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Antidepressant prescriptions for prenatal and postpartum women in Japan: A health administrative database study
Journal of Affective Disorders 264 (2020) 295–303
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Research paper
Antidepressant prescriptions for prenatal and postpartum women in Japan: A health administrative database study
T
⁎
Tomofumi Ishikawaa, Taku Obarab,c,d, , Saya Kikuchie, Natsuko Kobayashie,f, Keiko Miyakodag, Hidekazu Nishigorih, Hiroaki Tomitae, Manabu Akazawai, Nobuo Yaegashic,d,j, Shinichi Kuriyamac,d,k, Nariyasu Manoa,b a
Laboratory of Clinical Pharmacy, Tohoku University Graduate School of Pharmaceutical Sciences, 1-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8574 Japan Department of Pharmaceutical Sciences, Tohoku University Hospital, 1-1, Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8574 Japan c Tohoku Medical Megabank Organization, Tohoku University, 2-1, Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8573 Japan d Environment and Genome Research Center, Tohoku University Graduate School of Medicine, 2-1, Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8573 Japan e Department of Psychiatry, Tohoku University Graduate School of Medicine, 1-1, Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8574 Japan f Department of Health Sciences, Tohoku University Graduate School of Medicine, 2-1, Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8575 Japan g Clinical & Translational Research Center, Kobe University Hospital, 7-5-2 Kusunoki-cho, Chuo-ku, Kobe, Hyogo 650-0017 Japan h Fukushima Medical Center for Children and Women, Fukushima Medical University, Hikarigaoka, Fukushima, 960-1295 Japan i Department of Public Health and Epidemiology, Meiji Pharmaceutical University, 2-522-1, Noshio, Kiyose, Tokyo 204-8588 Japan j Department of Gynecology and Obstetrics, Tohoku University Graduate School of Medicine, 1-1, Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8574 Japan k Tohoku University International Research Institute for Disaster Science, 2-1, Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8573 Japan b
A R T I C LE I N FO
A B S T R A C T
Keywords: Administrative data Antidepressant Claim Depression Pharmacoepidemiology Pregnancy
Background: The prevalence and pattern of perinatal antidepressant prescriptions in Japan are unknown. Methods: The prevalence of antidepressant prescriptions between 180 days before pregnancy onset and 180 days postpartum was evaluated using a large administrative database. The dates of pregnancy onset and delivery were estimated using developed algorithms. Results: Of 33,941 women, at least one antidepressant was prescribed to 451 (133/10,000 deliveries) between 180 days before pregnancy and 180 days postpartum and to 241 (71/10,000 deliveries) during pregnancy. The prevalence of antidepressant prescriptions decreased during the first and second trimesters and increased in the postpartum period. Of 339 women with antidepressant prescriptions before pregnancy, 151 (44.5%) discontinued it during pregnancy. Selective serotonin-reuptake inhibitors were the most frequently prescribed class of antidepressants in the time period studied (356 women, 105/10,000 deliveries), followed by tricyclic/nontricyclic antidepressants (101 women, 30/10,000 deliveries). Of the 57 women who had at least one record of paroxetine prescription in the first trimester, 13 (22.8%) were prescribed >25 mg/day. Fifty-seven women (17/ 10,000 deliveries) were concurrently prescribed two or more classes of antidepressants between 180 days before pregnancy and 180 days postpartum. Limitations: It may not always have been the case that the prescribed antidepressants were used. Women whose pregnancy ended in an abortion or stillbirth were not included. Conclusions: Various antidepressants were prescribed to prenatal and postpartum women in Japan. Approximately half of pregnant women discontinued treatment with antidepressants after becoming pregnant. Women of childbearing age should select an appropriate antidepressant considering the risk/benefit profile.
1. Introduction Rates of depression during pregnancy are substantial (Bennett et al.,
2004; Molenaar et al., 2018). Perinatal depression is associated with an increased risk of premature delivery, low birth weight, gestational hypertension, and perinatal death (Molenaar et al., 2018). Perinatal
Abbreviations: ICD-10, International Classification of Diseases, 10th revision; JECS, Japan Environment and Children's Study; JMDC, Japan Medical Data Center; NaSSA, noradrenergic and specific serotonergic antidepressant; SNRI, serotonin norepinephrine reuptake inhibitor; SSRI, selective serotonin-reuptake inhibitor; TCA, tricyclic antidepressant ⁎ Corresponding author at: Department of Pharmaceutical Sciences, Tohoku University Hospital, 1-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8574, Japan. E-mail address: [email protected] (T. Obara). https://doi.org/10.1016/j.jad.2020.01.016 Received 12 September 2019; Received in revised form 16 December 2019; Accepted 3 January 2020 Available online 07 January 2020 0165-0327/ © 2020 Elsevier B.V. All rights reserved.
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specific visit from the date of the diagnosis. For example, when “delivery at week 39” was entered, then 39 weeks and 0 days was subtracted. If two or more pregnancies were identified for one woman, we included data from only one pregnancy – the one with the highest gestational age at the time of a specific visit available. Based on an assessment using administrative data from a university hospital, 92.8% of the estimated dates of pregnancy onset were within ± 7 days of the gold standard date of pregnancy onset (Ishikawa et al., 2018b). The date of delivery was estimated based on delivery-related entries described in our previous reports (Ishikawa et al., 2019; Ishikawa et al., 2018a) and the birth months of the infants. An algorithm was developed based on these findings in which the earliest dates of selected diagnoses and surgical procedures described elsewhere were primarily considered as delivery dates (Ishikawa et al., 2019). For those without such diagnoses or procedures, the earliest dates of any other deliveryrelated diagnoses, surgical or medical procedures, or injectable medications were considered the delivery dates. Based on the assessment using administrative data from a university hospital, 96.4% of the estimated delivery dates were within ± 7 days of the gold standard delivery date (Ishikawa et al., 2018b). Given that birth months and years are included with the infants’ eligibility information in the JMDC claims database, the dates of delivery-related entries were used only when the date was within the birth month of an infant. Delivery per se is not always covered by health insurance in Japan and related information is not entered when a delivery does not require procedures, medications, etc. that are covered by health insurance. In such cases, the 15th day of the neonatal birth month was considered the delivery date. A pregnancy that reaches or extends beyond 294 days of gestation is considered a post-term pregnancy and the induction of labor is recommended due to an increased risk of perinatal mortality (Minakami et al., 2014). Thus, when the difference between the dates of pregnancy onset and delivery estimated by the algorithms exceeded 294 days, a gestational period of 294 days was uniformly assigned and pregnancy onset was considered as 294 days before the claim-based delivery date. Pregnancies were divided into the first (from pregnancy onset to week 13 day 6 of gestation), second (week 14 day 0 to week 27 day 6), and third (week 28 day 0 to delivery) trimesters (Minakami et al., 2014).
depression can also lead to behavioral, emotional, cognitive, and motor problems in early childhood (Molenaar et al., 2018); thus, it is treated with antidepressants depending on the severity and risk-benefit balance of the medication (Molenaar et al., 2018; Japanese Society of Mood Disorders, 2017; Japanese Society of Perinatal Mental Health, 2017). In reports from Europe and North America, 2–13% of women are treated with antidepressants during pregnancy and the majority of antidepressants are selective serotonin-reuptake inhibitors (SSRIs) (Alwan et al., 2011; Charlton et al., 2015; Cooper et al., 2007; Huybrechts et al., 2013; Andrade et al., 2008; Bénard-Laribière et al., 2018; Petersen et al., 2011; Bérard and Sheehy, 2014). However, the prevalence and pattern of perinatal antidepressant prescriptions in Japan is unknown. Studies of antidepressants prescribed to prenatal and postpartum women could provide important indicators regarding the drugs that are most commonly prescribed before, during, and after pregnancy in Japan and catalyze programs to optimize antenatal prescribing. Health administrative databases are important sources of data that are used for pharmacoepidemiological evaluations of drug exposure during pregnancy (Daw et al., 2011; Strom and Carson, 1990). The objective of the present study was to evaluate the prevalence, timing, and patterns of antidepressant prescriptions to prenatal and postpartum women in Japan using a large administrative database. 2. Methods 2.1. Source of data Data were extracted from a large database of health insurance claims developed and maintained by the Japan Medical Data Center (JMDC, Tokyo, Japan) (Kimura et al., 2010). This database includes all inpatient, outpatient, and pharmacy claims received from insurers and is one of the largest claims databases in Japan. Claims contain diagnoses classified according to the International Classification of Diseases, 10th revision (ICD-10), surgical and medical procedures, and prescribed medications. Standardized disease classification and anonymous record linkage were used in the database (Kimura et al., 2010). More details of the database can be found in our previous reports (Ishikawa et al., 2019; Ishikawa et al. 2018a). This study was approved by the Institutional Review Board of Tohoku University School of Medicine on July 19, 2016 (registration number: 2016-1-230).
2.4. Antidepressant prescriptions Antidepressants evaluated in the present study were identified based on the latest treatment guideline for major depressive disorder prepared by the Japanese Society of Mood Disorders (Japanese Society of Mood Disorders, 2017) and included SSRIs, serotonin norepinephrine reuptake inhibitors (SNRIs), noradrenergic and specific serotonergic antidepressants (NaSSAs), and tricyclic antidepressants (TCAs)/nonTCAs. TCAs/non-TCAs included imipramine, clomipramine, trimipramine, lofepramine, amitriptyline, nortriptyline, amoxapine, dosulepin, maprotiline, mianserin, setiptiline, and trazodone; this covered all antidepressants approved in Japan. The dispensing date was preferentially used, but if the dispensing date was unavailable, the hospitalization date was used instead. Since the month and year were available for each claim, each drug was assigned to the 15th day of the month when either the dispensing date or hospitalization date was unavailable. The days of supply of each prescription were available in the database and were considered to determine the timing of exposure. Antidepressants were classified according to the route of administration and their generic names. In cases where two or more antidepressants with the same generic name and route of administration were prescribed on the same day, we calculated the sum of the doses when evaluating the maximum prescribed daily dose. Antidepressants intended for as-needed use based on claims were excluded when evaluating the maximum daily dose. Women who did not have sufficient daily dose information were also excluded from the maximum daily dose analysis. If two or more classes of antidepressants prescribed to a single woman had the same date (i.e.,
2.2. Study population The dataset that was available on February 27, 2017 was used and included 3,836,202 men and women covered by health insurance between January 2005 and August 2016. Mothers whose children who were born and could be identified were included. Mothers can be linked with their offspring in the JMDC claims database if their infants are enrolled with the same health insurer; this allows the identification of the month and year of birth (the date of birth is not available to avoid re-identification). Women who met the following eligibility criteria were selected to evaluate prescriptions during pregnancy: mothers whose infants were enrolled with the same health insurer during their birth month; mothers whose dates of pregnancy onset and delivery could be estimated; and those who were members of one of a number of health insurance schemes exclusively from 180 days before pregnancy onset through 180 days postpartum. 2.3. Estimation of the dates of pregnancy onset and delivery Neither the date of pregnancy onset nor the date of delivery is available in the Japanese claims database. Thus, the dates were estimated using algorithms described elsewhere (Ishikawa et al., 2019). Briefly, the date of pregnancy onset was estimated by subtracting the gestational age recorded as part of the diagnosis at the time of a 296
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Table 1 Antidepressant prescriptions between 180 days before pregnancy and 180 days postpartum. Non-proprietary name
Total
Before pregnancy Within –180 days
During pregnancy
Postpartum
–180 to –91 days
–90 to –1 days
Any trimester
First trimester
Second trimester
Third trimester†
Within 180 days
1 to 90 days
91 to 180 days
n (per 10,000) Total
451 (133)
339 (100)
295 (87)
277 (82)
241 (71)
229 (67)
89 (26)
74 (22)
212 (62)
143 (42)
178 (52)
SSRIs
356 (105)
263 (77)
225 (66)
217 (64)
188 (55)
174 (51)
65 (19)
57 (17)
161 (47)
133 (39)
60 (18) 87 (26) 108 (32) 145 (43)
26 (8) 70 (21) 84 (25) 105 (31)
18 59 65 94
17 55 72 83
18 51 59 68
16 49 58 58
4 (1) 21 (6) 20 (6) 21 (6)
4 (1) 19 (6) 17 (5) 19 (6)
32 32 46 62
110 (32) 15 (4) 25 (7) 37 (11) 39 (11)
SNRIs Duloxetine Milnacipran
47 (14) 39 (11) 10 (3)
32 (9) 26 (8) 7 (2)
27 (8) 21 (6) 7 (2)
26 (8) 22 (6) 5 (1)
21 (6) 19 (6) 4 (1)
20 (6) 18 (5) 4 (1)
8 (2) 5 (1) 3 (1)
8(2) 6 (2) 2 (1)
26 (8) 21 (6) 5 (1)
17 (5) 4 (1)
23 (7) 19 (6) 4 (1)
NaSSAs Mirtazapine
54 (16) 54 (16)
29 (9) 29 (9)
23 (7) 23 (7)
21 (6) 21 (6)
15 (4) 15 (4)
14 (4) 14 (4)
3 (1) 3 (1)
3 (1) 3 (1)
25 (7) 25 (7)
17 (5) 17 (5)
14 (4) 14 (4)
TCAs/non-TCAs Amitriptyline Amoxapine Clomipramine Dosulepin Imipramine Lofepramine Maprotiline Mianserin Nortriptyline Setiptiline Trazodone Trimipramine
101 (30) 16 (5) 22 (6) 12 (4) 1 (0) 7 (2) 1 (0) 8 (2) 11 (3) 6 (2) 1 (0) 27 (8) 1 (0)
74 (22) 12 (4) 13 (4) 10 (3) 1 (0) 5 (1) 1 (0) 6 (2) 7 (2) 4 (1)
64 (19) 9 (3) 12 (4) 10 (3) 1 (0) 5 (1) 1 (0) 3 (1) 7 (2) 4 (1)
58 (17) 8 (2) 9 (3) 10 (3)
54 (16) 6 (2) 9 (3) 9 (3)
46 (14) 5 (1) 7 (2) 8 (2)
22 (6) 2 (1) 2 (1) 4 (1)
14 (4)
33 (10) 4 (1) 10 (3) 2 (1)
17 (5) 3 (1) 2 (1)
29 (9) 4 (1) 8 (2) 2 (1)
3 1 6 6 3
1 1 3 4 2
1 1 2 2 1
1 1 2 4 2
18 (5)
4 (1) 1 (0) 5 (1) 7 (2) 2 (1) 1 (0) 12 (4)
1 1 2 3
21 (6) 1 (0)
4 (1) 1 (0) 6 (2) 8 (2) 2 (1) 1 (0) 14 (4)
Escitalopram Fluvoxamine Paroxetine Sertraline
(5) (17) (19) (28)
(5) (16) (21) (24)
(1) (0) (2) (2) (1)
16 (5) 1 (0)
(5) (15) (17) (20)
(5) (14) (17) (17)
(0) (0) (1) (1)
1 (0) 8 (2)
2 (1) 1 (0)
1 (0) 2 (1) 2 (1)
(9) (9) (14) (18)
(0) (0) (1) (1) (1)
10 (3)
(0) (0) (1) (1) (0)
6 (2)
27 24 35 53
(8) (7) (10) (16)
(0) (0) (1) (1) (1)
8 (2)
†
Denominator is the number of pregnant women who reached the third trimester (n = 33,836). Abbreviations: NaSSA = noradrenergic and specific serotonergic antidepressant, SNRI = serotonin norepinephrine reuptake inhibitor, SSRI = selective serotonin reuptake inhibitor, TCA = tricyclic antidepressant.
year, maternal age at delivery, gestational age at delivery, diagnosis of affective disorders before delivery, diagnosis of other mental and behavioral disorders before delivery, history of adverse pregnancy complications (ICD-10 code: O10-O16, O20-O29 and O30-O48), and multiple pregnancies. The prevalence of antidepressants prescribed between 180 days before pregnancy and 180 days postpartum was calculated for each delivery-based year. For antidepressants and each class and individual molecule that were prescribed to more than 20 women between 180 days before pregnancy and 180 days postpartum, the time trends of antidepressant prescriptions between 180 days before pregnancy and 180 days postpartum were analyzed using a multivariate logistic regression model adjusting for maternal age at delivery. The prescription prevalence of paroxetine was classified according to the maximum dose and 25 mg/day was considered a cut-off because gestational exposure to paroxetine above 25 mg/day has been associated with major congenital malformations (Bérard et al., 2007). The prevalence, timing, and patterns of potential combination therapy were described. The prevalence of antidepressant prescriptions is reported per 10,000 deliveries. The level of significance was 0.05. All data were analyzed using SAS version 9.4 (SAS Institute, Inc., Cary, NC, USA).
dispensing date, hospitalization date, or 15th day of the month of the claim), this was considered potential combination therapy.
2.5. Data analysis First, the prevalence of antidepressant prescriptions was determined for the periods of 180 days before pregnancy onset, during pregnancy, and 180 days postpartum. The prescribing prevalence was also calculated for 180 to 91 days and 90 to 1 days before pregnancy, for each trimester, and for 1 to 90 days and 91 to 180 days postpartum. The prevalence was calculated for antidepressants overall and then for each class and each individual molecule. The evaluation of antidepressant prescriptions was repeated for women whose delivery dates were estimated according to delivery-related entries and for whom the 15th day of the neonatal birth month was considered the delivery date separately to compare the results of these two subpopulations and discuss the effect of assigning the 15th day of the neonatal birth month as the delivery date. For those to whom antidepressants were prescribed within the 180 days before pregnancy, we examined when the treatment was discontinued and restarted regarding antidepressants overall and for each class. Multivariate logistic regression analyses were used to identify predictors of antidepressant prescription during pregnancy, including delivery year, maternal age at delivery, diagnosis of affective disorders (ICD-10 code: F30-F39) before pregnancy, diagnosis of other mental and behavioral disorders (ICD-10 code: F00-F99 excluding F30F39) before pregnancy, and history of pregnancy with abortive outcome (ICD-10 code: O00-O08) within 180 days before pregnancy; and predictors of antidepressant prescription postpartum, including delivery
3. Results Of the 3,836,202 men and women covered by health insurance between January 2005 and August 2016, 33,941 women met our eligibility criteria (Figure S1). No specific difference in their background was noted between mothers who met and did not meet our eligibility criteria (Table S1). Delivery dates were estimated based on 297
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prevalence of any class of antidepressant and the delivery-based year (Fig. 2). The most frequently prescribed SSRI was sertraline (145 women, 43 per 10,000 deliveries), followed by paroxetine (108 women, 32 per 10,000 deliveries), fluvoxamine (87 women, 26 per 10,000 deliveries), and escitalopram (60 women, 18 per 10,000 deliveries) (Table 1). The prescribing prevalence of both paroxetine (trend P < 0.0001) and fluvoxamine (trend P = 0.0227) significantly decreased and that of escitalopram significantly increased annually (trend P < 0.0001) (Fig. 2 and Table S5). Of 57 women who had at least one record of a paroxetine prescription in the first trimester, 13 (22.8%) were prescribed >25 mg/day (Fig. 3). Concerning potential combination therapy, 57 women (17 per 10,000 deliveries) concurrently received two or more classes of prescribed antidepressants between 180 days before pregnancy onset and 180 days postpartum, and 25 (7 per 10,000 deliveries) of them received the antidepressants during pregnancy (Table 2). The most popular combination was SSRI plus TCA/non-TCA (34 women, 10 per 10,000 deliveries) between 180 days before pregnancy onset and 180 days postpartum; the other combinations were relatively rare.
the earliest dates of selected diagnoses and surgical procedures for 12,604 women, earliest dates of any other delivery-related entries for 5,014 women, and the 15th day of the neonatal birth month for 16,323 women. A term of 294 days was uniformly assigned as the gestational period to 569 women (1.7%) whose gestational period exceeded this value. There were 11,288 records of antidepressant prescriptions among the 33,941 women. The timing of exposure was evaluated from 10,576 (93.7%) and 76 records (0.7%) based on the dispensing and hospitalization dates, respectively. For the other 636 records (5.6%), the 15th day of the month and year recorded in each claim were used. The mean age at delivery and length of gestation were 32.3 years (standard deviation [SD]: 4.5 years) and 270.1 days (SD: 13.5 days), respectively. Of 33,941 women, 33,836 (99.7%) reached the third trimester. There were 26,272 women (77.4%) who gave birth in or after 2012. Based on claims data, 111 (33 per 10,000 deliveries), 729 (215 per 10,000 deliveries), and 830 women (245 per 10,000 deliveries) were diagnosed with “bipolar affective disorder” (ICD-10 code: F31), “depressive episode” (ICD-10 code: F32), and “other anxiety disorders” (ICD-10 code: F41), respectively, before the delivery date (Table S2). At least one antidepressant was prescribed to 451 (133 per 10,000 deliveries) of 33,941 women between 180 days before pregnancy onset and 180 days postpartum (Table 1). In total, 339 (100 per 10,000 deliveries), 241 (71 per 10,000 deliveries), and 212 women (62 per 10,000 deliveries) had at least one record of an antidepressant prescription within 180 days before pregnancy, during pregnancy, and within 180 days postpartum, respectively. Compared to the pre-pregnancy period where an antidepressant was prescribed to 295 women (87 per 10,000 deliveries) 180 to 91 days before pregnancy and 277 women (82 per 10,000 deliveries) 90 to 1 days before pregnancy, the prevalence of antidepressant prescriptions decreased during the first (229 women, 67 per 10,000 deliveries) and second trimesters (89 women, 26 per 10,000 deliveries) and increased in the postpartum period where an antidepressant was prescribed to 143 women (42 per 10,000 deliveries) 1 to 90 days postpartum and 178 women (52 per 10,000 deliveries) 91 to 180 days postpartum (Table 1). Of 339 women with antidepressant prescriptions before pregnancy, 65 (19.2%) continued the antidepressant throughout pregnancy (Fig. 1), 123 (36.3%) discontinued the antidepressant before pregnancy, and 151 (44.5%) discontinued it during pregnancy. Of 33,602 women to whom an antidepressant was not prescribed before pregnancy, 21 women started antidepressants during pregnancy. In addition to the diagnosis of affective disorders (trend P <0.0001) and other mental and behavioral disorders (trend P <0.0001) before pregnancy, maternal age at delivery (trend P = 0.0007) was a significant predictor of antidepressant prescription during pregnancy (Table S3). Likewise, in addition to the diagnosis of affective disorders (trend P <0.0001) and other mental and behavioral disorders (trend P <0.0001) before delivery, maternal age at delivery (trend P = 0.0030) was also a significant predictor of antidepressant prescription postpartum (Table S3). The prevalence of each antidepressant prescription is shown in Table 1. SSRIs were the most frequently prescribed class of antidepressants in the time period studied (356 women, 105 per 10,000 deliveries), followed by TCAs/non-TCAs (101 women, 30 per 10,000 deliveries), NaSSAs (54 women, 16 per 10,000 deliveries), and SNRIs (47 women, 14 per 10,000 deliveries). The antidepressants of choice were similar between women whose delivery date was estimated according to delivery-related entries and those for whom the 15th day of the neonatal birth month was considered as the delivery date (Table S4). The status of those who discontinued or restarted SSRIs, SNRIs and/or NaSSAs, and TCAs/non-TCAs was similar to that of the overall results (Fig. 1). Of those without an SSRI prescription before pregnancy, 21 women started an SSRI during pregnancy. Similarly, during pregnancy, an SNRI or NaSSA was prescribed to five women without an SNRI or NaSSA prescription before pregnancy, and a TCA/non-TCA was prescribed to 11 women without a TCA/non-TCA prescription before pregnancy. No significant association was observed between the
4. Discussion To the best of our knowledge, this is the first evaluation of the status of antidepressant prescriptions for prenatal and postpartum women in Japan using a large administrative database with the estimation of dates of pregnancy onset and delivery calculated using developed algorithms. In the Japan Environment and Children's Study (JECS) (Nishigori et al., 2017a), the percentages of pregnant women that took an SSRI before diagnosis of pregnancy, between the time of diagnosis of pregnancy until week 12 of pregnancy, and after week 12 of pregnancy, were 0.53%, 0.18%, and 0.15%, respectively. In addition, the percentage of pregnant women that took an antidepressant drug excluding SSRIs before the diagnosis of pregnancy, between the time of diagnosis of pregnancy until week 12 of pregnancy, and after week 12 of pregnancy were 0.27%, 0.09%, and 0.08%, respectively. The prevalence of antidepressant use reported from the JECS is relatively lower than that in the present study; different methodologies in study design and observation periods may account for the difference. The JECS collected information on exposure during pregnancy using interviews, while the present study used a claims database to identify medication exposures. The prevalence of antidepressant use during pregnancy is approximately 2–3% in Europe (Bénard-Laribière et al., 2018; Petersen et al., 2011) and 5–13% in North America (Alwan et al., 2011; Andrade et al., 2008; Bérard and Sheehy, 2014; Cooper et al., 2007). There are several possible reasons. First, it has been reported that the prevalence of major depressive disorder is lower in pregnant Japanese women than in Europe and North America (Usuda et al., 2016). Second, the study comparing the evidence and recommendation levels for pregnancy information in the labelling showed that the “unclassified” evidence level was the highest in Japan (33.3%) and a “contraindicated” recommendation level in Japan (50.6%) was more common than in the USA (9.9%) (Noh et al., 2018). Third, benzodiazepines were frequently prescribed to patients diagnosed with major depression in Japan and, considering the risk and benefit of benzodiazepines, they seem to be over-prescribed for the treatment of major depression in Japan (Onishi et al., 2013). Fourth, the difference in methodologies, such as the difference in background characteristics of the population between studies, may possibly affect the results of this study. The study reporting that 13.3% had antidepressant exposure during pregnancy in the USA discussed that it included large numbers of Medicaid enrolees, who are known to have higher rates of chronic health conditions, including mental illness (Cooper et al., 2007). This may lead to variability in the prescribing prevalence across countries. Although antidepressants are generally considered safe to use during pregnancy, this remains 298
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Fig. 1. Discontinuation and restarting of antidepressant prescriptions from 180 days before pregnancy to 180 days postpartum Abbreviations: SSRI = selective serotonin reuptake inhibitor, SNRI = serotonin norepinephrine reuptake inhibitor, NaSSA = noradrenergic and specific serotonergic antidepressant, TCA = tricyclic antidepressant.
Around half of women to whom an antidepressant was prescribed before pregnancy onset discontinued treatment after becoming pregnant. This trend may indicate that women can be treated without an antidepressant as appropriate, or that treatment with an antidepressant can be discontinued once women become aware of their pregnancy. It has been reported that unplanned pregnancy was also a risk factor for abrupt discontinuation of SSRIs upon confirmation of pregnancy in women with depressive or anxiety disorder (Roca et al., 2013). Since depression during pregnancy carries the risk of adverse effects on both the mother and her child, treatment with antidepressants should be controlled before becoming pregnant (Japanese Society of Mood Disorders, 2017). According to a recent study reviewing the content of the internationally available guidelines on the treatment of perinatal depression and perinatal use of antidepressants, some guidelines advise continuing antidepressant use during pregnancy, while other guidelines mention the possibility of continuation but do not specifically advise or
controversial (Molenaar et al., 2018; Japanese Society of Perinatal Mental Health, 2017). It has been reported that antidepressant use is associated with an increased risk of congenital malformations (National Institute for Health and Care Excellence, 2018; Grigoriadis et al., 2013; Gao et al., 2018; Nishigori et al., 2017b), persistent pulmonary hypertension of the newborn (Grigoriadis et al., 2014), poor neonatal adaptation syndrome (National Institute for Health and Care Excellence, 2018; Grigoriadis et al., 2013), and psychiatric disorders in the offspring (Liu et al., 2017; Boukhris et al., 2016; Gentile, 2015). According to the guidelines available in Japan, the potential harms and benefits of antidepressants during pregnancy should be explained by the clinician to the patient so that patients can make well-informed decisions regarding their preferred treatment (Japanese Society of Mood Disorders, 2017; Japanese Society of Perinatal Mental Health, 2017), an approach that has reached international consensus (Molenaar et al., 2018). 299
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Fig. 2. Time trends of antidepressants prescribed between 180 days before pregnancy and 180 days postpartum *P<.05, **P<.0001 Abbreviations: SSRI = selective serotonin reuptake inhibitor, SNRI = serotonin norepinephrine reuptake inhibitor, NaSSA = noradrenergic and specific serotonergic antidepressant, TCA = tricyclic antidepressant.
Fig. 3. Maximum prescribed doses of paroxetine per day One woman was excluded from the analysis due to insufficient information regarding the prescribed daily dose.
300
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Table 2 Potential cases of combination therapy. Total
Before pregnancy Within –180 to –180 days –91 days
–90 to –1 days
During pregnancy Any trimester First trimester
Second trimester
Third trimester†
Postpartum Within 180 days
1 to 90 days
91 to 180 days
12 (4) 1 (0) 2 (1) 3 (1) 1 (0) 3 (1) 2 (1)
12 (4) 1 (0)
n (per 10,000) Total SSRI + SNRI SSRI + NaSSA SSRI + TCA/non-TCA SNRI + NaSSA SNRI + TCA/non-TCA NaSSA + TCA/non-TCA SSRI + SNRI + TCA/non-TCA SSRI + NaSSA + TCA/non-TCA
57 (17) 5 (1) 9 (3) 34 (10) 2 (1) 7 (2) 5 (1) 1 (0) 2 (1)
43 (13) 4 (1) 7 (2) 28 (8)
36 (11) 4 (1) 5 (1) 23 (7)
34 (10) 3 (1) 4 (1) 22 (6)
25 (7) 2 (1) 2 (1) 15 (4)
23 (7) 2 (1) 2 (1) 14 (4)
7 (2)
6 (2)
4 (1)
3 (1)
5 (1) 2 (1)
5 (1) 1 (0)
5 (1) 2 (1)
4 (1) 2 (1)
3 (1) 2 (1)
2 (1) 1 (0)
3 (1)
1 (0)
1 (0)
19 (6) 1 (0) 2 (1) 8 (2) 2 (1) 5 (1) 3 (1) 1 (0) 1 (0)
5 1 5 2 1 1
(1) (0) (1) (1) (0) (0)
†
Denominator is the number of pregnant women who reached the third trimester (n = 33,836). Abbreviations: NaSSA = noradrenergic and specific serotonergic antidepressant, SNRI = serotonin norepinephrine reuptake inhibitor, SSRI = selective serotonin reuptake inhibitor, TCA = tricyclic antidepressant.
utero exposure to TCAs/non-TCAs and adverse pregnancy outcomes, although the sample size was limited (McElhatton et al., 1996). Given that there may be possible synergistic or additive effects on neonatal outcomes when different drugs that act on the central nervous system are used concomitantly (Källén et al., 2013), women taking antidepressants during pregnancy should aim for monotherapy and avoid combination therapy as much as possible according to published guidelines (Japanese Society of Mood Disorders, 2017). In the present study, the prevalence of combination therapy may have been underestimated because we considered combination therapy only in cases in which the dates of two or more antidepressant prescriptions were the same. This study did have some limitations. First, a claims database was used, so it was not possible to evaluate the severity or symptoms of the disease, indications for the prescriptions, or if the prescribed antidepressants were actually used. Second, the timing of drug exposure might have sometimes been misclassified due to assumptions regarding the dates of delivery and dispensed drugs (Ishikawa et al., 2019; Ishikawa et al., 2018a; Ishikawa et al., 2018b). However, the antidepressants of choice were similar between women whose delivery date was estimated according to delivery-related entries and those for whom the 15th day of the neonatal birth month was considered as the delivery date. In addition, since the dispensing date was available for 93.7% of the drugs in the present study, the missing dates for drugs would not have affected the conclusions of this study. Third, the study population included only those with live-born children who were enrolled with the same health insurer as their mother because no algorithm has been developed and validated to identify pregnancy directly without information about the child's birth. Therefore, it was not possible to evaluate antidepressants prescribed to women whose pregnancy ended in an abortion or stillbirth. Fourth, although we have evaluated predictors of antidepressant prescription in prenatal and postpartum women, some important confounding factors that may be associated with antenatal depression, such as socio-demographic and economic risk factors including education level, status of employment, and income (Biaggi et al., 2016), and severity of depression were unavailable in the JMDC claims database. Further studies using different types of clinical databases and a prospective design are required to evaluate such predictors in detail. In conclusion, various antidepressants were prescribed to prenatal and postpartum women in Japan. It is suggested that approximately half of pregnant women discontinued treatment with antidepressants after becoming pregnant. SSRIs were the drug class of choice, followed by TCAs/non-TCAs. Women of childbearing age who require antidepressant treatment should select an appropriate antidepressant,
discourage continuation (Molenaar et al., 2018). Antidepressant prescription in the present study was more common among older mothers, which is consistent with a previous study (Cooper et al., 2007). Recently, SSRIs were found to be the most common antidepressants used by pregnant women and the use of other antidepressants is limited (Molenaar et al., 2018; Japanese Society of Mood Disorders, 2017; Andrade et al., 2008). A similar trend for SSRIs was observed in Japan. Although paroxetine was the second most frequently prescribed SSRI in the present study, in general, guidelines agree on avoiding paroxetine during pregnancy (Molenaar et al., 2018; Japanese Society of Perinatal Mental Health, 2017) since its use is associated with an increased risk of congenital cardiovascular malformations in newborns (National Institute for Health and Care Excellence, 2018; Grigoriadis et al., 2013; Bérard et al., 2016). A dose-dependent risk of cardiac defects has also been reported for paroxetine (Bérard et al., 2007). Although findings from other studies have shown conflicting results in terms of statistical significance (Ban et al., 2014), a trend remains towards an increased risk; thus, paroxetine should be avoided in consideration of the possibility of an increased risk of congenital cardiovascular malformations according to the guidelines (Molenaar et al., 2018; Japanese Society of Perinatal Mental Health, 2017). Sertraline is considered to have no significant association with cardiac malformations in infants (Myles et al., 2013). Sertraline is also named in the guidelines as a preferred medication in the postpartum period, mainly due to its low level in breast milk and infants’ serum (Molenaar et al., 2018). Concerning escitalopram and fluvoxamine, evidence of their associations with cardiac malformations is limited compared to paroxetine and sertraline and should be further accumulated. In the present study, the prescribing prevalence of paroxetine and fluvoxamine significantly decreased and that of escitalopram significantly increased annually. With evidence of an increased risk of congenital cardiovascular malformations with paroxetine treatment and the related recommendation to avoid paroxetine in pregnant women, the prescribing prevalence may have decreased, as shown in the present study. In addition, escitalopram consistently shows advantages in efficacy and tolerability profiles compared to classical SSRIs (Sanchez et al., 2014); thus, escitalopram may have gradually replaced paroxetine and fluvoxamine. The present study shows that TCAs/nonTCAs are more frequently selected in Japan than in the USA and France (Huybrechts et al., 2013; Bénard-Laribière et al., 2018). There is no concrete evidence regarding whether TCAs/non-TCAs are safe to use during pregnancy. Recently, a study using Swedish data showed that the congenital malformation rate increased after the maternal use of TCAs (Reis and Källén, 2010). In the European Network of Teratology Information Services, no causal relationship was established between in
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ideally before becoming pregnant, in consideration of the risk/benefit profile of the antidepressants, including the risks for the fetus and risk of relapse of major depression in untreated patients with depression.
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Ishikawa, T., Obara, T., Nishigori, H., Miyakoda, K., Ishikuro, M., Metoki, H., Ohkubo, T., Sugawara, J., Yaegashi, N., Akazawa, M., Kuriyama, S., Mano, N., 2018a. Antihypertensives prescribed for pregnant women in Japan: prevalence and timing determined from a database of health insurance claims. Pharmacoepidemiol. Drug Saf. 27, 1325–1334. https://doi.org/10.1002/pds.4654. Ishikawa, T., Obara, T., Nishigori, H., Miyakoda, K., Inoue, R., Hoshiai, T., Saito, M., Yaegashi, N., Mano, N., 2018b. Development of algorithms to determine the onset of pregnancy and delivery date using healthcare administrative data in a university hospital in Japan. Pharmacoepidemiol. Drug Saf. 27, 751–762. https://doi.org/10. 1002/pds.4444. Japanese Society of Mood Disorders, 2017. Treatment Guideline for Major Depressive Disorder Version 2. Igakushoin, Tokyo (in Japanese). Japanese Society of Perinatal Mental Health, 2017. Perinatal mental health consensus guideline 2017 (in Japanese). http://pmhguideline.com/consensus_guide/cq01-20. pdf(accessed 06 September 2019). Källén, B., Borg, N., Reis, M., 2013. The use of central nervous system active drugs during pregnancy. Pharmaceuticals (Basel) 6, 1221–1286. https://doi.org/10.3390/ ph6101221. Kimura, S., Sato, T., Ikeda, S., Noda, M., Nakayama, T., 2010. Development of a database of health insurance claims: standardization of disease classifications and anonymous record linkage. J. Epidemiol. 20, 413–419. https://doi.org/10.2188/jea.je20090066. Liu, X., Agerbo, E., Ingstrup, K.G., Musliner, K., Meltzer-Brody, S., Bergink, V., MunkOlsen, T., 2017. Antidepressant use during pregnancy and psychiatric disorders in offspring: Danish nationwide register based cohort study. BMJ 358, j3668. https:// doi.org/10.1136/bmj.j3668. McElhatton, P.R., Garbis, H.M., Eléfant, E., Vial, T., Bellemin, B., Mastroiacovo, P., Arnon, J., Rodríguez-Pinilla, E., Schaefer, C., Pexieder, T., Merlob, P., Dal Verme, S., 1996. The outcome of pregnancy in 689 women exposed to therapeutic doses of antidepressants. A collaborative study of the European Network of Teratology Information Services (ENTIS). Reprod. Toxicol. 10, 285–294. Minakami, H., Maeda, T., Fujii, T., Hamada, H., Iitsuka, Y., Itakura, A., Itoh, H., Iwashita, M., Kanagawa, T., Kanai, M., Kasuga, Y., Kawabata, M., Kobayashi, K., Kotani, T., Kudo, Y., Makino, Y., Matsubara, S., Matsuda, H., Miura, K., Murakoshi, T.,
Contributors All authors have contributed to this scientific work and approved the final version of the manuscript. TI and TO designed this study, performed the data analyses, and wrote the manuscript. SK, NK, KM, HN, and HT assisted with the data analyses and supervised the drafting of the manuscript. MA, NY, SK, and NM critically revised the manuscript. Role of the Funding Source This work was supported by grants from the Ministry of Health, Labour and Welfare of Japan (H23-iyaku-ippan-006), Japan Society for the Promotion of Science (19K09746), and Research Foundation for Pharmaceutical Sciences. These sponsors did not play a role in the study design; in the collection, analysis, or interpretation of data; in the writing of the report; or in the decision to submit the article for publication. Submission declaration No prior posting or presentation and no research sponsor is associated with this paper. Declaration of Competing Interest Tomofumi Ishikawa is an employee of Pfizer R&D Japan. Tomofumi Ishikawa is also a research collaborator at Tohoku University and contributed to the present study independently of Pfizer R&D Japan. Manabu Akazawa received i) consultation fees from Takeda Pharmaceutical Co., Ltd. and Pfizer Japan Inc., while performing collaborative research and ii) honoraria for presentations from Astellas Pharma Inc., and Eisai Co., Ltd. The other authors have no conflicts of interest to declare. Acknowledgements The authors would like to thank the Research Group for Health Administrative Data and JMDC Inc. Supplementary materials Supplementary material associated with this article can be found, in the online version, at doi:10.1016/j.jad.2020.01.016. References Alwan, S., Reefhuis, J., Rasmussen, S.A., Friedman, J.M., National Birth Defects Prevention Study, 2011. Patterns of antidepressant medication use among pregnant women in a United States population. J. Clin. Pharmacol. 51, 264–270. https://doi. org/10.1177/0091270010373928. Andrade, S.E., Raebel, M.A., Brown, J., Lane, K., Livingston, J., Boudreau, D., Rolnick, S.J., Roblin, D., Smith, D.H., Willy, M.E., Staffa, J.A., Platt, R., 2008. Use of antidepressant medications during pregnancy: a multisite study. Am. J. Obstet. Gynecol. 198 (194), e1–e5. https://doi.org/10.1016/j.ajog.2007.07.036. Ban, L., Gibson, J.E., West, J., Fiaschi, L., Sokal, R., Smeeth, L., Doyle, P., Hubbard, R.B., Tata, L.J., 2014. Maternal depression, antidepressant prescriptions, and congenital anomaly risk in offspring: a population-based cohort study. BJOG 121, 1471–1481. https://doi.org/10.1111/1471-0528.12682. Bénard-Laribière, A., Pambrun, E., Sutter-Dallay, A.L., Gautier, S., Hurault-Delarue, C., Damase-Michel, C., Lacroix, I., Bégaud, B., Pariente, A., 2018. Patterns of antidepressant use during pregnancy: a nationwide population-based cohort study. Br. J. Clin. Pharmacol. 84, 1764–1775. https://doi.org/10.1111/bcp.13608. Bennett, H.A., Einarson, A., Taddio, A., Koren, G., Einarson, T.R., 2004. Prevalence of depression during pregnancy: systematic review. Obstet. Gynecol. 103, 698–709. https://doi.org/10.1097/01.AOG.0000116689.75396.5f.
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Murotsuki, J., Ohkuchi, A., Ohno, Y., Ohshiba, Y., Satoh, S., Sekizawa, A., Sugiura, M., Suzuki, S., Takahashi, T., Tsukahara, Y., Unno, N., Yoshikawa, H., 2014. Guidelines for obstetrical practice in Japan: Japan Society of Obstetrics and Gynecology (JSOG) and Japan Association of Obstetricians and Gynecologists (JAOG) 2014 edition. J. Obstet. Gynaecol. Res. 40, 1469–1499. https://doi.org/10. 1111/jog.12419. Molenaar, N.M., Kamperman, A.M., Boyce, P., Bergink, V., 2018. Guidelines on treatment of perinatal depression with antidepressants: an international review. Aust. N. Z. J. Psychiatry 52, 320–327. https://doi.org/10.1177/0004867418762057. Myles, N., Newall, H., Ward, H., Large, M., 2013. Systematic meta-analysis of individual selective serotonin reuptake inhibitor medications and congenital malformations. Aust. N. Z. J. Psychiatry 47, 1002–1012. https://doi.org/10.1177/ 0004867413492219. National Institute for Health and Care Excellence. Antenatal and postnatal mental health: clinical management and service guidance. Clinical guideline [CG192]. April 2018. https://www.nice.org.uk/guidance/cg192(accessed 06 September 2019). Nishigori, H., Obara, T., Nishigori, T., Metoki, H., Ishikuro, M., Mizuno, S., Sakurai, K., Tatsuta, N., Nishijima, I., Fujiwara, I., Arima, T., Nakai, K., Mano, N., Kuriyama, S., Yaegashi, N., Japan Environment & Children’s Study Group, 2017. Drug use before and during pregnancy in Japan: the Japan Environment and Children’s Study. Pharmacy (Basel) 5, 21. https://doi.org/10.3390/pharmacy5020021. Nishigori, H., Obara, T., Nishigori, T., Mizuno, S., Metoki, H., Hoshiai, T., Watanabe, Z., Sakurai, K., Ishikuro, M., Tatsuta, N., Nishijima, I., Fujiwara, I., Kuriyama, S., Arima, T., Nakai, K., Yaegashi, N., Japan Environment & Children’s Study Group, 2017. Selective serotonin reuptake inhibitors and risk of major congenital anomalies for pregnancies in Japan: a nationwide birth cohort study of the Japan Environment and Children’s Study. Congenit. Anom. (Kyoto) 57, 72–78. https://doi.org/10.1111/cga. 12202. Noh, Y., Yoon, D., Song, I., Jeong, H.E., Bae, J.H., Shin, J.Y., 2018. Discrepancies in the
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Research paper
Antidepressant prescriptions for prenatal and postpartum women in Japan: A health administrative database study
T
⁎
Tomofumi Ishikawaa, Taku Obarab,c,d, , Saya Kikuchie, Natsuko Kobayashie,f, Keiko Miyakodag, Hidekazu Nishigorih, Hiroaki Tomitae, Manabu Akazawai, Nobuo Yaegashic,d,j, Shinichi Kuriyamac,d,k, Nariyasu Manoa,b a
Laboratory of Clinical Pharmacy, Tohoku University Graduate School of Pharmaceutical Sciences, 1-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8574 Japan Department of Pharmaceutical Sciences, Tohoku University Hospital, 1-1, Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8574 Japan c Tohoku Medical Megabank Organization, Tohoku University, 2-1, Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8573 Japan d Environment and Genome Research Center, Tohoku University Graduate School of Medicine, 2-1, Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8573 Japan e Department of Psychiatry, Tohoku University Graduate School of Medicine, 1-1, Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8574 Japan f Department of Health Sciences, Tohoku University Graduate School of Medicine, 2-1, Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8575 Japan g Clinical & Translational Research Center, Kobe University Hospital, 7-5-2 Kusunoki-cho, Chuo-ku, Kobe, Hyogo 650-0017 Japan h Fukushima Medical Center for Children and Women, Fukushima Medical University, Hikarigaoka, Fukushima, 960-1295 Japan i Department of Public Health and Epidemiology, Meiji Pharmaceutical University, 2-522-1, Noshio, Kiyose, Tokyo 204-8588 Japan j Department of Gynecology and Obstetrics, Tohoku University Graduate School of Medicine, 1-1, Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8574 Japan k Tohoku University International Research Institute for Disaster Science, 2-1, Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8573 Japan b
A R T I C LE I N FO
A B S T R A C T
Keywords: Administrative data Antidepressant Claim Depression Pharmacoepidemiology Pregnancy
Background: The prevalence and pattern of perinatal antidepressant prescriptions in Japan are unknown. Methods: The prevalence of antidepressant prescriptions between 180 days before pregnancy onset and 180 days postpartum was evaluated using a large administrative database. The dates of pregnancy onset and delivery were estimated using developed algorithms. Results: Of 33,941 women, at least one antidepressant was prescribed to 451 (133/10,000 deliveries) between 180 days before pregnancy and 180 days postpartum and to 241 (71/10,000 deliveries) during pregnancy. The prevalence of antidepressant prescriptions decreased during the first and second trimesters and increased in the postpartum period. Of 339 women with antidepressant prescriptions before pregnancy, 151 (44.5%) discontinued it during pregnancy. Selective serotonin-reuptake inhibitors were the most frequently prescribed class of antidepressants in the time period studied (356 women, 105/10,000 deliveries), followed by tricyclic/nontricyclic antidepressants (101 women, 30/10,000 deliveries). Of the 57 women who had at least one record of paroxetine prescription in the first trimester, 13 (22.8%) were prescribed >25 mg/day. Fifty-seven women (17/ 10,000 deliveries) were concurrently prescribed two or more classes of antidepressants between 180 days before pregnancy and 180 days postpartum. Limitations: It may not always have been the case that the prescribed antidepressants were used. Women whose pregnancy ended in an abortion or stillbirth were not included. Conclusions: Various antidepressants were prescribed to prenatal and postpartum women in Japan. Approximately half of pregnant women discontinued treatment with antidepressants after becoming pregnant. Women of childbearing age should select an appropriate antidepressant considering the risk/benefit profile.
1. Introduction Rates of depression during pregnancy are substantial (Bennett et al.,
2004; Molenaar et al., 2018). Perinatal depression is associated with an increased risk of premature delivery, low birth weight, gestational hypertension, and perinatal death (Molenaar et al., 2018). Perinatal
Abbreviations: ICD-10, International Classification of Diseases, 10th revision; JECS, Japan Environment and Children's Study; JMDC, Japan Medical Data Center; NaSSA, noradrenergic and specific serotonergic antidepressant; SNRI, serotonin norepinephrine reuptake inhibitor; SSRI, selective serotonin-reuptake inhibitor; TCA, tricyclic antidepressant ⁎ Corresponding author at: Department of Pharmaceutical Sciences, Tohoku University Hospital, 1-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8574, Japan. E-mail address: [email protected] (T. Obara). https://doi.org/10.1016/j.jad.2020.01.016 Received 12 September 2019; Received in revised form 16 December 2019; Accepted 3 January 2020 Available online 07 January 2020 0165-0327/ © 2020 Elsevier B.V. All rights reserved.
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specific visit from the date of the diagnosis. For example, when “delivery at week 39” was entered, then 39 weeks and 0 days was subtracted. If two or more pregnancies were identified for one woman, we included data from only one pregnancy – the one with the highest gestational age at the time of a specific visit available. Based on an assessment using administrative data from a university hospital, 92.8% of the estimated dates of pregnancy onset were within ± 7 days of the gold standard date of pregnancy onset (Ishikawa et al., 2018b). The date of delivery was estimated based on delivery-related entries described in our previous reports (Ishikawa et al., 2019; Ishikawa et al., 2018a) and the birth months of the infants. An algorithm was developed based on these findings in which the earliest dates of selected diagnoses and surgical procedures described elsewhere were primarily considered as delivery dates (Ishikawa et al., 2019). For those without such diagnoses or procedures, the earliest dates of any other deliveryrelated diagnoses, surgical or medical procedures, or injectable medications were considered the delivery dates. Based on the assessment using administrative data from a university hospital, 96.4% of the estimated delivery dates were within ± 7 days of the gold standard delivery date (Ishikawa et al., 2018b). Given that birth months and years are included with the infants’ eligibility information in the JMDC claims database, the dates of delivery-related entries were used only when the date was within the birth month of an infant. Delivery per se is not always covered by health insurance in Japan and related information is not entered when a delivery does not require procedures, medications, etc. that are covered by health insurance. In such cases, the 15th day of the neonatal birth month was considered the delivery date. A pregnancy that reaches or extends beyond 294 days of gestation is considered a post-term pregnancy and the induction of labor is recommended due to an increased risk of perinatal mortality (Minakami et al., 2014). Thus, when the difference between the dates of pregnancy onset and delivery estimated by the algorithms exceeded 294 days, a gestational period of 294 days was uniformly assigned and pregnancy onset was considered as 294 days before the claim-based delivery date. Pregnancies were divided into the first (from pregnancy onset to week 13 day 6 of gestation), second (week 14 day 0 to week 27 day 6), and third (week 28 day 0 to delivery) trimesters (Minakami et al., 2014).
depression can also lead to behavioral, emotional, cognitive, and motor problems in early childhood (Molenaar et al., 2018); thus, it is treated with antidepressants depending on the severity and risk-benefit balance of the medication (Molenaar et al., 2018; Japanese Society of Mood Disorders, 2017; Japanese Society of Perinatal Mental Health, 2017). In reports from Europe and North America, 2–13% of women are treated with antidepressants during pregnancy and the majority of antidepressants are selective serotonin-reuptake inhibitors (SSRIs) (Alwan et al., 2011; Charlton et al., 2015; Cooper et al., 2007; Huybrechts et al., 2013; Andrade et al., 2008; Bénard-Laribière et al., 2018; Petersen et al., 2011; Bérard and Sheehy, 2014). However, the prevalence and pattern of perinatal antidepressant prescriptions in Japan is unknown. Studies of antidepressants prescribed to prenatal and postpartum women could provide important indicators regarding the drugs that are most commonly prescribed before, during, and after pregnancy in Japan and catalyze programs to optimize antenatal prescribing. Health administrative databases are important sources of data that are used for pharmacoepidemiological evaluations of drug exposure during pregnancy (Daw et al., 2011; Strom and Carson, 1990). The objective of the present study was to evaluate the prevalence, timing, and patterns of antidepressant prescriptions to prenatal and postpartum women in Japan using a large administrative database. 2. Methods 2.1. Source of data Data were extracted from a large database of health insurance claims developed and maintained by the Japan Medical Data Center (JMDC, Tokyo, Japan) (Kimura et al., 2010). This database includes all inpatient, outpatient, and pharmacy claims received from insurers and is one of the largest claims databases in Japan. Claims contain diagnoses classified according to the International Classification of Diseases, 10th revision (ICD-10), surgical and medical procedures, and prescribed medications. Standardized disease classification and anonymous record linkage were used in the database (Kimura et al., 2010). More details of the database can be found in our previous reports (Ishikawa et al., 2019; Ishikawa et al. 2018a). This study was approved by the Institutional Review Board of Tohoku University School of Medicine on July 19, 2016 (registration number: 2016-1-230).
2.4. Antidepressant prescriptions Antidepressants evaluated in the present study were identified based on the latest treatment guideline for major depressive disorder prepared by the Japanese Society of Mood Disorders (Japanese Society of Mood Disorders, 2017) and included SSRIs, serotonin norepinephrine reuptake inhibitors (SNRIs), noradrenergic and specific serotonergic antidepressants (NaSSAs), and tricyclic antidepressants (TCAs)/nonTCAs. TCAs/non-TCAs included imipramine, clomipramine, trimipramine, lofepramine, amitriptyline, nortriptyline, amoxapine, dosulepin, maprotiline, mianserin, setiptiline, and trazodone; this covered all antidepressants approved in Japan. The dispensing date was preferentially used, but if the dispensing date was unavailable, the hospitalization date was used instead. Since the month and year were available for each claim, each drug was assigned to the 15th day of the month when either the dispensing date or hospitalization date was unavailable. The days of supply of each prescription were available in the database and were considered to determine the timing of exposure. Antidepressants were classified according to the route of administration and their generic names. In cases where two or more antidepressants with the same generic name and route of administration were prescribed on the same day, we calculated the sum of the doses when evaluating the maximum prescribed daily dose. Antidepressants intended for as-needed use based on claims were excluded when evaluating the maximum daily dose. Women who did not have sufficient daily dose information were also excluded from the maximum daily dose analysis. If two or more classes of antidepressants prescribed to a single woman had the same date (i.e.,
2.2. Study population The dataset that was available on February 27, 2017 was used and included 3,836,202 men and women covered by health insurance between January 2005 and August 2016. Mothers whose children who were born and could be identified were included. Mothers can be linked with their offspring in the JMDC claims database if their infants are enrolled with the same health insurer; this allows the identification of the month and year of birth (the date of birth is not available to avoid re-identification). Women who met the following eligibility criteria were selected to evaluate prescriptions during pregnancy: mothers whose infants were enrolled with the same health insurer during their birth month; mothers whose dates of pregnancy onset and delivery could be estimated; and those who were members of one of a number of health insurance schemes exclusively from 180 days before pregnancy onset through 180 days postpartum. 2.3. Estimation of the dates of pregnancy onset and delivery Neither the date of pregnancy onset nor the date of delivery is available in the Japanese claims database. Thus, the dates were estimated using algorithms described elsewhere (Ishikawa et al., 2019). Briefly, the date of pregnancy onset was estimated by subtracting the gestational age recorded as part of the diagnosis at the time of a 296
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Table 1 Antidepressant prescriptions between 180 days before pregnancy and 180 days postpartum. Non-proprietary name
Total
Before pregnancy Within –180 days
During pregnancy
Postpartum
–180 to –91 days
–90 to –1 days
Any trimester
First trimester
Second trimester
Third trimester†
Within 180 days
1 to 90 days
91 to 180 days
n (per 10,000) Total
451 (133)
339 (100)
295 (87)
277 (82)
241 (71)
229 (67)
89 (26)
74 (22)
212 (62)
143 (42)
178 (52)
SSRIs
356 (105)
263 (77)
225 (66)
217 (64)
188 (55)
174 (51)
65 (19)
57 (17)
161 (47)
133 (39)
60 (18) 87 (26) 108 (32) 145 (43)
26 (8) 70 (21) 84 (25) 105 (31)
18 59 65 94
17 55 72 83
18 51 59 68
16 49 58 58
4 (1) 21 (6) 20 (6) 21 (6)
4 (1) 19 (6) 17 (5) 19 (6)
32 32 46 62
110 (32) 15 (4) 25 (7) 37 (11) 39 (11)
SNRIs Duloxetine Milnacipran
47 (14) 39 (11) 10 (3)
32 (9) 26 (8) 7 (2)
27 (8) 21 (6) 7 (2)
26 (8) 22 (6) 5 (1)
21 (6) 19 (6) 4 (1)
20 (6) 18 (5) 4 (1)
8 (2) 5 (1) 3 (1)
8(2) 6 (2) 2 (1)
26 (8) 21 (6) 5 (1)
17 (5) 4 (1)
23 (7) 19 (6) 4 (1)
NaSSAs Mirtazapine
54 (16) 54 (16)
29 (9) 29 (9)
23 (7) 23 (7)
21 (6) 21 (6)
15 (4) 15 (4)
14 (4) 14 (4)
3 (1) 3 (1)
3 (1) 3 (1)
25 (7) 25 (7)
17 (5) 17 (5)
14 (4) 14 (4)
TCAs/non-TCAs Amitriptyline Amoxapine Clomipramine Dosulepin Imipramine Lofepramine Maprotiline Mianserin Nortriptyline Setiptiline Trazodone Trimipramine
101 (30) 16 (5) 22 (6) 12 (4) 1 (0) 7 (2) 1 (0) 8 (2) 11 (3) 6 (2) 1 (0) 27 (8) 1 (0)
74 (22) 12 (4) 13 (4) 10 (3) 1 (0) 5 (1) 1 (0) 6 (2) 7 (2) 4 (1)
64 (19) 9 (3) 12 (4) 10 (3) 1 (0) 5 (1) 1 (0) 3 (1) 7 (2) 4 (1)
58 (17) 8 (2) 9 (3) 10 (3)
54 (16) 6 (2) 9 (3) 9 (3)
46 (14) 5 (1) 7 (2) 8 (2)
22 (6) 2 (1) 2 (1) 4 (1)
14 (4)
33 (10) 4 (1) 10 (3) 2 (1)
17 (5) 3 (1) 2 (1)
29 (9) 4 (1) 8 (2) 2 (1)
3 1 6 6 3
1 1 3 4 2
1 1 2 2 1
1 1 2 4 2
18 (5)
4 (1) 1 (0) 5 (1) 7 (2) 2 (1) 1 (0) 12 (4)
1 1 2 3
21 (6) 1 (0)
4 (1) 1 (0) 6 (2) 8 (2) 2 (1) 1 (0) 14 (4)
Escitalopram Fluvoxamine Paroxetine Sertraline
(5) (17) (19) (28)
(5) (16) (21) (24)
(1) (0) (2) (2) (1)
16 (5) 1 (0)
(5) (15) (17) (20)
(5) (14) (17) (17)
(0) (0) (1) (1)
1 (0) 8 (2)
2 (1) 1 (0)
1 (0) 2 (1) 2 (1)
(9) (9) (14) (18)
(0) (0) (1) (1) (1)
10 (3)
(0) (0) (1) (1) (0)
6 (2)
27 24 35 53
(8) (7) (10) (16)
(0) (0) (1) (1) (1)
8 (2)
†
Denominator is the number of pregnant women who reached the third trimester (n = 33,836). Abbreviations: NaSSA = noradrenergic and specific serotonergic antidepressant, SNRI = serotonin norepinephrine reuptake inhibitor, SSRI = selective serotonin reuptake inhibitor, TCA = tricyclic antidepressant.
year, maternal age at delivery, gestational age at delivery, diagnosis of affective disorders before delivery, diagnosis of other mental and behavioral disorders before delivery, history of adverse pregnancy complications (ICD-10 code: O10-O16, O20-O29 and O30-O48), and multiple pregnancies. The prevalence of antidepressants prescribed between 180 days before pregnancy and 180 days postpartum was calculated for each delivery-based year. For antidepressants and each class and individual molecule that were prescribed to more than 20 women between 180 days before pregnancy and 180 days postpartum, the time trends of antidepressant prescriptions between 180 days before pregnancy and 180 days postpartum were analyzed using a multivariate logistic regression model adjusting for maternal age at delivery. The prescription prevalence of paroxetine was classified according to the maximum dose and 25 mg/day was considered a cut-off because gestational exposure to paroxetine above 25 mg/day has been associated with major congenital malformations (Bérard et al., 2007). The prevalence, timing, and patterns of potential combination therapy were described. The prevalence of antidepressant prescriptions is reported per 10,000 deliveries. The level of significance was 0.05. All data were analyzed using SAS version 9.4 (SAS Institute, Inc., Cary, NC, USA).
dispensing date, hospitalization date, or 15th day of the month of the claim), this was considered potential combination therapy.
2.5. Data analysis First, the prevalence of antidepressant prescriptions was determined for the periods of 180 days before pregnancy onset, during pregnancy, and 180 days postpartum. The prescribing prevalence was also calculated for 180 to 91 days and 90 to 1 days before pregnancy, for each trimester, and for 1 to 90 days and 91 to 180 days postpartum. The prevalence was calculated for antidepressants overall and then for each class and each individual molecule. The evaluation of antidepressant prescriptions was repeated for women whose delivery dates were estimated according to delivery-related entries and for whom the 15th day of the neonatal birth month was considered the delivery date separately to compare the results of these two subpopulations and discuss the effect of assigning the 15th day of the neonatal birth month as the delivery date. For those to whom antidepressants were prescribed within the 180 days before pregnancy, we examined when the treatment was discontinued and restarted regarding antidepressants overall and for each class. Multivariate logistic regression analyses were used to identify predictors of antidepressant prescription during pregnancy, including delivery year, maternal age at delivery, diagnosis of affective disorders (ICD-10 code: F30-F39) before pregnancy, diagnosis of other mental and behavioral disorders (ICD-10 code: F00-F99 excluding F30F39) before pregnancy, and history of pregnancy with abortive outcome (ICD-10 code: O00-O08) within 180 days before pregnancy; and predictors of antidepressant prescription postpartum, including delivery
3. Results Of the 3,836,202 men and women covered by health insurance between January 2005 and August 2016, 33,941 women met our eligibility criteria (Figure S1). No specific difference in their background was noted between mothers who met and did not meet our eligibility criteria (Table S1). Delivery dates were estimated based on 297
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prevalence of any class of antidepressant and the delivery-based year (Fig. 2). The most frequently prescribed SSRI was sertraline (145 women, 43 per 10,000 deliveries), followed by paroxetine (108 women, 32 per 10,000 deliveries), fluvoxamine (87 women, 26 per 10,000 deliveries), and escitalopram (60 women, 18 per 10,000 deliveries) (Table 1). The prescribing prevalence of both paroxetine (trend P < 0.0001) and fluvoxamine (trend P = 0.0227) significantly decreased and that of escitalopram significantly increased annually (trend P < 0.0001) (Fig. 2 and Table S5). Of 57 women who had at least one record of a paroxetine prescription in the first trimester, 13 (22.8%) were prescribed >25 mg/day (Fig. 3). Concerning potential combination therapy, 57 women (17 per 10,000 deliveries) concurrently received two or more classes of prescribed antidepressants between 180 days before pregnancy onset and 180 days postpartum, and 25 (7 per 10,000 deliveries) of them received the antidepressants during pregnancy (Table 2). The most popular combination was SSRI plus TCA/non-TCA (34 women, 10 per 10,000 deliveries) between 180 days before pregnancy onset and 180 days postpartum; the other combinations were relatively rare.
the earliest dates of selected diagnoses and surgical procedures for 12,604 women, earliest dates of any other delivery-related entries for 5,014 women, and the 15th day of the neonatal birth month for 16,323 women. A term of 294 days was uniformly assigned as the gestational period to 569 women (1.7%) whose gestational period exceeded this value. There were 11,288 records of antidepressant prescriptions among the 33,941 women. The timing of exposure was evaluated from 10,576 (93.7%) and 76 records (0.7%) based on the dispensing and hospitalization dates, respectively. For the other 636 records (5.6%), the 15th day of the month and year recorded in each claim were used. The mean age at delivery and length of gestation were 32.3 years (standard deviation [SD]: 4.5 years) and 270.1 days (SD: 13.5 days), respectively. Of 33,941 women, 33,836 (99.7%) reached the third trimester. There were 26,272 women (77.4%) who gave birth in or after 2012. Based on claims data, 111 (33 per 10,000 deliveries), 729 (215 per 10,000 deliveries), and 830 women (245 per 10,000 deliveries) were diagnosed with “bipolar affective disorder” (ICD-10 code: F31), “depressive episode” (ICD-10 code: F32), and “other anxiety disorders” (ICD-10 code: F41), respectively, before the delivery date (Table S2). At least one antidepressant was prescribed to 451 (133 per 10,000 deliveries) of 33,941 women between 180 days before pregnancy onset and 180 days postpartum (Table 1). In total, 339 (100 per 10,000 deliveries), 241 (71 per 10,000 deliveries), and 212 women (62 per 10,000 deliveries) had at least one record of an antidepressant prescription within 180 days before pregnancy, during pregnancy, and within 180 days postpartum, respectively. Compared to the pre-pregnancy period where an antidepressant was prescribed to 295 women (87 per 10,000 deliveries) 180 to 91 days before pregnancy and 277 women (82 per 10,000 deliveries) 90 to 1 days before pregnancy, the prevalence of antidepressant prescriptions decreased during the first (229 women, 67 per 10,000 deliveries) and second trimesters (89 women, 26 per 10,000 deliveries) and increased in the postpartum period where an antidepressant was prescribed to 143 women (42 per 10,000 deliveries) 1 to 90 days postpartum and 178 women (52 per 10,000 deliveries) 91 to 180 days postpartum (Table 1). Of 339 women with antidepressant prescriptions before pregnancy, 65 (19.2%) continued the antidepressant throughout pregnancy (Fig. 1), 123 (36.3%) discontinued the antidepressant before pregnancy, and 151 (44.5%) discontinued it during pregnancy. Of 33,602 women to whom an antidepressant was not prescribed before pregnancy, 21 women started antidepressants during pregnancy. In addition to the diagnosis of affective disorders (trend P <0.0001) and other mental and behavioral disorders (trend P <0.0001) before pregnancy, maternal age at delivery (trend P = 0.0007) was a significant predictor of antidepressant prescription during pregnancy (Table S3). Likewise, in addition to the diagnosis of affective disorders (trend P <0.0001) and other mental and behavioral disorders (trend P <0.0001) before delivery, maternal age at delivery (trend P = 0.0030) was also a significant predictor of antidepressant prescription postpartum (Table S3). The prevalence of each antidepressant prescription is shown in Table 1. SSRIs were the most frequently prescribed class of antidepressants in the time period studied (356 women, 105 per 10,000 deliveries), followed by TCAs/non-TCAs (101 women, 30 per 10,000 deliveries), NaSSAs (54 women, 16 per 10,000 deliveries), and SNRIs (47 women, 14 per 10,000 deliveries). The antidepressants of choice were similar between women whose delivery date was estimated according to delivery-related entries and those for whom the 15th day of the neonatal birth month was considered as the delivery date (Table S4). The status of those who discontinued or restarted SSRIs, SNRIs and/or NaSSAs, and TCAs/non-TCAs was similar to that of the overall results (Fig. 1). Of those without an SSRI prescription before pregnancy, 21 women started an SSRI during pregnancy. Similarly, during pregnancy, an SNRI or NaSSA was prescribed to five women without an SNRI or NaSSA prescription before pregnancy, and a TCA/non-TCA was prescribed to 11 women without a TCA/non-TCA prescription before pregnancy. No significant association was observed between the
4. Discussion To the best of our knowledge, this is the first evaluation of the status of antidepressant prescriptions for prenatal and postpartum women in Japan using a large administrative database with the estimation of dates of pregnancy onset and delivery calculated using developed algorithms. In the Japan Environment and Children's Study (JECS) (Nishigori et al., 2017a), the percentages of pregnant women that took an SSRI before diagnosis of pregnancy, between the time of diagnosis of pregnancy until week 12 of pregnancy, and after week 12 of pregnancy, were 0.53%, 0.18%, and 0.15%, respectively. In addition, the percentage of pregnant women that took an antidepressant drug excluding SSRIs before the diagnosis of pregnancy, between the time of diagnosis of pregnancy until week 12 of pregnancy, and after week 12 of pregnancy were 0.27%, 0.09%, and 0.08%, respectively. The prevalence of antidepressant use reported from the JECS is relatively lower than that in the present study; different methodologies in study design and observation periods may account for the difference. The JECS collected information on exposure during pregnancy using interviews, while the present study used a claims database to identify medication exposures. The prevalence of antidepressant use during pregnancy is approximately 2–3% in Europe (Bénard-Laribière et al., 2018; Petersen et al., 2011) and 5–13% in North America (Alwan et al., 2011; Andrade et al., 2008; Bérard and Sheehy, 2014; Cooper et al., 2007). There are several possible reasons. First, it has been reported that the prevalence of major depressive disorder is lower in pregnant Japanese women than in Europe and North America (Usuda et al., 2016). Second, the study comparing the evidence and recommendation levels for pregnancy information in the labelling showed that the “unclassified” evidence level was the highest in Japan (33.3%) and a “contraindicated” recommendation level in Japan (50.6%) was more common than in the USA (9.9%) (Noh et al., 2018). Third, benzodiazepines were frequently prescribed to patients diagnosed with major depression in Japan and, considering the risk and benefit of benzodiazepines, they seem to be over-prescribed for the treatment of major depression in Japan (Onishi et al., 2013). Fourth, the difference in methodologies, such as the difference in background characteristics of the population between studies, may possibly affect the results of this study. The study reporting that 13.3% had antidepressant exposure during pregnancy in the USA discussed that it included large numbers of Medicaid enrolees, who are known to have higher rates of chronic health conditions, including mental illness (Cooper et al., 2007). This may lead to variability in the prescribing prevalence across countries. Although antidepressants are generally considered safe to use during pregnancy, this remains 298
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Fig. 1. Discontinuation and restarting of antidepressant prescriptions from 180 days before pregnancy to 180 days postpartum Abbreviations: SSRI = selective serotonin reuptake inhibitor, SNRI = serotonin norepinephrine reuptake inhibitor, NaSSA = noradrenergic and specific serotonergic antidepressant, TCA = tricyclic antidepressant.
Around half of women to whom an antidepressant was prescribed before pregnancy onset discontinued treatment after becoming pregnant. This trend may indicate that women can be treated without an antidepressant as appropriate, or that treatment with an antidepressant can be discontinued once women become aware of their pregnancy. It has been reported that unplanned pregnancy was also a risk factor for abrupt discontinuation of SSRIs upon confirmation of pregnancy in women with depressive or anxiety disorder (Roca et al., 2013). Since depression during pregnancy carries the risk of adverse effects on both the mother and her child, treatment with antidepressants should be controlled before becoming pregnant (Japanese Society of Mood Disorders, 2017). According to a recent study reviewing the content of the internationally available guidelines on the treatment of perinatal depression and perinatal use of antidepressants, some guidelines advise continuing antidepressant use during pregnancy, while other guidelines mention the possibility of continuation but do not specifically advise or
controversial (Molenaar et al., 2018; Japanese Society of Perinatal Mental Health, 2017). It has been reported that antidepressant use is associated with an increased risk of congenital malformations (National Institute for Health and Care Excellence, 2018; Grigoriadis et al., 2013; Gao et al., 2018; Nishigori et al., 2017b), persistent pulmonary hypertension of the newborn (Grigoriadis et al., 2014), poor neonatal adaptation syndrome (National Institute for Health and Care Excellence, 2018; Grigoriadis et al., 2013), and psychiatric disorders in the offspring (Liu et al., 2017; Boukhris et al., 2016; Gentile, 2015). According to the guidelines available in Japan, the potential harms and benefits of antidepressants during pregnancy should be explained by the clinician to the patient so that patients can make well-informed decisions regarding their preferred treatment (Japanese Society of Mood Disorders, 2017; Japanese Society of Perinatal Mental Health, 2017), an approach that has reached international consensus (Molenaar et al., 2018). 299
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Fig. 2. Time trends of antidepressants prescribed between 180 days before pregnancy and 180 days postpartum *P<.05, **P<.0001 Abbreviations: SSRI = selective serotonin reuptake inhibitor, SNRI = serotonin norepinephrine reuptake inhibitor, NaSSA = noradrenergic and specific serotonergic antidepressant, TCA = tricyclic antidepressant.
Fig. 3. Maximum prescribed doses of paroxetine per day One woman was excluded from the analysis due to insufficient information regarding the prescribed daily dose.
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Table 2 Potential cases of combination therapy. Total
Before pregnancy Within –180 to –180 days –91 days
–90 to –1 days
During pregnancy Any trimester First trimester
Second trimester
Third trimester†
Postpartum Within 180 days
1 to 90 days
91 to 180 days
12 (4) 1 (0) 2 (1) 3 (1) 1 (0) 3 (1) 2 (1)
12 (4) 1 (0)
n (per 10,000) Total SSRI + SNRI SSRI + NaSSA SSRI + TCA/non-TCA SNRI + NaSSA SNRI + TCA/non-TCA NaSSA + TCA/non-TCA SSRI + SNRI + TCA/non-TCA SSRI + NaSSA + TCA/non-TCA
57 (17) 5 (1) 9 (3) 34 (10) 2 (1) 7 (2) 5 (1) 1 (0) 2 (1)
43 (13) 4 (1) 7 (2) 28 (8)
36 (11) 4 (1) 5 (1) 23 (7)
34 (10) 3 (1) 4 (1) 22 (6)
25 (7) 2 (1) 2 (1) 15 (4)
23 (7) 2 (1) 2 (1) 14 (4)
7 (2)
6 (2)
4 (1)
3 (1)
5 (1) 2 (1)
5 (1) 1 (0)
5 (1) 2 (1)
4 (1) 2 (1)
3 (1) 2 (1)
2 (1) 1 (0)
3 (1)
1 (0)
1 (0)
19 (6) 1 (0) 2 (1) 8 (2) 2 (1) 5 (1) 3 (1) 1 (0) 1 (0)
5 1 5 2 1 1
(1) (0) (1) (1) (0) (0)
†
Denominator is the number of pregnant women who reached the third trimester (n = 33,836). Abbreviations: NaSSA = noradrenergic and specific serotonergic antidepressant, SNRI = serotonin norepinephrine reuptake inhibitor, SSRI = selective serotonin reuptake inhibitor, TCA = tricyclic antidepressant.
utero exposure to TCAs/non-TCAs and adverse pregnancy outcomes, although the sample size was limited (McElhatton et al., 1996). Given that there may be possible synergistic or additive effects on neonatal outcomes when different drugs that act on the central nervous system are used concomitantly (Källén et al., 2013), women taking antidepressants during pregnancy should aim for monotherapy and avoid combination therapy as much as possible according to published guidelines (Japanese Society of Mood Disorders, 2017). In the present study, the prevalence of combination therapy may have been underestimated because we considered combination therapy only in cases in which the dates of two or more antidepressant prescriptions were the same. This study did have some limitations. First, a claims database was used, so it was not possible to evaluate the severity or symptoms of the disease, indications for the prescriptions, or if the prescribed antidepressants were actually used. Second, the timing of drug exposure might have sometimes been misclassified due to assumptions regarding the dates of delivery and dispensed drugs (Ishikawa et al., 2019; Ishikawa et al., 2018a; Ishikawa et al., 2018b). However, the antidepressants of choice were similar between women whose delivery date was estimated according to delivery-related entries and those for whom the 15th day of the neonatal birth month was considered as the delivery date. In addition, since the dispensing date was available for 93.7% of the drugs in the present study, the missing dates for drugs would not have affected the conclusions of this study. Third, the study population included only those with live-born children who were enrolled with the same health insurer as their mother because no algorithm has been developed and validated to identify pregnancy directly without information about the child's birth. Therefore, it was not possible to evaluate antidepressants prescribed to women whose pregnancy ended in an abortion or stillbirth. Fourth, although we have evaluated predictors of antidepressant prescription in prenatal and postpartum women, some important confounding factors that may be associated with antenatal depression, such as socio-demographic and economic risk factors including education level, status of employment, and income (Biaggi et al., 2016), and severity of depression were unavailable in the JMDC claims database. Further studies using different types of clinical databases and a prospective design are required to evaluate such predictors in detail. In conclusion, various antidepressants were prescribed to prenatal and postpartum women in Japan. It is suggested that approximately half of pregnant women discontinued treatment with antidepressants after becoming pregnant. SSRIs were the drug class of choice, followed by TCAs/non-TCAs. Women of childbearing age who require antidepressant treatment should select an appropriate antidepressant,
discourage continuation (Molenaar et al., 2018). Antidepressant prescription in the present study was more common among older mothers, which is consistent with a previous study (Cooper et al., 2007). Recently, SSRIs were found to be the most common antidepressants used by pregnant women and the use of other antidepressants is limited (Molenaar et al., 2018; Japanese Society of Mood Disorders, 2017; Andrade et al., 2008). A similar trend for SSRIs was observed in Japan. Although paroxetine was the second most frequently prescribed SSRI in the present study, in general, guidelines agree on avoiding paroxetine during pregnancy (Molenaar et al., 2018; Japanese Society of Perinatal Mental Health, 2017) since its use is associated with an increased risk of congenital cardiovascular malformations in newborns (National Institute for Health and Care Excellence, 2018; Grigoriadis et al., 2013; Bérard et al., 2016). A dose-dependent risk of cardiac defects has also been reported for paroxetine (Bérard et al., 2007). Although findings from other studies have shown conflicting results in terms of statistical significance (Ban et al., 2014), a trend remains towards an increased risk; thus, paroxetine should be avoided in consideration of the possibility of an increased risk of congenital cardiovascular malformations according to the guidelines (Molenaar et al., 2018; Japanese Society of Perinatal Mental Health, 2017). Sertraline is considered to have no significant association with cardiac malformations in infants (Myles et al., 2013). Sertraline is also named in the guidelines as a preferred medication in the postpartum period, mainly due to its low level in breast milk and infants’ serum (Molenaar et al., 2018). Concerning escitalopram and fluvoxamine, evidence of their associations with cardiac malformations is limited compared to paroxetine and sertraline and should be further accumulated. In the present study, the prescribing prevalence of paroxetine and fluvoxamine significantly decreased and that of escitalopram significantly increased annually. With evidence of an increased risk of congenital cardiovascular malformations with paroxetine treatment and the related recommendation to avoid paroxetine in pregnant women, the prescribing prevalence may have decreased, as shown in the present study. In addition, escitalopram consistently shows advantages in efficacy and tolerability profiles compared to classical SSRIs (Sanchez et al., 2014); thus, escitalopram may have gradually replaced paroxetine and fluvoxamine. The present study shows that TCAs/nonTCAs are more frequently selected in Japan than in the USA and France (Huybrechts et al., 2013; Bénard-Laribière et al., 2018). There is no concrete evidence regarding whether TCAs/non-TCAs are safe to use during pregnancy. Recently, a study using Swedish data showed that the congenital malformation rate increased after the maternal use of TCAs (Reis and Källén, 2010). In the European Network of Teratology Information Services, no causal relationship was established between in
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ideally before becoming pregnant, in consideration of the risk/benefit profile of the antidepressants, including the risks for the fetus and risk of relapse of major depression in untreated patients with depression.
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Contributors All authors have contributed to this scientific work and approved the final version of the manuscript. TI and TO designed this study, performed the data analyses, and wrote the manuscript. SK, NK, KM, HN, and HT assisted with the data analyses and supervised the drafting of the manuscript. MA, NY, SK, and NM critically revised the manuscript. Role of the Funding Source This work was supported by grants from the Ministry of Health, Labour and Welfare of Japan (H23-iyaku-ippan-006), Japan Society for the Promotion of Science (19K09746), and Research Foundation for Pharmaceutical Sciences. These sponsors did not play a role in the study design; in the collection, analysis, or interpretation of data; in the writing of the report; or in the decision to submit the article for publication. Submission declaration No prior posting or presentation and no research sponsor is associated with this paper. Declaration of Competing Interest Tomofumi Ishikawa is an employee of Pfizer R&D Japan. Tomofumi Ishikawa is also a research collaborator at Tohoku University and contributed to the present study independently of Pfizer R&D Japan. Manabu Akazawa received i) consultation fees from Takeda Pharmaceutical Co., Ltd. and Pfizer Japan Inc., while performing collaborative research and ii) honoraria for presentations from Astellas Pharma Inc., and Eisai Co., Ltd. The other authors have no conflicts of interest to declare. Acknowledgements The authors would like to thank the Research Group for Health Administrative Data and JMDC Inc. Supplementary materials Supplementary material associated with this article can be found, in the online version, at doi:10.1016/j.jad.2020.01.016. References Alwan, S., Reefhuis, J., Rasmussen, S.A., Friedman, J.M., National Birth Defects Prevention Study, 2011. Patterns of antidepressant medication use among pregnant women in a United States population. J. Clin. Pharmacol. 51, 264–270. https://doi. org/10.1177/0091270010373928. Andrade, S.E., Raebel, M.A., Brown, J., Lane, K., Livingston, J., Boudreau, D., Rolnick, S.J., Roblin, D., Smith, D.H., Willy, M.E., Staffa, J.A., Platt, R., 2008. Use of antidepressant medications during pregnancy: a multisite study. Am. J. Obstet. Gynecol. 198 (194), e1–e5. https://doi.org/10.1016/j.ajog.2007.07.036. Ban, L., Gibson, J.E., West, J., Fiaschi, L., Sokal, R., Smeeth, L., Doyle, P., Hubbard, R.B., Tata, L.J., 2014. Maternal depression, antidepressant prescriptions, and congenital anomaly risk in offspring: a population-based cohort study. BJOG 121, 1471–1481. https://doi.org/10.1111/1471-0528.12682. Bénard-Laribière, A., Pambrun, E., Sutter-Dallay, A.L., Gautier, S., Hurault-Delarue, C., Damase-Michel, C., Lacroix, I., Bégaud, B., Pariente, A., 2018. Patterns of antidepressant use during pregnancy: a nationwide population-based cohort study. Br. J. Clin. Pharmacol. 84, 1764–1775. https://doi.org/10.1111/bcp.13608. Bennett, H.A., Einarson, A., Taddio, A., Koren, G., Einarson, T.R., 2004. Prevalence of depression during pregnancy: systematic review. Obstet. Gynecol. 103, 698–709. https://doi.org/10.1097/01.AOG.0000116689.75396.5f.
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