Background: Prior studies reported that exposure to antidepressants during pregnancy may be associated with gestational hypertension. The aim of this study is to assess the association between the use of antidepressants during pregnancy and the risk of developing gestational hypertension. Methods: A retrospective cohort study using the prescription database IADB.nl was conducted among nulliparous women with singleton pregnancies between 1994 and 2015 in the Netherlands. Logistic regression analysis was used to estimate odds ratios (OR), adjusted OR (aOR) and their corresponding 95% confidence intervals (95% CI). Gestational hypertension as main outcome measure was defined as at least one dispensed record of an antihypertensive drug (methyldopa, nifedipine, labetalol, ketanserin, nicardipine) after 20 weeks of gestation until 14 days after delivery. Sub-analyses were conducted for class of antidepressant, duration and amount of use of antidepressant (≤30, ≥30 Defined Daily Doses or DDDs), and maternal age. Sensitivity analyses to assess uncertainties were conducted. Results: Twenty-eight thousand twenty women were included, of which 539 (1.92%) used antidepressants. The risk of gestational hypertension was doubled for women using antidepressant (aOR 2.00 95% CI 1.28–3.13). Significant associations were also found for the subgroup selective serotonin reuptake inhibitors (SSRIs) (aOR 2.07 95% CI 1.25–3.44), ≥30 DDDs (aOR 2.50 95% CI 1.55–3.99)and maternal ageof30–34 years (aOR 2.59 95% CI 1.35–4.98). Varying the theoretical gestational age showed comparable results. Conclusion: Prolonged use of antidepressants during the first 20 weeks of gestation appeared to be associated with an increased risk of developing gestational hypertension. When balancing the benefits and risks of using these drugs during pregnancy, this should be taken into account. Keywords: Antidepressive agents, Pregnancy, Gestational hypertension, Preeclampsia Background potentially associated with adverse maternal and neonatal During pregnancy, approximately 14 to 23% of pregnant outcomes. Current evidence suggests that antidepressants women suffer from depressive symptoms [1, 2]. In the use during pregnancy may be associated with gestational Netherlands, it was estimated that almost 2% of pregnant hypertension and preeclampsia [6–12]. These disorders women are exposed to antidepressants . Next to poten- are a major cause of morbidity and mortality for both the tial benefits of avoiding risks of an untreated depression mother and the offspring worldwide [13, 14], and imposes [4, 5], the use of antidepressants during pregnancy is also substantial burdens on the society, economy and health- care system [15, 16]. Gestational hypertension and pre- eclampsia share similar symptom, clinically recognized as * Correspondence: firstname.lastname@example.org new-onset hypertension after twenty completed weeks of Unit of PharmacoTherapy, -Epidemiology & -Economics (PTEE), Department gestation, in women who used to be normotensive. Al- of Pharmacy, University of Groningen, A. Deusinglaan 1, 9713, AV, Groningen, The Netherlands though, unlike gestational hypertension, preeclampsia is Full list of author information is available at the end of the article © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Zakiyah et al. BMC Pregnancy and Childbirth (2018) 18:187 Page 2 of 11 accompanied by proteinuria [17, 18]. Gestational hyper- complete overview of the individual’s medication prescrip- tension is also a known risk factor for pre-eclampsia, as tion history, except for medication prescribed during patients often later progress to pre-eclampsia . hospitalization and over-the-counter drugs. The database The primary cause of gestational hypertension is still is considered to be representative for the general Dutch poorly understood, but it has been suggested that genetic, population [23, 24]. environmental, and other predisposing factors such as In the pregnancy database, a validated method is used diabetes mellitus, anxiety, and depression may increase to link newborn children in the IADB.nl database to the risk of developing gestational hypertension [20, 21]. their parents . Also, the database contains the child’s Whether antidepressants affect the risk of developing birth date and the theoretical conception date was esti- gestational hypertension, independently of the underlying mated as the child’s birth date minus 273 days (i.e. gesta- disease itself, remains uncertain. Nevertheless, there is tional duration of 39 weeks). growing evidence that the use of antidepressants is as- sociated with gestational hypertension or preeclampsia. Eligible participants A recent review suggested that compared to evidence In accordance with definition from Dutch Society of of possible association between antidepressants use and Obstetrics and Gynaecology guidelines, gestational hyper- pre-eclampsia, the evidence on potential relation of tension was defined when the symptom appeared after antidepressants and gestational hypertension is rather 20 weeks of gestation. limited . It was reported that the exposure to selective Singleton pregnant women who were registered in the serotonin reuptake inhibitors (SSRIs), the most commonly IADB.nl pregnancy database during the period of 1994 used antidepressants among pregnant women, during the until 2015 were included in the study. Women had to be first and second trimester of the pregnancy may elevate enrolled in the database, at least 6 months prior to the the risk of gestational hypertension or preeclampsia. The theoretical conception date. Since gestational hyperten- adjusted relative risks were reported ranging between sion in a previous pregnancy increases the risk of devel- 1.05–3.16 for pre-eclampsia [6–8, 12] and 1.16–1.9 for oping gestational hypertension , only the first known gestational hypertension [8, 11, 22]. Other antidepressants, pregnancy in the database was included. Women using particularly serotonin-norepinephrine reuptake inhibitors antithrombotic agents (ATC code: B01A) were excluded (SNRIs) and tricyclic antidepressants (TCAs) were also since low-molecular weight heparin is associated with a re- reported to be associated with the increased risk of pre- duction in the risk of pre-eclampsia in women with throm- eclampsia [6, 7, 12] and gestational hypertension . bophilia and renal disease . Low-dosage acetylsalicylic In order to further assess the risk-benefit of antide- acid is also used for the prevention of pre-eclampsia, thus pressants use during pregnancy and provide additional users are excluded as well . information regarding the safety of these medications for Women using antidiabetic drugs (ATC code: A10) prior pregnant women, we conducted a retrospective cohort to conception and those with at least one dispensing rec- study to evaluate the extent to which the use of antide- ord of the antihypertensive drugs i.e. thiazides (ATC pressants during pregnancy may increase the risk of code C03AA), β-blocking agents (ATC code C07A), developing gestational hypertension. ACE-inhibitors (ATC code C09A), angiotensin-II antag- onists (ATC code: C09C) or calcium channel blockers Methods (ATC code: C08CA) in the period of 6 months before Study design and setting conception until 20 completed weeks of gestation were A retrospective cohort study was performed with a large also excluded, as both diabetes mellitus and chronic mother-infant subset from the University of Groningen’s hypertension are risk factors for developing gestational IADB.nl pharmacy prescription database, referred to as hypertension [27–29]. As migraine disorders are also “pregnancy database” . The IADB.nl database is a reported to be associated with the increased risk of devel- longitudinal database containing pharmacy-dispensing oping gestational hypertension, pregnant women having data from community pharmacies in the Netherlands prescriptions for medications to treat migraine disorders from 1994 to 2015, including approximately 600,000 (ATC code: N02C) 6 months before conception until patients. Each prescription record contains information twenty completed weeks of gestation were also ex- on the date of dispensing, the quantity and dose regimen, cluded [30, 31]. the number of days the drug is prescribed for, the number of defined daily dose (DDD), and the Anatomical Thera- Exposure peutic Chemical code (ATC code). Each patient has a Exposure was defined as at least one dispensing record unique anonymous identifier; the date of birth and gender of an antidepressant (ATC code: N06A) between the are known. As Dutch patients generally register at one theoretical conception date and 20 completed weeks of community pharmacy, the database contains an almost gestation, calculated as the date of birth minus 133 days Zakiyah et al. BMC Pregnancy and Childbirth (2018) 18:187 Page 3 of 11 (i.e. 39 weeks). We defined the non-exposed group as association varied by type of antidepressant, we subse- pregnant women that were without antidepressant pre- quently stratified different classes of antidepressants i.e. scriptions in the period of 6 months prior to the theor- non-selective monoamine reuptake inhibitors/ tricyclic an- etical conception date (calculated as the theoretical tidepressants or TCAs (ATC code: N06AA), selective sero- conception date minus 181 days) until 20 completed tonin reuptake inhibitors or SSRIs (ATC code: N06AB), weeks of gestation. non-selective monoamine oxidase inhibitors or MAOI (ATC code: N06AF), reversible inhibitors monoamine Outcome oxidase A or RIMA (ATC code: N06AG) and other an- The outcome was determined by identifying dispensed tidepressants (ATC code: N06AX). We also stratified antihypertensive drugs to treat gestational hypertension exposure by the total amount of antidepressants dis- according to Dutch Society of Obstetrics and Gynaecology pensed during pregnancy (≤30, ≥30 DDDs), the period . A woman was considered to have gestational of exposure (0–10 weeks,11–20 weeks, only the first hypertension when she had at least one prescription 10 weeks, and both periods from 0 to 20 weeks) and for methyldopa (ATC code: C02AB), nifedipine (ATC maternal age (15–19, 20–24, 25–29, 30–34, and 40+ code: C08CA05), labetalol (ATC code: C07AG01), ketan- years old). All statistical analyses were conducted using serin (ATC code: C02KD01), or nicardipine (ATC code: IBM SPSS Statistics 23. C08CA04) between 20 completed weeks of gestation and 14 days after delivery. This particular time was chosen Sensitivity analyses because gestational hypertension and pre-eclampsia is the Notably, the estimation of theoretical conception date most important reason for a first dispensing of hyperten- could have been overestimated because there is an in- sive treatment within 14 days after delivery, as an initi- creased risk of late preterm birth among women with ation of treatment or continuation of treatment during gestational hypertension or preeclampsia [36, 37]. There- hospital stay/delivery, by community pharmacy in The fore, a sensitivity analysis was performed to assess whether Netherlands. variation in the estimation of theoretical conception date had a substantial impact on the results. In addition to esti- Covariates mation of gestational duration of 39 weeks (birth date The following covariates that potentially confound the minus 273 days), we also estimated results for gestational association between maternal exposure to antidepressants durations of 37 weeks and 35 weeks, corresponding to and gestational hypertension were assessed: maternal age birth date minus 259 days and 245 days, respectively. at delivery as well as other medications before conception Additionally, there are several database-related uncer- and during pregnancy, i.e. the use of fertility treatment tainties that might affect the results. Firstly, previous (ATC codes: H01CA, H01CC, G03GA, G03GB, L02AE02, study has indicated that there has been a significant in- L02AE04 [33, 34] and maternal antibiotic prescriptions crease in the use of antidepressants among pregnant (ATC code: J01) . We also took into consideration women specifically in the Netherlands, over the last potential underlying condition that might affect the risk decades . Secondly, due to limited information on for developing preeclampsia i.e. mood disorders [9, 30] the actual use of the prescribed antidepressants and also and obesity , and used prescriptions of benzodiaze- indication for the prescriptions, confounding by indica- pines (ATC codes: N03AE, N05BA, N05CD or N05CF) tion might present in the estimation. In order to address and lipid modifying agents (ATC code: C10) as proxies for these uncertainties, we conducted additional series of aforementioned conditions. sensitivity analyses where we adjusted the multivariate model to calendar year, and also an analysis to minimize Statistical analysis confounding by indication by comparing women exposed A multivariate logistic regression was performed to esti- to antidepressants between the theoretical conception mate the odds ratio (OR) and their corresponding 95% date and 20 completed weeks of gestation to women who confidence intervals (95% CI) of the association between were exposed to the drugs in the sixth month before the- antidepressant exposure and gestational hypertension. In oretical conception date. We also assessed the exposure multivariate analysis, OR were adjusted for variables that group with at least two dispensing records of antidepres- were significantly associated with the outcome in univari- sants instead of one. ate analyses, to assess if there was a significant difference in distribution (p < 0.05) in the frequency or means of the Results covariates between exposed and non-exposed. The distri- Primary analysis bution of covariates was measure with Pearson Chi-square There were 28,020 pregnant women included in this co- test (for categorical variables) or the independent T-test hort study (Fig. 1). Among these, 539 (1.9%) were exposed (for continuous variables). To examine whether the to antidepressants between the theoretical gestation date Zakiyah et al. BMC Pregnancy and Childbirth (2018) 18:187 Page 4 of 11 Fig. 1 Flow diagram for participants’ selection in the analysis. *One woman could expose to multiple drugs listed in exclusion criteria and twenty completed weeks of gestation. A detailed list exposed to more than 30 DDDs of antidepressants, es- of included antidepressants and number of pregnant pecially SSRIs (aOR 2.50, 95% CI 1.55–3.99 and aOR women exposed is presented in Table 1. The majority of 2.27, 95% CI 1.44–3.60, for any type of antidepressants exposed women used SSRIs (73.10%) followed by TCAs and specific SSRIs, respectively). (16.5%). The vast majority of women who used antidepressants The mean maternal age at delivery was 31.1 and during pregnancy (506 women out of 539), were exposed 29.5 years for exposed and non-exposed pregnant women, to the drugs during the first 10 weeks of the pregnancy, respectively (see Table 2). The use of benzodiazepines and and more than half of them (257) continued the medication antibiotics were significantly higher amongst exposed during the following 10 weeks of gestation. Prolonged ex- compared to non-exposed women. In addition, there posure to antidepressants seemed to significantly increase were no substantial differences in the use of lipid the odds of developing gestational hypertension, with aOR modifying agents and fertility treatment between both of 2.13 (95% CI 1.36–3.34), 2.36 (95% CI 1.35–4.12) and groups. Within the exposed group, 22 (4.1%) suffered 2.66 (95% CI 1.52–4.65) for exposure in the period of 0– from a medically treated gestational hypertension, whereas 10 weeks of gestation including both women with and 571 (2.1%) of the non-exposed pregnant women were pre- without ongoing exposure,11–20 weeks of gestation, and scribed antihypertensive drugs in the period of twenty both periods, respectively. However, discontinuation of the completed weeks of gestation until 14 days after delivery. exposure after the first 10 weeks of gestation (or those After adjustment for maternal age, use of benzodiaze- without ongoing exposure) did not seem to be associated pines, and use of antibiotics, the exposure to antidepres- with increased risk of developing gestational hypertension. sants during pregnancy was associated with significant When the analysis was stratified based on maternal increased odds for developing gestational hypertension age, it appeared that only the age group of 30–34 years (aOR 2.00, 95% CI 1.28–3.13; see Table 3). Analyses ac- old had an association of increased risk of gestational cording to the class of antidepressants indicated that the hypertension, while the other age groups did not show risk of developing gestational hypertension was especially any significant associations (Table 3). increased among women who used SSRIs (aOR 2.07, 95% CI 1.25–3.44). When examining exposure to differ- Sensitivity analyses ent amounts of DDDs, the risk of developing gesta- The results from sensitivity analysis for theoretical gesta- tional hypertension was only increased among women tional durations of 37 weeks and 35 weeks demonstrated Zakiyah et al. BMC Pregnancy and Childbirth (2018) 18:187 Page 5 of 11 Table 1 Antidepressants included in the analysis and the similar results, with antidepressants being associated with number of pregnant women exposed increased risk of gestational hypertension, with aOR of ATC-code Medication Pregnant Note 2.17 (95% CI 1.37–3.44) and 2.21 (95% CI 1.37–3.56), re- women (N) spectively. SSRIs remained as the one antidepressant that N06AA TCA 89 is being prescribed for the vast majority of women during N06AA09 Amitriptyline 66 70 women used 1 type their pregnancy and exposure to SSRIs remained associ- of antidepressant and ated with significantly elevated odds of developing gesta- N06AA04 Clomipramine 31 19 women used 2 different tional hypertension with aOR of 2.14 (95% CI 1.28–3.60) types of antidepressants N06AA02 Imipramine 3 from TCAs class for 37 weeks and 2.09 (95% CI 1.20–3.64) for 35 weeks. N06AA10 Nortriptyline 3 As expected, the sub-analysis results also showed rather N06AA16 Dosulepin 2 similar results. Details for sensitivity analysis for the dur- N06AA06 Trimipramine 1 ation of gestation are provided in Table 4. N06AA21 Maprotiline 1 The series of additional sensitivity analyses with adjust- ment to calendar year and alternative assessment regard- N06AA12 Doxepin 1 ing exposure in the comparison group showed that the N06AB SSRIs 394 odds ratios in the primary analysis changed with these var- N06AB05 Paroxetine 202 353 women used 1 type iations. The above analyses suggested that antidepressants of antidepressant, 37 women N06AB03 Fluoxetine 83 used 2 different types of were still associated with an increased risk of gestational antidepressants and 4 women N06AB04 Citalopram 75 hypertension with aOR of 1.70 (95% CI 1.08–2.66) for ad- used 3 different types from N06AB08 Fluvoxamine 45 justment to calendar year. However, in the analysis with SSRIs class an alternative comparison regarding exposure, the associ- N06AB06 Sertraline 26 ation was still appeared but no longer statistically signifi- N06AB10 Escitalopram 8 cant (aOR:1.45 (95% CI 0.63–3.33). Nevertheless, analysis N06AF MAOI 1 with exposure to at least two dispensing records of antide- N06AF03 Phenelzine 1 – pressants resulted in similar outcome as the primary ana- N06AG RIMA 3 lysis with an aOR of 2.19 (1.40–3.43). Table 5 depicts the N06AG02 Moclobemide 3 – results of these estimations. N06AX Other 66 Discussion N06AX16 Venlafaxine 53 52 women used 1 type In this retrospective cohort, we observed that the odds of antidepressant and N06AX11 Mirtazapine 17 14 women used 2 different of developing gestational hypertension were doubled types of antidepressants N06AX21 Duloxetine 4 among pregnant women who were exposed to antide- from ‘other’ classes. N06AX05 Trazodone 3 pressants during their pregnancy compared to those with- N06AX12 Bupropion 2 out the exposure. Notably, the risks were even greater among women who exposed to SSRIs and with DDDs N06AX06 Nefazodone 1 more than 30. Prolonged used of antidepressants during TCAs tricyclic antidepressants, SSRIs selective serotonin reuptake inhibitors, MAOI non-selective monoamine oxidase inhibitors, RIMA reversible inhibitors both first and second trimesters seemed to further increase monoamine oxidase this risk. Varying the theoretical gestation age and exposure One patient can be exposed to multiple antidepressants to at least two dispensing records of antidepressants showed comparable results. The results did seem sensitive Table 2 Distribution of covariates in exposed and non-exposed to adjustment to calendar year and variation in comparison pregnant women group regarding exposure. Overall, these findings were in Maternal characteristics Exposed Non-exposed P-Value line with the results from previous studies, suggesting that (N = 539) (N = 27,481) the exposure of antidepressants during pregnancy is associ- Mean maternal age at 31.10 ± 5.64 29.45 ± 4.77 <.001 ated with higher risk of developing gestational hypertension delivery (years) or pre-eclampsia [6–8, 11, 12, 22, 39]. However, prior stud- Co-medication ies also reported conflicting results concerning the specific Benzodiazepines 151 (28.01%) 784 (2.85%) <.001 type of antidepressants that might be associated with Lipid Modifying Agents 3 (0.56%) 63 (0.23%) .121 the elevated risk of gestational hypertension and/or Antibiotics 321 (59.55%) 13,750 (50.03%) <.001 pre-eclampsia. Notably, several studies reported ele- Fertility Treatment 16 (2.97%) 1292 (4.70%) .059 vated risks for developing gestational hypertension and/ or among women who exposed to SSRIs during their Cases of gestational 22 (4.08%) 571 (2.08%) <.001 hypertension pregnancy [8, 11, 12, 39]. For example, Toh et al. sug- P-value by Chi-squared test or T-test gested more than 200% increased risk for developing Zakiyah et al. BMC Pregnancy and Childbirth (2018) 18:187 Page 6 of 11 Table 3 Unadjusted and adjusted odds ratio for the development of gestational hypertension after exposure to antidepressant drugs during pregnancy in the primary analysis Outcome N % Unadjusted OR (95% CI) P-Value Adjusted OR (95% CI) P-value Antidepressant use No exposure 27,481 98.08 Exposure 539 1.92 1.99 (1.29–3.09) .002 2.00 (1.28–3.13) .002 Type of antidepressant* TCAs (N06AA) 89 16.51 1.61 (0.51–5.11) .418 1.60 (0.50–5.09) .429 SSRIs (N06AB) 394 73.10 2.11 (1.30–3.45) .003 2.07 (1.25–3.44) .005 MAOI (N06AF) 1 –– – – – RIMA (N06AG) 3 –– – – – Other (N06AX) 66 12.25 1.44 (0.35–5.90) .611 1.43 (0.35–5.91) .618 DDD ≤ 30 150 27.64 0.64 (0.16–2.57) .524 0.68 (0.17–2.75) .584 ≥ 30 389 72.36 2.55 (1.61–4.02) <.001 2.50 (1.55–3.99) <.001 DDD SSRIs ≤ 30 91 16.70 0.52 (0.07–3.74) .516 1.28 (0.56–2.92) .561 ≥ 30 303 56.40 2.61 (1.57–4.35) <.001 2.27 (1.44–3.60) <.001 Period 0–10 weeks 506 93.88 2.14 (1.38–3.30) .001 2.13 (1.36–3.34) .001 11–20 weeks 290 53.80 2.38 (1.38–4.10) .002 2.36 (1.35–4.12) .003 0–10 weeks only 249 46,20 1.56 (0.77–3.17) .220 1.59 (0.78–3.26) .205 Both periods (0–20 weeks) 257 47.68 2.71 (1.57–4.67) <.001 2.66 (1.52–4.65) .001 Maternal age 15–19 474 1.69 –– – – 20–24 3636 12.98 1.11 (0.15–8.16) .919 –– 25–29 10,233 36.52 2.03 (0.89–4.65) .093 –– 30–34 9597 34.25 2.59 (1.35–4.98) .004 –– 34–39 3499 12.49 1.23 (0.38–3.95) .731 –– 40+ 581 2.07 1.26 (0.29–5.56) .758 –– OR odds ratio, CI confidence interval, TCAs tricyclic antidepressants, SSRIs selective serotonin reuptake inhibitors, MAOI non-selective monoamine oxidase inhibitors, RIMA reversible inhibitors monoamine oxidase A, DDD defined daily dose Adjusted for maternal age and medications use during pregnancy i.e. prescriptions of benzodiazepines and antibiotics *One patient can be exposed to multiple antidepressants gestational hypertension with preeclampsia for women lead to underestimation of the risk. Despite the differences, who continue to use SSRIs after their first trimester , our findings suggested that other classes of antidepressants while the other studies reported lesser elevated risk for ei- may also be associated with increased risk of gestational ther gestational hypertension or pre-eclampsia [11, 22, 39]. hypertension, although statistically significant relationship Two studies from Palmsten et al. [6, 7]reportedthatSSRIs was not observed. These findings were based on limited might not be associated with increased risk of developing sample size, however still highlighted the possible associ- pre-eclampsia while exposure to other antidepressants (par- ation as well. ticularly SNRIs and TCAs) during pregnancy was associ- In addition, it has been known that some antidepres- ated with 50% up to 220% increased risk of developing sants such as those in “other” class i.e. venlafaxine and pre-eclampsia. This discrepancy may be due to differences duloxetine, have a side effect of sustained elevation of in determining the primary exposure window. Palmsten et blood pressure that was found to be clinically significant al. only took exposure during the second trimester until the at high dosages . Regardless, as we already stratified end of the first half of the third trimester into account, i.e. the data based on class of antidepressant, comparison of 90 until 225 gestational days and excluded women exposed the medication with and without hypertension as an ad- to antidepressants during the first trimester, which could verse effect was assumed to have a comparable result. Zakiyah et al. BMC Pregnancy and Childbirth (2018) 18:187 Page 7 of 11 Table 4 Unadjusted and adjusted odds ratios for the development of gestational hypertension after exposure to antidepressant in the sensitivity analysis for the duration of gestation Outcome 37 weeks 35 weeks a a Unadjusted OR (95% CI) Adjusted OR (95% CI) P-Value Unadjusted OR (95% CI) Adjusted OR (95% CI) P-value Antidepressant use No exposure –– – –– – Exposure 2.13 (1.36–3.32) 2.17 (1.37–3,44) .001 2.14 (1.34–3.42) 2.21 (1.37–3.58) .001 Type of antidepressant TCAs 1.92 (0.60–6.11) 1,98 (0.62–6.34) .252 2.20 (0.69–7.02) 2,31 (0.72–7.44) .161 SSRIs 2.15 (1.29–3.57) 2.14 (1.28–3.60) .004 2.08 (1.21–3.57) 2.09 (1.20–3.64) .009 MAOI –– – –– – RIMA –– – –– – Other 1.62 (0.39–6.63) 1.64 (0.40–6.78) .495 1.92 (0.47–7.92) 1.98 (0.48–8.23) .348 DDD ≤ 30 0.72 (0.18–2.90) 0,79 (0.19–3.23) .744 1.35 (0.43–4.27) 1.45 (0.46–4.62) .529 ≥ 30 2.68 (1.68–4.29) 2.65 (1.63–4.29) <.001 2.41 (1.45–4.01) 2.44 (1.45–4.11) .001 DDD SSRIs ≤ 30 0.54 (0.07–3.90) 0.59 (0.08–4.31) .607 1.48 (0.36–6.06) 1.57 (0.38–6.49) .532 ≥ 30 2.68 (1.68–4.29) 2.65 (1.63–4.28) .001 2,23 (1.24–3.99) 2.20 (1.21–3.98) .010 Period 0–10 weeks 2.21 (1.40–3.49) 2.25 (1.41–3.61) .001 2.32 (1.43–3.74) 2.38 (1.46–3.90) .001 11–20 weeks 2.48 (1.47–4.20) 2.48 (1.45–4.26) .001 2.42 (1.43–4.10) 2.44 (1.43–4.20) .001 0–10 weeks only 1.56 (0.69–3.54) 1.64 (0.71–3.74) .242 1.50 (0.55–4.07) 1.59 (0.58–4.35) .365 Both periods (0–20 weeks) 2.69 (1.56–4.64) 2,69 (1.53–4.68) .001 2.74 (1.59–4.73) 2.75 (1.58–4.82) <.001 Maternal age 15–19 –– – –– – 20–24 1.31 (0.18–9.68) – .790 1.77 (0.24–13.15) – .579 25–29 1.97 (0.80–4.86) – .143 1.75 (0.64–4.78) – .278 30–34 2,88 (1.49–5.53) – .002 2.89 (1.45–5.75) – .003 34–39 1.29 (0.40–4.17) – .666 1.37 (0.42–4.41) – .600 40+ 1.30 (0.29–5.73) – .729 1.30 (0.29–5.73) .729 OR odds ratio, CI confidence interval, TCAs tricyclic antidepressants, SSRIs selective serotonin reuptake inhibitors, MAOI non-selective monoamine oxidase inhibitors, RIMA reversible inhibitors monoamine oxidase A, DDD defined daily dose Adjusted for maternal age and medications use during pregnancy i.e. prescriptions of benzodiazepines and antibiotics Furthermore, our results suggested that the risks of gestational hypertension for mothers who were more developing gestational hypertension were greater among than 30 years old and that the risk was higher in older women with DDDs more than 30. Higher DDDs in the groups . Another study suggested that the risk of analysis could mean polytherapy with multiple antidepres- pre-eclampsia was increased by approximately 4% for sants. Moreover, as our database contains only informa- every year for mothers who were more than 32 years of tion about dispensed prescriptions, there is a possibility age . Due to our limited size in older age groups, we that women who receive antidepressants only one time, could not reproduce these results. did not really use the medication. When a woman receives We also found that prolonged exposure of antidepres- an antidepressant more often during pregnancy, we can sants during first and second trimesters may be associated be more certain about real exposure to this medication. with increased risk of developing gestational hypertension, Our current results also indicated that the age group but not for those who discontinued the treatment after of 30–34 years old had an increased risk of gestational the first trimester. This finding was in line with the study hypertension. It is known that gestational hypertension by Toh et al.  which documented that continuation of is associated with advanced maternal age [41, 42]. A pre- antidepressants after the first trimester might be associ- vious study reported that there was an increased risk of ated with a higher risk for either gestational hypertension Zakiyah et al. BMC Pregnancy and Childbirth (2018) 18:187 Page 8 of 11 Table 5 Association between the development of gestational vasoconstrictors over vasodilators, that could be triggered hypertension after exposure of antidepressant in the series of by anxiety, stress, depression and –among other things- additional sensitivity analyses pharmacological interventions [8, 44]. Outcome Adjusted OR P-value Our study provides further evidence to the existing litera- (95% CI) ture regarding the risk of antidepressants use during preg- Primary analysis nancy and the association with adverse maternal health Antidepressant use outcomes. The strength of this study was that we obtained the data from widely researched pharmacy-dispensing data- No exposure base with proven accuracy in the prescription rates, there- Exposure 2.00 (1.28–3.13) .002 fore recall bias of the drug use was likely eliminated. The Additional sensitivity analyses database also contained a large sampled population with Adjusted to calendar year* 1.70 (1.08–2.66) .021 the possibility to observe the prescription for a long period Alternative comparison regarding 1.45 (0.63–3.33) .380 of time (1994–2015). As the relevant treatment guidelines exposure** as well as available treatments remained unchanged in Exposure to at least two dispensing 2.19 (1.40–3.43) .001 the Netherlands, we considered the aforementioned records time period as sufficient to still represent the present Exposure to at least two dispensing 1.84 (1.17–2.89) .008 Ψ conditions. Yet, we did a sensitivity analysis with ad- records and adjusted to calendar year* justment to calendar year with the assumption that OR, odds ratio there was increasing trend in antidepressants exposure Adjusted for maternal age and medications use during pregnancy i.e. prescriptions of benzodiazepines and antibiotics in pregnancy in the last decades . *Categorized into 1995–1999, 2000–2004, 2005–2009, and 2010–2015 Additionally, the database provided an almost complete **Women exposed to antidepressants between the theoretical conception date and 20 completed weeks of gestation were compared to women who overview of the individuals’ medication prescription, allow- were exposed to these drugs in the six-months period before theoretical ing us to take certain co-medications into account as pos- conception date, but not during pregnancy sible confounders . We also conducted a sensitivity The analysis was restricted to women having at least two dispensing records of an antidepressants from theoretical conception date until 20 completed analysis for the estimation of theoretical conception date. weeks of gestation This analysis allowed us to limit misclassification in the early exposure of antidepressants and eliminate the over- estimation of the risk. In the study design, we also consid- or preeclampsia when compared with discontinuation of ered the prescription of benzodiazepines as a proxy for theexposureduringthe firsttrimester ofpregnancy. A mood disorder. Benzodiazepines were assessed because it recent study also reported similar patterns, suggesting remains unclear if psychotropic medications affect the risk that continuers in the second half of pregnancy were of developing gestational hypertension, independently of significantly associated with increased risk for gesta- mood disorders [9, 30]. This design allowed us to adjust tional hypertension . Based on inconsistencies both and exclude the possibility that the increased risk of devel- in methodology and results in previous studies, it was oping gestational hypertension was due to underlying mood concluded that, although the relation of antidepressant disorder itself. use during pregnancy and the increased risk of develop- Our study has potential limitations. Although IADB.nl ing gestational hypertension or pre-eclampsia is implied reflects a large follow-up prescription database, we did in these studies, current evidence might be inadequate not have any information on the indication of the pre- to evidence a definite association, and suggests that de- scribed drugs nor the actual use of the drugs. The infor- finitive conclusion ideally requires further randomized mation of disease severity was also basically absent. In the controlled trials . However, as it is considered uneth- analysis, we decided to make a clear distinction between ical to perform randomized controlled trials in pregnant exposure and no exposure, with women receiving a pre- women to assess the relationship between maternal expo- scription for an antidepressant after theoretical conception sures and its related effects, only further series of ad- date being considered as exposed and women without any equately designed and performed observational studies prescription for an antidepressant as non-exposed. We can be used to inform such associations. also decided to exclude women receiving an antidepres- The stratification based on the period of exposure from sant during the 6 months before conception. This also ex- conception date might give another perspective, highlight- cludes women who choose to discontinue the medication ing that prolonged exposure during pregnancy may elevate as soon as they were aware of the pregnancy. Neverthe- the risk of gestational hypertension. Although the mechan- less, as an additional way to rule out potential confound- ism behind the association between antidepressants and ing by indication, we did sensitivity analysis comparing gestational hypertension is still uncertain, it has been hy- women exposed to antidepressants during the relevant pothesized that hypertension is a result of an imbalance in time window in pregnancy to those who were exposed to Zakiyah et al. BMC Pregnancy and Childbirth (2018) 18:187 Page 9 of 11 the drugs in the 6 months before theoretical conception Furthermore, SSRIs were the most prescribed antide- date. The outcome showed that the result was sensitive to pressants in our analysis. Consequently, other types of changing this definition of exposure and non-exposure. antidepressants may be confronted with a relative lack Confounding by indication could be an explanation for of statistical power to show associations. In the analysis, these results and future research needs to focus on disen- TCAs and other antidepressants showed increased risks tangling the effect of antidepressants from the effect of although the relations were not statistically significant. the underlying depression. Beside this, a great deal of un- Lastly, while pharmacy database has been widely used certainty remains around medication exposure during for research, the data were actually limited to drugs dis- pregnancy, especially concerning the optimal way to clas- pensing, where the information whether the medications sify exposure and non-exposure groups. Therefore, there were actually taken was simply beyond the observation. is a need for more attention regarding this matter to Another constraint was that the database did not con- minimize potential classification biases . tain information about specific characteristics of patients Additionally, we also could not distinguish between such as body mass index (BMI), smoking status, alcohol gestational hypertension and preeclampsia based on the use, socioeconomic status etc. available data. As women with the diagnosis of preeclamp- sia would be more likely to be admitted to the hospital for Conclusion delivery or expectant management , the women who This study suggests that exposure to antidepressants during included in this study were more likely to have gestational pregnancy is associated with an increased risk of gestational hypertension without proteinuria. hypertension. Since previous studies showed conflicting re- In the analysis, we included all eligible pregnant women sults, further observational studies based on more compre- with at least one dispensing of antihypertensive drugs, as hensive databases containing complete demographic and the prescription of these particular drugs during the second clinical information are needed to further confirm our part of pregnancy could be considered to be due to hyper- findings. They should also further focus on whether tensive problems with great certainty. In more severe cases, there is indeed a difference in the risk between types of when the antihypertensive medication is insufficient, the antidepressants, time of exposure and whether the risk pregnant women will likely be admitted to the hospital. is due to the underlying depression. In deciding on antide- However, the database did not cover information of medi- pressants use in pregnancy, potential benefits as well as cation dispensed during hospitalization, which may have risks of antidepressants should both be considered during led to underestimation of the actual number of cases. We pregnancy, explicitly been taken into account and ad- tried to overcome this by observing the outcome of gesta- equately discussed during pregnancy. tional hypertension until 14 days after the delivery. With this timeframe, women who were hospitalized and received Abbreviations antihypertensive treatment afterwards, would still be par- aOR: Adjusted odds ratios; ATC code: Anatomical Therapeutic Chemical code; CI: Confidence intervals; DDDs: Defined daily doses; MAOI: Non- tially visible in our analysis. The database lacks information selective monoamine oxidase inhibitors; OR: Odds ratios; RIMA: Reversible on demographic or personal characteristics of the patients, inhibitors monoamine oxidase; SNRIs: Serotonin-norepinephrine reuptake which might potentially confound the association between inhibitors; SSRIs: Selective serotonin reuptake inhibitors; TCAs: Tricyclic antidepressants the use of antidepressants and gestational hypertension. Moreover, we attempted to include relevant covariates that Availability of data and materials likely be potential confounders for the association. However The data and analyses is available from corresponding author upon request. due to the database-related limitation, it is impossible to as- sess all possible confounders in the analysis. For instance, Authors’ contributions All authors contributed to the design of the study. NZ and LFtH were uncontrolled asthma seems to be associated with increased responsible for drafting the manuscript under the supervision of CCMS-V, EH risks of gestational hypertension and pre-eclampsia and MJP. NZ, LtH, JHB, and CCMS-V performed the analysis and interpreted [46, 47]. However, due to lack of information on clinical the results. All authors contributed and approved the final version. status and actual drug use, it would be very difficult to distinguish controlled from uncontrolled asthma. This Ethics approval and consent to participate No ethics approval was required for this retrospective study, in accordance with is particularly important, because a previous study has the Dutch Guidelines for file research (http://www.ccmo.nl/en/file-research). reported that there is no significant increased risk of gestational hypertension for users of inhaled corticoste- Competing interests roids or those with controlled asthma . Regarding The authors declare that they have no competing interests. these limitations on the database, further research based on databases containing more pregnancy-specific Publisher’sNote and clinical information is advised to confirm our Springer Nature remains neutral with regard to jurisdictional claims in current findings. published maps and institutional affiliations. Zakiyah et al. BMC Pregnancy and Childbirth (2018) 18:187 Page 10 of 11 Author details maternal mortality during 1990–2013: a systematic analysis for the Global Unit of PharmacoTherapy, -Epidemiology & -Economics (PTEE), Department Burden of Disease Study 2013. Lancet. Elsevier. 2014;384:980–1004. of Pharmacy, University of Groningen, A. Deusinglaan 1, 9713, AV, Groningen, 16. Zakiyah N, Postma MJ, Baker PN, van Asselt ADI. Pre-eclampsia diagnosis The Netherlands. Department of Epidemiology, University Medical Center and treatment options: a review of published economic assessments. 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