BMJ 2014;349:g5252 doi: 10.1136/bmj.g5252 (Published 21 August 2014)
Page 1 of 2
Editorials
EDITORIALS Medication use during pregnancy Evaluating risk is an ongoing challenge Janet D Cragan medical officer National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention, Atlanta, GA, USA
Medication use during pregnancy is remarkably common. In the linked paper in this issue (doi:10.1136/bmj.g5159), Bech and colleagues assess the risk of spontaneous abortion and stillbirth after antiepileptic drug use during pregnancy, utilizing national health registers in Denmark from 1997 to 2008.1 The findings are largely reassuring, but studying the effects of drug use in pregnancy is always a challenge and confident conclusions about safety are rarely possible. Estimates of prescription drug use including vitamins and minerals during the first trimester have ranged from 33% to 69% in developed countries.2 The average number of over the counter and prescription drugs used by pregnant women in the United States increased from 2.5 in 1976-78 to 4.2 in 2006-08.3 And yet the quantity and quality of information about the risk to the fetus of medication use during pregnancy remains poor. A review of 172 medications approved by the US Food and Drug Administration between 2000 and 2010 found that for 97.7% the teratogenic risk in human pregnancy was undetermined; for 73.3% there were no available data about the risk in pregnancy.4 However, because many pregnancies occur unintentionally, women who take medications can be exposed in the early weeks of gestation before realizing they are pregnant.5 In addition, many acute and chronic conditions must be treated during pregnancy to ensure the health of both mother and fetus. Use of antiepileptic drugs is critical in many cases to control epilepsy, and such medications are used increasingly to treat non-epilepsy disorders.6 Some of these disorders, such as migraine, are more common than epilepsy.
Historically, ethical issues often ruled out premarketing clinical trials of the safety of medications for pregnant women and their unborn babies. Although some information about potential effects can be gleaned from animal studies, most evidence about effects on the fetus comes from the experience of women who use medications after they have been marketed. The range of possible adverse fetal effects is diverse and includes spontaneous abortion, stillbirth, preterm delivery, structural malformations, dysmorphic features, and neurodevelopmental effects. Studies of pregnancy outcomes after medication use face several challenges. While medication use overall is common, use of individual medications is rare.7 This, coupled with the rarity of outcomes such as specific congenital malformations, variability
in the quality of data about covariates from different data sources, and difficulties in assessing the timing and pattern of actual drug use, highlights the need for diverse and complementary studies that inform each other.8 9 In the United States, the Centers for Disease Control and Prevention’s Treating for Two initiative seeks to improve the evidence base and dissemination of information on which to make informed choices of medication use during pregnancy that consider the needs of both mother and fetus.10 However, there always will be limits to the level of risk that can be identified for different outcomes.11
Assessment of spontaneous abortion is particularly difficult because the frequency with which losses occur declines non-linearly throughout pregnancy. Studies that enroll women at different gestational ages usually cannot achieve large enough samples of exposed pregnancies to assess the incidence of spontaneous abortion using time dependent methods.12 However, spontaneous abortion and stillbirth are major public health issues. An estimated one million spontaneous fetal losses occur annually in the United States alone.13
One advantage of the Danish data sources is that they capture all clinically recognized pregnancies within the population from both inpatient and outpatient settings. This minimizes the problem of enrollment at varying gestational ages. The study comprises more than one million pregnancies including over 114 000 spontaneous abortions and almost 8000 stillbirths. Despite these apparently large numbers, only 581 pregnancies ending in spontaneous abortion and 21 ending in stillbirth were exposed to an antiepileptic. The small number of exposed stillbirths prevented further evaluation of the effects of individual drugs or the use of multivariate analyses.
Sufficient numbers of pregnancies ending in spontaneous abortion were available to assess the relative risk for only the five most commonly used antiepileptics. The authors employ sensitivity analyses to explore factors that could affect results, including antiepileptic drug use from prescriptions filled outside the study exposure window, potential effects of environmental and genetic factors, and exclusion of induced abortions. Although prescription filling does not necessarily reflect medication use or adjustments in dose made during pregnancy, documentation of these factors is challenging for many studies.
[email protected] For personal use only: See rights and reprints http://www.bmj.com/permissions
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BMJ 2014;349:g5252 doi: 10.1136/bmj.g5252 (Published 21 August 2014)
Page 2 of 2
EDITORIALS
Findings in this study include a 13% increase in the risk of spontaneous abortions after any antiepileptic drug use during pregnancy. However, further analysis suggested that the increased risk was confined to women without epilepsy. An increase only among women without epilepsy also was evident for each of the five most commonly used antiepileptics. This indicates that the effects of medication use could differ depending on the condition being treated.
Women who filled prescriptions for higher doses of antiepileptics had an increased risk of spontaneous abortion regardless of whether underlying epilepsy was mentioned, which might reflect the effects of severe disease rather than the medication. This study is unusual in its assessment of antiepileptic dose in relation to spontaneous abortion. Incorporation of dose into studies of medication effects on pregnancy outcomes is important, as changes in blood volume and other factors can require adjustments in dose throughout pregnancy. Bech and colleagues’ study highlights the potential roles of the conditions being treated, other confounding factors, and medication dose in any assessment of the risk-benefit balance of medication use during pregnancy. Similar studies for other medications are needed to help improve the currently limited information available to women and their healthcare providers. JDC is the sole author of this contribution and is a US Federal Government employee acting in the course of her employment. The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention.
For personal use only: See rights and reprints http://www.bmj.com/permissions
Competing interests: I have read and understood the BMJ policy on declaration of interests and declare the following interests: none. Provenance and peer review: Commissioned; not externally peer reviewed. 1 2 3 4 5 6 7 8 9 10 11 12 13
Bech BH, Kjaersgaard MIS, Pedersen HS, Howards PP, Sørensen MJ, Olsen J. Use of antiepileptic drugs during pregnancy and risk of spontaneous abortion and stillbirth: population based cohort study. BMJ 2014;349:g5159. Daw JR, Hanley GE, Greyson DL, Morgan SG. Prescription drug use during pregnancy in developed countries: a systematic review. Pharmacoepidemiol Drug Saf 2011;20:895-902. Mitchell AA, Gilboa SM, Werler MM, Kelley KE, Louik C, Hernandex-Diáz S, et al. Medication use during pregnancy, with particular focus on prescription drugs: 1976-2008. Am J Obstet Gynecol 2011;205:51.e1-8. Adam MP, Polifka JE, Friedman JM. Evolving knowledge of the teratogenicity of medications in human pregnancy. Am J Med Genet Part C Semin Med Genet 2011;176:175-82. Finer LB, Henshaw SK. Disparities in rates of unintended pregnancy in the United States, 1994 and 2001. Perspect Sex Reprod Health 2006;38:90-6. Adedinsewo DA, Thurman DJ, Luo Y-H, Williamson RS, Odewole OA, Oakley GP. Valproate prescriptions for nonepilepsy disorders in reproductive-age women. Birth Defects Res A Clin Mol Teratol 2013;97:403-8. Thorpe PG, Gilboa SM, Hernandex-Diáz S, Lind J, Cragan JD, Briggs G, et al. Medications in the first trimester of pregnancy: most common exposures and critical gaps in understanding fetal risk. Pharmacoepidemiol Drug Saf 2013;22:1013-8. Mitchell AA. Systematic identification of drugs that cause birth defects—a new opportunity. N Engl J Med 2003;349:2556-9. Lagoy CT, Joshi N, Cragan JD, Rasmussen SA. Medication use during pregnancy and lactation: an urgent call for public health action. J Womens Health 2005;14:104-9. Centers for Disease Control and Prevention. 2014. Treating for two. www.cdc.gov/ pregnancy/meds/treatingfortwo. Friedman JM. ABCDXXX: the obscenity of postmarketing surveillance for teratogenic effects. Birth Defects Res A Clin Mol Teratol 2012;94:670-6. Xu R, Chambers C. A sample size calculation for spontaneous abortion in observational studies. Reprod Toxicol 2011;32:490-3. Ventura SJ, Curtin SC, Abma JC, Henshaw SK. Estimated pregnancy rates and rates of pregnancy outcomes for the United States, 1990-2008. National Vital Statistics Reports. National Center for Health Statistics, 2012;60(7).
Cite this as: BMJ 2014;349:g5252 © BMJ Publishing Group Ltd 2014
Subscribe: http://www.bmj.com/subscribe
Page 1 of 2
Editorials
EDITORIALS Medication use during pregnancy Evaluating risk is an ongoing challenge Janet D Cragan medical officer National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention, Atlanta, GA, USA
Medication use during pregnancy is remarkably common. In the linked paper in this issue (doi:10.1136/bmj.g5159), Bech and colleagues assess the risk of spontaneous abortion and stillbirth after antiepileptic drug use during pregnancy, utilizing national health registers in Denmark from 1997 to 2008.1 The findings are largely reassuring, but studying the effects of drug use in pregnancy is always a challenge and confident conclusions about safety are rarely possible. Estimates of prescription drug use including vitamins and minerals during the first trimester have ranged from 33% to 69% in developed countries.2 The average number of over the counter and prescription drugs used by pregnant women in the United States increased from 2.5 in 1976-78 to 4.2 in 2006-08.3 And yet the quantity and quality of information about the risk to the fetus of medication use during pregnancy remains poor. A review of 172 medications approved by the US Food and Drug Administration between 2000 and 2010 found that for 97.7% the teratogenic risk in human pregnancy was undetermined; for 73.3% there were no available data about the risk in pregnancy.4 However, because many pregnancies occur unintentionally, women who take medications can be exposed in the early weeks of gestation before realizing they are pregnant.5 In addition, many acute and chronic conditions must be treated during pregnancy to ensure the health of both mother and fetus. Use of antiepileptic drugs is critical in many cases to control epilepsy, and such medications are used increasingly to treat non-epilepsy disorders.6 Some of these disorders, such as migraine, are more common than epilepsy.
Historically, ethical issues often ruled out premarketing clinical trials of the safety of medications for pregnant women and their unborn babies. Although some information about potential effects can be gleaned from animal studies, most evidence about effects on the fetus comes from the experience of women who use medications after they have been marketed. The range of possible adverse fetal effects is diverse and includes spontaneous abortion, stillbirth, preterm delivery, structural malformations, dysmorphic features, and neurodevelopmental effects. Studies of pregnancy outcomes after medication use face several challenges. While medication use overall is common, use of individual medications is rare.7 This, coupled with the rarity of outcomes such as specific congenital malformations, variability
in the quality of data about covariates from different data sources, and difficulties in assessing the timing and pattern of actual drug use, highlights the need for diverse and complementary studies that inform each other.8 9 In the United States, the Centers for Disease Control and Prevention’s Treating for Two initiative seeks to improve the evidence base and dissemination of information on which to make informed choices of medication use during pregnancy that consider the needs of both mother and fetus.10 However, there always will be limits to the level of risk that can be identified for different outcomes.11
Assessment of spontaneous abortion is particularly difficult because the frequency with which losses occur declines non-linearly throughout pregnancy. Studies that enroll women at different gestational ages usually cannot achieve large enough samples of exposed pregnancies to assess the incidence of spontaneous abortion using time dependent methods.12 However, spontaneous abortion and stillbirth are major public health issues. An estimated one million spontaneous fetal losses occur annually in the United States alone.13
One advantage of the Danish data sources is that they capture all clinically recognized pregnancies within the population from both inpatient and outpatient settings. This minimizes the problem of enrollment at varying gestational ages. The study comprises more than one million pregnancies including over 114 000 spontaneous abortions and almost 8000 stillbirths. Despite these apparently large numbers, only 581 pregnancies ending in spontaneous abortion and 21 ending in stillbirth were exposed to an antiepileptic. The small number of exposed stillbirths prevented further evaluation of the effects of individual drugs or the use of multivariate analyses.
Sufficient numbers of pregnancies ending in spontaneous abortion were available to assess the relative risk for only the five most commonly used antiepileptics. The authors employ sensitivity analyses to explore factors that could affect results, including antiepileptic drug use from prescriptions filled outside the study exposure window, potential effects of environmental and genetic factors, and exclusion of induced abortions. Although prescription filling does not necessarily reflect medication use or adjustments in dose made during pregnancy, documentation of these factors is challenging for many studies.
[email protected] For personal use only: See rights and reprints http://www.bmj.com/permissions
Subscribe: http://www.bmj.com/subscribe
BMJ 2014;349:g5252 doi: 10.1136/bmj.g5252 (Published 21 August 2014)
Page 2 of 2
EDITORIALS
Findings in this study include a 13% increase in the risk of spontaneous abortions after any antiepileptic drug use during pregnancy. However, further analysis suggested that the increased risk was confined to women without epilepsy. An increase only among women without epilepsy also was evident for each of the five most commonly used antiepileptics. This indicates that the effects of medication use could differ depending on the condition being treated.
Women who filled prescriptions for higher doses of antiepileptics had an increased risk of spontaneous abortion regardless of whether underlying epilepsy was mentioned, which might reflect the effects of severe disease rather than the medication. This study is unusual in its assessment of antiepileptic dose in relation to spontaneous abortion. Incorporation of dose into studies of medication effects on pregnancy outcomes is important, as changes in blood volume and other factors can require adjustments in dose throughout pregnancy. Bech and colleagues’ study highlights the potential roles of the conditions being treated, other confounding factors, and medication dose in any assessment of the risk-benefit balance of medication use during pregnancy. Similar studies for other medications are needed to help improve the currently limited information available to women and their healthcare providers. JDC is the sole author of this contribution and is a US Federal Government employee acting in the course of her employment. The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention.
For personal use only: See rights and reprints http://www.bmj.com/permissions
Competing interests: I have read and understood the BMJ policy on declaration of interests and declare the following interests: none. Provenance and peer review: Commissioned; not externally peer reviewed. 1 2 3 4 5 6 7 8 9 10 11 12 13
Bech BH, Kjaersgaard MIS, Pedersen HS, Howards PP, Sørensen MJ, Olsen J. Use of antiepileptic drugs during pregnancy and risk of spontaneous abortion and stillbirth: population based cohort study. BMJ 2014;349:g5159. Daw JR, Hanley GE, Greyson DL, Morgan SG. Prescription drug use during pregnancy in developed countries: a systematic review. Pharmacoepidemiol Drug Saf 2011;20:895-902. Mitchell AA, Gilboa SM, Werler MM, Kelley KE, Louik C, Hernandex-Diáz S, et al. Medication use during pregnancy, with particular focus on prescription drugs: 1976-2008. Am J Obstet Gynecol 2011;205:51.e1-8. Adam MP, Polifka JE, Friedman JM. Evolving knowledge of the teratogenicity of medications in human pregnancy. Am J Med Genet Part C Semin Med Genet 2011;176:175-82. Finer LB, Henshaw SK. Disparities in rates of unintended pregnancy in the United States, 1994 and 2001. Perspect Sex Reprod Health 2006;38:90-6. Adedinsewo DA, Thurman DJ, Luo Y-H, Williamson RS, Odewole OA, Oakley GP. Valproate prescriptions for nonepilepsy disorders in reproductive-age women. Birth Defects Res A Clin Mol Teratol 2013;97:403-8. Thorpe PG, Gilboa SM, Hernandex-Diáz S, Lind J, Cragan JD, Briggs G, et al. Medications in the first trimester of pregnancy: most common exposures and critical gaps in understanding fetal risk. Pharmacoepidemiol Drug Saf 2013;22:1013-8. Mitchell AA. Systematic identification of drugs that cause birth defects—a new opportunity. N Engl J Med 2003;349:2556-9. Lagoy CT, Joshi N, Cragan JD, Rasmussen SA. Medication use during pregnancy and lactation: an urgent call for public health action. J Womens Health 2005;14:104-9. Centers for Disease Control and Prevention. 2014. Treating for two. www.cdc.gov/ pregnancy/meds/treatingfortwo. Friedman JM. ABCDXXX: the obscenity of postmarketing surveillance for teratogenic effects. Birth Defects Res A Clin Mol Teratol 2012;94:670-6. Xu R, Chambers C. A sample size calculation for spontaneous abortion in observational studies. Reprod Toxicol 2011;32:490-3. Ventura SJ, Curtin SC, Abma JC, Henshaw SK. Estimated pregnancy rates and rates of pregnancy outcomes for the United States, 1990-2008. National Vital Statistics Reports. National Center for Health Statistics, 2012;60(7).
Cite this as: BMJ 2014;349:g5252 © BMJ Publishing Group Ltd 2014
Subscribe: http://www.bmj.com/subscribe
