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Abstract

Objective: To report the frequency of major malformations in lamotrigine-exposed pregnancies from September 1, 1992, through March 31, 2004, in the International Lamotrigine Pregnancy Registry.
Methods: Health care professionals throughout the world can voluntarily enroll lamotrigine-exposed pregnancies in this observational study. Only pregnancies with unknown outcomes at the time of enrollment were included in the analysis. The percentage of outcomes with major birth defects was calculated as the total number of outcomes with major birth defects divided by the sum of the number of outcomes with major birth defects + the number of live births without defects.
Results: Among 414 first-trimester exposures to lamotrigine monotherapy, 12 outcomes with major birth defects were reported (2.9%, 95% CI 1.6% to 5.1%). Among the 88 first-trimester exposures to lamotrigine polytherapy including valproate, 11 outcomes with major birth defects were reported (12.5%; 95% CI 6.7% to 21.7%). Among 182 first-trimester exposures to lamotrigine polytherapy excluding valproate, 5 outcomes with major birth defects were reported (2.7%, 95% CI 1.0% to 6.6%). No distinctive pattern of major birth defects was apparent among the offspring exposed to lamotrigine monotherapy or polytherapy.
Conclusions: The risk of all major birth defects after first-trimester exposure to lamotrigine monotherapy (2.9%) was similar to that in the general population and in other registries enrolling women exposed to antiepileptic monotherapy (3.3% to 4.5%). However, the sample size was too small to detect any but very large increases in specific birth defects.

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Letters to the Editor
8 June 2005
Reply from the authors to Hauser et al
Marianne C Cunnington, GlaxoSmithKline
Patricia Tennis, John Messenheimer

Drs. Hauser and Tomson raise important methodological issues. There are strengths and limitations inherent in any source of reference data. The choice of an external comparator for the Lamotrigine Registry is complicated by the international nature of this registry. While a range of reference data from general populations may be appropriate, robust estimates are missing from many participating countries and routine surveillance in these countries commonly under-estimates the risk. [4]

We aimed to identify a source of reference data similar to our registry in calendar time, malformation diagnostic criteria, and timing of malformation ascertainment. MACDP offers data from the same time period, includes ultrasound diagnoses and employs the same CDC defined malformation diagnostic criteria as the Lamotrigine Registry. The MACDP estimates a general population malformation risk of 2.2% at birth to 3.2% by age one [2], and most defects are reported to the Lamotrigine Registry during the first year of life.

We have reservations concerning the suggestion that the reference risk of 1.6%, estimated through a single US hospital over 20 years ago, be considered as the definitive reference for our and subsequent studies. [3] Use of these data, collected between 1972 and 1982, requires an assumption of no temporal trends in the frequency of birth defects and characteristics of women giving birth. Surveillance data do not support this assumption (e.g. increased fraction of births among high risk age groups and temporal changes in the risk of common birth defects). [5,6] Changes in antenatal healthcare, especially around ultrasound examinations, are also likely to have impacted birth defect ascertainment over time.

The Brigham and Women's study did not include prenatal ultrasound findings, only capturing defects of structural importance visible at birth, whereas the Lamotrigine Registry includes ultrasound findings.

Finally, while familial and mendelian traits were excluded from the Brigham and Women's study, they were not excluded in the Lamotrigine Registry. Due to the variation in screening for such traits across time and place and a common failure to test for such causes within the timeframe of malformation ascertainment, the Lamotrigine Registry and MACDP adopt this inclusive common approach.

We provide the available data and invite readers to consider the risk estimate of 2.9% from the Lamotrigine Registry compared to the MACDP population-based risk of 2.2 – 3.2%. We fail to see evidence of a substantial increase in overall malformation risk associated with lamotrigine exposure.

References

1) Cunnington M, Tennis P, and the International Lamotrigine Pregnancy Registry Scientific Advisory Committee. Lamotrigine and the risk of malformations in pregnancy. Neurology. 2005; 64: 955-60.

2) Honein MA, Paulozzi LJ, Cragan JD, Correa A. Evaluation of selected characteristics of pregnancy drug registries. Teratology 1999; 60: 3556-64.

3) Nelson K, Holmes LB. Malformations due to presumed spontaneous mutations in newborn infants. N Eng J Med. 1989; 320: 19-23.

4) Boyd PA, Armstrong B, Dolk H, Botting B, Pattenden S, Abramsky L et al. Congenital anomaly surveillance in England – ascertainment deficiencies in the national system. BMJ. 2005; 330: 27.

5) Reefhuis J, Honein MA.Maternal age and non-chromosomal birth defects, Atlanta--1968-2000: teenager or thirty-something, who is at risk? Birth Defects Res A Clin Mol Teratol. 2004 Sep;70:572-9.

6) Correa-Villasenor A, Cragan J, Kucik J, O'Leary L, Siffel C, Williams L. The metropolitan Atlanta Congenital Defects Program: 35 years of birth defects surveillance at the Centers for Disease Control and Prevention. Birth Defects Res Part A Clin Mol Teratol. 2003; 67: 617- 24.

8 June 2005
Reply from Editorialist
Patricia E. Penovich, Minnesota Epilepsy Group

The points brought up by Drs. Hauser and Thomson and countered by Cunnington are in themselves illustrative of the difficulties in ascertaining the true prevalence of fetal abnormalities due to AEDs taken during pregnancy. The real question may be whether a prospective mother will practically see a difference in risk numbers between 2.2-2.9%. Numbers from years ago are probably not relevant in that diets, prenatal care, and other environmental exposures cannot be assume to be the same. Although cell growth is occurring, a pregnancy is not a controlled cell culture in a Petri dish. The multiple potential risks to the fetus cannot be completely controlled or compared. We may always suffer from imperfect data but will need to learn to use it as best we can.

8 June 2005
Lamotrigine and the risk of malformations in pregnancy
W Allen Hauser, Department of Neurology, Sergievsky Center, College of Physicians and Surgeons, Columbia University
Torbjörn Tomson Department of Clinical Neuroscience, Section of Neurology, Karolinska Institutet, SE- 171 76 Stockholm, Sweden.

The article regarding lamotrigine and the risk for pregnancy malformations by Cunningham et al provides encouraging information for women with epilepsy and their families [1] but their conclusion that "the risk of all major birth defects after first trimester exposure to lamotrigine monotherapy (2.9%) was similar to that in the general population" may be exaggerated.

Population comparisons for these estimates are problematic. The authors use as a population comparison data from the Metropolitan Atlanta Congenital Defects Program (MACDP) between 1991 and 1995.[2] This population-based registry uses active case identification from multiple sources, undertakes direct chart review of potential cases, and includes all malformations identified through age five. MACDP reports a malformation prevalence of 3.2%. To provide a better comparison with registry data such as that provided in the report of Cunningham et al,MACDP provides a prevalence of "early diagnoses" of malformations (presumably those readily identifiable at or shortly after birth) of 2.2%. Both of these prevalence rates include children with chromosomal and genetic anomalies—a group appropriately excluded from the Lamotrigine Registry data.[1]

A more appropriate comparison for birth prevalence of malformations may be that from the Active Malformation Surveillance Program at Brigham and Women's Hospital in Boston.[3] The overall prevalence of malformations (2.3%) was similar to that for "early diagnoses" but the prevalence after exclusion of genetic and chromosomal anomalies was 1.6%. Confidence intervals for lamotrigine exposure include 1.6%, but also include 5.1%. A more accurate conclusion may be "the risk for major malformations associated with first trimester exposure to lamotrigine is only about twice that of the general population…" when similar definitions, inclusions and case identification strategies are used.

Some additional methodological limitations complicate the interpretation and hamper comparison with other antiepileptic drug (AED) and pregnancy registries. First, full information on lamotrigine dosing, duration of exposure, and use of concomitant AEDs was obtained only shortly after expected date of birth, (i.e. when outcome is likely to be known). Second, as lamotrigine treatment was an inclusion criterion, those assessing pregnancy outcome could not be blinded with respect to type of exposure.

The neurology community looks forward to confirmation from other pregnancy registries of the relatively low malformation rate reported in this paper for first trimester lamotrigine exposure. Independent confirmation will of course require exclusion of duplicated cases.

References

1. Cunningham M, Tennis P, and the International Lamotrigine Pregnancy Registry Scientific Advisory Committee. Lamotrigine and the risk of malformations in pregnancy. Neurology 2005;64:955-960.

2. Hoenin MA, Paulozzi LJ, Cragen JD, et al. Evaluation of selected characteristics of drug registries. Teratology 1999;60:356-364

3. Nelson K, Holmes LB. Malformation due to presumed spontaneous mutations in newborn infants. N Engl J Med 1989;320:19-23.

Disclosure: Professor Hauser has been a consultant to the following companies: Abbott Laboratories, Eli Lilly, Johnson and Johnson Pharmaceutical Research and Development. Professor Tomson has no conflicts to report.

Information & Authors

Information

Published In

Neurology®
Volume 64Number 6March 22, 2005
Pages: 955-960
PubMed: 15781807

Publication History

Published online: March 21, 2005
Published in print: March 22, 2005

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Authors

Affiliations & Disclosures

Marianne Cunnington, PhD
From GlaxoSmithKline, Worldwide Epidemiology, Harlow, UK.
Patricia Tennis, PhD
From GlaxoSmithKline, Worldwide Epidemiology, Harlow, UK.
the International Lamotrigine Pregnancy Registry Scientific Advisory Committee
From GlaxoSmithKline, Worldwide Epidemiology, Harlow, UK.

Notes

Address correspondence and reprint requests to Dr. M. Cunnington, GlaxoSmithKline, Worldwide Epidemiology, Harlow, UK; e-mail: [email protected]

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