ࡱ> [ePQRSTUVWXYZz`a#` | bjbjmm  B9B9B9B9n;n;n;t;j`j`j`2ag<;^6LV lP"$$$$$$$h#nHin;ė֘@HB9B9*g;g;g;HB9<:R"g;"g;g;A~:|L;"bBR @+Dj`-: BVLj0&B<900vBvBn;BLD g;$ !DDDHH:pDDD;;;"^;;;^;;;B9B9B9B9B9B9  POLICY FOR ORAL PRESENTATION OF DATA The sponsor encourages the responsible sharing of the information contained in this Report with health professionals who might benefit. In an attempt to standardize dissemination and interpretation of the data, the following guidelines have been developed for oral presentation (no written document may include the data in this document without written permission of GlaxoSmithKline): 1. The data contained in this Report will become out-of-date within 7 months of the date the publication is issued. Please contact the Lamotrigine Pregnancy Registry to ensure you have obtained the most recent published Report. 2. The data in Table 4 (Prospective Registry - Lamotrigine Exposure in Pregnancy by Earliest Trimester of Exposure and Outcome) is the most appropriate for presentation. Presentation of results stratified by earliest trimester of exposure is imperative. 3. A statement regarding the Committee Consensus must be referenced in any presentation of these data, including emphasis on the limitations of voluntary prenatal drug exposure registries such as this one. 4. When presenting data from the pregnancy Registry, please remind the audience that success of the study depends on reporting of exposures by health care professionals. Registry contact information should be presented. To maximize validity of the data, exposed pregnancies should be enrolled into the pregnancy Registry as early in the pregnancy as possible. Outside North America, Health Care Providers can enroll pregnancy exposures into the Lamotrigine Pregnancy Registry Through the medical director of your local GlaxoSmithKline company Or directly to the project office in the USA at: (910) 256-0549 (call collect) Within North America, Health care providers can enroll pregnancy exposures at: (800) 336-2176 (call toll-free) (910) 256-0549 (call collect) Alternatively, patients can enroll themselves into the North American AED Pregnancy Registry by calling (888) 233-2334 (call toll-free). Data forms are available at: http://www.kendle.com/registries/ GlaxoSmithKline International LAMOTRIGINE PREGNANCY REGISTRY Interim Report 1 September 1992 31 March 2008 PROJECT OFFICE Kendle International Inc. Research Park 1011 Ashes Drive Wilmington, North Carolina 28405 USA HM2008/00221/00  EMBED Word.Picture.8 TABLE OF CONTENTS TOC \o "1-2" \t "Heading 3,3,Heading 4,4,Heading 5,5,Heading 6,6,Heading 7,7,Heading 8,8,Heading 9,9,Caption:table,4"  EXECUTIVE SUMMARY  PAGEREF _Toc196734034 \h 1 1. INTRODUCTION  PAGEREF _Toc196734035 \h 4 2. BACKGROUND  PAGEREF _Toc196734036 \h 4 2.1 Animal Data  PAGEREF _Toc196734037 \h 4 3. PROSPECTIVE REGISTRY  PAGEREF _Toc196734038 \h 5 3.1 New Data  PAGEREF _Toc196734039 \h 5 3.2 All Data  PAGEREF _Toc196734040 \h 6 Table 1. Prospective Registry New Lamotrigine Data in Reporting Period  PAGEREF _Toc196734041 \h 6 Table 2. Prospective Registry Status of All Lamotrigine Exposures in Pregnancy  PAGEREF _Toc196734042 \h 7 Table 3. Prospective Registry Lamotrigine Exposure in Pregnancy by Country of Origin  PAGEREF _Toc196734043 \h 8 3.3 Excluded Birth Defects and Other Reported Conditions  PAGEREF _Toc196734044 \h 9 Table 4. Prospective Registry Lamotrigine Exposure in Pregnancy by  PAGEREF _Toc196734045 \h 10 Earliest Trimester of Exposure and Outcome  PAGEREF _Toc196734046 \h 10 Table 5. Prospective Registry Lamotrigine Exposure in Pregnancy Summaries of Major Defects by Earliest Trimester of Exposure and Polytherapy Status  PAGEREF _Toc196734047 \h 11 Table 6. Prospective Registry Gestational Age at Enrollment (weeks) First Trimester  PAGEREF _Toc196734048 \h 17 Monotherapy Exposure  PAGEREF _Toc196734049 \h 17 Table 7. Prospective Registry Lamotrigine Monotherapy and Antiepileptic Drug Polytherapy Exposure in Pregnancy by Trimester of Exposure and Outcome  PAGEREF _Toc196734050 \h 18 4. DATA FROM OTHER SOURCES  PAGEREF _Toc196734051 \h 20 4.1 Retrospective Reports  PAGEREF _Toc196734052 \h 20 Table 8. Reports of Birth Defects Retrospectively Reported 1 September 1992 - 31 March 2008  PAGEREF _Toc196734053 \h 20 4.2 Other Studies  PAGEREF _Toc196734054 \h 25 Table 9. Major Malformations Reported in the Australian Registry  PAGEREF _Toc196734055 \h 27 Table 10. Outcomes of Pregnancies Reported to the PEM with 6 Month Follow-up By Earliest Trimester of Lamotrigine Exposure  PAGEREF _Toc196734056 \h 30 Table 11. Outcomes of Pregnancies Reported to the PEM with 18 Month  PAGEREF _Toc196734057 \h 30 Follow-up By Earliest Trimester of Lamotrigine Exposure  PAGEREF _Toc196734058 \h 30 5. LITERATURE REVIEW  PAGEREF _Toc196734059 \h 31 Table 12. Reported Cases From the Medical Literature of Lamotrigine Exposure in Pregnancy  PAGEREF _Toc196734060 \h 31 6. DATA SUMMARY  PAGEREF _Toc196734061 \h 32 7. COMMITTEE CONSENSUS  PAGEREF _Toc196734062 \h 33 8. REGISTRY ENROLLMENT  PAGEREF _Toc196734063 \h 37 REFERENCES  PAGEREF _Toc196734064 \h 38 Appendix A: Methods  PAGEREF _Toc196734067 \h 41 Registration and Follow-up  PAGEREF _Toc196734068 \h 41 Institutional Review Board (IRB) Review  PAGEREF _Toc196734069 \h 42 HIPAA Privacy Rule: Protecting Personal Health Information in Research  PAGEREF _Toc196734070 \h 42 Classification of Outcomes  PAGEREF _Toc196734071 \h 42 Exclusions of Reported Exposures  PAGEREF _Toc196734072 \h 43 Analysis  PAGEREF _Toc196734073 \h 43 Appendix B: Minor Defects or Other Conditions Reported at the Outcome of Pregnancy  PAGEREF _Toc196734074 \h 45 Appendix C: Patient Reported Prenatal Lamotrigine Exposures  PAGEREF _Toc196734075 \h 51 Appendix D: Registry Enrollment and Data Forms  PAGEREF _Toc196734076 \h 52  FOREWORD This Report describes the experience of the ongoing study of prospectively and retrospectively reported pregnancy outcomes in the Lamotrigine Pregnancy Registry for all reporting countries, and covers the period 1 September 1992 through 31 March 2008, and replaces the previous Report covering the period 1 September 1992 through 30 September 2007. Lamotrigine is a second generation anticonvulsant therapy. The medical division of GlaxoSmithKline established this Registry as part of an ongoing program in postmarketing epidemiologic surveillance because of the potential for exposure in the first trimester of pregnancy, the potential risks for any new chemical entity, the known teratogenicity of specific existing anticonvulsants, and the suspected increased risk of teratogenicity with polytherapy. Through this study, patients exposed to lamotrigine during pregnancy are registered by health professionals, the pregnancies are followed, and the outcomes are ascertained through follow-up. The Registry is intended to provide an early signal of potential risks in advance of results from formal epidemiologic studies. Registry data are provided to supplement animal toxicology studies and to assist clinicians in weighing the potential risks and benefits of treatment for individual patients. The data in this Report represent the experience of what is, as yet, a relatively small number of pregnancies; recommendations for use in pregnancy based on this small sample size are therefore inappropriate. An Advisory Committee was established to review data, encourage referral of exposures, and disseminate information. Members of this Committee are listed below in alphabetical order: Janet Cragan, MD National Center on Birth Defects and Developmental Disabilities Centers for Disease Control and Prevention U.S. Public Health Service Atlanta, GeorgiaAllen A. Mitchell, MD Director Slone Epidemiology Center Professor of Epidemiology and Pediatrics Boston Univ. Schools of Public Health & Medicine Boston, Massachusetts Richard Lowensohn, MD Associate Professor Obstetrics and Gynecology Medical Informatics and Clinical Epidemiology Oregon Health & Science University Portland, OregonJohn Weil, MD Group Director Head Neurosciences and International Epidemiology GlaxoSmithKline R&D United KingdomJohn A. Messenheimer, MD CNS Clinical Research GlaxoSmithKline Research Triangle Park, North CarolinaMark Yerby, MD, MPH North Pacific Epilepsy Research Portland, Oregon  Lamotrigine Pregnancy Registry 1 September 1992 through 31 March 2008 EXECUTIVE SUMMARY Although there is no evidence of teratogenicity from preclinical studies of lamotrigine, the medical division of GlaxoSmithKline manages this Registry as part of an ongoing program in epidemiologic safety monitoring. Lamotrigine is not indicated for use in pregnancy; however, women with epilepsy may require or be unintentionally exposed to lamotrigine during pregnancy. This Registry is considered essential because of the potential for exposure in the first trimester of pregnancy, the unknown risks in pregnancy for any new chemical entity, the known teratogenicity of specific existing anticonvulsants, and the increased risk of teratogenicity with polytherapy. The purpose of this Registry is two-fold: a) to assess whether there is any large risk of major malformations following exposure to lamotrigine in pregnancy and b) to provide information on outcomes following pregnancy exposure to lamotrigine so that patients and physicians can best determine how to manage pregnancies exposed to lamotrigine. Registry data supplement animal toxicology studies and assist clinicians in weighing the potential risks and benefits of treatment for individual patients. No data on a comparison group are collected by the Registry, but proportions of major birth defects in lamotrigine-exposed pregnancies are compared to proportions of major defects reported in the literature. Because lamotrigine is used to treat women with epilepsy, results from this Registry are compared with published data on women with epilepsy who did not take lamotrigine. However, many women with epilepsy in this Registry receive one or more concomitant medications in addition to lamotrigine, some of which have been associated with an increased frequency of birth defects. For this reason, safety signals that may be generated from this Registry should be interpreted with caution and in the context of the potential effects of any concomitant medications and types of epilepsy being treated. This Registry Report contains a description of all prenatal exposures to lamotrigine voluntarily reported to the Registry. The intention of the Registry is to collect prospective registrations of pregnancies exposed to lamotrigine. Prospectively reported exposures are those reported before the pregnancy outcome is known. Because the reports are voluntary, they may be subject to selection biases and may not be representative of the target population. However, prospective reporting reduces ascertainment bias among the outcomes and permits estimation of the proportion of major birth defects among exposed pregnancies. This requires obtaining follow-up information to ascertain the pregnancy outcome. The Registry also receives and reviews retrospective reports, defined as those for which the pregnancy outcome is known at the time of reporting. Retrospective reports of birth defects can be biased toward more unusual and severe outcomes and are less likely to be representative of the general population experience. Therefore, calculation of the proportion of major defects among retrospective reports is inappropriate and can be misleading. The purpose of summarizing the retrospective reports of major birth defects is to assist in the detection of any unusual patterns. To provide consistency in definition of major defects, this Registry utilizes the Metropolitan Atlanta Congenital Defect Program (MACDP) list of birth defects. This 6-digit code list is available from the CDC web site at  HYPERLINK "http://www.cdc.gov/ncbddd/bd/macdp" http://www.cdc.gov/ncbddd/bd/macdp resources.htm. Because access to pediatric evaluations and records to obtain follow-up information about the presence of defects is beyond the scope of its methods, the Registry primarily monitors the frequency of major defects that are external, recognizable in the delivery room and/or symptomatic shortly after birth. Minor defects and those diagnosed on an out-patient basis weeks to months after delivery are not consistently ascertained. Conditions that do not meet the definition of a major malformation are listed in Appendix B as Minor Defects or Other Conditions Reported at Outcome of Pregnancy. As with retrospective reports, these are reviewed to detect any unusual patterns. Studies have shown that the rate of spontaneous abortion is high early in pregnancy and decreases progressively and substantially from week 8 to week 28. The cumulative estimated rate is 14%-22% (Kline et al, 1989). However, because pregnancies are reported to the Registry at different and sometimes imprecise times during gestation, calculation of the prevalence rate (throughout the remainder of the document prevalence rate will be referred to as rate) of spontaneous pregnancy loss from the Registry data is inappropriate and could lead to erroneous conclusions. The denominators in the following estimates include the number of live born infants with and without major birth defect(s) + the number of induced abortions and stillbirths with major birth defect(s), stratified by trimester of exposure. Lamotrigine Monotherapy: There were 33 outcomes with major defects among 1261 outcomes (2.6%) involving a first trimester monotherapy exposure (95% Confidence Interval: 1.8%-3.7%) (Fleiss 1981). There were 4 outcomes with a major defect among 73 outcomes following a second trimester monotherapy exposure and 1 outcome with a major defect among the 16 outcomes following a third trimester monotherapy exposure. Data obtained using the same methods as this Registry are not available for other antiepileptic drugs (AED). The most recent literature on frequency of birth defects in women with epilepsy has reported average frequency of malformations in cohorts of women using AED monotherapy ranging between 3.3% and 4.5% (Holmes et al, 2001, Morrow et al, 2001, Morrow et al, 2003, Morrow et al, 2006, Samren et al, 1999). The true rate of major malformations in women with epilepsy is not known, and may in fact be lower than 3.3%. Polytherapy including Valproate: There were 16 outcomes with major defects among 146 total outcomes (11.0%) involving first trimester exposure to lamotrigine and valproate, with or without one or more additional antiepileptic drugs (95% Confidence Interval: 6.6%-17.5%) (Fleiss 1981). There was 1 outcome with a major defect among the 6 outcomes following a second trimester exposure to lamotrigine and valproate, with or without one or more additional antiepileptic drugs. This exposure group has the highest proportion with major defects observed among first trimester exposures in the Registry. Polytherapy not including Valproate: There were 9 outcomes with major birth defects among 379 total outcomes (2.4%) involving first trimester exposure to lamotrigine and at least one other antiepileptic drug, excluding valproate (95% Confidence Interval: 1.2%-4.6%) (Fleiss 1981). There was 1 outcome with a major birth defect among the 3 total outcomes involving third trimester exposure to lamotrigine and at least one other antiepileptic drug, excluding valproate. There was no consistent pattern among the major birth defects reported prospectively to the Registry. Refer to Table 5 for a summary of major defects by earliest trimester of exposure (includes three chromosomal anomalies which are not included in the analysis because they are genetic disorders). The Lamotrigine Pregnancy Registry Advisory Committee notes the higher frequency of major malformations within the group exposed to the combinations including lamotrigine and valproate compared with other polytherapies or compared with lamotrigine monotherapy. The observed frequency of major defects (2.4% in women exposed to lamotrigine and at least one other antiepileptic drug, excluding valproate, and 11.0% in women exposed to lamotrigine and at least one other antiepileptic drug including valproate) is consistent with published studies which report that women using valproate have experienced elevated rates of specific birth defects (Arpino et al, 2000, Artama et al, 2005, Morrow et al, 2006, Omtzigt et al, 1992, Thisted et al, 1993, Wyszynski et al, 2005). However, it is beyond the scope of this Registry to assess the reported rates related to any specific AED within polytherapy combinations, and it is not conclusive whether the published observations on valproate exposures explain the higher frequency of all major defects in the lamotrigine and valproate group in this Registry. The Committee will continue to monitor the frequency and pattern of birth defects exposed to this combination. Because Morrow et al, 2006 noted a positive dose-response effect for major congenital malformations with lamotrigine use, the Lamotrigine Pregnancy Registry Advisory Committee examined the Registry data related to dose. No dose-effect at daily doses up to 400 mg was found. There was insufficient data at doses of 400 mg or more to confirm or refute a dose effect. The Committee will continue to monitor dose data. The Committee notes that the Registry has now considerably passed the milestone of 1000 outcomes for prospective first trimester exposures to lamotrigine monotherapy and thus has met its primary objective, which was to determine whether the overall rate of malformations was increased among the offspring of exposed women. The Registry has not detected an appreciable increase in the overall risk of major birth defects. It was further noted by the Committee that when the sample size exceeds 1000 exposed subjects without an excess of major birth defects as a singular outcome (background rate of 2%-3%), the confidence interval is sufficiently narrow to indicate that there is not an appreciable effect of the exposure on the risk of major birth defects overall. At the same time, the Committee recognizes that as the Registry exceeds 1000 subjects, the likelihood of chance findings for specific defects (which may occur at baseline rates of 1/1000 or less) increases, and the Committee agreed that other methods (e.g., various case-control approaches) are more appropriate and powerful to identify increases in the rate of specific defects. For these reasons, the Committee recommends termination of this Registry. Monitoring for an increase in specific defects could more productively continue through various other observational approaches, such as case control surveillance. 1. INTRODUCTION The purpose of the Registry is two-fold: a) to assess whether there is any large risk of major malformations following exposure to lamotrigine in pregnancy and b) to provide information on outcomes following pregnancy exposure to lamotrigine so that patients and physicians can best determine how to manage pregnancies. The combination of the large number of women with epilepsy who are of reproductive capacity and the lack of data concerning lamotrigine use during pregnancy makes such a Registry an essential component of the ongoing program of epidemiologic studies of the safety of lamotrigine. This study is an observational, exposure-registration, and follow-up study. Patient confidentiality is strictly upheld. Furthermore, the Registry has initiated a registration process which will protect patient anonymity at the Registry Office. The study has been reviewed and approved by an institutional review board (IRB). The IRB approval included a waiver from requiring patient informed consent for participation based on the Registrys process for protecting patient anonymity. The IRB approval also included a HIPAA authorization waiver. The intent of the Registry is to prospectively collect data concerning exposure to lamotrigine during pregnancy, potential confounding factors (such as exposure to other antiepileptic medications, the number and severity of seizures occurring during pregnancy), and information related to the outcome of the pregnancy. The Lamotrigine Pregnancy Registry is managed by GlaxoSmithKline considering the advice of the CDC, a U.S.-based institution, neurology, and teratology specialists. These individuals provide independent review of the data as members of the Advisory Committee for the Registry. The Registry began in September 1992. 2. BACKGROUND 2.1 Animal Data Lamotrigine is an antiepileptic medication indicated for oral use as adjunctive therapy in the control of partial seizures with or without generalized tonic-clonic seizures. It is also used as a monotherapy in a number of countries. Lamotrigine is a drug of the phenyltriazine class and is chemically unrelated to existing antiepileptic medications. Teratology studies were conducted in mice, rats, and rabbits at oral doses up to 10, 3, and 4 times the upper human dose (500 mg/day or 7 mg/kg/day), respectively, and revealed no evidence of teratogenicity. However, maternal toxicity and secondary fetal toxicity, resulting in reduced fetal weight and/or delayed ossification, were seen in mice, rats, and rabbits treated orally at these doses. Teratology studies were also conducted using bolus intravenous (i.v.) administration of the isethionate salt of lamotrigine in multiples of the projected human dose. Intravenous lamotrigine resulted in convulsions or impaired coordination in rat and rabbit dams at 30 mg/kg and 15 mg/kg, respectively. In rat dams, the 30 mg/kg i.v. dose produced an increased incidence of intrauterine death without signs of teratogenicity. Thus, even at maternally toxic levels leading to fetal death, there was no evidence of teratogenicity. Lamotrigine decreases fetal folate concentrations on rats, an effect known to be associated with teratogenesis in animals and humans. There are, however, no adequate or well-controlled studies in pregnant women. Clinical data indicate that lamotrigine has no effect on blood folate concentrations in adults; however, the effects of lamotrigine on fetal blood folate levels in utero are unknown. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. There is no evidence of carcinogenicity, mutagenicity, or impairment of fertility with lamotrigine. Lamotrigine was not mutagenic in microbial (Ames test) or mammalian (mouse lymphoma) mutagenicity tests, with or without metabolic activation. Lamotrigine was not associated with an increased incidence of structural or numerical chromosomal abnormalities in cultured human lymphocytes exposed to lamotrigine concentrations up to 1000 g/mL in the presence and absence of S9 metabolic activation. Lamotrigine was not associated with an increased incidence of structural or numerical chromosomal abnormalities in a rat in vivo cytogenetic test, in which rats were given oral doses up to 200 mg/kg. A reproduction/fertility study was conducted in rats. No evidence of impairment of fertility was encountered at oral lamotrigine doses up to 20 mg/kg/day. The effect of lamotrigine on human fertility, if any, is unknown. Evaluating the etiology of birth defects is difficult because numerous factors can influence pregnancy outcome. The difficulty in evaluating whether lamotrigine is teratogenic will be compounded by the additional unique characteristics of the population with epilepsy to be included in this Registry. In this population, the same elements that influence the outcome of pregnancies in the general population will be present, as will two additional factors: 1) other anticonvulsant medication exposures and 2) seizures during pregnancy. The desire to continue treating a woman already receiving lamotrigine may lead physicians to prescribe lamotrigine to pregnant women. Inadvertent use of lamotrigine by pregnant women has also been reported. This Registry is a mechanism to collect data concerning exposures to lamotrigine during pregnancy. A Report is distributed to the medical community on the outcomes of those pregnancies. This Registry supplements animal toxicology studies and the continuing lamotrigine post-marketing surveillance program. 3. PROSPECTIVE REGISTRY 3.1 New Data This Interim Report is issued semiannually following the Advisory Committees review of new data. Each issue, containing historical information, as well as new data known to the Registry, replaces all previous Reports. The new information in this Report includes data from all cases closed between 1 October 2007 and 31 March 2008 (see Table 1). Cases with birth defects are reported in Table 5. Minor defects and those diagnosed on an out-patient basis weeks to months after delivery are not consistently ascertained. Conditions that do not meet the definition of a major malformation are listed in Appendix B as minor defects or other conditions reported at outcome of pregnancy. As with retrospective reports, these are all included in the review to detect any unusual patterns. 3.2 All Data The status of all prospectively registered pregnancies with lamotrigine exposure is presented in Table 2. The distribution by country (40 countries) of the 2034 prospectively registered pregnancies with outcomes is presented in Table 3. Of the 2034 prospectively registered pregnancies, there were 2072 outcomes (36 sets of twins and 1 set of triplets). Pregnancy outcomes are presented by trimester of exposure and exposure status (monotherapy and polytherapy) in Table 4. A case history of each of the 70 major defects follows in Table 5 (includes four chromosomal anomalies which are not included in the analysis because they are genetic disorders and one spontaneous pregnancy loss which is not included in the analysis). Because prenatal testing is frequently performed after 16 weeks gestation, Table 6 presents the prospective reports for lamotrigine monotherapy cases with first trimester of exposure, stratified by gestational age at enrollment. Table 1. Prospective Registry New Lamotrigine Data in Reporting Period 1 October 2007 31 March 2008 StatusNewly Registered PregnanciesPreviously Registered Pregnancies Closed This PeriodTotalPending154N/A154Lost to Follow-up47276Closed12128140 Number of Outcomes12133*145 No Birth Defects Live Birth11127138 Fetal Death000 Induced Abortion000 Birth Defects Live Birth022 Fetal Death000 Induced Abortion000 Spontaneous Loss145 *Includes 5 set of twins Table 2. Prospective Registry Status of All Lamotrigine Exposures in Pregnancy 1 September 1992 31 March 2008 Total Pregnancies Registered3041Closed with known outcomes2034 Pending246 Lost to follow-up761 (27.2%)No response from registering health care provider63.0%Patient did not remain under the registering health care providers care19.0%Patient could not be identified by the registering health care provider7.0%Registering health care provider left the practice with no forwarding address8.0%No response from patient<0.1%Patient refused release of information2.0% Table 3. Prospective Registry Lamotrigine Exposure in Pregnancy by Country of Origin 1 September 1992 - 31 March 2008 CountryNumber of Reported PregnanciesaArgentina Australia1 29Austria17Belgium41Brazil1Canada22Costa Rica1Cyprus3Czech Republic23Denmark53Estonia1Finland40France19Germany68Greece1Holland10India1Iran3Ireland2Israel1Italy2Jordan3Lebanon22Luxemburg1Malta1Namibia1New Zealand6Norway17Poland211Portugal5Puerto Rico2Russia3South Africa5South Korea1Spain27Sweden52Switzerland8Turkey12United Kingdom91United States1227TOTAL2034a Includes only patients with known pregnancy outcomes 3.3 Excluded Birth Defects and Other Reported Conditions The distinction between a major vs. minor malformation or dysmorphism vs. a normal variation, and the significance of each, is an area of ongoing discussion among experts in the fields of dysmorphology and clinical genetics. To provide consistency in definition of major defects in this Registry, CDC MACDP criteria are used for evaluation of defects ( HYPERLINK "http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5701a2.htm_" http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5701a2.htm). Some of the conditions excluded from the MACDP criteria for major structural defects may actually have major clinical, functional or genetic significance, particularly when more than one condition is present in the same child. For example, the presence of multiple craniofacial dysmorphisms or variations may be associated with underlying developmental or neurologic deficits. However, not all patients with dysmorphisms exhibit such delays. Because the diagnosis of developmental or behavioral deficits may not be made until months to years after birth and may require subspecialty evaluation, monitoring the frequency of these abnormalities or assessing the impact of minor defects and dysmorphisms among children exposed prenatally to lamotrigine is beyond the scope of this Registrys methods. However, in the interest of complete disclosure, all reported birth defects which do not meet the criteria are listed in Appendix B. In addition, other reported outcomes which are not birth defects, e.g. biochemical abnormalities, transient conditions, are also listed in Appendix B. Table 4. Prospective Registry Lamotrigine Exposure in Pregnancy by Earliest Trimester of Exposure and Outcome 1 September 1992 - 31 March 2008 Lamotrigine Monotherapy Major Birth DefectsNo Major Birth Defects ReportedaSpontaneous Pregnancy Loss b,eTotal Outcomes dEarliest Trimester of ExposureLive BirthFetal Death cInduced AbortionLive BirthFetal Death cInduced AbortionFirst29131228629731369Second4006900073Third1001500016Unspecified00050005Total34131317629731463 f Lamotrigine Polytherapy with Valproate Major Birth DefectsNo Major Birth Defects ReportedaSpontaneous Pregnancy Loss b,eTotal Outcomes dEarliest Trimester of ExposureLive BirthFetal Death cInduced AbortionLive BirthFetal Death cInduced AbortionFirst1402130145156Second10051007Third00030003Unspecified00010001Total1502139245167 f Lamotrigine Polytherapy without Valproate Major Birth DefectsNo Major Birth Defects ReportedaSpontaneous Pregnancy Loss b,eTotal Outcomes dEarliest Trimester of ExposureLive BirthFetal Death cInduced AbortionLive BirthFetal Death cInduced AbortionFirst80137021820419Second0002000020Third10020003Unspecified00000000Total90139221820442 f a Birth defect not reported but cannot be ruled out b Pregnancy loss occurring < 20 weeks gestation c Pregnancy loss occurring ( 20 weeks gestation d Totals include 36 sets of twins and 1 set of triplets e Includes defect and non-defect reports. Due to the likelihood of misclassification bias, spontaneous pregnancy losses <20 weeks gestation are excluded from the calculation of the rate of birth defects. f Fetal deaths and induced abortions without reported birth defects and all spontaneous pregnancy losses are excluded from defect rate calculations Table 5. Prospective Registry Lamotrigine Exposure in Pregnancy Summaries of Major Defects by Earliest Trimester of Exposure and Polytherapy Status 1 September 1992 - 31 March 2008First Trimester Lamotrigine ExposuresLamotrigine Monotherapy100311.Live male infant. Cleft soft palate. 40 weeks gestation. Lamotrigine 200 mg/day preconception, 300 mg/day week 37 and throughout pregnancy.100522.Live female infant. Right club foot. 40 weeks gestation. Lamotrigine 500 mg/day preconception and throughout pregnancy.111703.Live male infant. Hydronephrosis with megaureter. 41 weeks gestation. Lamotrigine 100 mg/day preconception and throughout pregnancy.113614.Induced abortion. Anencephalic fetus. 20 weeks gestation. Lamotrigine 150 mg/day preconception.113965.Live male infant. Congenital atresia of anus with recto-cutaneous fistula reaching the perineum. 33 weeks gestation. Lamotrigine 25 mg/day from the first trimester, 50 mg/day week 20 and throughout pregnancy.116186.Live male infant. Ventricular septal defect. 41 weeks gestation. Lamotrigine 250 mg/day preconception to week 22.116917.Live female infant. Fetal hydronephrosis, oligohydramnios, intrauterine growth restriction. 34 weeks gestation. Lamotrigine 250 mg/day preconception and throughout pregnancy.119378.Live male infant. Minor subpulmonic muscular ventricular septal defect. Persistent foramen ovale-no surgery/intervention required. 41 weeks gestation. Lamotrigine 300 mg/day preconception to week 6, 250 mg/day week 6-7, 200 mg/day week 7-32, 250 mg/day week 32 and throughout pregnancy.11725 9.Live male infant. Bilateral club feet, requiring casting. 40 weeks gestation. Lamotrigine (dose unknown) preconception and throughout pregnancy.1215010.Live infant. Absent right kidney. 40 weeks gestation. Lamotrigine 12.5 mg/day preconception to week 5, 25 mg/day week 16-24, 100 mg/day week 24 and throughout pregnancy.1233611.Live male infant. Transposition of great vessels, ventricular septal defect requiring surgery/intervention. 39 weeks gestation. Lamotrigine 200 mg/day preconception to week 7.1230112.Live male infant. Left polycystic kidney. 39 weeks gestation. Lamotrigine (dose unknown) preconception, 500 mg/day week 1, 400 mg/day week 1, 300 mg/day week 1-2, 200 mg/day week 2, 100 mg/day week 2 and throughout pregnancy.1230913.**Live female infant. Down syndrome. No malformations noted (because this is a chromosomal anomaly, it is not included in the analysis). 37 weeks gestation. Lamotrigine 225 mg/day preconception and throughout pregnancy. *denotes cases that are new since the last Report **chromosomal anomaly or spontaneous pregnancy loss not included in the analysis  Table 5. Prospective Registry Lamotrigine Exposure in Pregnancy Summaries of Major Defects by Earliest Trimester of Exposure and Polytherapy Status (continued) 1 September 1992 - 31 March 2008Lamotrigine Monotherapy (continued)14.Live male infant. Hypospadias. 34 weeks gestation. Lamotrigine 200 mg/day preconception and throughout pregnancy.1246315.Live female infant. Minor cleft of upper lip and soft palate. 40 weeks gestation. Lamotrigine 100 mg/day preconception and throughout pregnancy.1272816.Live male infant. Hypoplastic left heart syndrome. The baby subsequently died. 39 weeks gestation. Lamotrigine 100 mg/day preconception and throughout pregnancy.1311617.Live female infant. Hypoplasia of left ventricle of the heart. The baby subsequently died. 37 weeks gestation. Lamotrigine 400 mg/day preconception and throughout pregnancy.1287018.Live male infant. Fluid on left kidney. 38 weeks gestation. Lamotrigine 550 mg/day preconception and throughout pregnancy.1307419.Live female infant. Cortical dysplasia. 41 weeks gestation. Lamotrigine 300 mg/day preconception and throughout pregnancy.1353420.Stillbirth. Diaphragmatic hernia with dislocation of abdominal organs in the thorax. 38 weeks gestation. Lamotrigine 200 mg/day preconception and throughout pregnancy.1389021.Induced abortion. Anencephaly diagnosed by prenatal ultrasound. 15 weeks gestation. Lamotrigine 400 mg/day preconception, 425 mg/day week 10 and throughout pregnancy.1365222.Induced abortion. Anencephaly. 19 weeks gestation. Lamotrigine 200 mg/day preconception to week 6.1369823.Live female infant. Bilateral hip dislocation, treated by an orthopedist with a Pavlik harness. 39 weeks gestation. Lamotrigine 200 mg/day preconception, 300 mg/day week 19, 400 mg/day week 26 and throughout pregnancy.1386924.Live male infant. Club feet, treated with casting. 39 weeks gestation. Lamotrigine 300 mg/day preconception and throughout pregnancy.1412225.Live female infant. Ventricular septal defect and patent foramen ovale. 40 weeks gestation. Lamotrigine 300 mg/day preconception to week 12, 400 mg/day week 12-21, 600 mg/day week 21 and throughout pregnancy.1420926.Live female infant. Transposition of the great vessels and transposition of the ventricles, requiring surgery. 40 weeks gestation. Lamotrigine 100 mg/day preconception to week 6, 100 mg/day week 15 and throughout pregnancy.1470627.Live infant. Pyloric stenosis, requiring pyloromyotomy. 39 weeks gestation. Lamotrigine (dose unknown) week 6 and throughout pregnancy. *denotes cases that are new since the last Report **chromosomal anomaly or spontaneous pregnancy loss not included in the analysis  Table 5. Prospective Registry Lamotrigine Exposure in Pregnancy Summaries of Major Defects by Earliest Trimester of Exposure and Polytherapy Status (continued) 1 September 1992 - 31 March 2008Lamotrigine Monotherapy (continued)28.Live female infant. Congenital diaphragmatic hernia; pulmonary hypoplasia; complex congenital heart defect (transposition of the great arteries, tetralogy of Fallot). Infant died at 24 hours of age from refractory hypoxia. 38 weeks gestation. Lamotrigine 500 mg/day preconception and throughout pregnancy.1501129.**Induced abortion. Prenatal ultrasound at approximately 19 weeks showed signs of Trisomy 21. Amniocentesis confirmed Trisomy 21 (because this is a chromosomal anomaly, it is not included in the analysis). 20 weeks gestation. Lamotrigine 250 mg/day preconception and throughout pregnancy.14870 twin30.Live female infant. 36 week twin infant with pulmonary stenosis. No immediate intervention; to be followed as an outpatient by the pediatric cardiologist. The co-twin has no defect. 36 weeks gestation. Lamotrigine 300 mg/day preconception and throughout pregnancy.1492631.Live male infant. Eleven toes. 37 weeks gestation. Lamotrigine 200 mg/day preconception to week 12, 300 mg/day week 12-29, 400 mg/day week 29 and throughout pregnancy.1498032.Live female infant. Six fingers on each hand, requiring surgery. There is a family history of polydactyly on the fathers side. 39 weeks gestation. Lamotrigine 200 mg/day preconception and throughout pregnancy.1501933.Live male infant. Minor heart defect, followed by pediatric cardiologist. No intervention required. 38 weeks gestation. Lamotrigine 250 mg/day preconception to week 36, 300 mg/day week 36 and throughout pregnancy.1519734.*Live infant. Pyloric stenosis. 40 weeks gestation. Lamotrigine 400 mg/day preconception to week 7, 25 mg/day week 7-9, 300 mg/day week 9 and throughout pregnancy. 1552535.*Live infant. Epidermolysis bullosa. 40 weeks gestation. Lamotrigine 200 mg/day preconception and throughout pregnancy.1572336.*,**Live infant. Down syndrome (because this is a chromosomal anomaly, it is not included in the analysis). 39 weeks gestation. Lamotrigine 450 mg/day preconception to week 3, 550 mg/day week 3-8, 600 mg/day week 8-11, 700 mg/day week 11-16, 800 mg/day week 16-20, 900 mg/day week 20-31, 800 mg/day week 31 and throughout pregnancy.Second Trimester Lamotrigine ExposuresLamotrigine Monotherapy 133181.Live female infant. Left sided hip dysplasia. 40 weeks gestation. Lamotrigine 50 mg/day week 20-24, 100 mg/day week 24 and throughout pregnancy. 144912.Live female infant. Sacrococcygeal teratoma; the infant also had pulmonary interstitial emphysema, cardiomyopathy, ascites and severe hydrops, and did not survive. 29 weeks gestation. Lamotrigine 100 mg/day week 18 and throughout pregnancy. *denotes cases that are new since the last Report **chromosomal anomaly or spontaneous pregnancy loss not included in the analysis  Table 5. Prospective Registry Lamotrigine Exposure in Pregnancy Summaries of Major Defects by Earliest Trimester of Exposure and Polytherapy Status (continued) 1 September 1992 - 31 March 2008Lamotrigine Monotherapy (continued) 144193.Live female infant. Torticollis. 39 weeks gestation. Lamotrigine 25 mg/day week 14-22, 50 mg/day week 22 and throughout pregnancy.  147714.Live male infant. Hypospadias. Webbed toes 2nd and 3rd toes both feet. 39 weeks gestation. Lamotrigine 25 mg/day week 27-28, 50 mg/day week 28-30, 100 mg/day week 32-34, 200 mg/day week 34 and throughout pregnancy. Third Trimester Lamotrigine ExposuresLamotrigine Monotherapy  144391.Live female infant. Mild unilateral hydronephrosis. 40 weeks gestation. Lamotrigine 25 mg/day week 29, 50 mg/day week 29-30, 75 mg/day week 30, 100 mg/day week 30-31, 150 mg/day week 31, 200 mg/day week 31, 400 mg/day (unknown gestation week) and throughout pregnancy.First Trimester Lamotrigine ExposuresLamotrigine with Antiepileptic (AED) Polytherapy without Valproate 26241.Live male infant. One extra digit on one hand. 40 weeks gestation. Lamotrigine 2000 mg/day preconception to week 7. Carbamazepine preconception and throughout pregnancy. 26892.Live male infant. Cardiac murmur and patent foramen ovale requiring banding around the pulmonary artery. 37 weeks gestation. Lamotrigine 600 mg/day preconception to week 37. Phenytoin and Primidone preconception and throughout pregnancy. 26933.Live male infant. Skin tags on left ear; no opening to ear canal on right ear. 37 weeks gestation. Lamotrigine 400 mg/day preconception to week 13, 600 mg/day week 13-17, 800 mg/day week 17 and throughout pregnancy. Gabapentin preconception and throughout pregnancy. 26964.Induced abortion. Lumbar neural tube defect with early evidence of ventriculomegaly and a derangement of the posterior fossa. 17 weeks gestation. Lamotrigine 700 mg/day preconception to week 17. Clobazam preconception and through first trimester. 101465.Live female infant. Patent (persistent) ductus arteriosis. Atrium septum defect. 38 weeks gestation. Lamotrigine 250 mg/day week 7-11, 400 mg/day week 11-22, 600 mg/day week 22 and throughout pregnancy. Oxcarbamazepine preconception and throughout pregnancy.106216.**Live male infant. 2 x chromosomes and ambiguous genitalia (because this is a chromosomal anomaly, it is not included in the analysis). 38 weeks gestation. Lamotrigine 400 mg/day preconception and throughout pregnancy. Carbamazepine 600 mg/day preconception and throughout pregnancy. *denotes cases that are new since the last Report **chromosomal anomaly or spontaneous pregnancy loss not included in the analysis  Table 5. Prospective Registry Lamotrigine Exposure in Pregnancy Summaries of Major Defects by Earliest Trimester of Exposure and Polytherapy Status (continued) 1 September 1992 - 31 March 2008Lamotrigine with Antiepileptic (AED) Polytherapy without Valproate (continued)125017.Live male infant. Hypospadias. 42 weeks gestation. Lamotrigine 200 mg/day preconception, 100 mg/day (unknown gestation week). Clonazepam preconception and through first trimester.52748.Live male infant. Oesophageal malformation repaired by surgery. 40 weeks gestation. Lamotrigine 25 mg/day preconception, 450 mg/day week 6 and throughout pregnancy. Carbamazepine (dose unknown) preconception.135139.Live female infant. Esophageal atresia and anal atresia, both requiring surgery. 41 weeks gestation. Lamotrigine 300 mg/day preconception and throughout pregnancy. Carbamazepine 800 mg/day preconception and throughout pregnancy.10.**Spontaneous pregnancy loss. Triploidy karyotype 69, xxx (because this is a spontaneous pregnancy loss, it is not included in the analysis). 14 weeks gestation. Lamotrigine 100 mg/day preconception to week 6. Tiagabine 800 mg/day preconception to first trimester.11.Live male infant. Hydroencephalopathy (HPE), muscle spasticity, AV fistula. 38 weeks gestation. Lamotrigine 200 mg/day preconception to week 6, 25 mg/day week 31 and throughout pregnancy. Clonazepam 1 mg/day preconception and through first trimester. Third Trimester Lamotrigine ExposuresLamotrigine with Antiepileptic (AED) Polytherapy without Valproate 151041.Live infant. Hypospadias and bilateral clubfoot. 40 weeks gestation. Lamotrigine 25 mg/day week 32-33, 50 mg/day week 33 and throughout pregnancy. Clonazepam 1 mg/day preconception and through first trimester.First Trimester Lamotrigine ExposuresLamotrigine with Antiepileptic (AED) Polytherapy with Valproate 26631.Live female infant. Bilateral talipes. Unknown gestational age. Lamotrigine 50 mg/day preconception to week 40. Valproic acid throughout pregnancy. 41452.Induced abortion. Ultrasound detection of hydrocephalus, sacral spina bifida (myelomeningocele), patent foramen ovale, ductus arteriosis. Antenatal ultrasound suggested Arnold-Chiari malformation. 17 weeks gestation. Lamotrigine 100 mg/day preconception to week 9. Valproate preconception and through second trimester.  50903.Live female infant. Cleft palate, hypertelorism, broad nasal bridge, low set and posteriorly rotated ears, down-turned mouth, bilateral transverse palmar creases, short proximal thumbs, supra-umbilical hernia. 39 weeks gestation. Lamotrigine 100 mg/day preconception to week 8, 50 mg/day week 8-39, 100 mg/day week 39. Valproate preconception and throughout pregnancy.  *denotes cases that are new since the last Report **chromosomal anomaly or spontaneous pregnancy loss not included in the analysis  Table 5. Prospective Registry Lamotrigine Exposure in Pregnancy Summaries of Major Defects by Earliest Trimester of Exposure and Polytherapy Status (continued) 1 September 1992 - 31 March 2008Lamotrigine with Antiepileptic (AED) Polytherapy with Valproate (continued) 101484.Live male infant. Atrial septal defect. 40 weeks gestation. Lamotrigine 300 mg/day week 8-33. Valproate during first trimester. 102865.Live male infant. Pulmonary stenosis after delivery, surgery performed. Baby subsequently died. 38 weeks gestation. Lamotrigine 200 mg/day preconception and throughout pregnancy. Valproate 1000 mg/day preconception and throughout pregnancy. 110436.Live female infant. Pylorostenosis during the second week of life. Surgery took place during the third week of life. 39 weeks gestation. Lamotrigine 25 mg/day week 8 and throughout pregnancy. Valproate 300 mg/day preconception and through first trimester with down titration. 112617.Live female infant. Cleft of the hard palate. Surgery was to be planned at the time of the report. 41 weeks gestation. Lamotrigine 300 mg/day preconception to week 18, 200 mg/day week 19-32, 300 mg/day week 32 and throughout pregnancy. Valproate preconception and throughout pregnancy. 118738.Live male infant. Small ventricular septum defect noted at 3 months of age. 41 weeks gestation. Lamotrigine 300 mg/day preconception throughout pregnancy. Valproate preconception and throughout pregnancy. 119879.Live male infant. Meningomyelocele; upper and lower limb deformities. Infant died. 42 weeks gestation. Lamotrigine 100 mg/day preconception to 5 weeks. Valproate preconception and throughout pregnancy. 1234210.Induced abortion. Microcephaly, abnormal posterior fossa, bony abnormality (location not specified), right occipital encephalocele, Chiari II malformation, Hind brain herniation, retrognathia. 20 weeks gestation. Lamotrigine 200 mg/day preconception. Valproate 500 mg/day preconception. 1235111.Live male infant. Transposition of great vessels. 38 weeks gestation. Lamotrigine 100 mg/day preconception, 150 mg/day week 11, 200 mg/day week 13 and throughout pregnancy. Valproate preconception and throughout the first trimester.12.Live female infant. Right ventricular hypoplasia with tricuspid regurgitation and cardiac decompensation, diagnosed by prenatal ultrasound. 28 weeks gestation. Lamotrigine 200 mg/day preconception to week 17, 400 mg/day week 17 and throughout pregnancy. Valproate reported, but dose and timing are unknown. *denotes cases that are new since the last Report **chromosomal anomaly or spontaneous pregnancy loss not included in the analysis  Table 5. Prospective Registry Lamotrigine Exposure in Pregnancy Summaries of Major Defects by Earliest Trimester of Exposure and Polytherapy Status (continued) 1 September 1992 - 31 March 2008Lamotrigine with Antiepileptic (AED) Polytherapy with Valproate (continued) 1292913.Live female infant. Cleft palate, small head, ears and nose, hypoplastic small mouth, long fingers and toes, overlip, typical middle face consistent with Valproate Syndrome per reporter. 40 weeks gestation. Lamotrigine 125 mg/day preconception and throughout pregnancy. Valproate 2100 mg/day preconception and through second trimester, 3000 mg/day in third trimester. Clonazepam 1 mg/day preconception and throughout pregnancy. Topiramate 50 mg/day preconception and throughout pregnancy. 1323014.Live male infant. Preaxial polydactyly with redundant left thumb. 42 weeks gestation. Lamotrigine 200 mg/day preconception, 650 mg/day week 20, 200 mg/day week 23 and throughout pregnancy. Valproate preconception and throughout pregnancy. 1382215.Live male infant. Gastroschisis; cleft lip and palate; left talipes equinovarus (clubfoot). The infant died. 29 weeks gestation. Lamotrigine 200 mg/day preconception and throughout pregnancy. Valproate 100 mg/day preconception and through second trimester. 1473016.Live male infant. Clubfeet. 39 weeks gestation. Lamotrigine 100 mg/day preconception to week 9. Valproate 1000 mg/day first, second, and third trimesters. Third Trimester Lamotrigine ExposuresLamotrigine with Antiepileptic (AED) Polytherapy with Valproate 153871.Live male infant. Single kidney with large ureter. Abnormal thoracic vertebrae, two fused vertebrae. 38 weeks gestation. Lamotrigine 125 mg/day week 25-31, 300 mg/day week 31 and throughout pregnancy. Topiramate 200 mg/day preconception and through first trimester. Valproate 2000 mg/day preconception and through first trimester. *denotes cases that are new since the last Report **chromosomal anomaly or spontaneous pregnancy loss not included in the analysis Table 6. Prospective Registry Gestational Age at Enrollment (weeks) First Trimester Monotherapy Exposure 1 September 1992 - 31 March 2008Number of Outcomes = 1261< 16 weeks16 20 weeks> 20 weeksUnknownTotal736 (58.4%)148 (11.7%)366 (29.0%)11 (0.9%)No Defect71614635511Defect202110 Table 7. Prospective Registry Lamotrigine Monotherapy and Antiepileptic Drug Polytherapy Exposure in Pregnancy by Trimester of Exposure and Outcome 1 September 1992 - 31 March 2008 Concomitant Antiepileptic Drug Exposures Outcomes Without Major Defects[1]  Outcomes Spont w/ Birth Live Fetal Ind Preg Defects Births Deaths Abort Loss Overall Exposure During First Trimester: Lamotrigine Monotherapy 33 1228 6 29 73 1369 Lamotrigine polytherapy with valproate valproate 15 101 1 4 4 125 carbamazepine & valproate 0 5 0 0 1 6 clonazepam & valproate 0 5 0 0 0 5 diazepam & valproate 0 2 0 0 0 2 ethosuximide & valproate 0 1 0 0 0 1 gabapentin & valproate 0 2 0 0 0 2 levetiracetam & valproate 0 1 0 0 0 1 phenytoin & valproate 0 7 0 0 0 7 valproate & vigabatrin 0 2 0 0 0 2 carbamazepine & clonazepam & 0 1 0 0 0 1 valproate carbamazepine & phenytoin & 0 1 0 0 0 1 valproate clonazepam & topiramate & valproate 1 0 0 0 0 1 gabapentin & phenobarbital & 0 1 0 0 0 1 valproate barbexaclone & carbamazepine & 0 1 0 0 0 1 phenytoin & valproate Lamotrigine polytherapy without valproate barbexaclone 0 1 0 0 0 1 carbamazepine 3 111 1 5 3 123 clobazam 1 4 0 0 0 5 clonazepam 2 42 0 1 3 48 clorazepate 0 0 1 0 0 1 diazepam 0 4 0 0 1 5 ethosuximide 0 6 0 0 1 7 felbamate 0 1 0 0 0 1 gabapentin 1 13 0 0 1 15 levetiracetam 0 25 0 0 2 27 methylphenobarbitone 0 2 0 0 0 2 oxcarbazepine 1 20 0 0 0 21 phenobarbital 0 10 0 3 1 14 phenytoin 0 30 0 2 0 32 primidone 0 5 0 0 0 5 tiagabine 0 4 0 0 1 5 topiramate 0 24 0 2 0 26 vigabatrin 0 4 0 0 0 4 zonisamide 0 5 0 0 0 5 carbamazepine & clobazam 0 4 0 0 0 4 carbamazepine & clonazepam 0 10 0 0 1 11 carbamazepine & clorazepate 0 0 0 0 1 1 carbamazepine & gabapentin 0 1 0 0 0 1 carbamazepine & methylphenobarbitone 0 1 0 0 0 1 carbamazepine & oxcarbazepine 0 1 0 0 1 2 carbamazepine & phenobarbital 0 1 0 0 0 1 carbamazepine & phenytoin 0 6 0 1 1 8 carbamazepine & topiramate 0 2 0 0 2 4 carbamazepine & vigabatrin 0 3 0 1 0 4 carbamazepine & zonisamide 0 1 0 0 0 1 clobazam & vigabatrin 0 1 0 0 0 1 clonazepam & diazepam 0 1 0 0 0 1 clonazepam & oxcarbazepine 0 2 0 0 0 2 clonazepam & phenytoin 0 2 0 0 0 2 clonazepam & primidone 0 1 0 0 0 1 clonazepam & topiramate 0 2 0 0 1 3 clonazepam & zonisamide 0 2 0 0 0 2 gabapentin & levetiracetam 0 1 0 0 0 1 gabapentin & phenobarbital 0 1 0 0 0 1 gabapentin & phenytoin 0 2 0 0 0 2 gabapentin & topiramate 0 2 0 0 0 2 levetiracetam & phenytoin 0 2 0 0 0 2 levetiracetam & zonisamide 0 1 0 0 0 1 oxcarbazepine & topiramate 0 1 0 0 0 1 phenobarbital & phenytoin 0 2 0 0 0 2 phenytoin & primidone 1 1 0 0 0 2 pregabalin & topiramate 0 0 0 1 0 1 Table 7. Prospective Registry Lamotrigine Monotherapy and Antiepileptic Drug Polytherapy Exposure in Pregnancy by Trimester of Exposure and Outcome (continued) 1 September 1992 - 31 March 2008 Concomitant Antiepileptic Drug Exposures Outcomes Without Major Defects[1]  Outcomes Spont w/ Birth Live Fetal Ind Preg Defects Births Deaths Abort Loss Overall Lamotrigine polytherapy without valproate (continued) carbamazepine & clobazam & 0 2 0 0 0 2 clonazepam carbamazepine & clonazepam & 0 1 0 0 0 1 levetiracetam carbamazepine & diazepam & 0 1 0 0 0 1 gabapentin carbamazepine & felbamate & 0 0 0 1 0 1 phenytoin carbamazepine & phenobarbital & 0 0 0 1 0 1 primidone clonazepam & levetiracetam & 0 1 0 0 0 1 phenobarbital & topiramate & zonisamide Exposure During Second Trimester: Lamotrigine Monotherapy 4 69 0 0 0 73 Lamotrigine polytherapy with valproate valproate 0 4 0 0 0 4 clonazepam & valproate 0 0 1 0 0 1 topiramate & valproate 1 1 0 0 0 2 Lamotrigine polytherapy without valproate carbamazepine 0 2 0 0 0 2 diazepam 0 1 0 0 0 1 gabapentin 0 2 0 0 0 2 levetiracetam 0 2 0 0 0 2 oxcarbazepine 0 2 0 0 0 2 phenobarbital 0 1 0 0 0 1 phenytoin 0 5 0 0 0 5 trimethadione 0 1 0 0 0 1 carbamazepine & phenobarbital 0 1 0 0 0 1 clonazepam & oxcarbazepine 0 1 0 0 0 1 ethosuximide & topiramate 0 1 0 0 0 1 gabapentin & topiramate 0 1 0 0 0 1 Exposure During Third Trimester: Lamotrigine Monotherapy 1 15 0 0 0 16 Lamotrigine polytherapy with valproate valproate 0 3 0 0 0 3 Lamotrigine polytherapy without valproate clonazepam 1 0 0 0 0 1 phenytoin 0 1 0 0 0 1 gabapentin & vigabatrin 0 1 0 0 0 1 Exposure During Unspecified Trimester: Lamotrigine Monotherapy 0 5 0 0 0 5 Lamotrigine polytherapy with valproate valproate 0 1 0 0 0 1 _________________________________________________________________________________________ [1] Birth defect not reported but cannot be ruled out. [2] May not be mutually exclusive across outcomes and may exceed more than 100% of the total. For example, 1 pregnancy resulting in 1 live birth and 1 fetal death will count as 1 in each category but will only count as 1 total. 4. DATA FROM OTHER SOURCES As other internal or external sources of data involving use of lamotrigine during pregnancy are identified they will be summarized in this section of the Interim Report. 4.1 Retrospective Reports Through its spontaneous reporting system, GlaxoSmithKline has received retrospective notification of lamotrigine-exposed pregnancies and their outcomes. Reports are considered retrospective when pregnancies involving lamotrigine exposure are reported after the pregnancy outcome is already known. Retrospective reports may be biased toward the reporting of more abnormal outcomes and are much less likely to be representative of the general population experience. These outcomes are reviewed because they may be helpful in detecting a possible pattern of defects suggestive of common etiology. Such reports are presented below. Retrospective Health Care Provider Reports Through 31 March 2008, there have been 137 pregnancy outcomes retrospectively reported involving birth defects. There were 117 that involved earliest lamotrigine exposure in the first trimester, 3 that involved earliest trimester of exposure in the second trimester, and 17 had an unspecified trimester of exposure. Seventy five defects involved lamotrigine monotherapy while 62 involved antiepileptic drug polytherapy. A description of the reported defects is included on Table 8. Table 8. Reports of Birth Defects Retrospectively Reported 1 September 1992 - 31 March 2008Lamotrigine Monotherapy26941.Live infant. Polydactyly, talipes (ankle joints), dysmorphic features. Normal chromosome analysis.33902.Live infant. Head circumference above the 97th percentile. Skull x-rays revealed sagittal synostosis. Surgery was performed, no other developmental sequelae.100533.Live infant. Cardiac abnormality.100944.Live infant. Hirschprungs disease.102375.Live infant. Aortic valve stenosis.102766.Induced abortion. Fetal diagnosis of anencephaly by prenatal ultrasound.103247.Live infant. Infantile spasms at approximately 2 months of age. Treated with vigabatrin, spasms resolved. Chest mass on MRI. Head scan done. Surgical diagnosis was neuroblastoma. Surgery was curative.104358.Live infant. Choanal atresia, to be surgically repaired in one year, hypothyroidism, treated with Synthroid.104369.Live infant. Right-sided talipes (mild). No treatment required.1046110.Live infant. Congenital anomaly of ureter.1048411.Live infant. Short stature.1048512.Live infant. Hypoplastic left heart on prenatal ultrasound. Placental abruption, infant died.1048613.Live infant. Born without a thyroid gland.1050714Live infant. Coarctation of aorta, anomalous coronary arteries.1052015.Live infant. Intestinal duplication. Surgery performed, infant was recovering.1073016.Live infant. Tetralogy of Fallot.1100617.Live infant. Cleft lip, but no cleft palate was observed. *denotes cases that are new since the last Report Table 8. Reports of Birth Defects Retrospectively Reported (continued) 1 September 1992 - 31 March 2008Lamotrigine Monotherapy (continued)1101718.Induced abortion. Absence of neural tissue above the base of the brain and above the orbits consistent with an anencephalic fetus, abnormal appearance to the cervical spine, dysraphism with a progressive widening of the caliber of the cervical spinal canal toward the foramen magnum.1147919.Live infant. Bowel blockage, also had seizures and was a premature birth. Surgery performed.1166220.Live infant. Ventricular septal hypertrophy.1180421.Live infant. Congenital structural cardiac defect - unspecified.1156722.Live infant. Symptomatic tetralogy of Fallot. Surgery was performed.1203723.Live infant. Down syndrome. Mosaicism.11931 24.Live infant. Slightly dysmorphic, elbows fixed at 90 degrees, low set ears, broad base nose, dimple in the middle of nose, arthrogryposis, large hydrocephalus - barely any brain tissue visible. Infant showed no intrauterine growth restriction, but scoliosis of the lumbar spine, bilateral talipes with deformed angulated feet and severe congenital hydrocephalus of unknown cause. Infant died within minutes of birth from hydrocephalus and arthrogryposis diagnosed antenatally.1201625.Induced abortion. Severe heart defects.1202826.Live infant. Hydrocephalus, initially noted on a prenatal ultrasound. Amniocentesis was apparently normal. A ventriculo-peritoneal shunt was placed after delivery.1238827.Live infant. Karyotype: 47, XX, +18. Multiple defect congenital syndrome (Hypotrophia Intrauterina, undeveloped auricles, cleft palate). Infant lived for only 15 hours.1224528.Live infant. Colon atresia, requiring surgery.1231729.Live infant. Congenital cataract.1267630.Induced abortion. Trisomy 9. 1267831.Live infant. Atrial fibrillation, requiring digoxin.1287932.Live infant. Cleft palate.1302533.Live infant. Pyloric stenosis (familial), congenital hypothyroidism, motor delays.1305134.Live infant. Valvular ejection murmur, persistent patent ductus arteriosus.1320335.Live infant. Down syndrome and atrial ventricular septal defect with a relatively large ventricular septal defect requiring surgery.1328136.Live infant. Aortic isthmus hypoplasia not requiring surgery.1329237.Live infant. Hydronephrosis.1343938.Live infant. Cerebral malformation and developmental delay.1345539.Induced abortion. Gastroschisis in right umbilical area, evisceration of small intestine, liver, stomach, and pancreas.1349940.Induced abortion. Probable Dandy-Walker Syndrome diagnosed by prenatal ultrasound. Posterior fossa cyst confirmed after delivery.1346641.Live infant. Tracheal-esophageal fistula, retinal deficiency, optic nerve hypoplasia, narrow ear canals and ossicular abnormality.1368942.Induced abortion. Down syndrome.1374043.Live infant. Microcephaly and severe developmental delay.1401344.Live infant. Ambiguous genitalia.1353245.Live infant. Wolf-Hirschhorn syndrome, cardiac and stomach anomalies (not otherwise specified). Infant died.1370546.Spontaneous pregnancy loss. Lymphangioma in abdomen, chest, and neck.1407447.Live infant. Cleft lip and palate. Surgical repair is planned.1409348.Live infant. Second, third, and fourth digits on left hand missing. Thumb and fifth digit curve inward and nails meet.1410449.Live infant. Sacral spine defect, covered by skin.1438550.Induced abortion. Hypoplasia of the right ventricular of the heart, diagnosed by prenatal echocardiography. *denotes cases that are new since the last Report Table 8. Reports of Birth Defects Retrospectively Reported (continued) 1 September 1992 - 31 March 2008Lamotrigine Monotherapy (continued)1449051.Live infant. Small ventricular septal defect.1378952.Live infant. Adenomatoid malformation of the lung.1438253.Live infant. Left sided hypoplastic heart defect, requiring surgery.1451154.Live infant. Left-sided torticollis.1443355.Live infant. Left forearm missing.1465256.Live infant. Bilateral cleft lip and palate.1465357.Induced abortion. Lumbosacral myelomeningocele with Arnold Chiari malformation diagnosed by prenatal ultrasound. 1495658.Live infant. Dysplastic brain, more in frontal lobes but parietal and temporal lobes are also abnormal. Microcephalic from distance. 1499659.Live infant. Large diaphragmatic herniation containing spleen, stomach, entire small intestine, ascending colon and left half of liver. Compressed non-aerated left lung, small aerated right lung; right ventricular hypertrophy, patent foramen ovale and patent ductus. Overlap of cranial bones. Fracture of left humerus. 1500560.Live infant. Isolated left congenital renal agenesis, requiring prolonged hospitalization.1511661.Live infant. Rib cage malformation; lymphangiectasia of the right lung with pulmonary hypoplasia. 1515862.Live infant. Born with the liver outside.1521663.Live infant. Absence of the septum pellucidum.1505964.Live infant. Infant born with spina bifida and developed hydrocephalus. Infant also has club foot bilaterally. Surgery to close spina bifida.1516865.Live infant. Spinal and musculoskeletal abnormality. The diagnosis by prenatal ultrasound included club foot. The child was in neonatal intensive care after birth for unstated reasons. 1535466.Live infant. Hypoplastic left ventricle.1552167.Live infant. Ductus arteriosus; cataract with persistent fetal vascularization in the left eye and retinal detachment; presumed cystic or polycystic kidneys.1561768.Live infant. Lissencephaly, presenting with a seizure at 3 months of age.1540969.Live infant. Hydrocephalus, due to aqueductal stenosis, first noted on prenatal ultrasound.1534470.Live infant. Pulmonary atresia with intact ventricular septum.1538871.*Induced abortion. Defects diagnosed by prenatal ultrasound: no radius, ulna or hand on the right; absent fibula in both legs; tibias short. The pregnancy was electively terminated at 20 weeks because of these defects.1580172.*Live infant. Cleft lip and palate.1580673.*Live infant. Term infant with gut malrotation, requiring surgery. Jitteriness, stiffness poor feeder, vomiting, irritability.1583074.*Live infant. Infantile spasms.1570075.*Live infant. Club foot, treated with casting.Lamotrigine with Antiepileptic (AED) Polytherapy without Valproate26351.Live infant. Choanal atresia; stenosis later perforated. Mother also received carbamazepine preconception and throughout pregnancy.26412.Live infant. Congenital teratogenic face with hypertelorism, downturned mouth, epicanthal folds, flattened nasal tip, micrognathia, slight bitemporal narrowing and marked hirsutes; has had jittery hypotonicity. At time of follow-up, developmental delay (functioning at a 3-month-old level at 6 months of age). Mother also received carbamazepine preconception and throughout pregnancy.30283.Live infant. Fetal hydrops and chylothorax. NICU care, mechanical ventilation, BP support, diuretics, problem with lung development and kidney failure. Mother also received felbamate throughout pregnancy.3389 twin4.Live infant. Multiple congenital abnormalities: Congenital cataracts, double outlet right ventricle, pulmonary atresia, high membranous ventricular septal defect, right sided arch, anorectal agenesis without fistula, abnormal rotation of the large intestine, tracheal agenesis/laryngeal agenesis, bronchi arising from esophagus, abnormal lobar formation of the right lung, ambiguous genitalia, testes in high intraabdominal position, abnormal twisted left ribs, sacral dysgenesis with hypoplasia and abnormal segmentation, hypertelorism, down sloping palpebral fissures. Mother also received carbamazepine throughout pregnancy. *denotes cases that are new since the last Report Table 8. Reports of Birth Defects Retrospectively Reported (continued) 1 September 1992 - 31 March 2008Lamotrigine with Antiepileptic (AED) Polytherapy without Valproate (continued)41615.Induced abortion. Diagnosis of anencephaly by ultrasound at 18 weeks gestation. Mother also received carbamazepine preconception and during the first and second trimesters.100286.Induced abortion. Diagnosis on a prenatal ultrasound: Derangement of the posterior fossa with no cerebellum seen, lumbosacral spina bifida, right talipes (clubfoot). Mother also received diazepam preconception and as needed.100397.Live infant. Umbilical cord with one artery, one kidney (right). Mother also received carbamazepine during the first and second trimesters.101038.Live infant. Hypospadias. Mother also received carbamazepine, clobazam, and topiramate preconception and throughout pregnancy.102149.Live infant. Ambiguous external genitalia. Mother also received carbamazepine preconception and throughout pregnancy.1023510.Live infant. Hip dysplasia. Mother also received topamax preconception and throughout pregnancy.1029811.Live infant. Deafness. Mother also received phenytoin.1036112.Live infant. Congenital anomaly of the hip (dislocated). Infant weighed 11 lbs. 5 ozs at birth. Mother also received phenytoin.1038713.Live infant. Microcephaly, bilateral deafness and developmental delay. Mother also received carbamazepine.1045714.Live infant. Absent kidney. Mother also received carbamazepine preconception and throughout pregnancy.1132915.Live infant. Esophageal atresia, tracheo-esophageal fistula, intrauterine growth retardation. Two days after birth the fistula was closed. Mother also received primidone and topiramate.1228916.Live infant. Cleft lip and palate, congenital skull malformation (not otherwise specified), chromosomal abnormality (not otherwise specified), hypertelorism of orbit, pterygium colli, and finger deformity (not otherwise specified). Mother also received clobazam during the second and third trimesters of pregnancy.1119217.Live infant. Severe malformation type total diaphragm agenesia with pulmonary hypertension requiring surgery. Infant later died. Mother also received carbamazepine and phenobarbital.1381818.Live infant. Moderate subaortic perimembranous ventricular septal defect. Mother also received levetiracetam during the second and third trimesters of pregnancy.1370219.Induced abortion. Holoprosencephaly presumably diagnosed by prenatal ultrasound. Mother also received gabapentin.1434820.Live infant. Hip dysplasia. Mother also received carbamazepine, clobazam, and topiramate.1452521.Live infant. Microcephaly. Mother also received carbamazepine preconception and throughout pregnancy.1478622.Spontaneous pregnancy loss. Down syndrome. Mother also received clobazam preconception and throughout pregnancy.1452023.Live infant. Atrial septal defect and organ failure. Mother also received topiramate preconception and throughout pregnancy.1451024.Live infant. Cleft lip; infant also had left anisocoria and died from severe ischemic encephalopathy following prolonged maternal seizure prior to delivery. Mother also received topiramate.1515525.Live infant. Asymmetric skull. Mother also received levetiracetam.1515926.Live infant. Symbrachydactyly. Mother also received topiramate during the first, second, and third trimesters of pregnancy.1516027.Live infant. Agenesis of the corpus callosum diagnosed by MRI at 2 years of age. The child had pervasive developmental disorder with decreased social activity, speech deficit, and developmental language disorder. Mother also received topiramate.1593728.*Live infant. Mild aortic coarctation first identified by prenatal ultrasound. Mother also received carbamazepine preconception and throughout pregnancy.1575329.*Live infant. Agenesis of the corpus callosum and colpocephaly documented by MRI. The report states the metabolic work-up and chromosomes were normal. The child has mild developmental delay at one year of age. Mother also received clonazepam during the first and second trimester.1577330.*Live infant. Cleft palate. Mother also received zonisamide preconception and throughout pregnancy. *denotes cases that are new since the last Report Table 8. Reports of Birth Defects Retrospectively Reported (continued) 1 September 1992 - 31 March 2008Lamotrigine with Antiepileptic (AED) Polytherapy with Valproate26081.Induced abortion. (Ultrasound detected neural tube defects). Spina bifida with meningocele, hydrocephalus, cerebellar deformity. Mother also received valproic acid preconception and throughout pregnancy.26882.Live infant. Described as abnormal, no details provided. Mother also received valproate preconception and throughout pregnancy.26913.Stillbirth. Multiple abnormalities including hydrocephalus. Mother also received valproate preconception and throughout pregnancy and clobazam in the third trimester.43234.Live infant. Stiff hands/wrists, mild contractures needing physiotherapy; reaction started when infant was 6 weeks old. Mother also received valproate preconception and throughout pregnancy.43255.Live infant. Eyes slightly upturned with minor epicanthal folds. High and narrow forehead, premature fusion of metopic sutures. Small for gestational age. Mother also received valproate preconception and during the first trimester.45486.Live infant. Left renal cysts; left kidney without function. Mother also received valproate preconception and throughout pregnancy.100607.Live infant. Plane cutaneous angioma-hemifacies o/s (right). Mother also received diazepam during the second and third trimesters, phenobarbital preconception and throughout pregnancy and valproate preconception and during the first trimester.100808.Live infant. Atrial septal defect, ventricular septal defect. Additional diagnoses from follow-up report: developmental delay, hypotonia, dysmorphic features hypertelorism, slightly small chin, nose upturned, shallow philtrum, lips with thin vermillion border. Mother also received valproate preconception and throughout the pregnancy.100939.Live infant. Congenital atrial septal defect, hypospadias/epispadias. Reporter suspects valproate syndrome. Mother also received valproate sodium throughout pregnancy.1024910.Live infant. Syndactyly, four webbed fingers on right hand. Mother also received folic acid, topiramate, and valproate preconception and throughout pregnancy.1035511.Live infant. Ventricular septal defect, breathing difficulties. Mother also received valproate preconception and throughout pregnancy.1036212.Induced abortion. Spina bifida, fetal growth delay in lower extremities, deformity of the skull, and dilatation of the right lateral ventricle identified at about 15 weeks gestation. Mother also received valproate preconception and throughout the pregnancy and folic acid.1074013.Live Infant. Minor malformations such as hypertelorism, flattened nasal bridge, low-set malformed auriculas, micrognathia, very small and bow-shaped mouth with thin upper lip, cleft palate and arachnodactyly. Her karyotype was 47, XXX and she had a 3 mm secondary atrial septal defect. Mother also received valproate preconception and throughout pregnancy.1123614.Induced abortion. Congenital malformations of fetus, neural tube defect and malrotation (intestinal). Mother also received valproate.1131115.Live infant. Pulmonary stenosis, cleft lip, multiple malformations, auricular defect, defect left eyelid. Mother also received valproate.1177716.Live infant. Infant of a diabetic mother with ASD, PDA, thickened ventricular septum defect and LV wall, hypoplastic left kidney, median cleft palate, Dandy-Walker syndrome, prominent forehead, adrenal gland hyperplasia. Mother also received diazepam and valproate.1180317.Live infant. Congenital structural cardiac defect - unspecified. Mother also received valproate.1182318.Live infant. Bilateral microphthalmia. CT of the brain revealed the left eyeball to be smaller than expected and the lens appeared to be misplaced. Ultrasound showed small mitral valve insufficiency, but no sign of heart defect. Chromosome test was normal. Mother also received valproate.1197219.Induced abortion. Renal anomaly, not otherwise specified, detected on prenatal ultrasound and expected to be fatal. Mother also received valproate preconception and in first trimester.1287620.Induced abortion. Lethal osteochondrodystroplasia diagnosed by prenatal ultrasound. Mother also received valproate and carbamazepine preconception.1224621.Live infant. Congenital anomaly (not otherwise specified). Infant died. Mother also received valproate.1361722.Live infant. Microcalcifications in the lenticulstriate zones of the brain. Mother also received clobazam and valproate in the third trimester. *denotes cases that are new since the last Report Table 8. Reports of Birth Defects Retrospectively Reported (continued) 1 September 1992 - 31 March 2008Lamotrigine with Antiepileptic (AED) Polytherapy with Valproate (continued)1451323.Live infant. Glandular hypospadias and mild retrognathia. Mother also received valproate preconception and throughout pregnancy.1460024.Live infant. Cleft palate. Mother also received levetiracetam preconception and throughout pregnancy and valproate in the first, second, and third trimesters.1515725.Live infant. Subependymal cysts in the 3rd ventricle of the brain. Abnormal arm, leg, and head flexion movements. Mother also received clobazam in first, second, and third trimesters and valproate.1515426.Live infant. Spina bifida. Mother also received clobazam in first, second, and third trimesters, levetiracetam and valproate.1560727.*Induced abortion. Hydrocephalus. Mother also received valproate preconception, first and second trimesters.1569428.*Live infant. Congenital club foot, congenital nervous system anomaly, unspecified. Mother also received valproate preconception and first trimester.1575129.*Induced abortion. Spina bifida, ventriculomegaly, Arnold-chiara malformation. Mother also received valproate.1592030.*Induced abortion. Myelomenigocele and hydrocephalus. Mother also received valproate preconception, first and second trimesters. Lamotrigine with Antiepileptic (AED) Polytherapy (Concomitant AED Unspecified)47091.Live infant. Dysmorphic features including limb shortening, multiple joint contractures, camptodactyly, cryptorchidism, hooded prepuce, small mouth, high palate, simple ears and prominent eyes with a flat bridge of the nose. Appearance of an arthrogryposis or a trisomy. Chromosomal analysis was normal. Other unknown antiepileptic medications were taken.48292.Live infant. Macrocephalia, bilateral camptodactyly of the 4th finger with reduced extension in the MCI joint, shortening of 4th and 5th fingers, striking dermatoglyphics and hypoplastic toenails, large distance between the mamillae, a split uvula and a wide neck fold. Other unknown antiepileptic medications were taken. *denotes cases that are new since the last Report Other Reported Events Some infants born without birth defects have been retrospectively reported to have other conditions or to be otherwise ill. See a list of these retrospective reports in Appendix B. 4.2 Other Studies There is a growing body of literature on the potential association between lamotrigine exposure during pregnancy and birth defects. This section summarizes the results of some of these studies. It is important to note that these studies vary widely in methodology, ascertainment and classification of birth defects, geographic location, sample size, and other factors that could affect results. The Swedish Medical Birth Registry The Swedish Medical Birth Registry, affiliated with the Swedish Government Department for Health and Welfare, was established in 1973 and collects data on nearly all births (>95%) in Sweden (Olsen et al, 2002, Wide et al, 2004). Information on the womens pregnancy is collected prospectively by the attending midwife or physician starting with an interview at the first antenatal visit at 10-12 weeks. The information collected includes maternal socio-demographics, alcohol use and smoking during pregnancy, medical history, and medication taken during pregnancy. Data on medication exposure have been collected since 1992. The pregnancy outcome is assessed at birth by the attending physician and any malformations are described, coded according to the ICD-9 classification system, and entered into a central computer system. As malformations are recorded descriptively, there is no differentiation of major and minor malformations. These birth data are downloaded from several population based registers (congenital malformations, hospital discharge, and birth registers) and can be linked through unique health identifiers to the mothers history of medication exposure during pregnancy. The following summary is based on delivery outcome among infants born to women who, at the first antenatal visit (usually week 10-12) reported the use of lamotrigine, irrespective of use of other drugs. The data represent all reported exposures between 1995 and 2006 (inclusive, though malformation data from 2006 not quite complete). The total number of women reporting the use of lamotrigine early in pregnancy (i.e. at first antenatal visit) was 536. Among these, 403 reported the use of lamotrigine in monotherapy and 133 reported the use of lamotrigine in combination with other anticonvulsants. The following malformations were recorded in infants exposed in utero to lamotrigine monotherapy during early pregnancy: MalformationRelatively major defects Atrial septal defect (ASD) (twins both with same defect) Atrial septal defect and endocardial cushion defect Unspecified cardiac defect Ventricular septal defect Median cleft palate with renal dyplasia Cleft lip with palate and ASD Cleft lip (2) Omphalocele with diagphragmatic malformation and ASD/ECD Hypospadias Syndactyly (fingers) Down syndrome (2)Minor defects Unstable hip (2) Undecended testicle (2) NevusTotal 18 malformations There were 18 reported malformations following exposures to lamotrigine monotherapy giving a rate of 4.5% (95% Confidence Interval: 2.7%-7.1%). This compares to a malformation rate of 3.5%-4.4% from the general population captured in the Swedish Birth Register. These included 13 relatively severe defects: four orofacial clefts (one cleft palate, one cleft lip with palate and two cleft lip), two atrial septal defects, one ventricular septal defect, one unspecified cardiac defect, one omphalocele, one hypospadias, one syndactyly, and two cases of Down syndrome, though the latter is unlikely to be associated with drug exposure. The Register currently reports 4 cases of orofacial clefts in 403 lamotrigine first trimester monotherapy exposures against an expected number of 1.0 based on data from the Swedish general population. The rate in lamotrigine monotherapy exposed pregnancies is 9.9 per 1000 versus a background general population rate of 2.0 per 1000 (data from 1995-2005). The Swedish Birth Register concluded that even though this excess could be random, it supports some other observations in the literature. Danish Multicenter Study of Epilepsy and Pregnancy Using linked data from the prospective Danish Medical Birth Pharmaco-epidemiological Prescription Registry Databases of North Jutland County, Sabers et al reviewed data from pregnant women with epilepsy with or without AED therapy from 6 university hospitals in Denmark (Sabers et al, 2004). A total of 138 women were exposed to AEDs in the first trimester, including 51 exposed to lamotrigine (figures for monotherapy and polytherapy). One malformation, a VSD, was reported after first trimester exposure to lamotrigine (150 mg) and oxcarbazepine (2400 mg). The Australian Registry of Antiepileptic Drugs in Pregnancy: experience after 30 months The Australian Pregnancy Registry was established in 1999 to prospectively monitor adverse pregnancy outcomes in women exposed to AEDs (Vajda et al, 2003, Vajda et al, 2005). Women eligible for enrollment are asked by healthcare providers to call a toll free number where information on the Registry is provided and consent for enrollment is sought. Once consent is given, a structured interview is completed to obtain maternal demographic and socioeconomic details as well as information on AED treatment history, the mothers medical history, and details of pregnancy itself. Further telephone interviews are completed at 7 months gestation, 4-8 weeks following the expected date of birth, and at 12 months after birth. The latter two interviews capture information concerning the infants health including the presence of major congenital malformations. In addition, the womans permission is sought to obtain information from healthcare providers to confirm details through medical records. The most detailed lamotrigine specific information comes from data collected up until December 2003 when 630 women had been enrolled in the Registry and 555 pregnancies had reached completion with 565 infants (including 10 sets of twins) (Vajda et al, 2004). Sixty-one women were exposed to lamotrigine monotherapy during the first trimester of pregnancy. No outcomes with major malformations were recorded. An additional 68 women were exposed to lamotrigine polytherapy including valproate during the first trimester with 4 recorded major malformations (Vajda et al, 2004). Table 9 describes the 4 major malformations (Vajda et al, 2003). Table 9. Major Malformations Reported in the Australian RegistryBirth DefectsAED (dose mg)Folate1. Spina bifida and hydrocephalus (aborted)valproate (2500), lamotrigine (150)Yes2. CHD (VSD), plagiocephaly, bronchial narrowing and hypospadias valproate (2000), lamotrigine (350)No3. Plagiocephalyphenytoin (200),lamotrigine (600), diazepam (10)Yes4. Facial bone anomalies and hypospadiasvalproate (2000), lamotrigine (150)YesMore recent data, reflecting 662 pregnancies with full outcome data, were presented at the American Epilepsy Society meeting in December 2005. A malformation rate of 5.6% was reported following lamotrigine monotherapy, though the trimester of exposure was not clear and the numerator and denominator were not given (Vajda et al, 2005). The Australian registry now forms part of EURAP, though country specific data continue to be analyzed. The New AEDs in Pregnancy - UK Epilepsy and Pregnancy Register, Lamotrigine Data The UK AED Pregnancy Registry was established in 1996 to prospectively monitor adverse pregnancy outcomes in women exposed to AEDs and is headed by Dr. James I. Morrow, Department of Neurology, Royal Victoria Hospital, Belfast, Northern Ireland. Women are enrolled, with their consent, through healthcare providers, most commonly general practitioners, neurologists, and obstetricians. These providers collect information on exposure to AEDs during pregnancy (therapy type, timing, and dosage), maternal demographics, medical history, and details of the pregnancy. Close to the expected date of delivery, the healthcare providers are contacted for details of the infants health. There is an additional follow-up at 3 months following birth. All malformation descriptions are reviewed by a geneticist affiliated with the Registry. The UK Epilepsy and Pregnancy Register has collected full outcome data on 3607 cases. The overall major congenital malformation rate for all AED exposed cases was 4.2% (95% Confidence Interval: 3.6%-5.0%). The rate was significantly higher in polytherapy (6.0%) compared to monotherapy (3.7%) exposures. The rate was significantly higher in women exposed to valproate (6.2%) compared to carbamazepine (2.2%). There were also fewer malformations in women exposed only to lamotrigine (3.2%, 95% Confidence Interval: 2.1%-4.9%). The rate for women with epilepsy who had not taken AEDs during pregnancy was 3.5% (95% Confidence Interval: 1.8%-6.8%). A positive dose response for major congenital malformations was noted for lamotrigine. The mean daily dose was significantly higher for those with a major congenital malformation compared with those without a major congenital malformation respectively (352.4 mg and 250.6 mg; p=0.005). (Morrow et al, 2006). North American Antiepileptic Drug (AED) Pregnancy Registry The North American Antiepileptic Drug (NAAED) Pregnancy Registry is an ongoing prospective, observational study. Women are recruited directly into the Registry when they call a toll free number that is advertised through healthcare providers, teratology counselors, epilepsy support foundations, and the lay and scientific press. Upon enrollment, women participate in a telephone interview to collect information on material demographic and socio-economic characteristics, AED exposure during pregnancy (therapy type, timing, and dosage), medical and prescription history, and details of the pregnancy. A further interview to confirm exposure information takes place at 7 months gestation and the health of the infant is established through an interview 4-8 weeks after the expected delivery date. Consent is also sought to access medical records to confirm details of the infants health. All malformation descriptions are reviewed by two dsymorphologists blinded to maternal exposure. Patients enroll themselves into this Registry. Contact information is provided at the end of this Report. The NAAED Pregnancy Registry has released findings on the frequency of major malformations in infants exposed to lamotrigine as monotherapy (Holmes et al, 2006, Holmes et al, 2008). As of March 2006, data were available for 684 infants exposed to lamotrigine monotherapy in the first trimester of pregnancy. Of these, 19 or 2.8% (95% Confidence Interval 1.7%-4.3%) had a major malformation. It is noteworthy that no evidence of a dose-response relationship was found. Five infants (7.3/1000) had isolated oral clefts: cleft palate (3), cleft lip (1), and cleft lip and palate (1). The rate among the lamotrigine exposed infants showed a 10.4-fold increase (95% Confidence Interval: 4.3%-24.9%) in comparison to 206,224 unexposed infants surveyed at birth at Brigham and Womens Hospital in Boston, where the prevalence of oral clefts was 0.7/1000. The prevalence of isolated oral clefts reported by NAAED is also higher than the range reported in the published literature (0.5-2.2/1000) (Bille et al, 2005, Christensen 1999, Croen et al, 1998, Das et al, 1995, DeRoo et al, 2003, Hashmi et al, 2005, Kallen 2003, Menegotto et al, 1991, Tolarova et al, 1998, Vallino-Napoli et al, 2004) (Holmes at al, 2006). European Registry of Anti-Epileptic Drug Use in Europe (EURAP) EURAP is an ongoing multi-AED pregnancy registry that was established in 2002. Recruitment was initially in Europe, but the registry has since expanded to recruit women from countries in Asia, Oceania, and Latin America. Networks of reporting physicians within the participating countries record, with patient permission, details of AED exposure and maternal risk factors (maternal demographics, maternal health, timings of AED treatment during pregnancy, history of maternal epilepsy, frequency of seizures during pregnancy, family history of epilepsy and other congenital and inherited conditions). The registry only includes pregnancies registered before the fetal outcome is known (prospective) and within the first 16 weeks of gestation for comparative risk assessments (against other AEDs). The infant outcome is monitored at regular intervals between enrollment and up to 14 months after birth (once a trimester, at birth, and at approximately one year of age). Each update form is reviewed by a national coordinator before transfer to the Central Registry in Milan for data input and analysis. In order to facilitate uniform and objective malformation assessments, malformation reports are regularly reviewed by an outcome assessment committee which remains blinded to the type of exposure. Data concerning the risk of major malformations with respect to in utero exposure to specific AEDs will not be released by EURAP until a set number of pregnancies have been enrolled (n=5000). This number has been pre-defined through power calculations. EURAP release twice yearly reports (www.eurapinternational.org). As of May 2007, there were 4427 AED exposures registered through 40 countries with one year follow-up data post delivery. These data included 3512 exposures to single AEDs (80.0%), 753 exposures to two AED combinations (17.1%) and 128 exposures to three or more AED combinations (2.9%). The prevalence of major malformations was 5.6% following first trimester AED monotherapy exposures and 9.0% following first trimester AED polytherapy exposures. There are currently 812 first trimester lamotrigine monotherapy exposures captured in the database. Prescription-Event Monitoring (PEM) Study A study was performed through prescription-event monitoring by the Drug Safety Research Unit, Southampton, United Kingdom (Mackay et al, 1997). The study population consists of all lamotrigine users obtaining drug prescription through a general practitioner in Britain from December 1991 through February 1995. During 6-month follow-up of 11,316 subjects exposed to lamotrigine, 66 pregnancies were identified. Of these 66, 60 involved earliest exposure during the first trimester and the remaining 6 involved either second or third trimester exposure only. Outcomes are shown in the following table. Table 10. Outcomes of Pregnancies Reported to the PEM with 6 Month Follow-up By Earliest Trimester of Lamotrigine Exposure December 1991 - February 1995Earliest Trimester of ExposureLive BirthSpontaneous Pregnancy Loss Missed AbortionInduced AbortionTotal OutcomesFirst40101960Second or Third Only60006Total46*101966* Includes: 1 infant born prematurely at 29 weeks. 1 infant diagnosed with IUGR and subsequent radiologic evidence of pyloric stenosis. 3 infants with congenital anomalies (3/46= 6.5%) described as: a. 1 infant with large ventricular septal defect; mother took concomitant phenobarbital and valproic acid throughout pregnancy. b. 1 infant with cleft palate and hypospadias; mother took concomitant carbamazepine and valproic acid during pregnancy. c. 1 infant born prematurely with hemiplegia and epilepsy after a preeclamptic pregnancy; mother took labetolol in last 4 months of pregnancy, but no other anticonvulsants. During 18-month follow-up of 3,994 subjects exposed to lamotrigine, there were 12 pregnancies, all involving earliest exposure in the first trimester. Outcomes are shown in the following table. Table 11. Outcomes of Pregnancies Reported to the PEM with 18 Month Follow-up By Earliest Trimester of Lamotrigine Exposure December 1991 - February 1995Earliest Trimester of ExposureLive BirthSpontaneous Pregnancy Loss Induced AbortionTotal OutcomesFirst912*12Total912*12 *Both induced abortions involved spina bifida and both mothers had taken concomitant valproic acid in the first trimester. 5. LITERATURE REVIEW We are continuing to review the published medical literature for case reports with outcomes of pregnancies exposed to lamotrigine. As of 31 March 2008, seven articles have been found and are listed in the following literature table. Table 12. Reported Cases From the Medical Literature of Lamotrigine Exposure in Pregnancy 1 September 1992 - 31 March 2008PublicationTreatmentOutcomeFirst AuthorYearLamotrigine DoseGestation Week Tx BeganAED polytherapyGestation week at outcomeOutcomeQuattrini, A1996200 mg/day0Carbamazepine 1000 mg/day Barbexaclone 200 mg/day 39Live infant no defects Rambeck, B1997 300 mg/day 0Valproic Acid in weeks 0-3 (dose unknown) 39 Live infant no defects Tomson, T1997200 mg/day week 0-20, 300 mg/day week 21-41 0none 41Live infant no defectsOhman, I2000A case series reported no birth defects in the pregnancies exposed to lamotrigine; however, these cases were collected for other purposes and may not be representative of all exposed pregnancies. Popescu, L2005200 mg/dayunknownPhenobarbital 200 mg/day (timing unknown) dose progressively switched with lamotrigineunknownLive infant clinodactyly, partial syndactyly, withdrawal symptoms including lack of appetite, neuromotor hyperexcitability, and irritability. Voermans, N2005unknownunknownnoneunknownLive infant no defects Gentile, S2005300 mg/day0none39Live infant no defects In addition, there are two cases series reported in the literature. A study monitoring the pharmacokinetics of lamotrigine during pregnancy, observed 12 infants born to women exposed to lamotrigine monotherapy and no malformations (de Haan et al, 2004). A second case series of 12 AED exposed pregnancies included two exposures to lamotrigine monotherapy. Neither of the infants had malformations (Cissoko et al, 2002). Literature References Quattrini A, Ortenzi A, Paggi A, Foschi N, Quattrini C. Lamotrigine and Pregnancy. Letter to Editor, Ital J Neurol Sci 1996;17:441-442. Rambeck B, Kurlemann G, Stodieck SRG, May TW, Jrgens U. Concentrations of lamotrigine in a mother on lamotrigine treatment and her newborn child. Eur J Clin Pharmacol 1997 51:481-484. Tomson T, Ohman I, Vitols S. Lamotrigine in pregnancy and lactation: a case report. Epilepsia 1997;38(9):1039-1041. Ohman I, Vitols S, Tomson T. Lamotrigine in Pregnancy: Pharmacokinetics during delivery, in the neonate, and during lactation. Epilepsia 2000;41(6):709-713. Popescu L, Marceanu M, Moleavin I. Withdrawal of lamotrigine caused by sudden weaning of a newborn: a case report. Presented at the 26th International Epilepsy Congress, Paris, August 28-September 1, 2005. Epilepsia 2005;46 (supplement 6),1351. Voermans NC, Zwarts MJ, Renier WO, et al. Epileptic seizures during childbirth in a patient with idiopathic generalised epilepsy. Ned Tijdschr Geneeskd 2005;149(25):1406-1411. Gentile S. Lamotrigine in pregnancy and lactation. Arch Women Ment Health 2005;8(1):57-58. de Haan GJ, Edelbroek P, Segers J, et al. Gestation-induced changes in lamotrigine pharmacokinetics: a monotherapy study. Neurology 2004;63(3):571-573. Cissoko H, Jonville-Bera AP, Autret-Leca E. New antiepileptic drugs in pregnancy: outcome of 12 exposed pregnancies. Therapie 2002;57(4):397-401. 6. DATA SUMMARY The Committee reviewed the accumulated data for 2072 prospectively reported pregnancy outcomes in the Registry according to the criteria described under Methods. Review of the composite data: Prospective Reports of First Trimester Exposure: Monotherapy Exposures: In the prospective reports with first trimester lamotrigine exposure as monotherapy, there were 33 major birth defects reported in 1261 outcomes (excluding fetal deaths and induced abortions not involving major defects and all spontaneous pregnancy losses). The observed proportion of births with major defects is 2.6% (95% Confidence Interval for observed proportion: 1.8%-3.7%) (Fleiss 1981). Table 6 presents gestational age at enrollment for this exposure group. The most recent literature on the average frequency of birth defects in women with epilepsy using AED monotherapy has reported frequency of malformations ranging between 3.3% and 4.5% (Holmes et al, 2001, Morrow et al, 2001, Morrow et al, 2003, Morrow et al, 2006, Samren et al, 1999). Polytherapy including Valproate: In the prospective reports with first trimester exposure to polytherapy including valproate, there were 16 major birth defects reported in 146 outcomes (excluding fetal deaths and induced abortions not involving major defects and all spontaneous pregnancy losses). The observed proportion of births with major defects is 11.0% (95% Confidence Interval: 6.6%-17.5%) (Fleiss 1981). This exposure group exhibited the highest proportion with major defects following first trimester exposures. Polytherapy not including Valproate: In the prospective reports with first trimester exposure to polytherapy not including valproate, there were 9 major birth defects reported in 379 outcomes (excluding fetal deaths and induced abortions not involving major defects and all spontaneous pregnancy losses). The observed proportion of births with major defects is 2.4% (95% Confidence Interval: 1.2%-4.6%) (Fleiss 1981). Prospective Reports of Second Trimester Exposure: Monotherapy Exposures: In the prospective reports with second trimester lamotrigine exposure as monotherapy, there were 4 major birth defects reported in 73 outcomes (excluding fetal deaths and induced abortions not involving major defects and all spontaneous pregnancy losses). Polytherapy including Valproate: In the prospective reports with second trimester exposure to polytherapy including valproate, there was 1 major birth defect reported in 6 outcomes (excluding fetal deaths and induced abortions not involving major defects and all spontaneous pregnancy losses). Prospective Reports of Third Trimester Exposure: Monotherapy Exposures: In the prospective reports with third trimester lamotrigine exposure as monotherapy, there was 1 major birth defect reported in 16 outcomes (excluding fetal deaths and induced abortions not involving major defects and all spontaneous pregnancy losses). Polytherapy not including Valproate: In the prospective reports with third trimester exposure to polytherapy not including valproate, there was 1 major birth defect reported in 3 outcomes (excluding fetal deaths and induced abortions not involving major defects and all spontaneous pregnancy losses). Review of Prospective and Retrospective Birth Defects: A review of all reported birth defects revealed no unique or consistent pattern to suggest a common cause. 7. COMMITTEE CONSENSUS The Lamotrigine Pregnancy Registry is a prospective, observational study which aims to detect a signal of any large risk of major malformations following exposure to lamotrigine during pregnancy. The percentage of pregnancies resulting in offspring with major malformations may vary across studies as the methodologies vary widely. Between-study variation in the reported rates of major birth defects can be related to such factors as the inclusion and exclusion criteria for major birth defects, the geographic regions included, how early in pregnancy women are enrolled, the source of pregnancy outcome information, the length and timing of follow-up, whether or not elective abortions are included, and the population of women included. Despite the methodological differences, consistency is emerging across several large AED pregnancy registries with the International Lamotrigine Pregnancy Registry reporting a rate of major congenital malformations following first trimester exposure monotherapy exposures of 2.6% (95% Confidence Interval: 1.8%-3.7%), NAAED reporting a rate of 2.3% (95% Confidence Interval: 1.3%-3.8%) (Holmes et al, 2008), and the UK Epilepsy and Pregnancy Register reporting a rate of 3.2% (95% Confidence Interval: 2.1%-4.9%) (Morrow et al, 2006). Because of the international scope of the Lamotrigine Pregnancy Registry, the voluntary nature of recruitment and other methods used, there is no directly comparable group of unexposed pregnant women against whom to evaluate the observed prevalence of birth defects in the Registry. The Registry uses the case definition of the Metropolitan Atlanta Congenital Defects Program (MACDP) for major birth defects, which includes chromosomal and genetic disorders, defects diagnosed solely by prenatal ultrasound, and those detected as incidental findings on postnatal diagnostic procedures. The overall frequency of major malformations in metropolitan Atlanta reported by the MACDP from 1968 through 2003 was 2.67%. Seventy-eight percent of these infants and fetuses had birth defects that were identified either prior to birth or during the first week of life (Correa et al, 2007). The prevalence of these early diagnoses is important for Registry comparisons since the majority of outcome reports are from clinicians who may have limited access to diagnoses made after the day of birth. Another study in a northeastern US hospital from a different time period (1972-1975 and 1979-1985), has reported a frequency of major malformations of 1.6%-2.2% at birth, depending on whether chromosomal anomalies and other genetic disorders are included (Nelson et al, 1989). Given the difficulty in identifying appropriate comparison groups for the Lamotrigine Pregnancy Registry, estimates on the frequency of birth defects in the offspring of women with epilepsy from the current literature are also presented. These range between 3.3% and 4.5% in cohorts of women using AED monotherapy (Holmes et al, 2001, Morrow et al, 2001, Morrow et al, 2003, Morrow et al, 2006, Samren et al, 1999). Therefore, comparing the rate of major birth defects in pregnancies exposed to lamotrigine monotherapy with that of pregnancies in the general population without epilepsy may overestimate the risk of lamotrigine use because of the hypothesized elevated risk among women with epilepsy. However, some published data have shown that women with epilepsy do not have an increased risk (Holmes et al, 2001). The 95% confidence interval around the rates of major birth defects following lamotrigine first trimester monotherapy (1.8%-3.7%) is consistent with the range reported in the literature for the average in women using monotherapy for epilepsy (3.3%-4.5%). The Registry has not detected evidence of an appreciable increase in the overall risk of major birth defects and this should provide some assurance when counseling patients. In particular, if the baseline frequency of total birth defects is 2-3 in 100 live births, a sample size of 1261 first trimester lamotrigine monotherapy exposures has an 80 percent chance (80% power) of correctly detecting at least a 1.44-1.54-fold increase over baseline in the overall rate of birth defects. Currently, the rate of major birth defects for first trimester monotherapy exposures in the Registry is 2.6% (95% Confidence Interval for observed proportion: 1.8%-3.7%) (Fleiss 1981). While this frequency is reassuring, the lamotrigine monotherapy sample size to date remains too small for formal comparisons of the rates of specific birth defects (e.g. cleft lip). For these relatively rare outcomes, the Registry may generate signals, defined as a report or reports of an event with an unknown causal relationship to treatment, around specific defects that are worthy of further exploration and continued surveillance. The Lamotrigine Pregnancy Registry Advisory Committee notes the two prospectively reported cases with severe cardiac defects as well as three cases of anencephaly. Attempts to obtain more information for purposes of classification of the cardiac defect cases were unsuccessful. For anencephaly other data sources were examined to look for consistency. No additional cases of anencephaly have been reported to five other ongoing AED registries with first trimester lamotrigine monotherapy with denominators ranging from 51 to 1000 and a total sample of 3100. The one case of anencephaly reported to the NAAED is a duplicate of a case in this Registry. One case of spina bifida has been reported from the UK Epilepsy and Pregnancy Register. In consideration of these data, the Committee considers there to be no consistent evidence to suggest an increased risk of neural tube defects associated with first trimester lamotrigine monotherapy. The Committee notes the signal of an increased risk of isolated oral clefts reported from the North American Anti-Epileptic Drug Registry and the Swedish Medical Birth Register (see Other Studies section 4.2). These two registries reported signals for differing types of cleft with potentially different underlying etiologies (cleft palate versus cleft lip with or without cleft palate, respectively) and the signal has not been confirmed within the Lamotrigine Pregnancy Registry. The Committee notes that a case control study was specifically mounted in the EUROCAT system to test the hypothesis of an association between first trimester lamotrigine exposure and isolated oral clefts, and the analysis did not support an increase. The odds ratio for all isolated oral clefts compared to other major malformations was 0.8 (95% Confidence Interval: 0.11%- 2.85%) (http://ctr.gsk.co.uk/Summary/lamotrigine/studylist.asp) (go to WEUKSTV2169/EPI40486). The Lamotrigine Pregnancy Registry Advisory Committee notes the higher frequency of major malformations within the group exposed to AED combinations that include both lamotrigine and valproate. Published studies report that women using valproate have experienced elevated rates of specific birth defects (Arpino et al, 2000, Artama et al, 2005, Omtzigt et al, 1992; Thisted et al, 1993, Wyszynski et al, 2005, Morrow et al, 2006, Vajda et al, 2004). However, it is not conclusive whether valproate exposure alone is sufficient to explain the higher frequency of major defects in the lamotrigine and valproate group in this Registry. In addition, because the number of AEDs used may be inextricably tied to the frequency and severity of seizures, it is difficult to assess the contribution of each of these factors to the risk of major malformations. Because Morrow et al, 2006 noted a positive dose-response effect for major congenital malformations with lamotrigine use, the Lamotrigine Pregnancy Registry Advisory Committee examined the Registry data related to dose. No increase in major defects with daily doses up to 400 mg was found. There were insufficient data at doses of 400 mg or more to confirm or refute a dose effect. The Committee will continue to monitor dose data. Several factors may introduce some bias into the calculation of the rate of major defects in the Registry data. As reporting of exposed pregnancies is totally voluntary, it is possible that high-risk pregnancies or low-risk pregnancies may be more frequently reported. It is also possible that outcomes among pregnancies lost to follow-up could differ from those with documented outcomes. Voluntary terminations and fetal deaths (pregnancy losses >20 weeks gestation) for which no defects have been detected and all spontaneous abortions (pregnancy losses <20 weeks gestation) are excluded from the rate calculations, but in reality, it is unknown what percentage of these pregnancies actually have defects. While the data collection form attempts to obtain information on birth defects detected at the time of the outcome, the reporting physician may not always know the condition of the aborted fetus. The rate of spontaneous abortion in the general population is 14%-22% (Kline et al, 1989). Comparisons across studies are problematic since the rate of spontaneous abortion declines throughout pregnancy and the observed rate will vary depending on the gestational week at which study follow-up begins. Because women are enrolled in the Lamotrigine Pregnancy Registry at different times in gestation, calculation of the rate of spontaneous abortion with lamotrigine exposure is beyond the scope of the Registry activities. While the Registry is limited to prospective reports, some pregnancy exposures are reported after the pregnancy outcome has occurred (retrospective reports). The Lamotrigine Pregnancy Registry Advisory Committee also reviews each retrospective report. In general, retrospective notification of outcomes following exposure to drugs can be biased toward reporting severe and unusual cases, and may not reflect the general experience with the drug. Moreover, information about the total number of exposed persons is unknown. Therefore, rates of outcomes cannot be calculated from the retrospective reports. However, a series of reported birth defects can be analyzed to detect specific patterns of defects and identify early signals of new drug risks. Table 8 describes all birth defects in retrospectively reported cases and all other events are described in Appendix B. The Committee does not note a specific pattern of defects among these cases. Despite these limitations, the Registry provides a useful tool for supplementing animal toxicology studies, other epidemiologic studies and clinical trials to assist clinicians in weighing the risks and benefits of treatment for individual patients. The Committee notes that the Registry has now considerably passed the milestone of 1000 outcomes for prospective first trimester exposures to lamotrigine monotherapy and thus has met its primary objective, which was to determine whether the overall rate of major malformations was increased among the offspring of exposed women. The Registry has not detected an appreciable increase in the singular outcome of major birth defects overall; as recognized the outset, however, the population monitored is only large enough to detect major teratogenicity and does not have the power to exclude increases in the rates of specific defects. It was further noted by the Committee that when the sample size exceeds 1000 exposed subjects without an excess of major birth defects as a singular outcome (background rate of 2%-3%), the confidence interval is sufficiently narrow to indicate that there is not an appreciable effect of the exposure on the risk of major birth defects overall. At the same time, the Committee recognizes that as the Registry exceeds 1000 subjects, the likelihood of chance findings for specific defects (which may occur at baseline rates of 1/1000 or less) increases, and the Committee agreed that other methods (e.g., various case-control approaches) are more appropriate and powerful to identify increases in the rates of specific defects. For these reasons, the Committee recommends termination of this Registry. Monitoring for an increase in specific defects could more productively continue through various other observational approaches, such as case control surveillance. REGISTRY ENROLLMENT Such a case registration approach is successful only with the continued participation of health professionals who register patients and assist in providing follow-up information postpartum. The assistance of health professionals who have provided information to the Registry is greatly appreciated, and the help of others is eagerly sought. The Lamotrigine Pregnancy Registry encourages reporting of all known exposures. Such referrals should be directed to the Medical Department at your local GlaxoSmithKline company or to the GlaxoSmithKline Lamotrigine Pregnancy Registry at Kendle International Inc., Research Park, 1011 Ashes Drive, Wilmington, N.C. 28405 USA, telephone (910) 256-0549 (call collect) or (800) 336-2176, toll-free in North America, (see Appendix D for enrollment forms). You may send a FAX to (800) 800-1052 (toll-free in North America) or (910) 256-0637 outside North America. This Lamotrigine Pregnancy Registry Interim Report is issued semiannually following the independent review of new data. Each Report includes the historical information as well as new data known to the Registry and, therefore, replaces all previous Reports. If your current Report is older than seven months, please request the updated Interim Report from your local GlaxoSmithKline company, or directly from the Registry. REFERENCES Arpino C, et al. Teratogenic effects of antiepileptic drugs: use of an international database on malformations and drug exposures (MADRE). Epilepsia 2000;41(11):1436-1443. Artama M, Auvinen A., Raudaskoski T, Isojarvi I, Isojarvi J. Antiepileptic drug use in women with epilepsy and congenital malformations in offspring. Neurology 2005;64:1874-1878. Bille C, Skytthe A, Vach W, et al. Parents age and the risk of oral clefts. Epidemiology 2005;6:311-316. Centers for Disease Control and Prevention: Metropolitan Atlanta Congenital Defects Program Procedure Manual. July 1989 (Revised January 1998); A1-B11. To access a copy of the MACDP defect code, please go to http://www.cdc.gov/ncbddd/bd/macdp_resources.htm and click on the link to the .pdf file. Centers for Disease Control and Prevention. Update on overall prevalence of major birth defects - Atlanta, Georgia, 1978-2005. MMWR 2008;57:1-5.  HYPERLINK "http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5701a2.htm_" http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5701a2.htm Christensen K. The 20th century Danish facial cleft population epidemiological and genetic-epidemiological studies. Cleft Palate Craniofacial Journal 1999;36:96-104. Chung CS, Myrianthopoulos NC. Factors affecting risks of congenital malformations: Reports from the Collaborative Perinatal Project. Series: Birth Defects Original Article Series 1975;11(10). Cissoko H, Jonville-Bera AP, Autret-Leca E. New antiepileptic drugs in pregnancy: outcome of 12 exposed pregnancies. Therapie 2002; 57(4):397-401. Correa-Villasenor A, Cragan J, Kucik J, OLeary 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 Research (Part A) 2003;67:617-624. Correa A, Cragan J, Kucik J, et al. Metropolitan Atlanta Congenital Defects Program 40th Anniversary Edition Surveillance Report: Reporting Birth Defects Surveillance Data 1968-2003. Birth Defects Research (Part A) 2007; 79:65-93. Croen LA, Shaw GM, Wasserman CR, et al. Racial and ethnic variations in the prevalence of orofacial clefts in California, 1983-92. Am J Med Genetics 1998;79:42-47. Das S, Runnels R Jr, Smith J, et al. Epidemiology of cleft lip and cleft palate in Mississippi. South Med J 1995;88:437-442. de Haan GJ, Edelbroek P, Segers J, et al. Gestation-induced changes in lamotrigine pharmacokinetics: a monotherapy study. Neurology 2004;63(3):571-573. DeRoo LA, Gaudino JA, Edmonds LD. Orofacial cleft malformations. Associations with maternal and infant characteristics in Washington state. Birth Defects Research (A) 2003;67:637-642. Food and Drug Administration. Guidance for Industry: Establishing pregnancy exposure registries. Rockville (MD): US Department of Health and Human Services, Center for Drug Evaluation and Research and Center for Biologics Evaluation and Research; 2002. Available from URL:  HYPERLINK http://www http://www.fda.gov/cber/gdlns/pregnancy.pdf. Fleiss JL. Statistical Methods for Rates and Proportions. New York: John Riley; 1981;14-15. Gentile S. Lamotrigine in pregnancy and lactation. Arch Women Ment Health 2005;8(1):57-58. Hashmi SS, Waller DK, Langlois P, et al. Prevalence of non-syndromic oral clefts in Texas: 1995-1999. Am J Med Genetics 2005;134(A):368-372. REFERENCES (continued) Holmes LB, Baldwin EJ, Smith CR, Habecker E, Glassman L, Wong SL, Wyszynski DF. Increased frequency of isolated cleft palates in infants exposed to lamotrigine during pregnancy. Neurology 2008;70:2152-2158. Holmes LB, Harvey EA, Coull BA, Huntington KB, Khoshbin S, Hayes AM, Ryan LM. The teratogenicity of anticonvulsant drugs. N Engl J Med 2001;344(15):1132-1138. Holmes LB, Wyszynski DF, Baldwin EJ, Haebecker E, Glassman LH, Smith CR. Increased risk for non-syndromic cleft palate among infants exposed to lamotrigine during pregnancy (abstract): Birth Defect Research Part A: Clinical and Molecular Teratology 2006;76(5)318. Honein MA, Paulozzi LJ, Cragan JD, Correa A. Evaluation of selected characteristics of pregnancy drug registries. Teratology 1999;60:356-364. Kallen B. Maternal drug use and infant cleft lip/palate with special reference to corticoids. Cleft Palate Craniofacial Journal 2003;40(6):624-628. Kline J, Stern Z, Susser M. Conception to birth. Epidemiology of prenatal development. New York: Oxford University Press; 1989;43-68. Mackay FJ, Wilton LV, Pearce GL, Freemantle SN, Mann RD. Safety of long-term lamotrigine in epilepsy. Epilepsia 1997;38(8):881-886. Management of Safety Information from Clinical Trials (Report of CIOMS Working Group VI) 2005. ISBN 92 9036 079 8. Menegotto BG, Salzano FM. Epidemiology of oral clefts in a large South American sample. Cleft Palate Craniofacial Journal 1991;28:373-377. Morrow JI, Russell A, Craig JJ, Morrison P, Robertson I, Guthrie E, Parsons L. Major malformations in the offspring of women with epilepsy: a comprehensive prospective study. Epilepsia 2001;42(suppl 2):125. Morrow JI, Craig JJ, Russell AJC, Irwin B, Guthrie E, Morrison P, Parsons L, Robertson I. Which antiepileptic drugs are safest in pregnancy? Epilepsia 2003;44(suppl 8):60. Morrow JI, Russell A, Gutherie E, Parsons L, Robertson I, Waddell R, Irwin B, Morrison P, McGivern CR, Craig J. Malformation risks of anti-epileptic drugs in pregnancy: A prospective study from the UK Epilepsy and Pregnancy Register. J Neurol Neurosurg Psy 2006;77:193-198. Nelson K, Holmes LB. Malformations due to presumed spontaneous mutations in newborn infants. New Engl J Med 1989;(320):19-23. Ohman I, Vitols S, Tomson T. Lamotrigine in Pregnancy: Pharmacokinetics during delivery, in the neonate, and during lactation. Epilepsia 2000;41(6):709-713. Olsen J, Czeizel A, Sorensen HT, Nielsen GL, de Jong van der Berg LTW, Irgens LM, Olesen C, Pedersen L, Larsen H, Lie RT, de Vries CS, Bergman U. How do we best detect toxic effects of drugs taken during pregnancy? Drug Safety 2002;25(1):21-32. Omtzigt JGC, et al. The risk of spina bifida aperta after first-trimester exposure to valproate in a prenatal cohort. Neurology 1992;42(suppl 5):119-125. Popescu L, Marceanu M, Moleavin I. Withdrawal of lamotrigine caused by sudden weaning of a newborn: a case report. Presented at the 26th International Epilepsy Congress, Paris, August 28-September 1, 2005. Epilepsia 2005;46 (supplement 6),1351. Quattrini A, Ortenzi A, Paggi A, Foschi N, Quattrini C. Lamotrigine and pregnancy. Letter to Editor, Ital J Neurol Sci 1996;17:441-442. Rambeck B, Kurlemann G, Stodieck SRG, May TW, Jrgens U. Concentrations of lamotrigine in a mother on lamotrigine treatment and her newborn child. Eur J Clin Pharmacol 1997;51:481-484. REFERENCES (continued) Sabers A, Dam M, a-Rogvi-Hansen B, Boas J, Sidenius P, Laue Friis M, Alving J, Dahl M, Ankerhus J, Mouritzen Dam A. Epilepsy and pregnancy: lamotrigine as main drug used. Acta Neurol Scand 2004;109:9-13. Samren EB, Van Dujjin CM, Christiaens GCML, Hoffman A, Lindout D. Antiepileptic drug regimens and major congenital abnormalities in the offspring. Ann Neurol 1999;46:739-746. Tolarova MM, Cervenka J. Classification and birth prevalence of orofacial clefts. Am J Med Genetics 1998;75:126-137. Thisted E, Ebbeson F. Malformations, withdrawal manifestations, and hypoglycemia after exposure to valproate in utero. Arch Dis Child 1993;69:288-291. Tomson T, Ohman I, Vitols S. Lamotrigine in pregnancy and lactation: a case report. Epilepsia 1997;38(9):1039-1041. Vajda F, Hitchcock A, Graham J, Solinas C, OBrien T, Lander C, Cook M, Eadie M. The Australian registry for women on antiepileptic medication. Data at 31 Dec. 2003. Presented at the Australian Association of Neurologists Conference in Perth, Australia, May 10-14, 2004. Vajda F, OBrien T, Hitchcock A, Graham J, Lander C. The Australian registry of anti-epileptic drugs in pregnancy: experience after 30 months. Journal of Clinical Neuroscience 2003;10(5):543-549. Vajda FJE, Eadie MJ. Maternal valproate dosage and foetal malformations. Acta Neurol Scand 2005;112:137-143. Vajda FJ, Lander C, Hitchcock A, Graham J, Solinas C, OBrien TJ, Eadie MJ. Five year data from the Australian Pregnancy Registry for Women on Antiepileptic Medication. Epilepsia 2005;46(S8):90. Vallino-Napoli LD, Riley MM, Halliday J. An epidemiologic study of isolated cleft lip, palate or both in Victoria, Australia from 1983-2000. Cleft Palate Craniofacial Journal 2004;41:185-194. Voermans NC, Zwarts MJ, Renier WO, et al. Epileptic seizures during childbirth in a patient with idiopathic generalised epilepsy. Ned Tijdschr Geneeskd 2005;149(25):1406-11. Wide K, Winbladh B, Kallen B. Major malformations in infants exposed to antiepileptic drugs in utero, with emphasis on carbamazepine and valproic acid: a nation-wide, population-based register study. Acta Paediatr 2004;93:174-176. Wyszynski DF, Nambisan M, Surve T, Alsdorf RM, Smith CR, Holmes LB. Increased rate of major malformations in offspring exposed to valproate during pregnancy. Neurology 2005;64:961-965. Appendix A: Methods Registration and Follow-up Reporting of exposed pregnancies is voluntary. Health care professionals with patients exposed to lamotrigine during pregnancy are encouraged to enroll each patient in the Registry as early in the pregnancy as possible. When a patient initiates contact with the Registry they are asked to provide permission, and sufficient contact information, for the Registry to follow-up with their health care professional for the purpose of disseminating Registry data and completing the pregnancy registration process. The Registry requires prospective registration of pregnancies exposed to lamotrigine. To further increase the validity of the data, the Registry strongly urges providers to enroll their patients as early in pregnancy as possible, if possible before any prenatal testing for defects is done. Prospectively reported pregnancies are those reported during pregnancy before the pregnancy outcome is known. Because the outcome of the pregnancy is unknown when the exposure is reported, follow-up to determine the outcome is required. Retrospective reports of outcomes with defects are also carefully reviewed by the Registry, although they may be biased toward the reporting of more abnormal outcomes and are much less likely to be representative of the general population experience. A sample copy of the data collection form is included in Appendix D. This form may be copied and sent to the Registry to report pregnancy exposures to lamotrigine. After receipt of registration information recorded on this form, the Registry will send a follow-up form near the time of delivery to ascertain the outcome of the pregnancy. When the pregnancy is prospectively reported, registration can be accomplished by calling the Registry and verbally furnishing requested data or completing a mailed questionnaire (Appendix D). To assure patient confidentiality the Registry will assign a Patient ID number, which will be used as the reference ID for follow-up communication with the reporting health professional. Near the estimated date of delivery, follow-up is obtained through a short follow-up form sent to the health professional who provides information on maternal risk factors, pregnancy outcome, and neonatal health. A report of an exposure is closed when clear information on the lamotrigine exposure and pregnancy outcome determination has been obtained. A report can also be closed as lost to follow-up when the Registry does not receive the above minimum requirements. Reports of exposures are closed as lost to follow-up only after the reporting health professional has been repeatedly contacted for follow-up information well beyond the expected delivery date, or if the reporting health professional can no longer locate the patient. Only data from closed reports of exposed pregnancies with known outcomes are summarized in this Report. The Registry has continually made efforts to assure patient confidentiality within the Registry. In the past, the Registry collected maternal date of birth, (but now collects mothers age at conception) and requested an unspecified identifier of the reporters choice (other than name), rather than patient initials and/or chart number. However, it is now felt that the Registry should make a further effort to assure patient anonymity in the Registry, and therefore, no patient identifier which could compromise patient confidentiality will be collected. The patient identifier from now on is a Registry assigned patient identification number provided to the reporter at the time the patient is registered. (See Appendix D for instructions on how to obtain Patient ID numbers.) Independent review by specialists in epidemiology, neurology, and teratology from the CDC and academic centers provide interpretation of the data and provide strategies for the dissemination of information regarding the Registry. Institutional Review Board (IRB) Review In accordance with the now published FDA Guidance to Industry: Establishing Pregnancy Exposure Registries, (FDA 2002), the Registry has sought IRB approval from Western IRB (WIRB) in December 2001. With the IRB approval of the protocol, the Registry was granted a waiver from having to obtain patient informed consent. The IRB reviews the Registry protocol annually with quarterly interim status reports required. HIPAA Privacy Rule: Protecting Personal Health Information in Research The HIPAA Privacy Rule allows covered entities (e.g., health care providers) to disclose protected health information (PHI) without subject authorization if the covered entity obtains documentation that an IRB has waived the requirement for authorization. On May 7, 2003, WIRB approved a request for a waiver of authorization for use and disclosure of PHI. WIRB determined that documentation received from this Registry satisfies the requirements for a waiver of authorization (Standards for Privacy of Individually Identifiable Health Information CRF 45, Part 160, Part 164 A-E,  HYPERLINK http://www.hhs.gov/ocr/hipaa; http://www.hhs.gov/ocr/hipaa; Protecting Personal Health Information in Research: Understanding the HIPAA Privacy Rule,  HYPERLINK http://privacyruleandresearch.nih.gov http://privacyruleandresearch.nih.gov). Classification of Outcomes The major interest of the Registry is to monitor lamotrigine exposures in pregnancy for major defects that may be attributable to the drug exposure. This Registry adopts for clarification the term birth defect for abnormalities usually referred to as congenital abnormality. For purposes of data reporting, pregnancy outcomes are categorized as one of the following: 1) outcomes with birth defects, 2) outcomes without birth defects, or 3) spontaneous pregnancy losses. The second category is further classified by: (a) live births, (b) fetal deaths, and (c) induced abortions. This Registry adopts the following definition from birth defects surveillance programs, which define a child with a birth defect as follows: any live or stillborn infant, or electively terminated fetus, of any gestational age with a major structural or chromosomal abnormality diagnosed before 6 years of age, however outcomes are generally reported during the first year of life. Because access to pediatric evaluations and records to obtain follow-up information about the presence of defects is beyond the scope of its methods, the Registry primarily monitors the frequency of major defects that are external, recognizable in the delivery room and/or symptomatic shortly after birth. Minor defects and those diagnosed on an out-patient basis, weeks to months after delivery, are not consistently ascertained and are therefore not included in the Registry. To provide consistency in definition of major defects in this Registry, the CDC MACDP criteria are used as a guide for evaluation of defects (Centers for Disease Control 1989, Correa-Villasenor et al, 2003, Correa et al, 2007). However, all reported defects are described in the report and are reviewed by the Advisory Committee for inclusion as major defects for analysis. Birth defects not meeting the inclusion criteria and conditions not classified as birth defects appear in Appendix B. The Registry disqualifies as defects those findings that are present in infants, 36 weeks gestation (or weighing 2500 gm, if gestation age is not available) and are attributable to prematurity itself, such as patent ductus arteriosus or inguinal hernias. Genetic disorders, such as Trisomy 21, are also excluded from the defects classification as they are not likely to be related to drug exposure. In addition, anatomic findings from prenatal sonography, such as mild hydronephrosis and choroid plexus cysts, which are not detected by the examining physician at birth, are excluded from the defects classification for this Registry. Likewise, infants with only transient or infectious conditions or biochemical abnormalities are classified as being without birth defects unless there is a possibility that the condition reflects an unrecognized birth defect. Exclusions of Reported Exposures For this Registry, emphasis is placed on prospective registration of pregnancies involving use of lamotrigine during pregnancy. However, the Registry encourages reporting of all known prenatal exposures to lamotrigine, though not all reports are appropriate for inclusion in the analysis of data. Pregnancies included in the data analysis are those prospectively registered by health care providers. Occasionally the Registry receives notification of prenatal exposures and pregnancy outcomes from patients, but without verification by a health care provider. Though the Committee also reviews these outcomes, the reports are not included in the data analysis but are summarized in Appendix C. Retrospective reports from health care providers are also received in the Registry. These outcomes are reviewed and are helpful for detecting a possible pattern of defects. Retrospective reports are excluded from the Registry data, but retrospectively reported birth defects are summarized in Section 4 as data from other sources. Analysis An important aspect of the Registry is the Advisory Committee formed to oversee the process and results. The Committee is composed of representatives from GlaxoSmithKline, the CDC, and specialists in epidemiology, neurology, obstetrics, and teratology, who review all the Registry data on an ongoing basis and meet twice a year to review the aggregate data. Members of the Committee agree on an interpretation of the data and provide strategies for the dissemination of information regarding the Registry. An Interim Report is prepared after each meeting to summarize these aggregate data. Since the Report contains historical information as well as the new data, it completely replaces all previous Reports. This Report is available to health care providers who treat this specialized population or who request this information. Pregnancy outcomes are stratified by the earliest trimester of exposure. Gestational weeks are counted from the date of the last menstrual period, the second trimester as beginning at week 14, and the third trimester as beginning at week 28. It should be noted that no birth defect rates are calculated in the various subgroups until a sufficient number of cases has been obtained. To determine if risk of birth defects in pregnancies exposed to lamotrigine could be elevated, the proportion of birth defects in all prospectively reported pregnancies is compared with those reported in the literature for the general population and for completed pregnancies in cohorts of women with epilepsy. Data from the Collaborative Perinatal Project which used a broader case definition, longer follow-up after birth, and prospective case ascertainment, have indicated birth defect rates as high as 5%-7% (Chung et al, 1975). Other sources using the CDC case definition and retrospective ascertainment show lower rates of all birth defects, approximately 3% (Correa et al, 2007). Comparison of rates of birth defects in the Lamotrigine Pregnancy Registry to rates observed in the general population could overestimate risk related to lamotrigine use because of 1) elevated risk associated with other antiepileptic drugs also used by women in this Registry and 2) elevated risk associated with maternal epilepsy. Because the increased risk of birth defects in the literature is associated with AED polytherapy, we monitor the frequency of polytherapy in the prospectively reported pregnancies. To determine whether there is a specific type of defect that could be associated with lamotrigine use, all prospectively and retrospectively reported defects are reviewed for patterns of birth defects that could suggest a specific etiology. Individual birth defects are evaluated for timing of exposure to lamotrigine relative to the origins of the defect, presence of other causes (e.g., recognized genetic or chromosomal defect or exposure to a known teratogen), whether the defect is totally unknown or a previously unseen event, and whether there is a unique combination of defects. The Data Summary section of this Report describes the independent reviewers assessment of the data according to these criteria. Studies have shown that rate of spontaneous abortion is high early in pregnancy and decreases substantially from week 8 to week 28, yielding a cumulative estimated rate of 14%-22% (Kline et al, 1989). Although the Advisory Committee reviews each pregnancy outcome, calculation of rates of spontaneous pregnancy losses overall is outside the scope of the Registry, should not be attempted, and cannot be compared to background rates because pregnancies in this Registry are reported at variable and, for some, imprecise duration of pregnancy. For example, if a pregnancy is registered at 10 weeks, only a spontaneous loss after this time can be detected and included in the prospective reports. Similarly, pregnancy losses occurring early in gestation may not be recognized and/or reported. Appendix B: Minor Defects or Other Conditions Reported at the Outcome of Pregnancy Infants with only transient or infectious conditions, biochemical abnormalities, or minor defects are classified as being without birth defects unless there is a possibility that the condition reflects an unrecognized birth defect. Detected and reported transient or infectious conditions or biochemical abnormalities in infants without birth defects and infants with minor defects are noted in the following tables of reports of infants with conditions other than birth defects. Prospective Registry 1st Trimester Exposure25921.First postnatal visit slight jitteriness of legs, not seen at second visit.25952.A primary anastomosis performed for localized volvulus of ileum with dilated loops filled with meconium of normal consistency. Colon contained meconium, but not Meckels diverticulum. The gall bladder, liver, spleen, and stomach were normal. Bowel rotation normal.25993.Suspected infection.26044.Mild jaundice.26205.Mild colic and gestational reflux.26366.Umbilical cord around infants neck at delivery.26397.Slight tapering of the distal metacarpals.26578.Respiratory rate = 60 at birth. Required oxygen at 1 hour. At 3 hours post delivery, good breath sounds but slightly indrawing.26769.Slight growth retardation.269510.Non-development of fetus.271611.Jaundice for 10 days.375212.Umbilical cord around the neck - slipped over.432813.Massive pulmonary hemorrhage immediately following birth; full resuscitation given along with blood, fresh frozen plasma and vitamin K. Infant was pronounced dead 3 hours after delivery. Postmortem showed no anatomical abnormalities.517614.Web toe (right foot middle digits) and jaundice.525215.Slight bruising.526816.Jaundice.531217.Cyanosis of the face observed for the first three days after birth, attributed to delivery.533218.Slight respiratory problem after birth observed for some hours.1018719.Ultrasound showed several periventricular cysts (pseudo cysts) thought to be secondary to intrauterine cytomegalovirus infection. Respiratory distress and a patent ductus arteriosus dilatation of side ventricle. A year later, no developmental defect noted.1022720.Amniotic fluid discolored.1025121.Respiratory distress and severe bradycardia immediately after birth. Apgar scores were 10/1, 1/5, 7/10. Treated for streptococcus pneumonia.1030622.The mother experienced placental abruption at week 32. The neonate was not able to be saved, the autopsy was normal.1025223.Umbilical cord around the neck. Prospective Registry 1st Trimester Exposure (continued)1030824.After the birth, the baby experienced apneic conditions 3 times. The reporter did not think the condition was related to lamotrigine.491725.**Facial asymmetry, especially of the mandible.527226.**Wide set eyes, no epicanthic folds, infraorbital creases, broad nose, large mouth, bilateral undescended testes, sinus-bridge of nose, right facial palsy, persistent patent ductus arteriosus (PDA) (M-ECHO, MRI normal).1018127.**Light facial dysmorphy: no philtrum, syndactyly 2nd and 3rd toes bilateral.1034428.Perinatal asphyxia; meconium trachea intake. The newborn baby was moved to ICU and intubated.1042929.Heart murmur was noted and later had disappeared. The pediatrician clarified that the child was healthy.1047330.4 nevi with growth tendency on head, ears, chest and feet. No other pathologic findings.1065431.Mild retrognathia and glandular hypospadias.1066632.Incidental 2.0 x .7 cm extra axial hemorrhage in right fronto-parietal temporal region (questionable epidural vs subdural) uncovered on CAT Scan when baby had confined apnea/bradycardia episode without sequel. Probably secondary to vacuum assists to non-spontaneous vaginal delivery in combination with moderately severe shoulder dystocia and variable decelerations.1071033.Intrauterine growth retardation. Premature delivery.1105734.Jaundice just after the birth, but did not need phototherapy.1092235.Two-vessel cord, but no problem noted.1092836.Heart murmur was heard at birth and taken for a defect, although it disappeared before any investigation was done.1110537.Acid reflux.1128538.Possible tracheomalacia, but baby was feeding well at time of the report.1148839.Patient had to undergo a caesarean section because of transient fetal low heart rate; at time of report the infants condition was fair.1065540.Respiratory problems atelectasis right lung. Child has slight asthmatic bronchitis.1109441.Slight bruising of little toe. Strawberry nevi. 1122142.Dehydration.1126843.Index fingers on both hands are longer than middle fingers.1157144.Mild left brachial plexus traction injury probably related to large size of fetus. Very mild weakness of left upper limb, completed resolved at one month.1179345.Intrauterine fetal demise at approximately 36 weeks. Per autopsy: 1) Segmental umbilical cord dilatation with marked dilatation of umbilical vein; no evidence of thrombosis; 2) Transverse skin/soft tissue depression at superior/medial aspect of both legs, probably due to umbilical cord entrapment; 3) Pedunculated rudimentary 6th digits at lateral proximal aspect of both 5th fingers; 4) Overlapped cranial plates; 5) Flattened nose; 6) Extensive skin sloughing; 7) Marked softening of internal organs; 8) No internal developmental abnormalities.1180046.Hypospadias and hydrocele. The child was examined at 7 weeks of age by a pediatrician who was not sure that the hypospadias was real. Ultrasound of kidney and urethra were normal.1189547.Second to last toe on each foot potentially slightly longer than others. Possible need for surgery in the future.1198248.Two vessel umbilical cord.1215049.Severe hypoglycemia at delivery.1219250.Innocent heart murmur. Cardiology consult was ok.Prospective Registry 1st Trimester Exposure (continued)1230351.Suspected amnion infection. Therapy with antibiotics for 7 days. Infection resolved.1259252.Infant lived about 30 minutes after birth. Placenta torn away from uterine wall.1234753.Infant transferred to NICU and subsequently died.1263554.Ultrasound examination of the infant's head revealed asymmetry of lateral chambers of the brain (left greater than right), bilateral hyperechogenicity of choroid plexuses accompanied by distension of region "C"; rounded occipital horn on the left side; third and fourth brain chambers with no changes. Umbilical cord was wrapped around the infant's neck two times and one time around the trunk. 1284255.Cord wrapped around neck and infant was initially slow to respond.1263456.Infant hospitalized due to staphyloccomia.1263957.Infant hospitalized due to prematurity.1270458.Intrauterine growth restriction, borderline small.1275559.Ring finger on both hands bends very far back.1278460.Infant small due to patients smoking.1282061.Possible blindness (genetic) and anemia of unknown etiology.1290162.Placental abruption. Prematurity requiring ventilation and tracheostomy.1292063.Meconium present in amniotic fluid.1300064.Anxiety and seizures secondary to absence Phenobarbital Syndrome.1312465.Infant delivered face up and requiring suctioning due to cord around neck.1318266.Vertical nystagmus/opsoclonus.1320467.Scar after a cleft lip surgery not required.1311868.Intense physiologic icterus of the newborn and an umbilical hernia.1312669.Meconium aspiration and breathing problems attributed to high altitude.1316170.Small hemangioma on arm.1319771.Cord wrapped around neck; infant died from strangulation.1321172.Heart murmur and cord wrapped around neck.1323673.Mitral incompetence. 1335174.Bilateral congenital dislocation of hips.1342775.Undeveloped lungs.1357776.Prematurity and jaundice.1353877.Nuchal cord wrapped twice.1356978.Home delivery, no fetal movement-infant did not survive.1371079.Fetal distress.1379380.Poor sucking reflex at birth.1382681.Jaundice.1383482.Lethargic at birth.1384783.Death due to aspiration of amniotic fluid, maceration, and pulmonary atelectasis.1385084.Benign heart murmur.1385685.Mild colic.1400286.Infant died 1 hour after birth. The placenta was tested and said to be abnormal. Prospective Registry 1st Trimester Exposure (continued)1406187.Abnormal placenta and meconium stained amniotic fluid.1432888.Port wine stain on forehead.1417389.Palpable metopic suture.1428090.Prolonged hypoglycemia.1429791.Spinal meningitis.1448692.Bilateral hydroceles, macropenis, grade 2/6 systolic heart murmur.1450793.Inguinal hernia, requiring surgical repair at less than two months of age.1459494.Tremors after delivery. 1473295.NICU for one week for undiagnosed etiology. 1496996.Shoulder fracture occurred secondary to the extraction.1502497.Jaundice and failed hearing test in left ear.1457698.Macrosomia.1473199.Infant hospitalized for 9 days, needed intubator.14763100.Infant swallowed meconium during delivery, was intubated and admitted to the NICU.14858101.Trouble nursing.15016102.Delivery complications. Infant had decreased heart rate during labor and meconium staining.15021103.Apnea and polycythemia. 15205104.Baby premature, on ventilator after delivery and had acid reflux. Infant hospitalized for double pneumonia.15263105.Infant remains in hospital requiring feeding, no longer needs artificial respiration.15328106.Baby remained in NICU for 48 hours due to low blood glucose.15085107.*Transient tachypnea.15090108.*Jaundice, blood glucose decreased. 15318109.*Neonatal adaptation disorder, Dystrophic habitus. The mother had idiopathic thrombocytopenic purpura during pregnancy.15372110.*Severe intrauterine growth retardation.15458111.*Prematurity.15512 twins112.*The infant was in the NICU prophylactically; fetal demise of a twin occurred at approximately 19 weeks gestation.15540113.*Neonatal abstinence syndrome related to mothers use of methadone.15605114.*Neonatal abstinence syndrome related to mothers use of methadone.Prospective Registry 2nd Trimester Exposure111801.Permeable ductus arteriosus and hip click at delivery. Both disappeared on repeat examination one hour later.123052.Mother reported infant disliked breastfeeding. Milk was grayish and watery. After breastfeeding, infant was awake and did not sleep. This improved when breastfeeding stopped.128363.Barbiturate found in newborns blood.131674.Reflux requiring hospitalization.136125.Jaundice and weight loss.136546.Missed labor, macerated fetus.14166 Prospective Registry 2nd Trimester Exposure (continued)141667.Fetal arrhythmia.142428.Right ear failed initial hearing screen.147679.Bilateral preauricular skin tags.1370310.Infant on continuous positive airway pressure after delivery.Prospective Registry 3rd Trimester Exposure133011.Intrauterine growth retardation.Retrospective Reports2681 (nv)1.Infant with squint (strong family history of squint).4368 (nv)2.Shivers.4750 (nv)3.Jitteriness.2687 (nv)4.Respiratory distress and acidosis requiring ventilation for 3 days.3750 (nv)5.Jaundice, Respiratory Distress Syndrome due to prematurity.3885 (nv)6.Respiratory insufficiency.4142 (nv) twins7.Abnormal on an oto-acoustic emission test; no emission on right side (small canal); normal emission on the left side, sepsis.4142 (nv) twins8.Hyaline membrane disease, sepsis.4184 (nv)9.Infant irritable.4186 (nv)10.Mild postnatal jaundice.4725,5156 (nv)11.Two reports of jaundice requiring readmission.4462 (nv)12.Poor head control at birth, mild tachypnea, mildly elevated temperature, both resolved. Muscle tone improved over the hospital stay. No dysmorphic features. Event attributed to the mothers use of magnesium during labor.10946 (nv)13.Infant was pale, had broad forehead, had very distinctive ears with pointed helix on left - ear measured 3.3 cm, prominent anti-helix on right - ear measured 3.0 cm, eyes were normal, broad nasal bridge, questionable trismus - palate normal, small chin, neck short with redundant skin, heart had slight gallop, right testes was retractile, left testes was not fully descended, extra hair on lower back, long fingers and toes with digitalized thumb.10850 (nv)14.Spontaneous abortion at week 12. The patient was told that the fetus was not normally developed.11111 (nv)15.Fetal valproate syndrome.11386 (nv)16.Autism/Aspergers syndrome.11378 (nv)17.Breathing problems immediately after birth, growing and drinking poorly at time of report.4553 (nv)18.Spontaneous abortion. Histology showed fetal tissue with chronic villi.4791,10102 (nv)19.Two reports of infants with finely tapered fingers.10274 (nv)20.Cerebral bleeding. Infant died within a week of birth.10388 (nv)21.Webbed feet (2nd and 3rd toes on both feet). 10250 (nv)22.Erbs palsy, brachial plexus palsy, congenital disorder.11629 (nv)23.Patent ductus arteriosus.10101 (nv)24.Slight joining of the 2nd and 3rd toes on both feet.11535 (nv)25.Laryngomalacia. Respiratory problems requiring hospital treatment. Infant died at five months of age due to respiratory problems and infections. Retrospective Reports (continued)11835 (nv)26.Right anterior leg nevus.13293 (nv)27.Apnea, gastro-esophageal reflux.13367 (nv)28.Meconium staining in amniotic fluid.14231 (nv)29.Peripheral facial paralysis; minor left inferior lip hypotonia resolved.14405 (nv)30.Empty amniotic sac without embryo.14524 (nv)31.Blind sacrococcygeal fistula.15117 (nv)32.Dermoid cysts on left brow and mouth.15156 (nv)33.Sacral dimple.15169 (nv) 34.Postnatal development of juvenile rheumatoid arthritis at ~1 year of age.15294 (nv)35.Dysmorphic face including extrusion of the tongue and slight epicanthus. The infant also had hypotonia and gastroesophageal reflux.15342 (nv)36.Baby died due to SIDS15375 (nv)37.Undescended right testicle.15642 (nv)38.Deafness.15643, 15264 (nv)39.Two reports of infants with facial palsy.15520 (nv)40.**Partial syndactyly of the skin (no bone involved) between the second and third digits (toes) bilaterally.Prospective Patient Reports12993 (nv)1.Lungs were not fully developed and infant had heart disease.Retrospective Patient Reports3804 (nv)1.Pyloric stenosis.11657 (nv)2.Pierre Robin Sequence, cleft palate complete, heart murmur. 15641 (nv)3.Down syndrome; septal heart defect, type not specified. The mother has Type 1, insulin-dependent diabetes, diagnosed prior to pregnancy.*denotes cases that are new since the last Report **denotes cases that were previously listed as birth defects and have now been classified as minor defects by the Lamotrigine Advisory Committee definition of birth defects ***denotes case that was previously classified as a birth defect and upon receipt of additional information, was reclassified as no defect. Appendix C: Patient Reported Prenatal Lamotrigine Exposures Criteria for inclusion in the prospective Registry requires registration and follow-up by a health care professional. Currently there are six prospectively registered prenatal lamotrigine exposures from patients with outcomes pending. Appendix D: Registry Enrollment and Data Forms Registration and Follow-up forms may be obtained from the Pregnancy Registry or may be copied from the included samples to prospectively report prenatal exposure to lamotrigine. Instructions for Completing Forms Patient Anonymity and Patient Identifiers In the past, the Registry has made efforts to assure patient confidentiality within the Registry. It is now felt that the Registry should make a further effort to assure patient anonymity in the Registry. Therefore, the Registry will no longer collect any identifiers that might inadvertently compromise patient confidentiality. The patient identifier is now a Registry assigned number provided to the reporter at the time the patient is registered. Patient IDs can be obtained by calling or faxing the Registry for a number (or a block of numbers, for providers who register patients on a regular basis). The Registry also provides a Patient Log as a possible way the reporter might cross-reference the patient with the Registry Patient ID number. Whatever method is used, please keep the record in a secure place (separate from the patients chart) to assist in protecting patient confidentiality at your site. Prospective Registration - (To be completed when notifying Registry of prenatal exposure while patient is still pregnant). Call or fax the Registry office for Patient ID number Track the Patient ID number with your own identification of the patient Secure the tracking log to protect patient confidentiality ( Copy all pages of the Registration Form Fill in as much information as is available at the time of reporting Report as early as possible after the exposure is known to you Return the form to the Registry. You will be sent a short Follow-up Form to report on the pregnancy outcome at or near the patients estimated date of delivery. Outside North America please return the completed form(s) to the Medical Director at your local GlaxoSmithKline company or directly to the Registry at: Lamotrigine Pregnancy Registry Kendle International Inc. Research Park 1011 Ashes Drive Wilmington, NC 28405 USA OR register via phone by dialing (910) 256-0549 (call collect) or (800) 336-2176 (toll-free in North America) OR send a FAX to (800) 800-1052 (toll-free in North America) or (910) 256-0637 outside North America Alternatively, patients can enroll themselves into the North American AED Pregnancy Registry by calling (888) 233-2334 (call toll-free). LAMOTRIGINE PREGNANCY REGISTRY PATIENT LOG Call the Registry Office for Patient (Log) ID Numbers (800) 336-2176 or (910) 256-0549 (phone) (800) 800-1052 or (910) 256-0637 (fax) In an effort to assure patient confidentiality and anonymity, the Registry does not collect identifying information (e.g., initials, chart number, date of birth) on patients enrolled in the Registry. The number used to refer to your patient for further follow-up on the outcome of this pregnancy will be a Patient (Log) ID number. This log is provided for your convenience. You may want to use this form to track your Registry patients and to easily cross-reference the Lamotrigine Registry Patient (Log) ID number with your patient. THIS LOG IS FOR YOUR USE ONLY, DO NOT RETURN THIS TO THE REGISTRY FOR QUICK REFERENCE, KEEP SEPARATE FROM PATIENTS CHART Please call the Registry Office at (800) 336-2176 if you have questions. Patient (Log) IDSuggested information to use to reference this patient when Registry follow-up is necessaryassigned by the RegistryPatient NameChart numberEDDDate Registry form completed00001Jane Doe12365601 Jun 200812 Jan 2008 Lamotrigine PREGNANCY REGISTRYFOR OFFICE USE ONLY Page 1 of 2 Registry ID______________ HCP ID ____________Registration Form WPSP ID ______________ Country ___________________Return by FAX to: 800-800-1052 910-256-0637 (All International Faxes) Registry date of notification _____ _____ _____  FORMCHECKBOX  Phone day month year  FORMCHECKBOX  Transcribed Patient (Log) ID ____________________Registry-assigned ID number. Call / Fax the Registry Office for a non-patient identifying number (800-336-2176 US / Canada, 910-256-0549 Intl, phone) 800-800-1052 US / Canada, 910-256-0637 Intl, Fax)Note: To help assure patient confidentiality the Registry uses a Registry-assigned patient ID to refer to your patient to obtain follow-up and outcome information. A patient log will be sent to you, if this is your first registrant. The Log will help cross-reference this ID with your own identifier(s) for this patient. Keep the log in a secure place.Maternal DataRace  FORMCHECKBOX  White  FORMCHECKBOX Black  FORMCHECKBOX  Hispanic  FORMCHECKBOX  Asian  FORMCHECKBOX Other Patient Age _____If patient is included in another Registry, please specify  FORMCHECKBOX  EURAP  FORMCHECKBOX  North American AED  FORMCHECKBOX  Other Is there evidence of a defect from a prenatal test?  FORMCHECKBOX  Yes  FORMCHECKBOX  No If yes, indicate which test(s) showed evidence of birth defect  FORMCHECKBOX  Ultrasound  FORMCHECKBOX  Amniocentesis  FORMCHECKBOX  MSAFP  FORMCHECKBOX  Other: ______________ Last Menstrual Period ____ ____ ____ day month year Estimated Date of Delivery ____ ____ ____ day month year How was the Estimated Date of Delivery determined?  FORMCHECKBOX  by Last Menstrual Period  FORMCHECKBOX  by Ultrasound  FORMCHECKBOX  by Other Method: All lamotrigine doses during this pregnancy Indication  FORMCHECKBOX  Epilepsy  FORMCHECKBOX  Bipolar Disorder  FORMCHECKBOX  Other ________________Course Began (d/m/y)Daily Dose (total mg/day)Course Began* (gestation week from LMP)Course Ended (gestation week from LMP)If Ongoing (symbol 214 \f "Symbol") Course 1___ ___ __________________________________ FORMCHECKBOX Course 2___ ___ __________________________________ FORMCHECKBOX Course 3___ ___ __________________________________ FORMCHECKBOX * If Course 1 began prior to conception, enter 0 Health care Provider InformationNameSpecialtyAddressPhoneFaxAlternate ContactProvider's SignatureDate____ _____ ____ day month year  Lamotrigine Pregnancy Registry Registration Form Page 2 of 2Return by FAX to: 800-800-1052 (U.S., Canada) Registry ID________________ 910-256-0637 (All International Faxes) (FOR OFFICE USE ONLY) Patient (Log) ID________________________The Registry-assigned ID number Other Antiepileptic/psychotropic drugs (within 1 month of conception or during this pregnancy)Trimester of PregnancyOther Antiepileptic/ Psychotropic DrugsPrior to ConceptionFirst TrimesterSecond TrimesterThird Trimester((and include total dose for all that apply)(SYMBOL 214 \f "Symbol")Total Daily Dosage (mg/day)(SYMBOL 214 \f "Symbol")Total Daily Dosage (mg/day)(SYMBOL 214 \f "Symbol")Total Daily Dosage (mg/day)(SYMBOL 214 \f "Symbol")Total Daily Dosage (mg/day)amitriptiline (Elavil) FORMCHECKBOX  FORMCHECKBOX  FORMCHECKBOX  FORMCHECKBOX bupropion (Wellbutrin) FORMCHECKBOX  FORMCHECKBOX  FORMCHECKBOX  FORMCHECKBOX carbamazepine (Tegretol) FORMCHECKBOX  FORMCHECKBOX  FORMCHECKBOX  FORMCHECKBOX citalopram (Celexa) FORMCHECKBOX  FORMCHECKBOX  FORMCHECKBOX  FORMCHECKBOX clomipramine (Anafranil) FORMCHECKBOX  FORMCHECKBOX  FORMCHECKBOX  FORMCHECKBOX clonazepam (Klonopin) FORMCHECKBOX  FORMCHECKBOX  FORMCHECKBOX  FORMCHECKBOX clozapine (Clozaril) FORMCHECKBOX  FORMCHECKBOX  FORMCHECKBOX  FORMCHECKBOX diazepam (Valium) FORMCHECKBOX  FORMCHECKBOX  FORMCHECKBOX  FORMCHECKBOX ethosuximide (Zarontin) FORMCHECKBOX  FORMCHECKBOX  FORMCHECKBOX  FORMCHECKBOX felbamate (Felbatol) FORMCHECKBOX  FORMCHECKBOX  FORMCHECKBOX  FORMCHECKBOX fluoxetine (Prozac) FORMCHECKBOX  FORMCHECKBOX  FORMCHECKBOX  FORMCHECKBOX gabapentin (Neurontin) FORMCHECKBOX  FORMCHECKBOX  FORMCHECKBOX  FORMCHECKBOX haloperidol (Haldol) FORMCHECKBOX  FORMCHECKBOX  FORMCHECKBOX  FORMCHECKBOX lithium FORMCHECKBOX  FORMCHECKBOX  FORMCHECKBOX  FORMCHECKBOX olanzapine (Zyprexa) FORMCHECKBOX  FORMCHECKBOX  FORMCHECKBOX  FORMCHECKBOX paroxetine (Paxil) FORMCHECKBOX  FORMCHECKBOX  FORMCHECKBOX  FORMCHECKBOX phenobarbital FORMCHECKBOX  FORMCHECKBOX  FORMCHECKBOX  FORMCHECKBOX phenytoin (Dilantin) FORMCHECKBOX  FORMCHECKBOX  FORMCHECKBOX  FORMCHECKBOX primidone (Mysoline) FORMCHECKBOX  FORMCHECKBOX  FORMCHECKBOX  FORMCHECKBOX quetiapine (Seroquel) FORMCHECKBOX  FORMCHECKBOX  FORMCHECKBOX  FORMCHECKBOX risperidone (Risperdal) FORMCHECKBOX  FORMCHECKBOX  FORMCHECKBOX  FORMCHECKBOX sertraline (Zoloft) FORMCHECKBOX  FORMCHECKBOX  FORMCHECKBOX  FORMCHECKBOX topiramate (Topamax) FORMCHECKBOX  FORMCHECKBOX  FORMCHECKBOX  FORMCHECKBOX trimethadione (Tridione) FORMCHECKBOX  FORMCHECKBOX  FORMCHECKBOX  FORMCHECKBOX valproate (Depakote) FORMCHECKBOX  FORMCHECKBOX  FORMCHECKBOX  FORMCHECKBOX venlafaxine (Effexor) FORMCHECKBOX  FORMCHECKBOX  FORMCHECKBOX  FORMCHECKBOX vigabatrin (Sabril) FORMCHECKBOX  FORMCHECKBOX  FORMCHECKBOX  FORMCHECKBOX other: ______________ FORMCHECKBOX  FORMCHECKBOX  FORMCHECKBOX  FORMCHECKBOX  Lamotrigine PREGNANCY REGISTRYFOR OFFICE USE ONLY Page 1 of 3 Registry ID ______________ HCP ID ____________Followup Form WPSP ID _______________ Country _______________Return by FAX to: 800-800-1052 (U.S., Canada) 910-256-0637 (All International Faxes)Date case closed _____ _____ _____  FORMCHECKBOX  Phone day month year  FORMCHECKBOX  Transcribed MATERNAL DATA Patient (Log) ID_______________________The Registry-assigned ID number  All lamotrigine doses during this pregnancy Indication  FORMCHECKBOX  Epilepsy  FORMCHECKBOX  Bipolar Disorder  FORMCHECKBOX  Other ________________Course Began (d/m/y)Daily Dose (total mg/day)Course Began* (gestation week from LMP)Course Ended (gestation week from LMP)If Ongoing at Delivery (SYMBOL 214 \f "Symbol") Course 1___ ___ __________________________________ FORMCHECKBOX Course 2___ ___ __________________________________ FORMCHECKBOX Course 3___ ___ __________________________________ FORMCHECKBOX  *If Course 1 began prior to conception; enter 0 seizure history during this pregnancy Trimester of PregnancyAverage Number of Seizures Per TrimesterFirstSecondThird Complex/simple partial_______________________ Generalized tonic/clonic _____________________ Other________________________________________ Lamotrigine Pregnancy Registry Followup Form Page 2 of 3Return by FAX to: 800-800-1052 (U.S., Canada) Registry ID________________ 910-256-0637 (All International Faxes) (FOR OFFICE USE ONLY) Patient (Log) ID _____________________The Registry-assigned ID number Other Antiepileptic/psychotropic drugs (within 1 month of conception or during this pregnancy)Trimester of PregnancyOther Antiepileptic/ Psychotropic DrugsPrior to ConceptionFirst TrimesterSecond TrimesterThird Trimester((and include total dose for all that apply)(SYMBOL 214 \f "Symbol")Total Daily Dosage (mg/day)(SYMBOL 214 \f "Symbol")Total Daily Dosage (mg/day)(SYMBOL 214 \f "Symbol")Total Daily Dosage (mg/day)(SYMBOL 214 \f "Symbol")Total Daily Dosage (mg/day)amitriptiline (Elavil) FORMCHECKBOX  FORMCHECKBOX  FORMCHECKBOX  FORMCHECKBOX bupropion (Wellbutrin) FORMCHECKBOX  FORMCHECKBOX  FORMCHECKBOX  FORMCHECKBOX carbamazepine (Tegretol) FORMCHECKBOX  FORMCHECKBOX  FORMCHECKBOX  FORMCHECKBOX citalopram (Celexa) FORMCHECKBOX  FORMCHECKBOX  FORMCHECKBOX  FORMCHECKBOX clomipramine (Anafranil) FORMCHECKBOX  FORMCHECKBOX  FORMCHECKBOX  FORMCHECKBOX clonazepam (Klonopin) FORMCHECKBOX  FORMCHECKBOX  FORMCHECKBOX  FORMCHECKBOX clozapine (Clozaril) FORMCHECKBOX  FORMCHECKBOX  FORMCHECKBOX  FORMCHECKBOX diazepam (Valium) FORMCHECKBOX  FORMCHECKBOX  FORMCHECKBOX  FORMCHECKBOX ethosuximide (Zarontin) FORMCHECKBOX  FORMCHECKBOX  FORMCHECKBOX  FORMCHECKBOX felbamate (Felbatol) FORMCHECKBOX  FORMCHECKBOX  FORMCHECKBOX  FORMCHECKBOX fluoxetine (Prozac) FORMCHECKBOX  FORMCHECKBOX  FORMCHECKBOX  FORMCHECKBOX gabapentin (Neurontin) FORMCHECKBOX  FORMCHECKBOX  FORMCHECKBOX  FORMCHECKBOX haloperidol (Haldol) FORMCHECKBOX  FORMCHECKBOX  FORMCHECKBOX  FORMCHECKBOX lithium FORMCHECKBOX  FORMCHECKBOX  FORMCHECKBOX  FORMCHECKBOX olanzapine (Zyprexa) FORMCHECKBOX  FORMCHECKBOX  FORMCHECKBOX  FORMCHECKBOX paroxetine (Paxil) FORMCHECKBOX  FORMCHECKBOX  FORMCHECKBOX  FORMCHECKBOX phenobarbital FORMCHECKBOX  FORMCHECKBOX  FORMCHECKBOX  FORMCHECKBOX phenytoin (Dilantin) FORMCHECKBOX  FORMCHECKBOX  FORMCHECKBOX  FORMCHECKBOX primidone (Mysoline) FORMCHECKBOX  FORMCHECKBOX  FORMCHECKBOX  FORMCHECKBOX quetiapine (Seroquel) FORMCHECKBOX  FORMCHECKBOX  FORMCHECKBOX  FORMCHECKBOX risperidone (Risperdal) FORMCHECKBOX  FORMCHECKBOX  FORMCHECKBOX  FORMCHECKBOX sertraline (Zoloft) FORMCHECKBOX  FORMCHECKBOX  FORMCHECKBOX  FORMCHECKBOX topiramate (Topamax) FORMCHECKBOX  FORMCHECKBOX  FORMCHECKBOX  FORMCHECKBOX trimethadione (Tridione) FORMCHECKBOX  FORMCHECKBOX  FORMCHECKBOX  FORMCHECKBOX valproate (Depakote) FORMCHECKBOX  FORMCHECKBOX  FORMCHECKBOX  FORMCHECKBOX venlafaxine (Effexor) FORMCHECKBOX  FORMCHECKBOX  FORMCHECKBOX  FORMCHECKBOX vigabatrin (Sabril) FORMCHECKBOX  FORMCHECKBOX  FORMCHECKBOX  FORMCHECKBOX other: ______________ FORMCHECKBOX  FORMCHECKBOX  FORMCHECKBOX  FORMCHECKBOX  Lamotrigine Pregnancy Registry Followup Form Page 3 of 3Return by FAX to: 800-800-1052 (U.S., Canada) Registry ID________________ 910-256-0637 (All International Faxes) (FOR OFFICE USE ONLY) Patient (Log) ID _____________________The Registry-assigned ID number  pregnancy outcome Date of Outcome _____ _____ _____ day month year Gestational Age ______________ weeks Gender  FORMCHECKBOX  Male  FORMCHECKBOX  Female Length __________cm/in. (circle one) Birth Weight ________________ grams Head Circumference __________ cm/in. (circle one)Outcome Birth Defect Noted?  FORMCHECKBOX  Live Infant  FORMCHECKBOX  Yes  FORMCHECKBOX  No  FORMCHECKBOX  Abortion, Spontaneous  FORMCHECKBOX  Yes  FORMCHECKBOX  No  FORMCHECKBOX  Abortion, Induced  FORMCHECKBOX  Yes  FORMCHECKBOX  No  FORMCHECKBOX  Stillbirth  FORMCHECKBOX  Yes  FORMCHECKBOX  No Method of Delivery  FORMCHECKBOX  Normal Vaginal  FORMCHECKBOX  Caesarean Section  FORMCHECKBOX  Forceps  FORMCHECKBOX  Other If any birth defects were noted, please list the birth defect(s) and any factors that may have had an impact on this outcome: To what do you attribute the defect(s)? Did the defect require surgery/intervention?  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A Project Conducted by GlaxoSmithKline Project Office: Please contact: Kendle International Inc. 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