Release of Negative Information
A Timing Dilemma
A major decision confronting the directors of all pregnancy registries is the timing of reporting and releasing any negative (ie, no effect) findings that emerge from analysis of registry data. This is a question of both ethics and scientific integrity. In terms of scientific rigor, the most prudent action is to withhold findings until analyses showed that effects related to a particular antiepileptic drug (AED) were significantly different than those related to other AEDs. For malformations that are quite rare, however, it might take extremely large numbers of women taking each AED before such differences are seen. Very large numbers of pregnant women would need to take the AED in question for assurance that non-equivalence is not statistically likely. Thus there is the dilemma: release a finding perhaps prematurely, leading to a drug that may be needed being under prescribed versus the possibility of harming developing fetuses by withholding the finding. Investigators, registry directors, scientific advisory boards, and regulatory officials must grapple with this dilemma.
The Current Situation
Currently, there are significant findings reported for a small number of AEDs. This makes it difficult for physicians and other healthcare professionals to advise their patients about the safest course of treatment during pregnancy. The information available is too sparse to permit the development of evidence-based guidelines. So, practitioners must rely on the data reported combined with case reports and anecdotal information. To add to the difficulty in making informed recommendations, it is hard to interpret the data when the registries report varying or contradictory results. In this circumstance it is necessary to consider carefully the differences in registry protocols that might account for such a difference. For example, the timing of outcome determination is very likely to influence results. Some malformations are not readily apparent in the early days or even weeks following birth.
Registries have wide differences in timing, with the follow-up for assessing major malformations at 5 days of life for the North American registry versus at 1 year of life for EURAP and the Australian registry. The UK registry falls between these with a follow-up at 3 months. None of the current registries have a sufficiently long follow-up time (~ 6 years) for an adequate determination of cognitive outcome.
The United States Food and Drug Administration (FDA) is in the process of drafting new regulations for labeling prescription drugs and for specifying use during pregnancy and lactation. The information used for the labeling needs to be current, clinically relevant, and scientifically accurate. The stated goal is to assist physicians and patients as they make therapeutic decisions.
- Should registries report their findings to date, whatever they may be, on a pre-specified timetable? Or, should registries wait until a finding is statistically significant?
- Is there a “tipping point,” a number of offspring affected by an anatomical or cognitive effect of an AED that warrants release of those findings?
When are the data sufficiently robust for public release? When negative data inform therapeutic decisions, it must be recognized that prescribing habits are likely to change.
Edited by Steven C. Schachter, MD
- Morrow J, Russell A, Guthrie E, Parsons L, Robertson I, Waddell R, Irwin B, McGivern RC, Morrison PJ, Craig J. Malformation risks of antiepileptic drugs in pregnancy: a prospective study from the UK Epilepsy and Pregnancy Register. J Neurol Neurosurg Psychiatry. 2006 Feb;77(2):193-8.
- Cunnington M, Tennis P; International Lamotrigine Pregnancy Registry Scientific Advisory Committee. Lamotrigine and the risk of malformations in pregnancy.
Neurology. 2005 Mar 22;64(6):955-60.
- EURAP Study Group. Seizure control and treatment in pregnancy: observations from the EURAP epilepsy pregnancy registry. Neurology 2006;66(3):354-360.
- Holmes LB, Wyszynski DF, Lieberman ES. The AED (antiepileptic drug) Pregnancy Registry: A 6-year experience. Arch Neurol 2004;61:673-678.
- Vajda FJE, Hitchcock A, Graham J, et al. Foetal malformations and seizure control: 52 months data of the Australian Pregnancy Registry. Eur J Neurology 2006;13:645-654.
Back to top
Return to Articles and Publications