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Keywords:

  • Lamotrigine;
  • Dose;
  • Major birth defects;
  • Pregnancy

Abstract

  1. Top of page
  2. Abstract
  3. METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgments
  7. REFERENCES

Summary:  Data from the International Lamotrigine Pregnancy Registry were analyzed to examine the effect of maximal first-trimester maternal dose of lamotrigine monotherapy on the risk of major birth defects (MBDs). Among 802 exposures, the frequency of MBDs was 2.7% (95% confidence interval [CI] 1.8–4.2%). The distribution of dose did not differ between infants with and those without MBDs (mean 248.3 milligrams per day [mg/day] and 278.9 mg/day, respectively, median 200 mg/day for both groups). A logistic regression analysis showed no difference in the risk of MBDs as a continuous function of dose (summary odds ratio [OR] per 100 mg increase =0.999, 95% CI 0.996–1.001). There was also no effect of dose, up to 400 mg/day, on the frequency of MBDs.

Women with epilepsy often require chronic anticonvulsant therapy, giving the potential for fetal exposure to medication during gestation. Pregnancy registries conduct prospective, observational studies that monitor for a signal of major teratogenicity associated with medication exposure during pregnancy. Registry data can also be assessed for patterns of specific defect types or trends in defect frequency by dose. The International Lamotrigine Pregnancy Registry has monitored the effects of lamotrigine use in pregnancy since 1992 (Cunnington et al., 2005) and other pregnancy registries considering all antiepileptic drugs (AEDs) are also active (Holmes et al., 2001, 2004; Vajda and Eadie, 2005; Morrow et al., 2006).

The potential impact of lamotrigine dose on the associated major birth defect (MBD) risk during pregnancy is of increasing interest in light of findings from the United Kingdom (UK) Epilepsy and Pregnancy Register, which reported a statistically higher frequency of MBDs among 647 first-trimester lamotrigine monotherapy exposures at doses exceeding 200 milligrams per day (mg/day) (Morrow et al., 2006). The Australian Registry of Antiepileptic Drugs failed to confirm these findings among 128 monotherapy exposures (Vajda and Eadie, 2005). Although dose is a poor surrogate for exposure to an AED, due to changes in drug clearance during pregnancy (Pennell et al., 2004), AED blood levels are not systematically sought in registries. Dose information is the only available surrogate for exposure (Vajda and Eadie, 2005; Morrow et al., 2006). This analysis of data from the International Lamotrigine Pregnancy Registry was undertaken to further examine the effect of maternal lamotrigine monotherapy dose on risk of MBDs using the largest sample of first trimester exposures currently available.

METHODS

  1. Top of page
  2. Abstract
  3. METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgments
  7. REFERENCES

The International Lamotrigine Pregnancy Registry is a prospective, observational study initiated and funded by GlaxoSmithKline, and coordinated by Kendle International, with the advice of an independent scientific committee. Procedures for enrollment, data collection, and data analysis are described elsewhere (Cunnington et al., 2005, Lamotrigine Pregnancy Registry, 2006). Pregnancy exposure and outcome information is supplied on a voluntary basis by health care providers. Pregnancy outcomes are categorized as with or without MBDs, defined according to criteria developed for the Centers for Disease Control and Prevention's Metropolitan Atlanta Congenital Defects Program (MACDP) (National Center on Birth Defects and Developmental Disabilities, 2004) and are reviewed by a clinician on the scientific committee. Data are stratified by trimester (the first trimester being before 14 weeks gestation) and by birth outcome (live birth, stillbirth, or elective termination).

This analysis included pregnancies among all women enrolled from inception of the registry in 1992 through March 31, 2006 exposed to lamotrigine monotherapy during the first trimester and for whom there was complete first trimester lamotrigine dose information collected prior to birth. Fifty-eight percent of women were recruited before 16 weeks gestation when prenatal screening was less likely to have occurred. All women were recruited prior to the birth of the infant. The percentage of infants with MBDs, overall and by dose strata, was calculated as: the number of outcomes with MBDs / (the number of outcomes with MBDs + the number of live births without defects). All spontaneous pregnancy losses, as well as elective terminations and fetal deaths without reported defects and pregnancies lost to follow up, were excluded from the denominator due to the potential lack of systematic defect ascertainment in those situations. The 95% confidence intervals (CIs) for risk estimates were calculated using the Wilson score method with continuity correction (Newcombe, 1998).

The mean and median maximal first-trimester doses were calculated for the groups with and those without MBD and a comparison was performed using the Wilcoxon rank sum test. A logistic regression tested for a dose–response relationship with the presence of an MBD as the dependent variable and the lamotrigine monotherapy dose as the continuous independent variable. A one-sided test for a significant positive association was performed using the Wald statistic. A 90% CI of the odds ratio for a 100 mg increase in dose was also calculated. The risk of MBDs by 100-mg increments was also calculated to ascertain whether there was a threshold dose for increased risk. Statistical tests were not applied, as this analysis was hypothesis generating.

RESULTS

  1. Top of page
  2. Abstract
  3. METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgments
  7. REFERENCES

As of March 31, 2006, the database included 802 (95.6% of total first trimester monotherapy exposures) prospectively reported pregnancies with known outcomes, first-trimester exposure to lamotrigine monotherapy and complete dosing data. MBDs occurred in 22 (2.7%; 95% CI 1.8–4.2%) (Table 1).

Table 1. Description of birth defects following first trimester lamotrigine monotherapy exposure
Description of major birth defectMaximal first trimester lamotrigine dose (milligrams/day)
Anencephaly (3)150, 200, 425
Oral-facial clefts [(2) cleft lip and palate, cleft palate only]100, 200
Hypoplastic left heart syndrome (2)100, 400
Ventricular septal defect (3)200, 250, 300
Hydronephrosis (2)100, 250
Renal [(3) absent, polycystic, fluid on kidney]12.5, 500, 550
Cortical dysplasia300
Hypospadias200
Diaphragmatic hernia with dislocation of abdominal organs200
Congenital atresia of anus25
Bilateral hip dislocation200
Club feet [(3) two bilateral, one right foot]Dose unknown, 300, 500

The most commonly prescribed dose was 200 mg/day. The mean maximal first trimester maternal dose of lamotrigine monotherapy was 248.3 mg/day for infants with MBDs and 278.9 mg/day for infants without MBDs. The median maximal maternal dose was 200 mg/day in both groups. There was no significant difference in the distribution of doses between the groups with and those without defects (p-value for Wilcoxon rank sum test = 0.26). The dose distribution is described in Table 2.

Table 2. Distribution of daily dose among women who took lamotrigine during the first trimester
Maximal daily dose (milligrams)Number of women (%)Number of pregnancy outcomes with defects (%)Number of pregnancy outcomes without defects (%)
1–100126 (15.7)5 (22.7) 121 (15.5)
101–200290 (36.2)7 (31.8) 283 (36.3)
201–300160 (20.0)5 (22.7) 155 (19.9)
301–400110 (13.7)1 (4.5) 109 (14.0)
401–500 57 (7.1)3 (13.6)  54 (6.9)
501–600 36 (4.5)1 (4.5)  35 (4.5)
601–700  4 (0.5)0 (0)   4 (0.5)
701–800 13 (1.6)0 (0)  13 (1.7)
801–900  5 (0.6)0 (0)   5 (0.6)
901–1,000  0 (0)0 (0)   0 (0)
1,001–1,100  0 (0)0 (0)   0 (0)
1,101–1,200  1 (0.1)0 (0)   1 (0.1)
Total   802 22    780

The frequency of MBDs did not differ as a continuous function of dose according to a logistic regression model with monotherapy doses up to 1,200 mg/day, though doses above 400 mg/day were rare. The overall odds ratio for MBDs per 100-mg increase in lamotrigine was 0.999 (95% CI 0.996–1.001).

Fig. 1 illustrates the risk of MBDs by 100-mg increment. Above 400 mg/day, the width of the CIs reflects the data being insufficient to provide robust MBD risk estimates. A cutoff dose above which the risk of defects was substantially increased was not indicated.

image

Figure 1. Risk of all major birth defects by in utero lamotrigine exposure dose (with 95% CIs).

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DISCUSSION

  1. Top of page
  2. Abstract
  3. METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgments
  7. REFERENCES

The current analysis on 802 first-trimester lamotrigine monotherapy exposures does not suggest a dose–response relationship, nor a clear cutoff for increased risk. However, data on exposure to daily doses >400 mg were insufficient to allow comment on any relationship above that dose. While the number of exposures in this analysis might not be sufficient to detect a moderate dose–response relationship, these results are inconsistent with data from the UK registry that reported an increased risk with exposure to daily doses greater than 200 mg (Morrow et al., 2006).

The UK registry described an increase in MBD risk across lamotrigine dose categories (1.3% for <100 mg/day, 1.9% for 100–200 mg/day, and 5.4% with >200 mg/day), though no formal statistical testing was completed (Morrow, 2006). We have since tested the UK data for a dose–response trend across those categories using the exact version of the two-sided Cochrane-Armitage trend test. This reached a level of marginal statistical significance (p = 0.05).

The UK and international lamotrigine registries employ differing methodologies, mainly in terms of recruitment and length of follow-up postdelivery (3 months vs. at birth, respectively). These variations, as well as a lack of random sampling, potential underascertainment of defects, loss to follow up (26.4% in the International registry and 8.1% in the UK registry) and differing exposure reporting accuracy, could account for the inconsistencies. The differences could reflect dose being a poor surrogate for exposure given the changes in drug clearance during pregnancy (Pennell et al., 2004). Changes in medication dose during pregnancy could also have introduced a potential exposure misclassification bias. Although, 12.5% of women changed their lamotrigine monotherapy dose during the first trimester (8.5% increased the dose), consideration of the maximal dose aimed to prevent an underestimation of dose effect. Finally, both registries might have suffered confounding by severity of epilepsy and frequency of seizures during pregnancy: women with more severe epilepsy or seizure frequency might have been prescribed higher doses of lamotrigine. A possible underlying association between both epilepsy and seizures during pregnancy and fetal outcome could have introduced confounding by indication. Additional dosing pattern data by epilepsy type would help to predict this type of confounding. Unfortunately, these data are frequently missing from registries.

Despite the differences in dose data, there is growing consistency across pregnancy registries in the overall risk of MBDs associated with first-trimester lamotrigine monotherapy exposure: 2.8% (n = 831, 95% CI 1.8–4.2) in the international lamotrigine registry; 3.2% (n = 647, 95% CI 2.1–4.9%) in the UK registry (Morrow et al., 2006); 2.7% (n = 564, 95% CI 1.6–4.5%) in the North American Antiepileptic Drug Registry (Holmes et al., 2006). While a small increase in risk cannot be ruled out, each individual registry is adequately powered to exclude a two- to three-fold increase in risk compared to estimates from general population MBD surveillance systems (1.6% from a Boston hospital program (Nelson and Holmes 1989) and 2.2% from MACDP (Honein et al., 1999). Continued recruitment will strengthen future conclusions.

In conclusion, no evidence of an effect of lamotrigine dose on the frequency of MBDs was found in a database of 802 pregnancies exposed to lamotrigine monotherapy during the first trimester up through a daily dose of 400 mg. Above that level, data were too scarce to allow robust estimates of risk.

Acknowledgments

  1. Top of page
  2. Abstract
  3. METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgments
  7. REFERENCES

Acknowledgments:  The International Lamotrigine Pregnancy Registry Scientific Advisory Committee consists of the following members: Dr. Janet Cragan, National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention (CDC), Atlanta, Georgia; Dr. Richard Lowensohn, Oregon Health and Science University, Portland, Oregon; Dr. John Messenheimer, Neuroscience Clinical Research, GlaxoSmithKline, Research Triangle Park, North Carolina; Dr. James I. Morrow, The Royal Victoria Hospital, Belfast, Northern Ireland; Dr. Mark Yerby, North Pacific Epilepsy Research, Portland, Oregon; and Dr. John Weil, Worldwide Epidemiology, GlaxoSmithKline, Harlow, United Kingdom.

REFERENCES

  1. Top of page
  2. Abstract
  3. METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgments
  7. REFERENCES
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