Lamotrigine Pregnancy Registry (LAM05)
Study Details
Study Description
Brief Summary
Antiepileptic drugs (AEDs) are not indicated for use in pregnancy. However, women with epilepsy, and other approved indications including bipolar disorder, may require or be unintentionally exposed to AEDs during pregnancy. Prior to an AED being marketed there are few data available on drug safety in pregnancy: data from animal models may not translate directly to humans and pregnant women are routinely excluded from clinical trials. The International Lamotrigine Pregnancy Registry was established by GlaxoSmithKline (GSK) in 1992 to monitor the safety of lamotrigine during pregnancy.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Detailed Description
The International Lamotrigine Pregnancy Registry aims to assess whether there is a substantial increase in the risk of major congenital malformations (MCMs) following in utero exposure to lamotrigine. Exposure during the first trimester is of primary interest as this represents the period of organogenesis. The Registry is a primarily prospective enrolment and follow-up study. Patients exposed to lamotrigine during pregnancy are enrolled, on a voluntary basis, by their healthcare provider. Enrolment is encouraged early in pregnancy and if possible prior to any prenatal testing. The healthcare provider provides initial information concerning patient demographics; details of the pregnancy including the estimated delivery date and results of any prenatal testing; and the timing, duration and dosage of lamotrigine exposure in pregnancy. The registry accepts exposure reports from anywhere in the world. Within the United States (US) the healthcare provider can contact the registry using a toll free number. Outside of the US enrolments are made through the GlaxoSmithKline local operating company.
Close to the estimated date of delivery the healthcare provider is contacted by the Registry to provide follow up information concerning the pregnancy outcome (live or still birth, spontaneous or induced abortion), the presence or absence of a MCM, and the history of exposure to lamotrigine as well other antiepileptics and antipsychotics during pregnancy. Up to six attempts are made to contact the healthcare provider to obtain pregnancy outcome information. After six attempts, the record is closed as lost to follow up. Pregnancy outcomes are classified as outcomes with MCMs, outcomes without MCMs and spontaneous abortions. The outcomes with and without MCMs are further classified as live births, stillbirths/fetal deaths and induced abortions. Spontaneous abortions are reported separately due to potential for inconsistent identification of malformations in that situation.
It is beyond the scope of the Registry to consistently access pediatric evaluations and medical records. For this reason the main outcome is restricted to major congenital malformations that are external and recognizable in the delivery room or shortly after birth. To provide consistency, reported congenital malformations are classified as major or minor according to criteria used by the Centers for Disease Control and Prevention (CDC)'s Metropolitan Atlanta Congenital Defects Program (MACDP). All malformation reports are reviewed and classified by a paediatrician from the CDC and further information is requested as necessary.
Analyses are restricted to prospectively enrolled pregnancies (enrolment prior to knowledge of the birth outcome). Retrospectively enrolled pregnancies are reviewed for patterns of defect types, but are not included in formal analyses as retrospective reporting can be biased towards more unusual and severe outcomes and are less likely to be representative of the general population experience. The proportion of infants with MCMs among prospectively reported exposures is calculated as: the total number of outcomes with major birth defects (number of outcomes with major birth defects + the number of live births without defects).
Chromosomal malformations are reported descriptively, but are not included in the numerator as it is very unlikely that they are associated with drug exposure during pregnancy. All spontaneous pregnancy losses, as well as induced abortions and fetal deaths without reported defects, are excluded from the denominator due to the potential for inconsistent identification of malformations in those situations. The 95% confidence intervals (CIs) for risk estimates are calculated using exact methods based on the binomial distribution.
Analyses are stratified according to trimester of exposure (with the second trimester starting at week 14 and the third trimester at week 28 of gestation) and by exposure group (lamotrigine monotherapy, lamotrigine polytherapy including valproate and lamotrigine polytherapy without valproate).
The registry does not have an internal comparator group, but descriptive comparisons are made with MCM rates from general population studies in the literature and from other ongoing AED pregnancy registries. Prospective reports are also reviewed to detect any unusual patterns of malformation types that may warrant further investigation. The data from the International Lamotrigine Pregnancy Registry are reviewed, and conclusions developed, by an independent scientific advisory committee. A semi-annual interim report summarizing aggregate data is provided to disseminate information on a regular basis.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Women exposed to lamotrigine during pregnancy
|
Drug: Lamotrigine monotherapy
Lamotrigine monotherapy
Drug: Lamotrigine polytherapy including valproate
Lamotrigine polytherapy including valproate
Drug: Lamotrigine polytherapy without valproate
Lamotrigine polytherapy without valproate
|
Outcome Measures
Primary Outcome Measures
- Birth Outcomes by Earliest Pregnancy Trimester of Exposure to Lamotrigine Monotherapy [Although reports and diagnoses of major congenital malformations are accepted up to six years after the birth, the majority of malformations are reported after assessments made in the delivery room or shortly after birth]
The number of live births, fetal deaths, induced abortions, and spontaneous pregnancy losses were recorded according to the time at which women were first exposed to lamotrigine monotherapy. Due to inconsistent identification of major congenital malformations (MCMs) among spontaneous losses, no comment is made concerning the presence or absence of MCMs.
- Birth Outcomes by Earliest Pregnancy Trimester of Exposure to Lamotrigine Polytherapy With Valproate [Although reports and diagnoses of MCMs are accepted up to six years after the birth, the majority of malformations are reported following assessments made in the delivery room or shortly after birth]
The number of live births, fetal deaths, induced abortions, and spontaneous pregnancy losses were recorded according to the time at which women were first exposed to lamotrigine polytherapy with valproate. Due to inconsistent identification of major congenital malformations (MCMs) among spontaneous losses, no comment is made concerning the presence or absence of MCMs.
- Birth Outcomes by Earliest Pregnancy Trimester of Exposure to Lamotrigine Polytherapy Without Valproate [Although reports and diagnoses of MCMs are accepted up to six years after the birth, the majority of malformations are reported following assessments made in the delivery room or shortly after birth]
The number of live births, fetal deaths with pregnancy loss occurring >=20 weeks gestation, induced abortions, and spontaneous pregnancy losses were recorded according to the time at which women were first exposed to lamotrigine polytherapy without valproate. Due to inconsistent identification of major congenital malformations (MCMs) among spontaneous losses, no comment is made concerning the presence or absence of MCMs. Although birth defects may not have been reported, they cannot be ruled out.
- Number of Infants With Major Congenital Malformations by Earliest Trimester of Exposure to Lamotrigine Monotherapy [Although reports and diagnoses of MCMs are accepted up to six years after the birth, the majority of malformations are reported after assessments made in the delivery room or shortly after birth]
Among lamotrigine monotherapy exposures: live births, fetal deaths, induced abortions with birth defects, and live births without defects. Due to the likelihood of inconsistent identification of birth defects among spontaneous losses, fetal deaths, and induced abortions without reported birth defects, these offspring were not included in analyses.
- Number of Infants With Major Congenital Malformations (MCMs) by Earliest Trimester of Exposure to Lamotrigine Polytherapy With Valproate [Although reports and diagnoses of MCMs are accepted up to six years after the birth, the majority of malformations are reported following assessments made in the delivery room or shortly after birth]
The number of infants with major congenital malformations were counted and are presented by earliest trimester of exposure to lamotrigine polytherapy with valproate.
- Number of Infants With Major Congenital Malformations (MCMs) by Earliest Trimester of Exposure to Lamotrigine Polytherapy Without Valproate [Although reports and diagnoses of MCMs are accepted up to six years after the birth, the majority of malformations are reported following assessments made in the delivery room or shortly after birth]
The number of infants with major congenital malformations were counted and are presented by earliest trimester of exposure to lamotrigine polytherapy without valproate.
- Number of Infants With the Indicated Major Congenital Malformations Following the First Trimester of Exposure to Lamotrigine Monotherapy According to Dose Received [Although reports and diagnoses of MCMs are accepted up to six years after the birth, the majority of malformations are reported after assessments made in the delivery room or shortly after birth]
The number of infants with the reported MCM following first trimester lamotrigine monotherapy exposure were counted. Registry personnel contacted the enrolling physician to obtain information on the pregnancy outcome, lamotrigine dosing and duration of exposure, and use of concomitant antiepileptic drugs during pregnancy.
- Number of Infants With the Indicated Major Congenital Malformations Following First Trimester of Exposure to Lamotrigine Polytherapy With Valproate According to Dose of Lamotrigine Received [Although reports and diagnoses of MCMs are accepted up to six years after the birth, the majority of malformations are reported after assessments made in the delivery room or shortly after birth]
The number of infants with the reported MCM following first trimester exposure to lamotrigine polytherapy with valproate were counted.
- Number of Infants With the Indicated Major Congenital Malformations Following First Trimester of Exposure to Lamotrigine Polytherapy Without Valproate According to Dose of Lamotrigine Received [Although reports and diagnoses of MCMs are accepted up to six years after the birth, the majority of malformations are reported after assessments made in the delivery room or shortly after birth]
The number of infants with the reported MCM following first trimester exposure to lamotrigine polytherapy without valproate were counted.
Eligibility Criteria
Criteria
Inclusion Criteria:
-
Women exposed in utero to lamotrigine (as monotherapy or in a polytherapy combination) during pregnancy. Exposure can occur at any time during pregnancy, though exposure in the first trimester is of primary interest.
-
Pregnancies exposed to lamotrigine and reported before the outcome of the pregnancy is known (prospective reporting). Ideally exposed pregnancies are registered prior to prenatal testing, but only those pregnancies enrolled after prenatal testing has diagnosed a birth defect are excluded.
-
Retrospectively reported exposures (i.e. exposures registered once the pregnancy outcome is known) are included in the registry, but are considered descriptively and are not included in risk analyses.
Exclusion Criteria:
-
Retrospectively reported exposures (i.e. exposures registered once the pregnancy outcome is known) are included in the registry, but are reviewed separately and descriptively. These are not included in risk analyses.
-
Patient reported exposures and outcomes that are not verified by a healthcare provider.
Contacts and Locations
Locations
No locations specified.Sponsors and Collaborators
- GlaxoSmithKline
Investigators
- Study Director: GSK Clinical Trials, GlaxoSmithKline
Study Documents (Full-Text)
None provided.More Information
Publications
- Cunnington M, Ferber S, Quartey G; International Lamotrigine Pregnancy Registry Scientific Advisory Committee. Effect of dose on the frequency of major birth defects following fetal exposure to lamotrigine monotherapy in an international observational study. Epilepsia. 2007 Jun;48(6):1207-10. Epub 2007 Mar 22.
- 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.
- Cunnington MC, Weil JG, Messenheimer JA, Ferber S, Yerby M, Tennis P. Final results from 18 years of the International Lamotrigine Pregnancy Registry. Neurology. 2011 May 24;76(21):1817-23. doi: 10.1212/WNL.0b013e31821ccd18.
- Cunnington MC. The International Lamotrigine pregnancy registry update for the epilepsy foundation. Epilepsia. 2004 Nov;45(11):1468.
- Lamotrigine Pregnancy Registry. Interim Report 1 September 1992 through 31 March 2010. Issued July 2010. Available at: http://pregnancyregistry.gsk.com/index.html
- Tennis P, Eldridge RR; International Lamotrigine Pregnancy Registry Scientific Advisory Committee. Preliminary results on pregnancy outcomes in women using lamotrigine. Epilepsia. 2002 Oct;43(10):1161-7.
- 112913
- 105905
- EPI40048
Study Results
Participant Flow
| Recruitment Details | |
|---|---|
| Pre-assignment Detail |
| Arm/Group Title | Lamotrigine Monotherapy Pregnancy Exposures | Lamotrigine Polytherapy With Valproate Pregnancy Exposures | Lamotrigine Polytherapy Without Valproate Pregnancy Exposures |
|---|---|---|---|
| Arm/Group Description | Prospectively enrolled pregnancies exposed to lamotrigine monotherapy at doses between 0-1200 mg/day | Prospectively enrolled pregnancies exposed to lamotrigine polytherapy with valproate, all dose ranges | Prospectively enrolled pregnancies exposed to lamotrigine polytherapy without valproate, all dose ranges |
| Period Title: Overall Study | |||
| STARTED | 2567 | 219 | 630 |
| COMPLETED | 1776 | 171 | 497 |
| NOT COMPLETED | 791 | 48 | 133 |
Baseline Characteristics
| Arm/Group Title | Lamotrigine Monotherapy Pregnancy Exposures | Lamotrigine Polytherapy With Valproate Pregnancy Exposures | Lamotrigine Polytherapy Without Valproate Pregnancy Exposures | Total |
|---|---|---|---|---|
| Arm/Group Description | Prospectively enrolled pregnancies exposed to lamotrigine monotherapy at doses between 0-1200 mg/day | Prospectively enrolled pregnancies exposed to lamotrigine polytherapy with valproate, all dose ranges | Prospectively enrolled pregnancies exposed to lamotrigine polytherapy without valproate, all dose ranges | Total of all reporting groups |
| Overall Participants | 2567 | 219 | 630 | 3416 |
| Age (years) [Mean (Standard Deviation) ] | ||||
| Mean (Standard Deviation) [years] |
27.9
(5.84)
|
25.8
(5.49)
|
28.1
(6.08)
|
27.8
(5.89)
|
| Sex: Female, Male (Count of Participants) | ||||
| Female |
2567
100%
|
219
100%
|
630
100%
|
3416
100%
|
| Male |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
Outcome Measures
| Title | Birth Outcomes by Earliest Pregnancy Trimester of Exposure to Lamotrigine Monotherapy |
|---|---|
| Description | The number of live births, fetal deaths, induced abortions, and spontaneous pregnancy losses were recorded according to the time at which women were first exposed to lamotrigine monotherapy. Due to inconsistent identification of major congenital malformations (MCMs) among spontaneous losses, no comment is made concerning the presence or absence of MCMs. |
| Time Frame | Although reports and diagnoses of major congenital malformations are accepted up to six years after the birth, the majority of malformations are reported after assessments made in the delivery room or shortly after birth |
Outcome Measure Data
| Analysis Population Description |
|---|
| Prospectively enrolled pregnancies exposed to lamotrigine monotherapy. |
| Arm/Group Title | First Exposure During First Trimester | First Exposure During Second Trimester | First Exposure During Third Trimester | Unspecified Trimester of Exposure |
|---|---|---|---|---|
| Arm/Group Description | The first trimester begins at conception | The second trimester begins at 14 weeks gestation | The third trimester begins at 28 weeks gestation | The earliest trimester of exposure was not specified |
| Measure Participants | 1699 | 95 | 18 | 5 |
| Live Birth (Birth Defects Reported) |
31
|
4
|
1
|
0
|
| Fetal Death (Birth Defects Reported) |
1
|
0
|
0
|
0
|
| Induced Abortion (Birth Defects Reported) |
3
|
0
|
0
|
0
|
| Live Birth (No Birth Defects Reported) |
1523
|
91
|
17
|
5
|
| Fetal Death (No Birth Defects Reported) |
10
|
0
|
0
|
0
|
| Induced Abortion (No Birth Defects Reported) |
33
|
0
|
0
|
0
|
| Spontaneous Pregnancy Loss |
98
|
0
|
0
|
0
|
| Title | Birth Outcomes by Earliest Pregnancy Trimester of Exposure to Lamotrigine Polytherapy With Valproate |
|---|---|
| Description | The number of live births, fetal deaths, induced abortions, and spontaneous pregnancy losses were recorded according to the time at which women were first exposed to lamotrigine polytherapy with valproate. Due to inconsistent identification of major congenital malformations (MCMs) among spontaneous losses, no comment is made concerning the presence or absence of MCMs. |
| Time Frame | Although reports and diagnoses of MCMs are accepted up to six years after the birth, the majority of malformations are reported following assessments made in the delivery room or shortly after birth |
Outcome Measure Data
| Analysis Population Description |
|---|
| Prospectively enrolled pregnancies exposed to lamotrigine polytherapy with valproate. |
| Arm/Group Title | First Exposure During First Trimester | First Exposure During Second Trimester | First Exposure During Third Trimester | Unspecified Trimester of Exposure |
|---|---|---|---|---|
| Arm/Group Description | The first trimester begins at conception | The second trimester begins at 14 weeks gestation | The third trimester begins at 28 weeks gestation | The earliest trimester of exposure was not specified |
| Measure Participants | 161 | 8 | 3 | 1 |
| Live Birth (Birth Defects Reported) |
14
|
1
|
0
|
0
|
| Fetal Death (Birth Defects Reported) |
0
|
0
|
0
|
0
|
| Induced Abortion (Birth Defects Reported) |
2
|
0
|
0
|
0
|
| Live Birth (No Birth Defects Reported) |
134
|
6
|
3
|
1
|
| Fetal Death (No Birth Defects Reported) |
1
|
1
|
0
|
0
|
| Induced Abortion (No Birth Defects Reported) |
4
|
0
|
0
|
0
|
| Spontaneous Pregnancy Loss |
6
|
0
|
0
|
0
|
| Title | Birth Outcomes by Earliest Pregnancy Trimester of Exposure to Lamotrigine Polytherapy Without Valproate |
|---|---|
| Description | The number of live births, fetal deaths with pregnancy loss occurring >=20 weeks gestation, induced abortions, and spontaneous pregnancy losses were recorded according to the time at which women were first exposed to lamotrigine polytherapy without valproate. Due to inconsistent identification of major congenital malformations (MCMs) among spontaneous losses, no comment is made concerning the presence or absence of MCMs. Although birth defects may not have been reported, they cannot be ruled out. |
| Time Frame | Although reports and diagnoses of MCMs are accepted up to six years after the birth, the majority of malformations are reported following assessments made in the delivery room or shortly after birth |
Outcome Measure Data
| Analysis Population Description |
|---|
| Prospectively enrolled pregnancies exposed to the lamotrigine polytherapy without valproate |
| Arm/Group Title | First Exposure During First Trimester | First Exposure During Second Trimester | First Exposure During Third Trimester | Unspecified Trimester of Exposure |
|---|---|---|---|---|
| Arm/Group Description | The first trimester begins at conception | The second trimester begins at 14 weeks gestation | The third trimester begins at 28 weeks gestation | The earliest trimester of exposure was not specified |
| Measure Participants | 474 | 25 | 3 | 0 |
| Live Birth (Birth Defects Reported) |
11
|
0
|
1
|
|
| Fetal Death (Birth Defects Reported) |
0
|
0
|
0
|
|
| Induced Abortion (Birth Defects Reported) |
1
|
0
|
0
|
|
| Live Birth (No Birth Defects Reported) |
418
|
25
|
2
|
|
| Fetal Death (No Birth Defects Reported) |
3
|
0
|
0
|
|
| Induced Abortion (No Birth Defects Reported) |
19
|
0
|
0
|
|
| Spontaneous Pregnancy Loss |
22
|
0
|
0
|
| Title | Number of Infants With Major Congenital Malformations by Earliest Trimester of Exposure to Lamotrigine Monotherapy |
|---|---|
| Description | Among lamotrigine monotherapy exposures: live births, fetal deaths, induced abortions with birth defects, and live births without defects. Due to the likelihood of inconsistent identification of birth defects among spontaneous losses, fetal deaths, and induced abortions without reported birth defects, these offspring were not included in analyses. |
| Time Frame | Although reports and diagnoses of MCMs are accepted up to six years after the birth, the majority of malformations are reported after assessments made in the delivery room or shortly after birth |
Outcome Measure Data
| Analysis Population Description |
|---|
| Among lamotrigine monotherapy exposures: live births, fetal deaths, induced abortions with birth defects, and live births without defects. Due to the likelihood of inconsistent identification of birth defects among spontaneous losses, fetal deaths, and induced abortions without reported birth defects, these offspring were not included in analyses. |
| Arm/Group Title | First Exposure During First Trimester | First Exposure During Second Trimester | First Exposure During Third Trimester | Unspecified Trimester of Exposure | All Trimesters |
|---|---|---|---|---|---|
| Arm/Group Description | The first trimester begins at conception | The second trimester begins at 14 weeks gestation | The third trimester begins at 28 weeks gestation | The earliest trimester of exposure was not specified | Exposure during any trimester of pregnancy |
| Measure Participants | 1558 | 95 | 18 | 5 | 1676 |
| Number [infants] |
35
|
4
|
1
|
0
|
40
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | First Exposure During First Trimester |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Wilson Score with Continuity Correction |
| Estimated Value | 2.2 | |
| Confidence Interval |
() 95% 1.6 to 3.1 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | The percentage of infants with MBDs was calculated as: the number of outcomes with MBDs divided by (the number of outcomes with MBDs + the number of live births without defects). | |
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | First Exposure During Second Trimester |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Wilson Score with Continuity Correction |
| Estimated Value | 4.2 | |
| Confidence Interval |
() 95% 1.4 to 11.0 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | The percentage of infants with MBDs was calculated as: the number of outcomes with MBDs divided by (the number of outcomes with MBDs + the number of live births without defects). | |
Statistical Analysis 3
| Statistical Analysis Overview | Comparison Group Selection | All Trimesters |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Wilson Score with Continuity Correction |
| Estimated Value | 2.4 | |
| Confidence Interval |
() 95% 1.7 to 3.3 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | The percentage of infants with MBDs was calculated as: the number of outcomes with MBDs divided by (the number of outcomes with MBDs + the number of live births without defects). | |
| Title | Number of Infants With Major Congenital Malformations (MCMs) by Earliest Trimester of Exposure to Lamotrigine Polytherapy With Valproate |
|---|---|
| Description | The number of infants with major congenital malformations were counted and are presented by earliest trimester of exposure to lamotrigine polytherapy with valproate. |
| Time Frame | Although reports and diagnoses of MCMs are accepted up to six years after the birth, the majority of malformations are reported following assessments made in the delivery room or shortly after birth |
Outcome Measure Data
| Analysis Population Description |
|---|
| Among lamotrigine polytherapy with valproate exposures: live births, fetal deaths, induced abortions with defects, and live births without defects. Due to the likelihood of inconsistent identification of defects among spontaneous losses, fetal deaths, and induced abortions without reported defects, these offspring were not included in analyses. |
| Arm/Group Title | First Exposure During First Trimester | First Exposure During Second Trimester | First Exposure During Third Trimester | Unspecified Trimester of Exposure | All Trimesters |
|---|---|---|---|---|---|
| Arm/Group Description | The first trimester begins at conception | The second trimester begins at 14 weeks gestation | The third trimester begins at 28 weeks gestation | The earliest trimester of exposure was not specified | Exposure during any trimester of pregnancy |
| Measure Participants | 150 | 7 | 3 | 1 | 161 |
| Number [infants] |
14
|
1
|
0
|
0
|
1
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | First Exposure During First Trimester |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Wilson Score with Continuity Correction |
| Estimated Value | 10.7 | |
| Confidence Interval |
() 95% 6.4 to 17.0 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | All Trimesters |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Wilson Score with Continuity Correction |
| Estimated Value | 9.3 | |
| Confidence Interval |
() 95% 5.5 to 15.2 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | The percentage of infants with MBDs was calculated as: the number of outcomes with MBDs divided by (the number of outcomes with MBDs + the number of live births without defects). | |
| Title | Number of Infants With Major Congenital Malformations (MCMs) by Earliest Trimester of Exposure to Lamotrigine Polytherapy Without Valproate |
|---|---|
| Description | The number of infants with major congenital malformations were counted and are presented by earliest trimester of exposure to lamotrigine polytherapy without valproate. |
| Time Frame | Although reports and diagnoses of MCMs are accepted up to six years after the birth, the majority of malformations are reported following assessments made in the delivery room or shortly after birth |
Outcome Measure Data
| Analysis Population Description |
|---|
| Among lamotrigine polytherapy without valproate exposures: live births, fetal deaths, induced abortions with defects, and live births without defects. Due to the likelihood of inconsistent identification of defects among spontaneous losses, fetal deaths, and induced abortions without reported defects, these offspring were not included in analyses. |
| Arm/Group Title | First Exposure During First Trimester | First Exposure During Second Trimester | First Exposure During Third Trimester | Unspecified Trimester of Exposure | All Trimesters |
|---|---|---|---|---|---|
| Arm/Group Description | The first trimester begins at conception | The second trimester begins at 14 weeks gestation | The third trimester begins at 28 weeks gestation | The earliest trimester of exposure was not specified | Exposure during any trimester of pregnancy |
| Measure Participants | 430 | 25 | 3 | 0 | 458 |
| Number [infants] |
12
|
0
|
1
|
13
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | First Exposure During First Trimester |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Wilson Score with Continuity Correction |
| Estimated Value | 2.8 | |
| Confidence Interval |
() 95% 1.5 to 5.0 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | All Trimesters |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Wilson Score with Continuity Correction |
| Estimated Value | 2.8 | |
| Confidence Interval |
() 95% 1.6 to 4.9 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | The percentage of infants with MBDs was calculated as: the number of outcomes with MBDs divided by (the number of outcomes with MBDs + the number of live births without defects). | |
| Title | Number of Infants With the Indicated Major Congenital Malformations Following the First Trimester of Exposure to Lamotrigine Monotherapy According to Dose Received |
|---|---|
| Description | The number of infants with the reported MCM following first trimester lamotrigine monotherapy exposure were counted. Registry personnel contacted the enrolling physician to obtain information on the pregnancy outcome, lamotrigine dosing and duration of exposure, and use of concomitant antiepileptic drugs during pregnancy. |
| Time Frame | Although reports and diagnoses of MCMs are accepted up to six years after the birth, the majority of malformations are reported after assessments made in the delivery room or shortly after birth |
Outcome Measure Data
| Analysis Population Description |
|---|
| Among lamotrigine monotherapy exposures in the first trimester: live births, fetal deaths, induced abortions with defects, and live births without defects. Due to the likely inconsistent identification of defects among spontaneous losses, fetal deaths, and induced abortions without reported defects, these offspring were not included in analyses. |
| Arm/Group Title | Doses Lower Than Prescribed | Prescribed Doses | Dose Higher Than Prescribed | Unknown Maximal Dose in Exposed Trimester |
|---|---|---|---|---|
| Arm/Group Description | >0 to 200 mg/day maximal dose in first trimester | 201-400 mg/day maximal dose in first trimester | >400 mg/day maximal dose in first trimester | |
| Measure Participants | 15 | 12 | 6 | 2 |
| Anencephaly |
2
|
0
|
1
|
0
|
| Orofacial clefts |
2
|
0
|
0
|
0
|
| Hypoplastic left heart/left ventricle hypoplasia |
1
|
0
|
1
|
0
|
| Transposition of great vessels |
2
|
0
|
0
|
0
|
| Ventricular septal defects |
0
|
3
|
0
|
0
|
| Minor heart defect, unspecified |
0
|
1
|
0
|
0
|
| Pulmonary stenosis |
0
|
1
|
0
|
0
|
| Hydronephrosis |
1
|
1
|
0
|
0
|
| Renal defect (absent, polysystic, fluid on kidney) |
1
|
0
|
2
|
0
|
| Cortical dysplasis |
0
|
1
|
0
|
0
|
| Hypospadias |
1
|
1
|
0
|
0
|
| Pyloric stenosis |
0
|
1
|
0
|
1
|
| Diaphragmatic hernia |
1
|
0
|
1
|
0
|
| Congenital atresia of anus |
1
|
0
|
0
|
0
|
| Hip dislocation |
1
|
0
|
0
|
0
|
| Club feet |
0
|
1
|
1
|
1
|
| Polydactyly |
1
|
1
|
0
|
0
|
| Epidermolysis bullosa |
1
|
0
|
0
|
0
|
| Light spot across entire abdomen |
0
|
1
|
0
|
0
|
| Title | Number of Infants With the Indicated Major Congenital Malformations Following First Trimester of Exposure to Lamotrigine Polytherapy With Valproate According to Dose of Lamotrigine Received |
|---|---|
| Description | The number of infants with the reported MCM following first trimester exposure to lamotrigine polytherapy with valproate were counted. |
| Time Frame | Although reports and diagnoses of MCMs are accepted up to six years after the birth, the majority of malformations are reported after assessments made in the delivery room or shortly after birth |
Outcome Measure Data
| Analysis Population Description |
|---|
| Among lamotrigine polytherapy with valproate exposures in the first trimester: live births, fetal deaths, induced abortions with defects, and live births without defects. Due to the likely inconsistent identification of defects among spontaneous losses, fetal deaths, and induced abortions without reported defects, those offspring were excluded. |
| Arm/Group Title | Doses Lower Than Prescribed | Prescribed Doses | Doses Higher Than Prescribed | Unknown Maximal Dose in Exposed Trimester |
|---|---|---|---|---|
| Arm/Group Description | >0 to 200 mg/day maximal dose in first trimester | 201-400 mg/day maximal dose in first trimester | >400 mg/day maximal dose in first trimester | |
| Measure Participants | 13 | 3 | 0 | 0 |
| Hydrocephalus/spina bifida |
1
|
0
|
||
| Meningomyelocele |
1
|
0
|
||
| Microcephaly |
1
|
0
|
||
| Orofacial clefts |
2
|
1
|
||
| Cardiac septal defects |
0
|
2
|
||
| Transposition of great vessels |
1
|
0
|
||
| Ventricular hypoplasia |
1
|
0
|
||
| Pulmonary stenosis |
1
|
0
|
||
| Pyloric stenosis |
1
|
0
|
||
| Gastroschisis |
1
|
0
|
||
| Club foot |
2
|
0
|
||
| Polydactyly |
1
|
0
|
| Title | Number of Infants With the Indicated Major Congenital Malformations Following First Trimester of Exposure to Lamotrigine Polytherapy Without Valproate According to Dose of Lamotrigine Received |
|---|---|
| Description | The number of infants with the reported MCM following first trimester exposure to lamotrigine polytherapy without valproate were counted. |
| Time Frame | Although reports and diagnoses of MCMs are accepted up to six years after the birth, the majority of malformations are reported after assessments made in the delivery room or shortly after birth |
Outcome Measure Data
| Analysis Population Description |
|---|
| Among lamotrigine polytherapy without valproate exposures in the first trimester: live births, fetal deaths, induced abortions with defects, and live births without defects. Due to the likely inconsistent identification of defects among spontaneous losses, fetal deaths, and induced abortions without reported defects, those offspring were excluded. |
| Arm/Group Title | Doses Lower Than Prescribed | Prescribed Doses | Doses Higher Than Prescribed | Unknown Maximal Dose in Exposed Trimester |
|---|---|---|---|---|
| Arm/Group Description | >0 to 200 mg/day maximal dose in first trimester | 201-400 mg/day maximal dose in first trimester | >400 mg/day maximal dose in first trimester | |
| Measure Participants | 2 | 4 | 6 | 0 |
| Neural tube defect |
0
|
0
|
1
|
|
| Cardiac septal defect/murmur |
0
|
1
|
1
|
|
| Coarctation of aorta |
0
|
1
|
0
|
|
| Tetralogy of Fallot |
0
|
0
|
1
|
|
| Esophageal defects |
0
|
1
|
1
|
|
| Hypospadias |
1
|
0
|
0
|
|
| Hydroencephalopathy |
1
|
0
|
0
|
|
| Omphalocele |
0
|
1
|
0
|
|
| Extra digit |
0
|
0
|
1
|
|
| Skin tags on ear |
0
|
0
|
1
|
Adverse Events
| Time Frame | ||||||
|---|---|---|---|---|---|---|
| Adverse Event Reporting Description | This was a prospective enrollment/follow-up study based on exposure/outcome data collected using structured enrollment and birth outcome report forms completed by healthcare providers of pregnant women. This observational study was designed to investigate birth defects, a specific group of serious adverse events (SAEs); no other SAEs were measured. | |||||
| Arm/Group Title | Lamotrigine Monotherapy Pregnancy Exposures | Lamotrigine Polytherapy With Valproate Pregnancy Exposures | Lamotrigine Polytherapy Without Valproate Pregnancy Exposures | |||
| Arm/Group Description | Prospectively enrolled pregnancies exposed to lamotrigine monotherapy with completed pregnancy outcome (does not include those lost to follow up where outcome information could not be obtained) | Prospectively enrolled pregnancies exposed to lamotrigine polytherapy with valproate exposures with completed pregnancy outcome (does not include those lost to follow up where outcome information could not be obtained) | Prospectively enrolled pregnancies exposed to lamotrigine polytherapy without valproate exposures with completed pregnancy outcome (does not include those lost to follow up where outcome information could not be obtained) | |||
All Cause Mortality |
||||||
| Lamotrigine Monotherapy Pregnancy Exposures | Lamotrigine Polytherapy With Valproate Pregnancy Exposures | Lamotrigine Polytherapy Without Valproate Pregnancy Exposures | ||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | / (NaN) | / (NaN) | / (NaN) | |||
Serious Adverse Events |
||||||
| Lamotrigine Monotherapy Pregnancy Exposures | Lamotrigine Polytherapy With Valproate Pregnancy Exposures | Lamotrigine Polytherapy Without Valproate Pregnancy Exposures | ||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 35/1776 (2%) | 16/171 (9.4%) | 12/497 (2.4%) | |||
| Congenital, familial and genetic disorders | ||||||
| Anencephaly | 3/1776 (0.2%) | 0/171 (0%) | 0/497 (0%) | |||
| Cardiac septal defect/murmur | 0/1776 (0%) | 2/171 (1.2%) | 2/497 (0.4%) | |||
| Club foot | 3/1776 (0.2%) | 2/171 (1.2%) | 0/497 (0%) | |||
| Coarctation of aorta | 0/1776 (0%) | 0/171 (0%) | 1/497 (0.2%) | |||
| Congenital atresia of anus | 1/1776 (0.1%) | 0/171 (0%) | 0/497 (0%) | |||
| Cortical dysplasis | 1/1776 (0.1%) | 0/171 (0%) | 0/497 (0%) | |||
| Diaphragmatic hernia | 2/1776 (0.1%) | 0/171 (0%) | 0/497 (0%) | |||
| Epidermolysis bullosa | 1/1776 (0.1%) | 0/171 (0%) | 0/497 (0%) | |||
| Esophageal defects | 0/1776 (0%) | 0/171 (0%) | 2/497 (0.4%) | |||
| Gastroschisis | 0/1776 (0%) | 1/171 (0.6%) | 0/497 (0%) | |||
| Hip dislocation | 1/1776 (0.1%) | 0/171 (0%) | 0/497 (0%) | |||
| Hydrocephalus/spina bifida | 0/1776 (0%) | 1/171 (0.6%) | 0/497 (0%) | |||
| Hydroencephalopathy | 0/1776 (0%) | 0/171 (0%) | 1/497 (0.2%) | |||
| Hydronephrosis | 2/1776 (0.1%) | 0/171 (0%) | 0/497 (0%) | |||
| Hypoplastic left heart/left ventricle hypoplasia | 2/1776 (0.1%) | 0/171 (0%) | 0/497 (0%) | |||
| Hypospadias | 2/1776 (0.1%) | 0/171 (0%) | 1/497 (0.2%) | |||
| Light spot across entire abdomen | 1/1776 (0.1%) | 0/171 (0%) | 0/497 (0%) | |||
| Meningomyelocele | 0/1776 (0%) | 1/171 (0.6%) | 0/497 (0%) | |||
| Microcephaly | 0/1776 (0%) | 1/171 (0.6%) | 0/497 (0%) | |||
| Minor heart defect, unspecified | 1/1776 (0.1%) | 0/171 (0%) | 0/497 (0%) | |||
| Neural tube defect | 0/1776 (0%) | 0/171 (0%) | 1/497 (0.2%) | |||
| Omphalocele | 0/1776 (0%) | 0/171 (0%) | 1/497 (0.2%) | |||
| Orofacial clefts | 2/1776 (0.1%) | 3/171 (1.8%) | 0/497 (0%) | |||
| Polydactyly | 2/1776 (0.1%) | 1/171 (0.6%) | 1/497 (0.2%) | |||
| Pulmonary stenosis | 1/1776 (0.1%) | 1/171 (0.6%) | 0/497 (0%) | |||
| Pyloric stenosis | 2/1776 (0.1%) | 1/171 (0.6%) | 0/497 (0%) | |||
| Renal defect (absent, polysystic, fluid on kidney) | 3/1776 (0.2%) | 0/171 (0%) | 0/497 (0%) | |||
| Skin tags on ear | 0/1776 (0%) | 0/171 (0%) | 1/497 (0.2%) | |||
| Tetralogy of Fallot | 0/1776 (0%) | 0/171 (0%) | 1/497 (0.2%) | |||
| Transposition of great vessels | 2/1776 (0.1%) | 1/171 (0.6%) | 0/497 (0%) | |||
| Ventricular hypoplasia | 0/1776 (0%) | 1/171 (0.6%) | 0/497 (0%) | |||
| Ventricular septal defects | 3/1776 (0.2%) | 0/171 (0%) | 0/497 (0%) | |||
Other (Not Including Serious) Adverse Events |
||||||
| Lamotrigine Monotherapy Pregnancy Exposures | Lamotrigine Polytherapy With Valproate Pregnancy Exposures | Lamotrigine Polytherapy Without Valproate Pregnancy Exposures | ||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 0/0 (NaN) | 0/0 (NaN) | 0/0 (NaN) | |||
Limitations/Caveats
More Information
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
GSK agreements may vary with individual investigators, but will not prohibit any investigator from publishing. GSK supports the publication of results from all centers of a multi-center trial but requests that reports based on single-site data not precede the primary publication of the entire clinical trial.
Results Point of Contact
| Name/Title | GSK Response Center |
|---|---|
| Organization | GlaxoSmithKline |
| Phone | 866-435-7343 |
- 112913
- 105905
- EPI40048