Short‐ and long‐term complications of in utero exposure to lamotrigine

Abstract

Aims

The present study evaluates the effect of antenatal lamotrigine exposure, on short‐ and long‐term paediatric outcome.

Methods

The study included the children of 83 epileptic women treated with lamotrigine during pregnancy, at a tertiary medical centre between 2004–2014. All newborns were monitored for vital signs, congenital malformations and Finnegan score. In addition, the parents completed a questionnaire regarding their child's development and health up to the age of 12 years.

Results

No major malformations were found in the newborns. None of the newborns had significant withdrawal symptoms by Finnegan score. The children were followed‐up to the age of 12 years (56.6% were 6–12 years at the time of evaluation). There were no significant findings in the incidence of neurodevelopmental disorders.

Conclusions

According to our experience, lamotrigine is generally safe for pregnancy use, associated with minimal short‐term complications with no long‐term effects on the outcome.

What is Already Known About this Subject

• There is no consensus regarding a direct association of lamotrigine use in pregnancy on short‐ and long‐term prognosis.

• Previous studies have demonstrated conflicting results, some finding higher prevalence of congenital malformations in newborns exposed in utero and higher risk for adverse score on autistic traits and language at 36 months.

• Other studies found no significant effect of lamotrigine on congenital malformations and on IQ at the age of 6 years.

What this Study Adds

• The present study, which is, to the best of our knowledge, the first to use the Finnegan score to evaluate newborns and children exposed to lamotrigine during pregnancy, provides further evidence that in utero exposure to lamotrigine does not increase the risk of birth malformations or neonatal complications.

• This study provides the most extensive long‐term report regarding children whose mothers took lamotrigine during pregnancy.

• Long‐term assessment could not find neurodevelopmental symptoms up to age 12 years.

Introduction

There is a growing body of evidence reporting an increased incidence of malformations and/or long‐term neurodevelopmental disorders in infants of epileptic mothers taking antiepileptic drugs (AEDs) during pregnancy as compared to epileptic mothers not taking AEDs 1, 2, 3, 4, 5, 6. These risks need to be weighed against the critical implications of withholding medical treatment from epileptic mothers 7. This latency and the widespread use of an AED in women of childbearing age lead to uncertainty about the best course of action 2, 4, 5. Most available data on antiepileptic medication refer to the use of the older generation AEDs such as phenobarbital and valproic acid 8. The shift to newer AEDs (such as lamotrigine) might lead to lower risks 9.

Lamotrigine is designated by International Union of Pharmacology (IUPHAR) 10 as a new‐generation AED. The exact mechanism of action of lamotrigine is unknown but is believed to arise from inhibition at voltage‐sensitive sodium channels and/or calcium channels 10, 11. Lamotrigine has a broad‐spectrum efficacy, wide clinical range and a good tolerability and safety profile 10, 11, 12. It is known to cross the placenta. However, there is no consensus regarding a direct association of lamotrigine use in pregnancy and congenital malformations 8, 13.

The reports regarding lamotrigine long‐term prognosis among children exposed in‐utero include reports on higher IQ scores than in children exposed to other AEDs, as well as reports on a higher risk for adverse score on autistic traits and language at the age of 36 months 3, 14. Two different longer‐term studies found no significant effect of lamotrigine on IQ at age 6 years 5, 15.

The aim of this study was to evaluate further the short‐ and long‐term physiological, cognitive and emotional development of children exposed to lamotrigine in utero to the age of 12 years. We hypothesized that results might be more stable, and more strongly related to adult performance.

Methods

Patients and setting

This cohort study included all 83 women who gave birth at Rabin Medical Center–Beilinson Hospital, Israel between January 2004 and August 2014 who were treated with lamotrigine during the first trimester of pregnancy. The women were identified by a search of the Beilinson Teratology Information Service. Only patients for whom the system contained complete records were included in the study. Women with any chronic diseases other than epilepsy were excluded, as were women who were using medications known to influence their child's short and long‐term outcome including opioids, selective serotonin reuptake inhibitors or serotonin–norepinephrine reuptake inhibitors.

Ethical approval

The study was approved by the hospital's institutional review board (Helsinki) committee.

Data collection

Perinatal data were obtained retrospectively from the medical charts of the mothers and the neonates and departmental records (including Finnegan score). Long‐term data obtained from the medical files and by a telephone interview using an ad‐hoc questionnaire. The questionnaire covered: child's age, number of hospitalizations, reasons for hospitalizations, chronic diagnoses, medication(s), advisory doctor's appointments, growing percentiles, neurological symptoms, convulsions, global developmental delay, speech delay, motor delay, coordination disturbance, sensory disturbance, emotional disturbance, slower development, other types of delay, learning disabilities and autism.

Departmental protocol

According to departmental protocol, all newborns exposed to maternal medications in utero are monitored. The Finnegan score is calculated every 8 h for the first 48 h. A score of ≤3 indicates no withdrawal symptoms, 4–7 = light withdrawal symptoms and ≥8 = significant withdrawal symptoms 16. If the score is >3 at 48 h, follow‐up is extended to once every 8 h until it drops. At age 2 h, blood pressure, saturation and glucose level are measured. After the first 48 h, neonates continue to be monitored for an additional 24 h of rooming‐in by the obstetric nursing team.

Statistical analysis

Data were analysed using Medical Statistical Software version 12.5 (Ostend, Belgium, 2013). Univariate analysis was performed to identify differences between the study and control groups. Student t test, Pearson chi‐square test and Fisher exact test were applied as appropriate. Statistical significance was set at P < 0.05. ANOVA with repeated measures was used to assess neonatal adverse signs.

Nomenclature of targets and ligands

Key protein targets and ligands in this article are hyperlinked to corresponding entries in http://www.guidetopharmacology.org, the common portal for data from the IUPHAR/BPS Guide to PHARMACOLOGY 17, and are permanently archived in the Concise Guide to PHARMACOLOGY 2015/16 10.

Results

Data were gathered from 83 mothers with epilepsy and their children. Lamotrigine was administered as monotherapy in 76 mothers with epilepsy (91.6%) combined with other medications in seven (8.4%) as follows: clonazepam (four patients), carbamazepine (two), and quetiapine, levetiracetam and phenytoin in one woman each. Some women were treated with more than one medication. Statistical analysis performed separately for the monotherapy and combined therapy subgroups yielded no significant differences for any of the variables; therefore, all lamotrigine‐treated patients were considered as a single group. The dose effect did not affect the results. No major malformations were found in the newborns and rates of minor malformations were similar to in the general population in Israel.

The maximal Finnegan score was available for 81 newborns (two mothers stopped taking lamotrigine several months prior to delivery). Seventy‐one newborns (87.6%) had no withdrawal symptoms (maximal score < 4) and 10 had mild withdrawal symptoms (maximal score 4–7). None of the newborns had significant withdrawal symptoms (score ≥ 8). The adverse findings in the newborns with a maximum Finnegan score of 3 are shown in Figure 1. There was no correlation of lamotrigine dose during pregnancy or of lamotrigine monotherapy vs. combined therapy and the Finnegan score. Unfortunately, we do not hold data regarding breastfeeding practices in this cohort.

Figure 1.

Prevalence of withdrawal symptoms (Finnegan score >3) in newborns exposed to lamotrigine in utero

Long‐term follow‐up was made at a single point up to the age of 12 years. The results were compared to an equal number of children born at the same hospital to healthy women matched for gestational age and date of birth. Most of the group (56.6% = 47 children) were 6–12 years old when evaluated. The findings of long‐term follow‐up of the children exposed to lamotrigine are shown in Table 1. The only significant difference between the groups was found in speech delay, with a lower rate in the lamotrigine group compared to the control group (six children, 7.2% vs. 15 children, 18.0%, P = 0.036).

Table 1.

Neurological follow‐up of children exposed to lamotrigine in utero and controls

Diagnosis	Prevalence		P value
	Control group	Lamotrigine group
Neurological symptoms	5 (6%)	6 (7.2%)	0.755
Febrile convulsions	3 (3.6%)	2 (2.4%)	0.65
Endocrinology disorders	0	0	>0.999
Atopy	17 (20.5%)	16 (19.3%)	0.846
Failure to thrive	3 (3.6%)	7 (8.4%)	0.192
Autism	1 (1.2%)	0	0.316
Learning disabilities	4 (4.8%)	5 (6%)	0.732
Developmental delay	19 (22.8%)	12 (14.4%)	0.163
Speech delay	15 (18%)	6 (7.2%)	0.036
Motor delay	2 (2.4%)	0	0.155
Coordination disturbance	3 (3.6%)	2 (2.4%)	0.650
Sensory disturbance	0	0	>0.999
Emotional disturbance	0	2 (2.4%)	0.155
Slow development	2 (2.4%)	3 (3.6%)	0.650
Other	5 (6%)	4 (4.8%)	0.732
Hospitalizations	14 (16.9%)	24 (28.9%)	0.065
Chronic medications	1 (1.2%)	2 (2.4%)	0.56

Data are presented as n (%). Bold indicates significance at P < 0.05

Discussion

This study sought to evaluate the effect of in utero exposure to lamotrigine on the neonatal physiological adjustment, congenital malformations and long‐term neurodevelopmental status.

In accordance with previous reports 8, 18, 19, we found that children who were exposed in utero to lamotrigine did not have an increased likelihood of birth defects. Exposure to lamotrigine was not associated with increased postnatal complications 20, 21, 22, 23. We used the Finnegan score to evaluate overall condition of the newborns. Finnegan score was developed to assess withdrawal symptoms in any infant suspected suffer from neonatal abstinence syndrome 24. Originally it was used in infants who were exposed to opioids in utero 16, 24. Finnegan score lists all relevant clinical signs of withdrawal in newborn infants during the first days of life comprehensively, and assesses central nervous system hyperirritability, gastrointestinal dysfunction, respiratory distress and vague autonomic signs 16. Later Finnegan score was used for withdrawal symptoms assessment in infants exposed to other drugs including selective serotonin reuptake inhibitors, gabapentin, phenobarbital and clonidine 21, 25, 26. Zimmerman et al. applied the score to a cohort of nonaddicted neonates and infants to define its variability in the absence of drug withdrawal, its day–night cycles and its course with age 16. According to this study, a score of 7 corresponds with the 95th percentile for nonexposed infants. A score of >8 is highly suggestive of neonatal abstinence syndrome, even in those denying opioid use during pregnancy 16.

Our results showed that most of the newborns in the study group did not experience any withdrawal symptoms (maximal score < 4), few had mild withdrawal symptoms (maximal score 4–7). None of the newborns had significant withdrawal symptoms (score ≥ 8). These data are similar to a previous study in nonaddicted neonates 16. It is noteworthy that no relationship was found between the maternal lamotrigine dosage and the newborn's Finnegan score.

Lamotrigine did not apparently have adverse long‐term neurological effects on the children, with no significant differences between the two groups in growth parameters, neurological symptoms and atopic symptoms. Additionally, according to parent reports, no significant differences were observed in autistic characteristics, learning disabilities or developmental delays. These findings are supported by previous studies who found no difference in neurodevelopmental symptoms between 6‐year‐old children whose mothers took lamotrigine during pregnancy and matched group of children whose mothers did not 5, 15. Interestingly, a closer look at the types of developmental delays revealed that the control group had a higher rate of language delay than the lamotrigine group. This finding does not support previous studies results 15. We assume that compared with measurements assessed at younger ages, 6–12 years of age assessment is a more stable measure, more strongly related to adult performance and more predictive of future neurodevelopmental performance 9, 15, 27. We could not find such long‐term assessment regarding the neurodevelopmental effects of AED in the literature.

In our population, high level of developmental speech and language delay was reported by the parents. This high incidence might be due to our well baby care centres that are very accurate and sensitive in developmental assessment. However, the cultural reaction of the parents to the information giving to them showed no differences between lamotrigine and control groups. It may be also possible that mothers with epilepsy are more aware of possible developmental delays and therefore tend to emphasize language and communication skills.

Several limitations of this study should be considered. The study used a convenience sample. All participating children were born at a single tertiary centre in Israel, and therefore are not representative of the whole Israeli population. Furthermore, we used a longitudinal (2004–2014) retrospective design with a single follow‐up survey using ad hoc questionnaire at a current age. This necessarily led to the inclusion of a wide range of children from different age groups (2–12 years). As the size of each age group was limited, some of the comparisons are not reliable. Emphasized neurodevelopmental status by parents may over‐ or underestimate findings and may not be representing. The use of medical records instead of direct evaluation may have resulted in missing data.

The present study provides further evidence that in utero exposure to lamotrigine does not increase the risk of birth malformations and neonatal complications. This study, to our knowledge, is the first to use the Finnegan score to evaluate newborns and children exposed to lamotrigine during pregnancy. None of the newborns had significant withdrawal symptoms.

Long‐term assessment found no difference in neurodevelopmental symptoms up to the age 12 years. This study provides the most extensive long‐term report regarding children whose mothers took lamotrigine during pregnancy compared to matched group of children whose mothers did not. Most of the study group (56.6%) was age 6–12 years when evaluated while in the literature the most long‐term follow‐up did not extend evaluation to age >6 years.

In conclusion, in light of the actual data, our provisional conclusion is that there appears to be no significant adverse effect of in utero exposure to lamotrigine on the physiological parameters of newborns and children. There is also no evidence for abnormal neurodevelopmental parameters.

Larger prospective multicentre studies are needed to corroborate these findings, with incorporation of additional variables, including demographic and socioeconomic data, parental height, maternal prepregnancy weight and parental cognitive measurements. In addition, more in‐depth evaluation of children using interviews and questionnaires and neurodevelopmental cognitive tests at different time points will improve the reliability of our findings.

Competing Interests

There are no competing interests to declare.

Cohen‐Israel, M. , Berger, I. , Martonovich, E. Y. , Klinger, G. , Stahl, B. , and Linder, N. (2018) Short‐ and long‐term complications of in utero exposure to lamotrigine. Br J Clin Pharmacol, 84: 189–194. doi: 10.1111/bcp.13437.