Drugs in Pregnancy| Volume 38, ISSUE 12, P1120-1123.e1, December 2016

Bias Against the Null Hypothesis in Retrospective Registries of Gestational Drug Exposure



      The findings in retrospective pregnancy registries related to prenatal drug exposure (collected after pregnancy outcome is known) are commonly reported in regulatory documents and in the medical literature. However, there is little information about the accuracy of the estimates of risk from such registries. We therefore sought to compare the rates of major congenital malformations reported in retrospective and prospective registries for the same drug to quantify the potential bias of retrospective reports.


      We searched for all fetal safety reports related to medications for which information from both prospective and retrospective registries was available. These were published either in the peer-reviewed literature or as pharmaceutical company documents between 1984 and 2011.


      For all drugs registries studied, estimates of major congenital malformations from retrospective registries tended to be higher than the rates in prospective registries; median estimates of risk were higher by a factor of 4.18 ± 1.23 (range 2.13–5.97).


      The present study confirms a major and consistent bias against the null hypothesis in studies of teratogenic risk using retrospective registries, and this must be considered when interpreting such data. Spontaneous reporting of outcomes after exposure to a drug is highly selective towards adverse events, which families with normal pregnancy outcomes are less likely to report.



      Les constatations tirées de registres rétrospectifs d’exposition prénatale aux médicaments (dont les données sont recueillies une fois l’issue de la grossesse connue) sont régulièrement citées dans des documents réglementaires et dans la littérature médicale. Toutefois, les renseignements quant à l’exactitude de l’estimation des risques effectuée à partir de ces registres sont limités. Nous avons donc cherché à comparer le taux de malformations congénitales majeures déclarées dans des registres rétrospectifs et prospectifs pour un même médicament afin de quantifier le biais potentiel associé aux rapports rétrospectifs.


      Nous avons cherché tous les rapports sur l’innocuité pour le fœtus portant sur des médicaments pour lesquels nous disposions de données tirées de registres rétrospectifs et prospectifs. Il s’agissait de documents produits par des pharmaceutiques ou d’articles publiés dans des revues évaluées par les pairs entre 1984 et 2011.


      Dans l’ensemble, les estimations du taux de malformations congénitales majeures basées sur les données de registres rétrospectifs avaient tendance à être supérieures à celles associées aux registres prospectifs. L’estimation médiane du risque était supérieure d’un facteur de 4,18 ± 1,23 (étendue: 2,13–5,97).


      La présente étude a confirmé l’existence d’un biais important et constant contre l’hypothèse nulle dans les études sur le risque tératogène fondées sur des registres rétrospectifs. Il faut être conscient de ce biais au moment d’interpréter les données de ces registres. La déclaration spontanée de l’issue de grossesse après l’exposition à un médicament dépend grandement de la survenue d’événements indésirables; en effet, les familles sont moins susceptibles de déclarer une issue de grossesse normale.

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