessica Healy-Profitós

  3. Department of Obstetrics and Gynecology, McGill University, Montreal, QC, Canada

    Ashley I. Naimi

  4. Department of Obstetrics and Gynecology, Sherbrooke University Hospital Research Centre, Sherbrooke, QC, Canada

    William D. Fraser

  5. Sainte-Justine Hospital Research Centre, University of Montreal, Montreal, QC, Canada

    William D. Fraser, Zhong-Cheng Luo & Anne Monique Nuyt

  6. Department of Pediatrics, University of Montreal, Montreal, QC, Canada

    Anne Monique Nuyt

  7. Department of Epidemiology, Biostatistics and Occupational Health, McGill University, Montreal, QC, Canada

    Jay S. Kaufman

Authors
  1. Nathalie Auger
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  2. Ashley I. Naimi
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  3. William D. Fraser
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  4. Jessica Healy-Profitós
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  5. Zhong-Cheng Luo
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  6. Anne Monique Nuyt
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  7. Jay S. Kaufman
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Correspondence to Nathalie Auger.

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Auger, N., Naimi, A.I., Fraser, W.D. et al. Three alternative methods to resolve paradoxical associations of exposures before term. Eur J Epidemiol 31, 1011–1019 (2016). https://doi.org/10.1007/s10654-016-0175-1

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  • DOI: https://doi.org/10.1007/s10654-016-0175-1

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