Bias Toward the Null Hypothesis in Pregnancy Drug Studies That Do Not Include Data on Medical Terminations of Pregnancy: The Folic Acid Antagonists

Authors

  • Dr Amalia Levy MPH, PhD,

    Corresponding author
    1. Departments of Epidemiology, Ben Gurion University of the Negev; Social Work Services
    2. BeMORE collaboration (Ben-Gurion Motherisk Obstetric Registry of Exposure collaboration
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  • Dr Ilan Matok MS, Pharm, PhD,

    1. Departments of Epidemiology, Ben Gurion University of the Negev; Social Work Services
    2. Beer-Sheva, Israel; The Motherisk Program, Division of Clinical Pharmacology-Toxicology, Hospital for Sick Children, The University of Toronto, Toronto, Canada
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  • Dr Rafael Gorodischer MD,

    1. Pediatrics, Ben Gurion University of the Negev; Social Work Services
    2. Soroka Medical Center, Division of Clinical Pharmacology-Toxicology, Hospital for Sick Children, The University of Toronto, Toronto, Canada
    3. Clalit Health Services (Southern District), Division of Clinical Pharmacology-Toxicology, Hospital for Sick Children, The University of Toronto, Toronto, Canada
    4. BeMORE collaboration (Ben-Gurion Motherisk Obstetric Registry of Exposure collaboration
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  • Dr Michael Sherf MD, MPH,

    1. Soroka Medical Center, Division of Clinical Pharmacology-Toxicology, Hospital for Sick Children, The University of Toronto, Toronto, Canada
    2. Clalit Health Services (Southern District), Division of Clinical Pharmacology-Toxicology, Hospital for Sick Children, The University of Toronto, Toronto, Canada
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  • Dr Arnon Wiznitzer MD,

    1. Obstetrics and Gynecology, Ben Gurion University of the Negev; Social Work Services
    2. Soroka Medical Center, Division of Clinical Pharmacology-Toxicology, Hospital for Sick Children, The University of Toronto, Toronto, Canada
    3. Clalit Health Services (Southern District), Division of Clinical Pharmacology-Toxicology, Hospital for Sick Children, The University of Toronto, Toronto, Canada
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  • Ms Elia Uziel MSc,

    1. Faculty of Health Sciences, Ben Gurion University of the Negev; Social Work Services
    2. Soroka Medical Center, Division of Clinical Pharmacology-Toxicology, Hospital for Sick Children, The University of Toronto, Toronto, Canada
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  • Dr Gideon Koren MD, FABMT, FRCPC

    1. Beer-Sheva, Israel; The Motherisk Program, Division of Clinical Pharmacology-Toxicology, Hospital for Sick Children, The University of Toronto, Toronto, Canada
    2. BeMORE collaboration (Ben-Gurion Motherisk Obstetric Registry of Exposure collaboration
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Address for correspondence: Amalia Levy, Epidemiology and Health Services Evaluation Department, Faculty of Health Sciences, Ben-Gurion University of the Negev, P.O. Box 653, Beer Sheva 84105, Israel; e-mail: lamalia@bgu.ac.il.

Abstract

Most studies on safety/risk of drugs in pregnancy consider the proportion of births (but not pregnancy terminations) affected by the drug from all exposed infants. Lack of data on pregnancy terminations could bias results. A computerized database for medications dispensed to pregnant women in southern Israel was linked with records from the district hospital; 84 823 deliveries and 998 medical pregnancy terminations took place; 571 of the women were exposed to folic acid antagonists in the first trimester. When only births were examined, there was no association between folic acid antagonists and fetal malformations. When data on pregnancy terminations were examined and births and pregnancy terminations were combined, there was a significant risk (neural tube defects: odds ratio 18.83, 95% confidence interval 9.24–38.37; cardiovascular defects: odds ratio 3.86, 95% confidence interval 1.67–8.88; and neural tube defects: odds ratio 6.30, 95% confidence interval 3.34–9.15; cardiovascular defects: odds ratio 1.76, 95% confidence interval 1.05–2.92, respectively). Inclusion of only birth data in observational studies of drugs in pregnancy constitutes a source of bias toward the null hypothesis.

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