J Neurol (2014) 261:842–844 DOI 10.1007/s00415-014-7312-0
JOURNAL CLUB
Pregnancy and drug use in neurological disease M. Aguirregomozcorta • N. P. Robertson
Published online: 27 March 2014 Ó Springer-Verlag Berlin Heidelberg 2014
The use of drugs in pregnant women with neurological disease is problematic, not only because of the recognised adverse effects of established medications such as anti-epileptics, but also an understandable maternal anxiety to avoid even the lowest levels of risk when considering the health of an unborn child. The result of this is that mothers and physicians commonly adopt a default position to avoid therapeutic interventions in pregnancy and the pre-conceptual period. However, it remains important that this avoidance is carefully balanced against the risk of the disorder itself and the effects of under treatment for both mother and baby. With little in the way of evidence-based data available to inform clinical decisions, and a paucity of safety data as a result of limited exposure in women of reproductive age, counselling and risk analysis is often problematic and clinical management needs to be carefully tailored to the wishes of individual patients. An increasing range of treatments are now becoming available for neurological conditions which commonly impact women of childbearing age. Drug safety in pregnancy has, therefore, become a growing concern and informed knowledge of common drug effects is essential for neurologists managing these disorders. However, although pregnancy related adverse events are an important overall consideration in drug licensing, clinical trials in chronic neurological disease are unlikely ever to include a pregnant population. As a result data relating to outcomes are likely to rely on large cohort observational studies or analysis of risk registers, which have latterly often become a prerequisite for the issuing of a licence for new medications. Since this is, by necessity, a rather slow and M. Aguirregomozcorta N. P. Robertson (&) Department of Neurology, Institute of Psychological Medicine and Clinical Neuroscience, Cardiff University, Cardiff, UK e-mail: [email protected]
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laborious process it is not likely to be able to effectively keep pace with drug development, but remains an important monitoring process in order that information can be disseminated to inform clinical practice. So far teratogenicity has been the main focus of these registries in neurological disease. However, this is a single outcome measure in a much more complex area that demands closer examination and remains largely unexplored. Examples of other important considerations include neonatal and childhood development, breastfeeding and fertility. All these issues will be of vital importance for pregnant women and those of childbearing age and result in complex questions in the clinical setting for which we need to be able to provide some guidance for our patients. In this month’s Journal Club, we review three papers which attempt to address some of these questions by examining the effects of antenatal exposure to drugs in three different neurological conditions. Two of the studies are large epidemiological studies based on the same Scandinavian population cohort and analyse the risk of impaired early child development as the result of antenatal exposure to antiepileptic drugs as well through breastfeeding, and the effect of triptans on pregnancy. The third study examines adverse effects on the children of mothers who were treated with disease modifying drugs (DMT) for Multiple Sclerosis (MS) from an existing risk registry.
Early child development and exposure to antiepileptic drugs prenatally and through breastfeeding: a prospective cohort study on children of women with epilepsy Antiepileptic drugs potentially influence foetal development throughout pregnancy. Available evidence indicates
J Neurol (2014) 261:842–844
that prenatal exposure to antiepileptic drugs can have effects on cognition, motor function and behaviour. In addition, the impact of breastfeeding remains controversial. This prospective study utilises data from a large population cohort study to assess whether exposure to antiepileptic drugs either prenatally or through breastfeeding has an effect on child development. Data were acquired from questionnaires completed by mothers and fathers focused on their medical history prior to conception and also included child data including nutrition, health and development at 6, 18 and 36 months. Maternal rating of child development and behaviour provided the main outcome variables. Between 1999 and 2009, 108,976 children were registered within the Norwegian Mother and Child Cohort Study. At 6 months, 503 children formed the maternal epilepsy group of which 223 had been exposed to one or more antiepileptic drugs during pregnancy. The control group was made up of 77,770 children together with a further disease comparison group of 471 children whose fathers had epilepsy, also included to evaluate potential genetic or socioeconomic effects of parental epilepsy on child outcomes. Offspring of mothers using antiepileptic drugs had an increased risk of delayed fine motor skills at age 6 months. This risk was higher for both fine motor and social skills if exposed to polytherapy but was not seen in the children of those mothers with epilepsy who had not taken medication during pregnancy or in the children whose fathers had epilepsy. However, no deleterious effect on the neonate was identified with continuous breastfeeding; indeed there was a tendency toward improved outcome for all developmental domains at 6 months regardless of maternal antiepileptic drug treatment. Eighteen months after delivery, children in the drug-exposed group had an increased risk of impaired development compared with the control group. Although these risks tended to be lower in children with continuous breastfeeding (especially for autistic traits), at 36 months the risk of autistic traits was equivalent in both breastfed and non-breastfed groups. Comments and discussion. Perhaps most importantly, this study indicates that continuous breastfeeding is not associated with a worse outcome and might even offer a short-lived benefit. However, this work confirms the wider adverse effects of prenatal exposure to anti-epileptic drugs with the finding of impaired fine motor skills at 6 months. Unfortunately, study numbers were not large enough to analyse outcomes associated with each individual medication for comparison. The longer term impact of these drugs in later childhood, adolescence and adulthood remains unclear, but this cohort may provide a basis for answering these important issues over time. Veiby et al. JAMA Neurology 2013; 70(11):1367–1374.
843
Triptan safety during pregnancy: a Norwegian population registry Uncontrolled migraine can be associated with significant complications in pregnant women, including gestational hypertension, preeclampsia and pregnancy-related stroke, as well as an increased foetal risk relating to premature delivery, low infant birth weight, placental abruption, and foetal heart rate deceleration during delivery. As a result, more active management of migraine during pregnancy is recommended in selected cases which commonly involve the use of triptans, although little is known of their safety in pregnancy. Data from 181,125 pregnant women were included in this study and were divided into three groups: 1,465 women were exposed to triptans during pregnancy (the triptan group), 1,095 women who had taken triptans between 1 and 7 months prior to pregnancy (the disease comparison group), a further 178,565 women formed a control group. Outcomes included: live birth, congenital malformations, birth weight \2,500 g, gestational age \37 weeks, small for gestational age, Apgar score \7 at 5 min, transfer to a special care baby unit and postpartum haemorrhage [500 ml. Both the triptan group and disease comparison group had a higher frequency of hypertensive disorders during pregnancy and also a higher risk of postpartum haemorrhage and low birth weight. In addition, children born from mothers in the disease comparison group were at a higher risk of major congenital malformations and preterm birth. Comments and discussion. Studies have previously reported association between severe migraine and hypertensive disorders including preeclampsia and gestational hypertension which in turn may cause low birth weight of the neonate. This large study found a slightly higher risk of complications in the disease comparison group than in the triptan group, suggesting that they are associated with disease and not treatment. This study has focused on triptan intake, but further studies that include data about the characteristics and severity of migraine, and their relationship to outcome are also needed. Nezvalova-Henriksen et al. Eur J Epidemiol 2013; 28:759–769.
Long-term effects of exposure to disease-modifying drugs in the offspring of mothers with multiple sclerosis: a retrospective chart review The only current recommendation for women with MS intending to become pregnant is to stop all treatment. Two recent systematic reviews have concluded that foetal malformations, neonatal deaths and immediate postnatal
123
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complications are not significantly more frequent in women who underwent treatment with disease-modifying drugs for MS during pregnancy. However, there is a paucity of data concerning the potential impact on the subsequent lives of these children. This is a retrospective study that evaluates the long-term effects of exposure of the foetus to drugs used for treating MS in the mother. Data were obtained from the medical records of patients attending regular consultations with their neurologists. One hundred and eighty cases of women with MS whose children were at least 1 year old were included. Ninety-five of them had not been exposed to any drugs for at least 3 months prior to conception formed the control group, and 85 who had been treated for at least 2 weeks during pregnancy formed the drug exposure group. There were 39 exposures to glatiramer acetate, 39 exposures to interferon beta, three exposures to methylprednisolone, two exposures to immunoglobulin, one exposure to azathioprine and one to rituximab. There was no consistent finding of excess obstetric occurrences, neonatal complications, infections, allergies, neuropsychological motor development or other diagnosis that could be considered drug-related.
123
J Neurol (2014) 261:842–844
Comments and discussion. This is the first study in looking into long-term side-effects from prenatal exposure to disease modifying drugs for MS and it is encouraging. However, further studies with larger numbers and with standardised neurodevelopment measures are needed in order to confirm these findings. Fragoso et al. CNS Drugs 2013; 27:955–961. Conclusion. These three papers have been able to shed some light on this complex area of drug safety in pregnancy and have also suggested a number of new issues to investigate. Reassuringly, the overall message appears to be that the drugs examined appear relatively benign in terms of their impact on pregnancy and early child development. However, it is clear that more information is required concerning longer term outcome and their impact on general health, psychomotor and social development. In addition, although these studies provide some guidance for individual patients, the quality and quantity of data is still not sufficient to enable publication of more generalised recommendations.
JOURNAL CLUB
Pregnancy and drug use in neurological disease M. Aguirregomozcorta • N. P. Robertson
Published online: 27 March 2014 Ó Springer-Verlag Berlin Heidelberg 2014
The use of drugs in pregnant women with neurological disease is problematic, not only because of the recognised adverse effects of established medications such as anti-epileptics, but also an understandable maternal anxiety to avoid even the lowest levels of risk when considering the health of an unborn child. The result of this is that mothers and physicians commonly adopt a default position to avoid therapeutic interventions in pregnancy and the pre-conceptual period. However, it remains important that this avoidance is carefully balanced against the risk of the disorder itself and the effects of under treatment for both mother and baby. With little in the way of evidence-based data available to inform clinical decisions, and a paucity of safety data as a result of limited exposure in women of reproductive age, counselling and risk analysis is often problematic and clinical management needs to be carefully tailored to the wishes of individual patients. An increasing range of treatments are now becoming available for neurological conditions which commonly impact women of childbearing age. Drug safety in pregnancy has, therefore, become a growing concern and informed knowledge of common drug effects is essential for neurologists managing these disorders. However, although pregnancy related adverse events are an important overall consideration in drug licensing, clinical trials in chronic neurological disease are unlikely ever to include a pregnant population. As a result data relating to outcomes are likely to rely on large cohort observational studies or analysis of risk registers, which have latterly often become a prerequisite for the issuing of a licence for new medications. Since this is, by necessity, a rather slow and M. Aguirregomozcorta N. P. Robertson (&) Department of Neurology, Institute of Psychological Medicine and Clinical Neuroscience, Cardiff University, Cardiff, UK e-mail: [email protected]
123
laborious process it is not likely to be able to effectively keep pace with drug development, but remains an important monitoring process in order that information can be disseminated to inform clinical practice. So far teratogenicity has been the main focus of these registries in neurological disease. However, this is a single outcome measure in a much more complex area that demands closer examination and remains largely unexplored. Examples of other important considerations include neonatal and childhood development, breastfeeding and fertility. All these issues will be of vital importance for pregnant women and those of childbearing age and result in complex questions in the clinical setting for which we need to be able to provide some guidance for our patients. In this month’s Journal Club, we review three papers which attempt to address some of these questions by examining the effects of antenatal exposure to drugs in three different neurological conditions. Two of the studies are large epidemiological studies based on the same Scandinavian population cohort and analyse the risk of impaired early child development as the result of antenatal exposure to antiepileptic drugs as well through breastfeeding, and the effect of triptans on pregnancy. The third study examines adverse effects on the children of mothers who were treated with disease modifying drugs (DMT) for Multiple Sclerosis (MS) from an existing risk registry.
Early child development and exposure to antiepileptic drugs prenatally and through breastfeeding: a prospective cohort study on children of women with epilepsy Antiepileptic drugs potentially influence foetal development throughout pregnancy. Available evidence indicates
J Neurol (2014) 261:842–844
that prenatal exposure to antiepileptic drugs can have effects on cognition, motor function and behaviour. In addition, the impact of breastfeeding remains controversial. This prospective study utilises data from a large population cohort study to assess whether exposure to antiepileptic drugs either prenatally or through breastfeeding has an effect on child development. Data were acquired from questionnaires completed by mothers and fathers focused on their medical history prior to conception and also included child data including nutrition, health and development at 6, 18 and 36 months. Maternal rating of child development and behaviour provided the main outcome variables. Between 1999 and 2009, 108,976 children were registered within the Norwegian Mother and Child Cohort Study. At 6 months, 503 children formed the maternal epilepsy group of which 223 had been exposed to one or more antiepileptic drugs during pregnancy. The control group was made up of 77,770 children together with a further disease comparison group of 471 children whose fathers had epilepsy, also included to evaluate potential genetic or socioeconomic effects of parental epilepsy on child outcomes. Offspring of mothers using antiepileptic drugs had an increased risk of delayed fine motor skills at age 6 months. This risk was higher for both fine motor and social skills if exposed to polytherapy but was not seen in the children of those mothers with epilepsy who had not taken medication during pregnancy or in the children whose fathers had epilepsy. However, no deleterious effect on the neonate was identified with continuous breastfeeding; indeed there was a tendency toward improved outcome for all developmental domains at 6 months regardless of maternal antiepileptic drug treatment. Eighteen months after delivery, children in the drug-exposed group had an increased risk of impaired development compared with the control group. Although these risks tended to be lower in children with continuous breastfeeding (especially for autistic traits), at 36 months the risk of autistic traits was equivalent in both breastfed and non-breastfed groups. Comments and discussion. Perhaps most importantly, this study indicates that continuous breastfeeding is not associated with a worse outcome and might even offer a short-lived benefit. However, this work confirms the wider adverse effects of prenatal exposure to anti-epileptic drugs with the finding of impaired fine motor skills at 6 months. Unfortunately, study numbers were not large enough to analyse outcomes associated with each individual medication for comparison. The longer term impact of these drugs in later childhood, adolescence and adulthood remains unclear, but this cohort may provide a basis for answering these important issues over time. Veiby et al. JAMA Neurology 2013; 70(11):1367–1374.
843
Triptan safety during pregnancy: a Norwegian population registry Uncontrolled migraine can be associated with significant complications in pregnant women, including gestational hypertension, preeclampsia and pregnancy-related stroke, as well as an increased foetal risk relating to premature delivery, low infant birth weight, placental abruption, and foetal heart rate deceleration during delivery. As a result, more active management of migraine during pregnancy is recommended in selected cases which commonly involve the use of triptans, although little is known of their safety in pregnancy. Data from 181,125 pregnant women were included in this study and were divided into three groups: 1,465 women were exposed to triptans during pregnancy (the triptan group), 1,095 women who had taken triptans between 1 and 7 months prior to pregnancy (the disease comparison group), a further 178,565 women formed a control group. Outcomes included: live birth, congenital malformations, birth weight \2,500 g, gestational age \37 weeks, small for gestational age, Apgar score \7 at 5 min, transfer to a special care baby unit and postpartum haemorrhage [500 ml. Both the triptan group and disease comparison group had a higher frequency of hypertensive disorders during pregnancy and also a higher risk of postpartum haemorrhage and low birth weight. In addition, children born from mothers in the disease comparison group were at a higher risk of major congenital malformations and preterm birth. Comments and discussion. Studies have previously reported association between severe migraine and hypertensive disorders including preeclampsia and gestational hypertension which in turn may cause low birth weight of the neonate. This large study found a slightly higher risk of complications in the disease comparison group than in the triptan group, suggesting that they are associated with disease and not treatment. This study has focused on triptan intake, but further studies that include data about the characteristics and severity of migraine, and their relationship to outcome are also needed. Nezvalova-Henriksen et al. Eur J Epidemiol 2013; 28:759–769.
Long-term effects of exposure to disease-modifying drugs in the offspring of mothers with multiple sclerosis: a retrospective chart review The only current recommendation for women with MS intending to become pregnant is to stop all treatment. Two recent systematic reviews have concluded that foetal malformations, neonatal deaths and immediate postnatal
123
844
complications are not significantly more frequent in women who underwent treatment with disease-modifying drugs for MS during pregnancy. However, there is a paucity of data concerning the potential impact on the subsequent lives of these children. This is a retrospective study that evaluates the long-term effects of exposure of the foetus to drugs used for treating MS in the mother. Data were obtained from the medical records of patients attending regular consultations with their neurologists. One hundred and eighty cases of women with MS whose children were at least 1 year old were included. Ninety-five of them had not been exposed to any drugs for at least 3 months prior to conception formed the control group, and 85 who had been treated for at least 2 weeks during pregnancy formed the drug exposure group. There were 39 exposures to glatiramer acetate, 39 exposures to interferon beta, three exposures to methylprednisolone, two exposures to immunoglobulin, one exposure to azathioprine and one to rituximab. There was no consistent finding of excess obstetric occurrences, neonatal complications, infections, allergies, neuropsychological motor development or other diagnosis that could be considered drug-related.
123
J Neurol (2014) 261:842–844
Comments and discussion. This is the first study in looking into long-term side-effects from prenatal exposure to disease modifying drugs for MS and it is encouraging. However, further studies with larger numbers and with standardised neurodevelopment measures are needed in order to confirm these findings. Fragoso et al. CNS Drugs 2013; 27:955–961. Conclusion. These three papers have been able to shed some light on this complex area of drug safety in pregnancy and have also suggested a number of new issues to investigate. Reassuringly, the overall message appears to be that the drugs examined appear relatively benign in terms of their impact on pregnancy and early child development. However, it is clear that more information is required concerning longer term outcome and their impact on general health, psychomotor and social development. In addition, although these studies provide some guidance for individual patients, the quality and quantity of data is still not sufficient to enable publication of more generalised recommendations.
