pharmacoepidemiology and drug safety 2014; 23: 526–533 Published online 4 March 2014 in Wiley Online Library (wileyonlinelibrary.com) DOI: 10.1002/pds.3600
ORIGINAL REPORT
Use of ADHD medication during pregnancy from 1999 to 2010: a Danish register-based study Katia Buch Hærvig, Laust Hvas Mortensen, Anne Vinkel Hansen and Katrine Strandberg-Larsen* Section of Social Medicine, Department of Public Health, University of Copenhagen, Copenhagen K, Denmark
ABSTRACT Objective This study aimed to describe the trends in use of Attention Deficit Hyperactivity Disorders (ADHD) medication during pregnancy in Denmark from 1999 to 2010, as well as to explore characteristics of women who use ADHD medication during pregnancy and whether exposure is associated with outcome of pregnancy. Method A linkage between various Danish national health registries was performed to identify all recorded pregnancies from 1999 to 2010. Use of ADHD medication was defined as a redeemed prescription on methylphenidate, modafinil, or atomoxetine from 28 days prior to the first day of the last menstrual period until the end of pregnancy. Results Of the 1 054 494 registered pregnancies, 480 were exposed to ADHD medication. From 2003 to the first quarter of 2010, use of ADHD medication during pregnancy increased from 5 to 533 per 100 000 person-years. A similar increase was observed among Danish women of childbearing age. Compared with unexposed, women who used ADHD medication during pregnancy were more often younger, single, lower educated, received social security benefits, and used other psychopharmaca. Exposed pregnancies were more likely to result in induced abortions on maternal request (odds ratio = 4.70, 95%CI = 3.77–5.85), induced abortions on special indication (odds ratio = 2.99, 95%CI = 1.34–6.67), and miscarriage (odds ratio = 2.07, 95%CI = 1.51–2.84) compared with unexposed pregnancies. Conclusions The number of pregnancies exposed to ADHD medication has increased similarly to the increase in use of ADHD medication among women of childbearing age. Use of ADHD medication in pregnancy was associated with different indicators of maternal disadvantage and with increased risk of induced abortion and miscarriage. Copyright © 2014 John Wiley & Sons, Ltd. key words—pregnancy; pregnancy outcome; attention deficit/hyperactivity disorder; ADHD; psychostimulants; ADHD medication; pharmacoepidemiology Received 25 June 2013; Revised 22 January 2014; Accepted 23 January 2014
INTRODUCTION During the last decade, there has been a notable increase in the number of adults treated with ADHD medication.1–3 As cohorts of girls treated for ADHD during childhood reach an age where they become sexually active, the number of pregnancies exposed to ADHD medication will likely increase, and this is perhaps particularly true for pregnancies that are unplanned.4 The safety of use during pregnancy is unknown, and all kinds of ADHD medication are therefore contraindicated in pregnancy.5 First trimester exposure to methylphenidate, which is the most common type of ADHD medication, was *Correspondence to: Katrine Strandberg-Larsen, Section of Social Medicine, Department of Public Health, University of Copenhagen, Øster Farimagsgade 5, DK-1014 Copenhagen K, Denmark. E-mail: [email protected]
Copyright © 2014 John Wiley & Sons, Ltd.
not associated with increased risk of congenital malformations in a recently published review.4 Nevertheless, it still seems plausible that exposure to ADHD medication during pregnancy may be detrimental, as the pharmacological actions of ADHD medication are similar to those of amphetamine and cocaine,6,7 both of which are known to be detrimental to the fetus.8 Animal studies show that amphetamines are transferred across the placenta, but there is no supporting data on humans concerning ADHD medication.9 It is thus important to monitor the use of ADHD medication during pregnancy. We describe the trends in use of ADHD medication during pregnancy in Denmark from 1999 to 2010. Moreover, we explore characteristics of women who use ADHD medication during pregnancy and whether exposure to ADHD medication is associated with outcome of pregnancy.
use of adhd medication during pregnancy
METHOD For the period of interest, we identified all pregnancies ending in either a live birth or stillbirth registered in the Medical Birth Registry, miscarriage or pregnancy termination registered in the National Patient Registry or the Register of Legal Induced Abortions. All of these registries have nationwide and universal coverage. We identified a total of 1 054 494 pregnancies starting later than 1 April 1998 and ending before 31 December 2010, as these pregnancies were at risk of being exposed to ADHD medication between 1999 to the first quarter of 2010. In Denmark, we have a civil registration system tracking all persons alive and living in Denmark using a unique personal identification number that is assigned to every Danish citizen at time of birth or when getting permanent residency.10 The personal identification number for every women registered with a pregnancy was used to link information from, for example, the National Prescription Registry,11 the Psychiatric Central Research Registry,12 and Statistics Denmark.
527
was defined as country of origin of the pregnant woman’s mother. When we were unable to identify the mother in the registries, ethnicity was defined from the woman’s own country of origin. Ethnicity was divided into the following: native born, western origin and non-western origin.14 Different regions of Denmark were defined by the municipal code and categorized into the following: the Capital Region, Zealand, Central Denmark, Southern Denmark, and Northern Denmark.2 Data on educational level, occupational status, and personal income were obtained from the same year as the estimated LMP. Educational level was defined as the last terminated or currently ongoing education categorized into the following: primary/lower secondary school, upper secondary school, vocational, and bachelor/master or higher education. Data on occupational status were categorized as belonging to one of the following groups: a student, receiver of social security benefits, early retired, part of the workforce, and others. The woman’s own annual disposable income was divided into quintiles. The division was carried out by year to allow for inflation and changes in income levels.
Exposure to ADHD medication during pregnancy The exposure of interest was redeemed prescription of ADHD medication from 28 days before the first day of the last menstrual period (LMP), estimated from the gestational age recorded in the National Patient Registry, until the end of pregnancy. The National Prescription Registry contains information of all prescriptions dispensed for Danish residents at outpatient pharmacies from 1995 and onwards. The prescriptions are recorded according to the Anatomic Therapeutic Chemical (ATC) classification system by the World Health Organization.13 We defined ADHD medication as the following chemical substances: methylphenidate (ATC-code: N06BA04), modafinil (ATC-code: N06BA07), and atomoxetin (ATC-code: N06BA09). Demographic characteristics Data on demographic characteristics were identified through Statistics Denmark. Maternal age at time of conception was calculated by subtracting the day of conception, defined as LMP plus 14 days, from the woman’s day of birth. The maternal age was categorized as follows: 40. Civil status was categorized as follows: married or in a registered relationship, single, and divorced/widow. The very low number of widowed women and none among the pregnancies exposed to ADHD medication did not allow us to distinguish between divorced and widowed women. Ethnicity Copyright © 2014 John Wiley & Sons, Ltd.
Other characteristics Parous was categorized as never given birth before and given birth one or more times before: 0 and 1+. Births included both live births and stillbirths. Information on previously induced abortions was obtained from the National Patient Registry and the Register of Legal Induced Abortions. This included both induced abortions on maternal request and induced abortions on special indication. Data on redeemed prescriptions of anxiety medication (ATC-code: N05B) and Selective Serotonin Reuptake Inhibitor (SSRI) (ATC-code: N06AB) were identified through the National Prescription Registry. Use of these medications was defined as one or more redeemed prescriptions from 28 days before LMP to end of pregnancy. Moreover, information on ADHD diagnosis, given any time before LMP, was derived from the Psychiatric Central Research Registry and divided into the following categories: yes and no. Patients are only registered in the Psychiatric Central Research Registry when psychiatric hospitals or departments are involved. Patients only in contact with general practitioners are thus not recorded in the register. Outcome of pregnancy and congenital malformations Information on outcome of pregnancy was obtained from the Medical Birth Registry, the National Patient Registry, and the Register of Legal Induced Abortions. The outcome was categorized as induced abortion on Pharmacoepidemiology and Drug Safety, 2014; 23: 526–533 DOI: 10.1002/pds
528
k. b. hærvig et al.
maternal request (
ORIGINAL REPORT
Use of ADHD medication during pregnancy from 1999 to 2010: a Danish register-based study Katia Buch Hærvig, Laust Hvas Mortensen, Anne Vinkel Hansen and Katrine Strandberg-Larsen* Section of Social Medicine, Department of Public Health, University of Copenhagen, Copenhagen K, Denmark
ABSTRACT Objective This study aimed to describe the trends in use of Attention Deficit Hyperactivity Disorders (ADHD) medication during pregnancy in Denmark from 1999 to 2010, as well as to explore characteristics of women who use ADHD medication during pregnancy and whether exposure is associated with outcome of pregnancy. Method A linkage between various Danish national health registries was performed to identify all recorded pregnancies from 1999 to 2010. Use of ADHD medication was defined as a redeemed prescription on methylphenidate, modafinil, or atomoxetine from 28 days prior to the first day of the last menstrual period until the end of pregnancy. Results Of the 1 054 494 registered pregnancies, 480 were exposed to ADHD medication. From 2003 to the first quarter of 2010, use of ADHD medication during pregnancy increased from 5 to 533 per 100 000 person-years. A similar increase was observed among Danish women of childbearing age. Compared with unexposed, women who used ADHD medication during pregnancy were more often younger, single, lower educated, received social security benefits, and used other psychopharmaca. Exposed pregnancies were more likely to result in induced abortions on maternal request (odds ratio = 4.70, 95%CI = 3.77–5.85), induced abortions on special indication (odds ratio = 2.99, 95%CI = 1.34–6.67), and miscarriage (odds ratio = 2.07, 95%CI = 1.51–2.84) compared with unexposed pregnancies. Conclusions The number of pregnancies exposed to ADHD medication has increased similarly to the increase in use of ADHD medication among women of childbearing age. Use of ADHD medication in pregnancy was associated with different indicators of maternal disadvantage and with increased risk of induced abortion and miscarriage. Copyright © 2014 John Wiley & Sons, Ltd. key words—pregnancy; pregnancy outcome; attention deficit/hyperactivity disorder; ADHD; psychostimulants; ADHD medication; pharmacoepidemiology Received 25 June 2013; Revised 22 January 2014; Accepted 23 January 2014
INTRODUCTION During the last decade, there has been a notable increase in the number of adults treated with ADHD medication.1–3 As cohorts of girls treated for ADHD during childhood reach an age where they become sexually active, the number of pregnancies exposed to ADHD medication will likely increase, and this is perhaps particularly true for pregnancies that are unplanned.4 The safety of use during pregnancy is unknown, and all kinds of ADHD medication are therefore contraindicated in pregnancy.5 First trimester exposure to methylphenidate, which is the most common type of ADHD medication, was *Correspondence to: Katrine Strandberg-Larsen, Section of Social Medicine, Department of Public Health, University of Copenhagen, Øster Farimagsgade 5, DK-1014 Copenhagen K, Denmark. E-mail: [email protected]
Copyright © 2014 John Wiley & Sons, Ltd.
not associated with increased risk of congenital malformations in a recently published review.4 Nevertheless, it still seems plausible that exposure to ADHD medication during pregnancy may be detrimental, as the pharmacological actions of ADHD medication are similar to those of amphetamine and cocaine,6,7 both of which are known to be detrimental to the fetus.8 Animal studies show that amphetamines are transferred across the placenta, but there is no supporting data on humans concerning ADHD medication.9 It is thus important to monitor the use of ADHD medication during pregnancy. We describe the trends in use of ADHD medication during pregnancy in Denmark from 1999 to 2010. Moreover, we explore characteristics of women who use ADHD medication during pregnancy and whether exposure to ADHD medication is associated with outcome of pregnancy.
use of adhd medication during pregnancy
METHOD For the period of interest, we identified all pregnancies ending in either a live birth or stillbirth registered in the Medical Birth Registry, miscarriage or pregnancy termination registered in the National Patient Registry or the Register of Legal Induced Abortions. All of these registries have nationwide and universal coverage. We identified a total of 1 054 494 pregnancies starting later than 1 April 1998 and ending before 31 December 2010, as these pregnancies were at risk of being exposed to ADHD medication between 1999 to the first quarter of 2010. In Denmark, we have a civil registration system tracking all persons alive and living in Denmark using a unique personal identification number that is assigned to every Danish citizen at time of birth or when getting permanent residency.10 The personal identification number for every women registered with a pregnancy was used to link information from, for example, the National Prescription Registry,11 the Psychiatric Central Research Registry,12 and Statistics Denmark.
527
was defined as country of origin of the pregnant woman’s mother. When we were unable to identify the mother in the registries, ethnicity was defined from the woman’s own country of origin. Ethnicity was divided into the following: native born, western origin and non-western origin.14 Different regions of Denmark were defined by the municipal code and categorized into the following: the Capital Region, Zealand, Central Denmark, Southern Denmark, and Northern Denmark.2 Data on educational level, occupational status, and personal income were obtained from the same year as the estimated LMP. Educational level was defined as the last terminated or currently ongoing education categorized into the following: primary/lower secondary school, upper secondary school, vocational, and bachelor/master or higher education. Data on occupational status were categorized as belonging to one of the following groups: a student, receiver of social security benefits, early retired, part of the workforce, and others. The woman’s own annual disposable income was divided into quintiles. The division was carried out by year to allow for inflation and changes in income levels.
Exposure to ADHD medication during pregnancy The exposure of interest was redeemed prescription of ADHD medication from 28 days before the first day of the last menstrual period (LMP), estimated from the gestational age recorded in the National Patient Registry, until the end of pregnancy. The National Prescription Registry contains information of all prescriptions dispensed for Danish residents at outpatient pharmacies from 1995 and onwards. The prescriptions are recorded according to the Anatomic Therapeutic Chemical (ATC) classification system by the World Health Organization.13 We defined ADHD medication as the following chemical substances: methylphenidate (ATC-code: N06BA04), modafinil (ATC-code: N06BA07), and atomoxetin (ATC-code: N06BA09). Demographic characteristics Data on demographic characteristics were identified through Statistics Denmark. Maternal age at time of conception was calculated by subtracting the day of conception, defined as LMP plus 14 days, from the woman’s day of birth. The maternal age was categorized as follows: 40. Civil status was categorized as follows: married or in a registered relationship, single, and divorced/widow. The very low number of widowed women and none among the pregnancies exposed to ADHD medication did not allow us to distinguish between divorced and widowed women. Ethnicity Copyright © 2014 John Wiley & Sons, Ltd.
Other characteristics Parous was categorized as never given birth before and given birth one or more times before: 0 and 1+. Births included both live births and stillbirths. Information on previously induced abortions was obtained from the National Patient Registry and the Register of Legal Induced Abortions. This included both induced abortions on maternal request and induced abortions on special indication. Data on redeemed prescriptions of anxiety medication (ATC-code: N05B) and Selective Serotonin Reuptake Inhibitor (SSRI) (ATC-code: N06AB) were identified through the National Prescription Registry. Use of these medications was defined as one or more redeemed prescriptions from 28 days before LMP to end of pregnancy. Moreover, information on ADHD diagnosis, given any time before LMP, was derived from the Psychiatric Central Research Registry and divided into the following categories: yes and no. Patients are only registered in the Psychiatric Central Research Registry when psychiatric hospitals or departments are involved. Patients only in contact with general practitioners are thus not recorded in the register. Outcome of pregnancy and congenital malformations Information on outcome of pregnancy was obtained from the Medical Birth Registry, the National Patient Registry, and the Register of Legal Induced Abortions. The outcome was categorized as induced abortion on Pharmacoepidemiology and Drug Safety, 2014; 23: 526–533 DOI: 10.1002/pds
528
k. b. hærvig et al.
maternal request (
