Antidepressant discontinuation before or during pregnancy and risk of psychiatric emergency in Denmark: A population-based propensity score-matched cohort study.

BACKGROUND: Women prescribed antidepressants face the dilemma of whether or not to continue their treatment during pregnancy. Currently, limited evidence is available on the efficacy of continuing versus discontinuing antidepressant treatment during pregnancy to aid their decision. We aimed to estimate whether antidepressant discontinuation before or during pregnancy was associated with an increased risk of psychiatric emergency (ascertained by psychiatric admission or emergency room visit), a proxy measure of severe exacerbation of symptoms/mental health crisis. METHODS AND
FINDINGS: We carried out a propensity score-matched cohort study of women who gave birth to live-born singletons between January 1, 1997 and June 30, 2016 in Denmark and who redeemed an antidepressant prescription in the 90 days before the pregnancy, identified by Anatomical Therapeutic Chemical (ATC) code N06A. We constructed 2 matched cohorts, matching each woman who discontinued antidepressants before pregnancy (N = 2,669) or during pregnancy (N = 5,467) to one who continued antidepressants based on propensity scores. Maternal characteristics and variables related to disease severity were used to generate the propensity scores in logistic regression models. We estimated hazard ratios (HRs) of psychiatric emergency in the perinatal period (pregnancy and 6 months postpartum) using stratified Cox regression. Psychiatric emergencies were observed in 76 women who discontinued antidepressants before pregnancy and 91 women who continued. There was no evidence of higher risk of psychiatric emergency among women who discontinued antidepressants before pregnancy (cumulative incidence: 2.9%, 95% confidence interval [CI]: 2.3% to 3.6% for discontinuation versus 3.4%, 95% CI: 2.8% to 4.2% for continuation; HR = 0.84, 95% CI: 0.61 to 1.16, p = 0.298). Overall, 202 women who discontinued antidepressants during pregnancy and 156 who continued had psychiatric emergencies (cumulative incidence: 5.0%, 95% CI: 4.2% to 5.9% versus 3.7%, 95% CI: 3.1% to 4.5%). Antidepressant discontinuation during pregnancy was associated with increased risk of psychiatric emergency (HR = 1.25, 95% CI: 1.00 to 1.55, p = 0.048). Study limitations include lack of information on indications for antidepressant treatment and reasons for discontinuing antidepressants.
CONCLUSIONS: In this study, we found that discontinuing antidepressant medication during pregnancy (but not before) is associated with an apparent increased risk of psychiatric emergency compared to continuing treatment throughout pregnancy.

Introduction

Depression and anxiety are the most common mental disorders, affecting millions of adults worldwide [1]. Antidepressants are the first-line agents for treating these disorders, and over the years, antidepressant prescriptions have increased significantly [2], as has long-term maintenance treatment with antidepressants to prevent relapse of psychiatric disorders [3]. Similarly, antidepressant use during pregnancy is common: Approximately 2% to 8% of pregnant women in Europe [4] and 8% to 13% in the United States of America [5] receive antidepressant prescriptions at some point in their pregnancy. However, concerns have been raised about offspring sequelae of in utero antidepressant exposure [6,7], and, consequently, more than 50% of women discontinue antidepressants during pregnancy [8].

Whether or not antidepressants can be discontinued safely before or during pregnancy is unclear. A limited number of studies have compared relapse risk in pregnant women who discontinued antidepressants with those who continued, with mixed results: Two studies suggested that discontinuing antidepressants increased relapse risk compared with continuing [9,10], and 2 did not demonstrate clear benefits of continuing antidepressant treatment in pregnancy [11,12], while another study reported reduced risk associated with antidepressant discontinuation [13]. The magnitude of the relative risk of relapse for antidepressant discontinuation versus continuation ranges from 0.45 to 8.79 [9-13]. A recent meta-analysis pooled these results and found a borderline increased relapse risk of depression during pregnancy for women who discontinued antidepressants (risk ratio = 1.74, 95% confidence interval [CI]: 0.97 to 3.10) [14]. However, all studies differed by study populations, depression severity, time of discontinuation, relapse assessment, and a high degree of heterogeneity between studies was reported (I2 = 94%). Unsurprisingly, current guidelines on antidepressant treatment in the perinatal period give few specific recommendations [15].

Untreated or incompletely treated depression or anxiety during pregnancy is associated with poor maternal health and adverse health outcomes in offspring [16,17], or at its worst, suicide or infanticide in the perinatal period [18], and thus should be avoided, in particular, to prevent severe exacerbations requiring admission or emergency room visits. Women are more vulnerable to severe psychiatric episodes during the perinatal period than at any other point during their lives [19]. Earlier studies suggested that the risks of suicidal ideation and admissions are high following antidepressant discontinuation, but these studies were small and had selected patient populations [9,20]. In contrast, a large register-based study found lower prevalence of hospitalization late in pregnancy in women who discontinued (9%) versus women who continued antidepressants (17%) [13].

In the present large and nationally representative study, we aimed to evaluate the risk of psychiatric emergency, measured as psychiatric admissions or emergency room visits in a population of pregnant women who discontinued antidepressants before or during pregnancy. We did this by defining psychiatric emergency as a proxy of severe exacerbation of symptoms/mental health crisis. We were interested in 2 time periods: pregnancy and the first 6 months postpartum (the perinatal period), and we hypothesized that women who discontinued treatment before or during pregnancy would be more likely to have a subsequent psychiatric emergency in the perinatal period than women who continued antidepressants.

Methods

This study is reported as per the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guideline (S1 STROBE Checklist). There is no documented analysis plan associated with the study. We planned our analyses through detailed discussion between the authors and agreed on an outline for how the work would be carried out, as described in the Methods. One change to the preplanned analysis was to include a sensitivity analysis by including age at pregnancy and age at first affective disorder treatment as linear splines, implemented in response to peer reviewer comments.

Study population

We conducted a population-based propensity score–matched cohort study utilizing data from Danish nationwide registers. A detailed description of registers used in this study can be found in S1 Text. Through the linkage of the Danish Medical Birth Registry and the Danish National Prescription Registry, we identified 23,189 women aged 18 years or older when they were pregnant and with pregnancies resulting in live-born singletons between January 1, 1997 and June 30, 2016, who redeemed an antidepressant prescription in the 90 days before the index pregnancy started (Fig 1), among whom 9,573 (41.3%) had a psychiatric diagnosis before pregnancy recorded in the Danish Psychiatric Central Research Register. The start of pregnancy was estimated by subtracting gestational age (primarily based on first or second trimester ultrasound scan) from birth date [21]. When no ultrasound data were available, the first day of the mother’s last menstrual period was used. We included only the first pregnancy meeting the inclusion criteria.

Fig 1

Flowchart illustrating the identification of study population.

Exposure of interest: Antidepressant continuation during pregnancy

Information on antidepressant use was obtained from the Danish National Prescription Registry identified with the Anatomical Therapeutic Chemical (ATC) code of N06A. Antidepressants were categorized into 3 groups: selective serotonin reuptake inhibitors (SSRIs), serotonin–norepinephrine reuptake inhibitors (SNRIs), and tricyclic antidepressants [TCAs] or monoamine oxidase inhibitors [MAOIs]. The number of days’ supply per prescription was calculated by multiplying the number of defined daily doses per packet by the number of packets dispensed. Prescriptions for the same antidepressants issued on the same day were counted as a single prescription and the days’ supply combined [22].

We defined antidepressant continuation throughout pregnancy as continuous treatment from 3 months prior to until the end of the pregnancy based on the supply of antidepressants (number of days), allowing a 14-day grace period to account for missed doses [13]. If another prescription was not redeemed before the date when supply was expected to finish plus the 14-day grace period, the treatment was defined as discontinued on that date. Women who switched to other antidepressants within the date when the last supply finished plus the 14 days were considered as continuing treatment. Note, these definitions were applied to all individuals included in the study. We categorized all individuals who discontinued antidepressants according to time of discontinuation: before (within 90 days before conception) or during pregnancy. We also considered an alternative definition of antidepressant discontinuation, using a longer (30 days) grace period in the sensitivity analyses [23].

Propensity score–matched cohorts

Propensity score matching is commonly used to control for confounding in pharmacoepidemiological studies, especially when outcomes are rare, many confounders are present, and/or there are systematic differences in characteristic distribution between groups [24]. We calculated the exposure propensity score from the predicted probability of discontinuing antidepressants estimated in a logistic regression model containing all variables listed below, and then we matched each woman who discontinued antidepressants before pregnancy to one woman who continued antidepressants on propensity score using the nearest neighbor matching algorithm, within caliper widths of 0.1 without replacement. We similarly matched each woman who discontinued antidepressants during pregnancy to one woman who continued antidepressants (Fig 1). We chose caliper widths of 0.1 over the recommended 0.2 [25] based on the following considerations: (1) a tighter caliper leads to significantly reduced bias [26]; and (2) the increase in the number of matched pairs using caliper widths of 0.2 in our study was negligible.

The following variables considered potentially prognostically important for psychiatric emergency [24] were included to generate the propensity score:

Characteristics measured at the start of pregnancy: age (18 to 25, 26 to 29, 30 to 34, or ≥35 years), parity (first or second and above), marital status (married or cohabiting or single, divorced, or widowed), level of education (mandatory school comprising 9 school years or above mandatory school), age at the first affective episode (≤18, 19 to 25, 26 to 29, 30 to 34, or ≥35 years), history of suicide attempts (yes or no), diagnosed psychiatric disorders (substance abuse disorder, schizophrenia, bipolar disorder, depression, other mood disorders, neurotic, stress-related, and somatoform disorders, personality disorders, and other disorders; yes or no), the number of previous psychiatric emergency prior to 90 days before pregnancy, i.e., psychiatric admission or emergency room visit (0, 1, 2, 3 to 4, or ≥5), nonpsychiatric comorbidity scores (0, 1, or ≥2) based on the 19 conditions included in the Charlson comorbidity index [27]. The 19 conditions and Charlson comorbidity index score can be seen in S2 Text. We retrieved data on comorbidity from the Danish National Patient Register [28]. Age at first affective disorder was defined as the first hospital contact for the affective disorder (ICD-8 codes 296.x9, 298.09, 298.19, 300.49, 301.19, 300.x9, 305.x9, 305.68, and 307.99 excluding 296.89; ICD-10 codes F30 to F39 and F40 to F48) or first prescription redeemed for antidepressants (ATC code N06A) or anxiolytics (ATC code N05B), whichever occurred first. We also repeated our analyses by including age at pregnancy as linear splines with 4 knots and age at first affective disorder as linear splines with 5 knots at specified values based on age groups mentioned above to test the robustness of our results. Suicide attempts were defined as an admission or outpatient visit for self-harm identified from the Danish Psychiatric Central Research Register or the Danish National Patient Register [29]. Detailed criteria for defining suicide attempts can be found in S3 Text and ICD codes for subgroups of psychiatric disorders in S1 Table. We further included calendar year of the index pregnancy when calculating the propensity score to account for changes in prescribing patterns.

Variables related to the severity of disorders measured in the 90 days prior to pregnancy: classes of antidepressant treatment (SSRIs, SNRIs, and TCAs or MAOIs), psychiatric admission/emergency room visit (yes or no), and comedications (benzodiazepine, anxiolytics, antipsychotics, opioid, barbiturates, antiepileptics, and other hypnotics; yes or no). Detailed ATC codes for classes of antidepressants and comedications are shown in S2 and S3 Tables.

Outcome of interest: Psychiatric emergency

Our primary outcome was first admission or emergency room visit with the main diagnosis of any mental disorders except for mental retardation (hereafter referred to as psychiatric emergency; the entire F chapter excluding F70 to F79 in ICD-10) during follow-up as a proxy for severe exacerbation of symptoms/mental health crisis. We also explored suicide attempts as an outcome. However, suicide attempts were rare, 0.4% to 0.5% in the matched cohorts, and therefore did not provide a meaningful outcome.

Statistical analysis

For women who discontinued antidepressants, follow-up began on the date of discontinuation or the first day of pregnancy, whichever occurred later. Follow-up in the reference women (i.e., those who continued treatment) started at the same point in relation to the start of pregnancy as the woman they were matched to. For example, if an index woman discontinued antidepressants 50 days after pregnancy, follow-up commenced from 50 days after pregnancy for both this woman and her matched reference. For both the index and reference women, follow-up ended at the earliest of the following: psychiatric inpatient, emergency room visit, death, emigration, or 6 months after childbirth. Fewer than 5 women emigrated or died in the matched cohort for antidepressant discontinuation before pregnancy; 12 women emigrated, and fewer than 5 women died in the matched cohort for antidepressant discontinuation during pregnancy by the end of follow-up. We employed a running line least squares smoothing technique [30] to smooth Kaplan–Meier curves to illustrate the cumulative incidence of psychiatric emergency following the start of follow-up by antidepressant continuation/discontinuation.

We calculated standardized differences to assess covariate balance before and after propensity score matching between groups; meaningful imbalances were defined by an absolute standardized difference of more than 0.1 [31]. Stratified Cox regression [32] was used to estimate the hazard ratio (HR) and 95% CIs for the relationship between antidepressant discontinuation versus continuation and psychiatric emergency. Each matched pair constituted a separate stratum, and each stratum had its baseline hazard function. In the case of the remaining imbalance, we additionally adjusted for the imbalanced covariates [33]. To determine whether the risk of psychiatric emergency changed over time, we investigated the risk during pregnancy and the postpartum period separately, and the date at delivery was used to define the end of follow-up for pregnancy and the start of follow-up for postpartum period. Analyses were performed in Stata, version 15.0 (Stata, College Station, Texas, US).

Ethical approval

The study was approved by the Danish Data Protection Agency. By Danish law, no informed consent is required for a register-based study on the basis of anonymized data.

Results

Of 23,189 women included in the study, 4,368 (18.8%) discontinued antidepressants before pregnancy, 13,258 (57.2%) discontinued during pregnancy, and 5,563 (24.0%) continued antidepressant treatment throughout the entire pregnancy (see S1 Fig for an overview of timing of discontinuation). Women who continued antidepressants differed from women who discontinued antidepressants before or during pregnancy; for instance, women who continued treatment were more likely to have a psychiatric disorder diagnosis and an earlier onset of affective episode. For further characteristics of the entire unpaired study population, see S4 Table. The distributions of propensity score among antidepressant discontinuation and antidepressant group before matching are shown in S2 and S3 Figs.

In total, 2,669 women who discontinued antidepressants before pregnancy and 5,467 women who discontinued treatment during pregnancy were each matched to one woman who continued treatment (Fig 1). Propensity score matching provided a good covariate balance between groups except for, in the cohort of 2,669 matched pairs, women who discontinued antidepressants before pregnancy had shorter education duration and were less likely to receive TCAs/MAOIs in the 90 days before pregnancy, as assessed by standardized difference <0.1. In the cohort of 5,467 matched pairs, those who discontinued antidepressants during pregnancy had a shorter education duration and were younger at first affective disorder episode (Table 1).

Table 1

Characteristics of the study population after propensity score matching.

	Antidepressant discontinuation before pregnancy and its matched continuation group			Antidepressant discontinuation during pregnancy and its matched continuation group
Characteristics	Discontinuation group (N = 2,669)	Continuation group (N = 2,669)	Absolute standardized differences	Discontinuation group (N = 5,467)	Continuation group (N = 5,467)	Absolute standardized differences
Age at the index pregnancy
18 to 25	727 (27.2)	695 (26.0)	0.09	1,161 (21.2)	1,174 (21.5)	0.09
26 to 29	676 (25.3)	758 (28.4)		1,416 (25.9)	1,547 (28.3)
30 to 34	785 (29.4)	808 (30.3)		1,761 (32.2)	1,805 (33.0)
≥35	481 (18.0)	408 (15.3)		1,129 (20.7)	941 (17.2)
Parity
First	1,244 (46.6)	1,230 (46.1)	0.01	2,705 (49.5)	2,660 (48.7)	0.02
Second and above	1,425 (53.4)	1,439 (53.9)		2,762 (50.5)	2,807 (51.3)
Marital status
Married or cohabiting	1,856 (69.5)	1,796 (67.3)	0.00	4,104 (75.1)	3,890 (71.2)	0.02
Single, divorced, or widowed	813 (30.5)	873 (32.7)		1,363 (24.9)	1,577 (28.8)
Level of education
Mandatory school comprising 9 school years	960 (36.0)	747 (28.0)	0.21	1,688 (30.9)	1,389 (25.4)	0.15
Above mandatory school	1,630 (61.1)	1,880 (70.4)		3,607 (66.0)	3,969 (72.6)
Unknown	79 (3.0)	42 (1.6)		172 (3.1)	109 (2.0)
Age at first affective episode
≤18	338 (12.7)	300 (11.2)	0.08	930 (17.0)	751 (13.7)	0.11
19 to 25	1,152 (43.2)	1,217 (45.6)		2,613 (47.8)	2,581 (47.2)
26 to 29	623 (23.3)	647 (24.2)		1,097 (20.1)	1,243 (22.7)
30 to 34	425 (15.9)	406 (15.2)		673 (12.3)	729 (13.3)
≥35	131 (4.9)	99 (3.7)		154 (2.8)	163 (3.0)
History of suicide attempts before pregnancy	209 (7.8)	207 (7.8)	0.00	469 (8.6)	476 (8.7)	0.00
Psychiatric diagnosis before pregnancy
Substance abuse disorder	92 (3.4)	89 (3.3)	0.01	212 (3.9)	216 (4.0)	0.00
Schizophrenia	14 (0.5)	20 (0.7)	0.03	29 (0.5)	30 (0.5)	0.00
Bipolar disorder	19 (0.7)	21 (0.8)	0.01	112 (2.1)	105 (1.9)	0.01
Depression	519 (19.4)	553 (20.7)	0.03	1,654 (30.3)	1,430 (26.2)	0.09
Other mood disorder	30 (1.1)	33 (1.2)	0.01	112 (2.0)	105 (1.9)	0.01
Neurotic, stress-related, and somatoform disorders	660 (24.7)	645 (24.2)	0.01	1,946 (35.6)	1,694 (31.0)	0.10
Personality disorders	368 (13.8)	377 (14.1)	0.01	1,079 (19.7)	938 (17.2)	0.07
Child onset psychiatric disorders	67 (2.5)	63 (2.4)	0.01	149 (2.7)	152 (2.8)	0.00
Other disorders	283 (10.6)	288 (10.8)	0.01	815 (14.9)	729 (13.3)	0.05
Nonpsychiatric comorbidity scores
0	2,350 (88.0)	2,352 (88.1)	0.02	4,771 (87.3)	4,768 (87.2)	0.02
1	249 (9.3)	256 (9.6)		541 (9.9)	560 (10.2)
≥2	70 (2.6)	61 (2.3)		155 (2.8)	139 (2.5)
Number of previous psychiatric emergencies prior to 90 days before pregnancy
0	2,079 (77.9)	2,057 (77.1)	0.03	3,756 (68.7)	3,944 (72.1)	0.08
1	293 (11.0)	305 (11.4)		792 (14.5)	678 (12.4)
2	118 (4.4)	116 (4.3)		383 (7.0)	327 (6.0)
3 to 4	102 (3.8)	116 (4.3)		278 (5.1)	279 (5.1)
≥5	77 (2.9)	75 (2.8)		258 (4.7)	239 (4.4)
Psychiatric emergency in the 90 days before pregnancy	61 (2.3)	63 (2.4)	0.00	112 (2.1)	113 (2.1)	0.00
Classes of antidepressant treatment in the 90 days before pregnancy a
SSRIs	2,046 (76.7)	1,932 (72.4)	0.10	4,759 (87.0)	4,579 (83.8)	0.09
SNRIs	744 (27.9)	772 (28.9)	0.02	812 (14.9)	948 (17.3)	0.07
TCAs or MAIOs	91 (3.4)	158 (5.9)	0.12	141 (2.6)	188 (3.4)	0.05
Comedications in the 90 days before pregnancy
Benzodiazepine	273 (10.2)	271 (10.2)	0.00	585 (10.7)	541 (9.9)	0.03
Anxiolytics	5 (0.2)	5 (0.2)	0.00	13 (0.2)	10 (0.2)	0.01
Antipsychotics	157 (5.9)	152 (5.7)	0.01	503 (9.2)	448 (8.2)	0.04
Opioid	122 (4.6)	131 (4.9)	0.02	199 (3.6)	211 (3.9)	0.01
Antiepileptics	94 (3.5)	111 (4.2)	0.03	312 (5.7)	292 (5.3)	0.02
Other hypnotics	12 (0.5)	7 (0.3)	0.03	19 (0.4)	20 (0.4)	0.00
Calendar year at the index pregnancy
1995 to 2004	698 (26.2)	747 (28.0)	0.04	1,055 (19.3)	1,055 (19.3)	0.03
2005 to 2009	1,306 (48.9)	1,257 (47.1)		2,853 (52.2)	2,790 (51.0)
2011 to 2015	665 (24.9)	665 (24.9)		1,559 (28.5)	1,622 (29.7)

aThe number of classes of antidepressant does not add up to the total number of women since some women received more than one class of antidepressants.

Values are numbers (%) unless stated otherwise.

MAOI, monoamine oxidase inhibitor; SNRI, serotonin–norepinephrine reuptake inhibitor; SSRI, selective serotonin reuptake inhibitor; TCA, tricyclic antidepressant.

Antidepressant discontinuation before pregnancy and subsequent psychiatric emergency in the perinatal period

Of 2,669 matched pairs, 76 women who discontinued antidepressant treatment before pregnancy and 91 women who continued had a psychiatric emergency in the perinatal period (cumulative incidence = 2.9%, 95% CI: 2.3% to 3.6% versus 3.4%, 95% CI: 2.8% to 4.2%, respectively). Fig 2 shows the Kaplan–Meier curves for psychiatric emergency in the perinatal period by antidepressant discontinuation before pregnancy versus continuation during pregnancy. Antidepressant discontinuation before pregnancy was not significantly associated with increased psychiatric emergency risk (HR = 0.84, 95% CI: 0.61 to 1.16, p = 0.298). The risk of psychiatric emergency associated with antidepressant discontinuation before pregnancy did not differ between the pregnancy and the postpartum periods (p-value for interaction = 0.410).

Fig 2

Propensity score–matched smoothed Kaplan–Meier curves for psychiatric emergency since the start of pregnancy among antidepressant discontinuation before pregnancy group versus matched continuation during pregnancy group*.

*The cumulative incidence curve is smoothed to avoid personal identification according to the Data Protection Regulation in Denmark.

Antidepressant discontinuation during pregnancy and subsequent psychiatric emergency in the perinatal period

Of 5,467 matched pairs, 202 women who discontinued antidepressants during pregnancy and 156 who continued had a psychiatric emergency in the perinatal period (cumulative incidence = 5.0%, 95% CI: 4.2% to 5.9% versus 3.7%, 95% CI: 3.1% to 4.5%). Fig 3 shows the Kaplan–Meier curves for psychiatric emergency in the perinatal period by antidepressant discontinuation versus continuation during pregnancy. The risk of psychiatric emergency among women who discontinued antidepressants during pregnancy was 1.25 (95% CI: 1.00% to 1.55%) times women who continued antidepressants (p = 0.048). The risk of psychiatric emergency associated with antidepressant discontinuation was increased during the observation time of pregnancy (HR = 1.52, 95% CI: 1.08 to 2.15, p = 0.016) but not during the postpartum period (HR = 1.09, 95% CI: 0.80 to 1.47, p = 0.596) (Table 2). There was no statistically significant interaction between antidepressant discontinuation during pregnancy and time of observation of psychiatric emergency (p = 0.153).

Fig 3

Propensity score–matched smoothed Kaplan–Meier curves for psychiatric emergency since the start of pregnancy among antidepressant discontinuation during pregnancy group versus matched continuation during pregnancy group*.

*The cumulative incidence curve is smoothed to avoid personal identification according to the Data Protection Regulation in Denmark.

Table 2

Risk of psychiatric emergency associated with antidepressant discontinuation in propensity score–matched cohort analyses.

Matched groups according to the time of discontinuation of the exposed group	Antidepressant discontinuation group				Antidepressant continuation group				Unadjusted HRs (95% CI)	Adjusted HRs (95% CI)b	p-Values for adjusted analyses
	No. of women	No. of events	Person-years	Incidence/1,000 person-years	No. of women	No. of events	Person-years	Incidence/1,000 person-years
Antidepressant discontinuation prior to pregnancy	2,669	76	3,309.28	23.0	2,669	91	3,258.89	27.9	0.84 (0.62 to 1.15)	0.84 (0.61 to 1.16)	0.298
During pregnancy	2,669	40	2,002.38	20.0	2,669	52	1,959.36	26.5	0.75 (0.50 to 1.14)	0.74 (0.47 to 1.15)	0.175
Within 6 months postpartum	2,578	36	1,281.34	28.1	2,578	38	1,280.20	29.7	0.97 (0.61 to 1.56)	0.98 (0.60 to 1.60)	0.946
Antidepressant discontinuation during pregnancy	5,467	202	5,335.86	37.9	5,467	156	5,312.48	29.4	1.29 (1.05 to 1.59)	1.25 (1.00 to 1.55)	0.048
During pregnancy	5,467	92	2,677.95	34.4	5,467	58	2,632.62	22.0	1.59 (1.14 to 2.20)	1.52 (1.08 to 2.15)	0.016
Within 6 months postpartum	5,316	106	2,630.23	40.3	5,316	98	2,635.26	37.2	1.15 (0.85 to 1.54)	1.09 (0.80 to 1.47)	0.596

aThe numbers of cases of psychiatric emergency occurred during pregnancy and within 6 months postpartum do not add up to the whole period since only matched individuals contribute to the analyses.

bAdjustment for imbalanced variables: level of education status and the use of TCAs or MAOIs in the 90 days before pregnancy for the estimate of antidepressant discontinuation before pregnancy and the level of education and age at first affective disorder for the estimate of antidepressant discontinuation during pregnancy.

CI, confidence interval; HR, hazard ratio; MAOI, monoamine oxidase inhibitor; TCA, tricyclic antidepressant.

Sensitivity analyses

When applying a less restrictive grace period of 30 days, in contrast to that of 14 days applied in the main analyses, findings were similar; however, the association between antidepressant discontinuation during pregnancy and psychiatric emergency was attenuated and not statistically significant (HR = 1.16, 95% CI: 0.96 to 1.41, p = 0.156), and antidepressant discontinuation before pregnancy was associated with a reduced risk of psychiatric emergency (HR = 0.66, 95% CI: 0.44 to 0.99, p = 0.044) (S5 Table). To investigate whether risk was affected by the class of antidepressants used in the 90 days before pregnancy, we limited our analyses to women who used SSRIs only. The associations remained similar, although they did not reach statistical significance: The HR was 0.74 (95% CI: 0.47 to 1.17, p = 0.137) for SSRI discontinuation before pregnancy and 1.16 (95% CI: 0.88 to 1.53, p = 0.302) for SSRI discontinuation during pregnancy, compared to women who continued SSRIs. To examine whether the associations differed by the severity of underlying episodes, we defined patients with severe disorders as being admitted to a psychiatric hospital, emergency room visits, or suicide attempts before the start of pregnancy and moderate disorders otherwise. The association between antidepressant discontinuation during pregnancy and risk of psychiatric emergency was greater for women with severe disorders (HR = 2.68, 95% CI: 0.91 to 7.89, p = 0.708) than those with moderate disorders (HR = 1.38, 95% CI: 1.00 to 1.89, p = 0.050), although associations did not meet statistical significance and the CIs overlapped. Numbers were too small to give an accurate estimate for the matched cohort on antidepressant discontinuation before pregnancy. The results remained similar by including maternal age at pregnancy and age at the first affective disorder in the models using linear splines instead of categorical variables in the primary analysis (S6 Table).

Discussion

Conducting a propensity score–matched cohort study, we found that antidepressant discontinuation during pregnancy was associated with an increased risk of psychiatric emergency during the perinatal period. There was no evidence of an association between antidepressant discontinuation before pregnancy and subsequent risk of psychiatric emergency.

Antidepressant discontinuation during pregnancy and psychiatric emergency risk

Most studies on antidepressant treatment during pregnancy have so far centered on potential negative childhood outcomes, e.g., congenital malformations, neonatal persistent pulmonary hypertension, and neurodevelopment and psychiatric outcomes [6,7,34]. In contrast, the effectiveness of antidepressants in preventing psychiatric emergencies during pregnancy has not received similar attention. A limited number of previous studies on relapse or worsening of symptoms after discontinuing antidepressants during pregnancy report conflicting findings [9-13]. In the current study, we found an increased risk of psychiatric emergency among women who discontinued antidepressants during pregnancy compared to those who continued treatment (HR = 1.25, 95% CI: 1.00 to 1.55). Although inconclusive due to limited numbers, the point estimate suggests that the increased risk of psychiatric emergencies following antidepressant discontinuation may be more pronounced among women with severe psychiatric disorders, in line with the recent meta-analysis [14]. We note that our observed effect size is smaller than previously reported 5.0 (95% CI: 2.8 to 9.1) or 8.1 (95% CI: 2.4 to 27.0) [9,10], which most likely reflects that previous studies were performed on small and selected study populations, applying different methods, or outcome measurements.

It could be argued that women on continuous treatment may interact more regularly with the healthcare system and potentially experience positive effects of routine monitoring. We specifically note that 95% of the women who discontinued antidepressants did not experience our defined outcome, psychiatric emergency in the perinatal period, which could be seen as a reassuring message for women contemplating discontinuing their treatment. We also noted that the increased risk associated with antidepressant discontinuation was more pronounced in pregnancy (HR = 1.52, 95% CI: 1.08 to 2.15) than in the postpartum period (HR = 1.09, 95% CI: 0.80 to 1.47). We speculate that women who discontinue antidepressants during pregnancy may restart their medication treatment, in particular, after childbirth [35] and thus reduce the risk of a psychiatric emergency. Notably, the 95% CIs overlapped, and the difference in the risk noted should be interpreted with caution.

Furthermore, our results should be interpreted with caution because psychiatric emergency is a severe outcome. In contrast, a larger proportion of these women may have a recurrent episode that does not necessarily lead to emergency room visits or admissions. It would be interesting to investigate less severe outcomes such as worsening of symptoms or affective instability in future prospective clinical studies. Moreover, future efforts should also be made to identify which women are at low or high risk of psychiatric emergency to guide more nuanced treatment recommendations (e.g., preventive nonpharmacological treatment) [36].

Antidepressant discontinuation before pregnancy and psychiatric emergency risk

To the best of our knowledge, no previous studies have investigated the risk of psychiatric emergency in women who discontinued antidepressants before pregnancy. We found that antidepressant discontinuation in 90 days before pregnancy was not associated with an increased risk of psychiatric emergency in the primary analysis, suggesting that women who discontinued antidepressants before pregnancy may differ from those who discontinued treatment during pregnancy. Although not investigated in this study, we speculate that women who discontinue antidepressants prior to conception do this as part of pregnancy planning or represent a selected population of women, which may not be directly comparable to women who discontinue during pregnancy. Discontinuation during pregnancy might be associated with an unplanned pregnancy, and women might more often stop immediately instead of gradually tapering off their medication, which is an identified risk factor for worsening of mood [37]. A further reduced risk was observed when applying a less restrictive grace period of 30 days, in contrast to 14 days, although the 95% CIs overlapped. One explanation for this particular difference could relate to differences in pregnancy planning between the 2 groups; however, any explanations are at this point highly speculative, as we do not have information on reasons for starting and stopping medication use.

Decisions on whether or not to continue antidepressants during pregnancy

Our findings add to the limited evidence on the efficacy of continued antidepressant treatment during pregnancy to prevent a psychiatric emergency, which has direct clinical relevance. We acknowledge that decisions on antidepressant continuation depend not only on evidence-based knowledge of the benefits and risks but also on the women’s perceptions of risk, values, and treatment preferences [38]. In our study, over 50% of women discontinued antidepressants during pregnancy. Although we do not know the reasons these women discontinued antidepressants, we speculate that perception of fetal risk may be the main reason [6,39,40], despite the fact that evidence on the potential effect of antidepressant exposure in utero is inconclusive and the absolute potential risk is low [6,34,40]. Available data suggest that antidepressants are not major teratogens [34], but the evidence on longer-term outcomes in offspring is inconclusive [7]. Regardless, the provision of evidence-based risk–benefit information through counseling can help women attain more nuanced risk perceptions.

Strengths and limitations

Our study exhibits several strengths. It was based on a representative cohort of women from the entire Danish population and included all pregnant women treated with antidepressants in the 90 days prior to pregnancy. The linkage of several national registers enabled us to control, at least partially, for confounding by the underlying condition through adjustment for several covariates which may be a proxy of disease severity, such as previous psychiatric diagnosis, psychiatric emergency, and concomitant use of medications in the 90 days prior to pregnancy. The use of propensity score matching enabled us to achieve comparability between discontinuation and continuation groups and thus get a more accurate estimate of the effectiveness of continuous antidepressant treatment on psychiatric emergencies in the perinatal period.

Our study also has some limitations. First, some women who filled the prescriptions may not take antidepressants, and we might misclassify them as continued treatment. However, adherence to antidepressant treatment during pregnancy is high in Denmark [41]. Therefore, misclassification is likely to be limited. Moreover, we did not have accurate information on the duration of antidepressant discontinuation. We estimated this based on number of defined daily doses; however, as dosage may vary between individuals, we would have misclassified antidepressant continuation versus discontinuation status for some individuals. This would have biased the association of psychiatric emergency with antidepressant discontinuation toward the null. Similarly, we may have misclassified the time of discontinuation, making the associations with discontinuation before pregnancy and during pregnancy more similar. Second, information on reasons for discontinuing, diagnoses from general practitioners, and nonpharmaceutical treatment is not available in the registers. We further do not know the indication for initiating antidepressant treatment. The national registers provide detailed information on hospital and pharmaceutical treatment, and we tried to control for the unmeasured disorder severity by using propensity score matching. Nonetheless, we have no data on symptom severity and detailed baseline symptoms, leading to residual confounding. Third, some women were excluded from the matched cohort when we matched women who continued treatment during pregnancy to those who discontinued antidepressants before pregnancy.

Conclusions

A substantial proportion of women discontinue antidepressant treatment around the time of conception. This large propensity score–matched cohort study suggests that discontinuing antidepressants specifically during pregnancy is associated with an increased risk of psychiatric emergency, compared to continuous antidepressant treatment without interruption. However, we observed that the absolute risk difference of psychiatric emergency is low (cumulative incidence of 5.0% in women who discontinue versus 3.7% in women who continue antidepressants). While causality cannot be determined from this study, if the association we observed indicates a causal relationship, continuing antidepressant treatment across pregnancy may be effective in reducing psychiatric emergency risk.

Checklist of items that should be included in reports of cohort studies.

STROBE, Strengthening the Reporting of Observational Studies in Epidemiology.

(PDF)

Click here for additional data file.

Detailed description of Danish national registers used in this study.

(PDF)

Click here for additional data file.

Charlson comorbidity index.

(PDF)

Click here for additional data file.

Definition of suicide attempts.

(PDF)

Click here for additional data file.

The ICD-8 or ICD-10 codes for subgroup diagnosis of psychiatric comorbidities.

(PDF)

Click here for additional data file.

Classes of antidepressant treatment during pregnancy.

(PDF)

Click here for additional data file.

ATC codes for comedications in the 90 days prior to pregnancy.

ATC, Anatomical Therapeutic Chemical.

(PDF)

Click here for additional data file.

Characteristics of the study population before propensity score matching.

(PDF)

Click here for additional data file.

Risk of psychiatric emergency associated with antidepressant discontinuation in propensity score matched cohort analyses using a less restrictive 30-day grace period.

(PDF)

Click here for additional data file.

Risk of psychiatric emergency associated with antidepressant discontinuation in propensity score–matched cohort analyses including age at pregnancy and age at first affective disorders as linear splines.

(PDF)

Click here for additional data file.

The distribution of time of antidepressant discontinuation.

(TIFF)

Click here for additional data file.

The distribution of propensity score of discontinuing antidepressants before pregnancy before matching.

(TIFF)

Click here for additional data file.

The distribution of propensity score of discontinuing antidepressants during pregnancy before matching.

(TIFF)

Click here for additional data file.

9 Mar 2021

Dear Dr Liu,

Thank you for submitting your manuscript entitled "Antidepressant discontinuation before or during pregnancy and risk of psychiatric emergency: a population-based propensity score-matched cohort study" for consideration by PLOS Medicine.

Your manuscript has now been evaluated by the PLOS Medicine editorial staff as well as by an academic editor with relevant expertise and I am writing to let you know that we would like to send your submission out for external peer review.

However, before we can send your manuscript to reviewers, we need you to complete your submission by providing the metadata that is required for full assessment. To this end, please login to Editorial Manager where you will find the paper in the 'Submissions Needing Revisions' folder on your homepage. Please click 'Revise Submission' from the Action Links and complete all additional questions in the submission questionnaire.

Please re-submit your manuscript within two working days, i.e. by .

Login to Editorial Manager here: https://www.editorialmanager.com/pmedicine

Once your full submission is complete, your paper will undergo a series of checks in preparation for peer review. Once your manuscript has passed all checks it will be sent out for review.

Feel free to email us at plosmedicine@plos.org if you have any queries relating to your submission.

Kind regards,

Dr Raffaella Bosurgi

Executive Editor

PLOS Medicine

20 Sep 2021

Dear Dr. Liu,

Thank you very much for submitting your manuscript "Antidepressant discontinuation before or during pregnancy and risk of psychiatric emergency: a population-based propensity score-matched cohort study" (PMEDICINE-D-21-01037R1) for consideration at PLOS Medicine.

Your paper was evaluated by a senior editor and discussed among all the editors here. It was also discussed with an academic editor with relevant expertise, and sent to four independent reviewers, including a statistical reviewer. The reviews are appended at the bottom of this email and any accompanying reviewer attachments can be seen via the link below:

[LINK]

The reviewers have pointed out some significant concerns, I am afraid that we will not be able to accept the manuscript for publication in the journal in its current form, but we will consider a revised version that addresses the reviewers' and editors' comments. Obviously we cannot make any decision about publication until we have seen the revised manuscript and your response, and we plan to seek re-review by one or more of the reviewers.

In revising the manuscript for further consideration, your revisions should address the specific points made by each reviewer and the editors. Please also check the guidelines for revised papers at http://journals.plos.org/plosmedicine/s/revising-your-manuscript for any that apply to your paper. In your rebuttal letter you should indicate your response to the reviewers' and editors' comments, the changes you have made in the manuscript, and include either an excerpt of the revised text or the location (eg: page and line number) where each change can be found. Please submit a clean version of the paper as the main article file; a version with changes marked should be uploaded as a marked up manuscript.

In addition, we request that you upload any figures associated with your paper as individual TIF or EPS files with 300dpi resolution at resubmission; please read our figure guidelines for more information on our requirements: http://journals.plos.org/plosmedicine/s/figures. While revising your submission, please upload your figure files to the PACE digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email us at PLOSMedicine@plos.org.

We expect to receive your revised manuscript by Oct 11 2021 11:59PM. Please email us (plosmedicine@plos.org) if you have any questions or concerns.

***Please note while forming your response, if your article is accepted, you may have the opportunity to make the peer review history publicly available. The record will include editor decision letters (with reviews) and your responses to reviewer comments. If eligible, we will contact you to opt in or out.***

We ask every co-author listed on the manuscript to fill in a contributing author statement, making sure to declare all competing interests. If any of the co-authors have not filled in the statement, we will remind them to do so when the paper is revised. If all statements are not completed in a timely fashion this could hold up the re-review process. If new competing interests are declared later in the revision process, this may also hold up the submission. Should there be a problem getting one of your co-authors to fill in a statement we will be in contact. YOU MUST NOT ADD OR REMOVE AUTHORS UNLESS YOU HAVE ALERTED THE EDITOR HANDLING THE MANUSCRIPT TO THE CHANGE AND THEY SPECIFICALLY HAVE AGREED TO IT. You can see our competing interests policy here: http://journals.plos.org/plosmedicine/s/competing-interests.

Please use the following link to submit the revised manuscript:

https://www.editorialmanager.com/pmedicine/

Your article can be found in the "Submissions Needing Revision" folder.

To enhance the reproducibility of your results, we recommend that you deposit your laboratory protocols in protocols.io, where a protocol can be assigned its own identifier (DOI) such that it can be cited independently in the future. Additionally, PLOS ONE offers an option to publish peer-reviewed clinical study protocols. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols

Please ensure that the paper adheres to the PLOS Data Availability Policy (see http://journals.plos.org/plosmedicine/s/data-availability), which requires that all data underlying the study's findings be provided in a repository or as Supporting Information. For data residing with a third party, authors are required to provide instructions with contact information for obtaining the data. PLOS journals do not allow statements supported by "data not shown" or "unpublished results." For such statements, authors must provide supporting data or cite public sources that include it.

We look forward to receiving your revised manuscript.

Sincerely,

Caitlin Moyer, PhD

Associate Editor

PLOS Medicine

plosmedicine.org

-----------------------------------------------------------

Requests from the editors:

1. We note that there are major concerns raised by the reviewers, especially reviewer 3, relating to the validity of the analyses. Please do respond to and address the comments of all the reviewers.

2. Data availability statement: The Data Availability Statement (DAS) requires revision. For each data source used in your study:

a) If the data are freely or publicly available, note this and state the location of the data: within the paper, in Supporting Information files, or in a public repository (include the DOI or accession number).

b) If the data are owned by a third party but freely available upon request, please note this and state the owner of the data set and contact information for data requests (web or email address). Note that a study author cannot be the contact person for the data.

c) If the data are not freely available, please describe briefly the ethical, legal, or contractual restriction that prevents you from sharing it. Please also include an appropriate contact (web or email address) for inquiries (again, this cannot be a study author).

3. Throughout: Please include line numbers with the revised version.

4. Abstract: Please combine the Methods and Findings sections into one section, “Methods and findings”.

5. Abstract: Methods and Findings: Please include the population and setting, number of participants, and years during which the study took place.

6. Abstract: Methods and Findings: Please include the important dependent variables that are adjusted for in the analyses.

7. Abstract: Methods and Findings: Please quantify the main results with both 95% CIs and p values.

8. Abstract: Methods and Findings: In the last sentence of the Abstract Methods and Findings section, please describe the main limitation(s) of the study's methodology.

9. Throughout: Please use square brackets for in-text citations, placed before the sentence punctuation. Where multiple references are included within brackets, please do not include spaces.

10. Methods: Please ensure that the study is reported according to the STROBE guideline, and include the completed STROBE checklist as Supporting Information. Please add the following statement, or similar, to the Methods: "This study is reported as per the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guideline (S1 Checklist)."

The STROBE guideline can be found here: http://www.equator-network.org/reporting-guidelines/strobe/

When completing the checklist, please use section and paragraph numbers, rather than page numbers.

11. Methods: Did your study have a prospective protocol or analysis plan? Please state this (either way) early in the Methods section.

a) If a prospective analysis plan (from your funding proposal, IRB or other ethics committee submission, study protocol, or other planning document written before analyzing the data) was used in designing the study, please include the relevant prospectively written document with your revised manuscript as a Supporting Information file to be published alongside your study, and cite it in the Methods section. A legend for this file should be included at the end of your manuscript.

b) If no such document exists, please make sure that the Methods section transparently describes when analyses were planned, and when/why any data-driven changes to analyses took place.

c) In either case, changes in the analysis-- including those made in response to peer review comments-- should be identified as such in the Methods section of the paper, with rationale.

12. Methods: Please provide more detail on the Danish nationwide registers used for the cohort study.

13. Methods: Please comment on whether it is possible to examine recurrent illness that may not necessarily present in the ER/ hospital perhaps due to being less severe relative to those illnesses that may present in the ER/hospital.

14. Results: Please present both 95% CIs and p values for all results described in the text; for example, for the association of antibdepressant discontinuation with psychiatric emergency risk.

15. Results: Please note where the results to support this statement are presented: “The risk of psychiatric emergency associated with antidepressant discontinuation before pregnancy did not differ between the pregnancy and the postpartum periods” (please note where the results for the interaction test can be found).

16. Results: Please clarify for the analysis of those who discontinued medication during pregnancy, that the interaction between time of observing the outcome of psychiatric emergency (during pregnancy or postpartum) did not reach significance. This seems to suggest that the different risk noted should be interpreted with caution given the lack of an interaction.

17. Results: “When applying a less restrictive grace period of 30-days, in contrast to that of 14-days applied in the main analyses, findings were similar; however, associations were attenuated (HR=1.16, 95%CI:0.96–1.41)...” Please clarify which associations are being referred to here.

18. Results: Sensitivity analysis: Please include in the discussion some interpretation on why the association between discontinuation during pregnancy and psychiatric emergency might reverse direction with the 30 day rather than 14 day grace period. Please note in the text the sensitivity analyses for which associations observed in main analyses were attenuated/statistical significance no longer apparent.

19. Discussion: Please present and organize the Discussion as follows: a short, clear summary of the article's findings; what the study adds to existing research and where and why the results may differ from previous research; strengths and limitations of the study; implications and next steps for research, clinical practice, and/or public policy; one-paragraph conclusion.

20. Discussion: “No previous studies have investigated risk of psychiatric emergency in women who discontinued antidepressants before pregnancy.” Please qualify this and any similar statements with “To the best of our knowledge…” or similar.

21. Conclusions: “This large propensity score-matched cohort study suggests that discontinuing antidepressants specifically during pregnancy increases risk of psychiatric emergency…” Please avoid the use of language implying causality, here and throughout the manuscript.

22. References: Please use the "Vancouver" style for reference formatting, and see our website for other reference guidelines https://journals.plos.org/plosmedicine/s/submission-guidelines#loc-references

23. Table 2 and eTable 5: Please also provide the results of the unadjusted analyses.

Comments from the reviewers:

Reviewer #1: I confine my remarks to statistical aspects of this paper. These were generally very well done, and I almost voted to accept, but I have a couple of suggestions that the authors might implement, especially if they have to make other revisions.

p. 2 Results - there was, in fact, some evidence of *lower* risk among those who discontinued before pregnancy.

p. 4 It would be good to give effect size estimates of the other studies.

The results of the meta-analysis are very odd. There must have been huge heterogeneity to get such a large confidence interval. The authors might discuss this.

p, 7 Although the results of the propensity analysis were very good, they might be even better if the authors used splines of age as a continuous variable, rather than catgegorizing it.

Peter Flom

Reviewer #2: Overall, this is interesting, important, rigorous work. I appreciate the detailed description of the cohort and matching. Outcomes (emergency visit or admission) are somewhat narrow, as acknowledged by authors, in that this probably does not capture the spectrum of the burden of recurrent illness during pregnancy/postpartum and many (perhaps most) women are probably not making a decision to continue or discontinue medication during pregnancy based on those outcomes, unless they have previously experienced those events.

Several minor comments.

Abstract: It might be more accurate to say that there is limited evidence on continuing vs discontinuing antidepressants in pregnancy.

Introduction:

2-8% of pregnant women in Europe and 8-13% in the US receive an antidepressant prescription at some time during their pregnancy (versus continuous use).

Untreated/undertreated depression and anxiety should also be avoided to prevent maternal/fetal/infant death.

Methods:

If 41.3% had a psychiatric diagnosis, what were the indications for antidepressant use in the rest of the cohort? This is brought up in methods and again the discussion. Would be helpful to understand if having a documented psychiatric diagnosis indicates more severe illness.

Can you comment on if there was a group of women discontinued antidepressants before or during pregnancy and then restarted them during pregnancy or during postpartum?

Reviewer #3: The authors try to address the exceedingly important question of navigating the risk benefit decision with respect to antidepressant use during pregnancy: to continue or to discontinue AD treatment given the relative knowns and unknowns associated with fetal exposure to this class of medication . The analytic exercise performed is profoundly flawed and does not contribute to enhanced ability to navigate the clinical dilemma . Indeed , there are some conflicting data on the question of benefit of antidepressant continuation during pregnancy . And yet this paper looks at an outcome variable - psychiatric emergency /ER visit /psych admission with respect to AD discontinuation that does not inform in any way . Do the authors make the argument that they have the ability to adjust for confounding based on the data in hand from an administrative database ? The variables in the propensity score model are appropriate but the reader can have sparse confidence that data reflecting accurately those variables is obtainable. An even greater limitation of this analysis is the failure to know the status of subjects in each cohort at baseline : were these women euthymic at baseline , before they discontinued treatment ? What value is the analysis if we do not know how women were clinically before looking at the outcome of interest . This may also be relevant as treatment of depression before , during and after pregnancy has certainly evolved across the interval of interest noted in the paper - 1996-2016.

Two other smaller issues : First , the reference to adverse effects of AD exposure during pregnancy being associated with persistent pulmonary hypertension of the newborn is puzzling as the concern has been put to rest in multiple reports . And yet these authors note as an outcome of concern with respect to fetal exposure to AD. Second , there is no discussion as to why there is no observation of increased frequency of the outcome postpartum which would be expected .

There is a responsibility as studies get conducted in this area to make an effort to refine the risk benefit decision regarding the use of AD before, during and after pregnancy in reproductive age women . This manuscript does not advance the effort .

Reviewer #4: This manuscript is a cohort study that examines the effects of antidepressant discontinuation before and during pregnancy. The authors report an increased risk of psychiatric emergency in women who discontinue antidepressants during pregnancy. The risk is smaller than has been previously observed in the literature but clinically significant. There are several strengths of this manuscript including large sample size, transparent and thoughtful methodology, use of propensity score matching and a well-written paper. There are some minor critiques that I have of this manuscript that could improve it with revision but overall it is an important and meaningful work.

(1) Please define which medications are defined as antidepressants in the methods section. It is clear this is SSRI, SNRI, TCA and MAOI from table 1 but this should be mentioned in the text of the manuscript.

(2) I wish the authors discussed more extensively the evidence (or lack thereof) of congenital malformations with antidepressant exposure. This is important when discussing the risk/benefits of antidepressant discontinuation during pregnancy.

(3) Although the absolute risk of psychiatric emergency is smaller than previous studies, I am not sure I would necessarily qualify it as that small of an absolute risk (not to mention it is not a small relative risk). The NNT seems to be around 77 and is probably much higher in individuals with mdoerate-to-severe illness or at the higher end of your propensity score.

(4) I also wish the authors commented on the high rate of women that discontinued antidepressant medication during pregnancy. it would be useful to examine whether there was any relationship between propensity score and decision to discontinue medication during pregnancy.

Any attachments provided with reviews can be seen via the following link:

[LINK]

5 Oct 2021

Submitted filename: rebuttal letter.docx

Click here for additional data file.

3 Dec 2021

Dear Dr. Liu,

Thank you very much for re-submitting your manuscript "Antidepressant discontinuation before or during pregnancy and risk of psychiatric emergency: a population-based propensity score-matched cohort study" (PMEDICINE-D-21-01037R2) for review by PLOS Medicine.

I have discussed the paper with my colleagues and the academic editor and it was also seen again by three reviewers. I am pleased to say that provided the remaining editorial and production issues are dealt with we are planning to accept the paper for publication in the journal.

The remaining issues that need to be addressed are listed at the end of this email. Any accompanying reviewer attachments can be seen via the link below. Please take these into account before resubmitting your manuscript:

[LINK]

***Please note while forming your response, if your article is accepted, you may have the opportunity to make the peer review history publicly available. The record will include editor decision letters (with reviews) and your responses to reviewer comments. If eligible, we will contact you to opt in or out.***

In revising the manuscript for further consideration here, please ensure you address the specific points made by each reviewer and the editors. In your rebuttal letter you should indicate your response to the reviewers' and editors' comments and the changes you have made in the manuscript. Please submit a clean version of the paper as the main article file. A version with changes marked must also be uploaded as a marked up manuscript file.

Please also check the guidelines for revised papers at http://journals.plos.org/plosmedicine/s/revising-your-manuscript for any that apply to your paper. If you haven't already, we ask that you provide a short, non-technical Author Summary of your research to make findings accessible to a wide audience that includes both scientists and non-scientists. The Author Summary should immediately follow the Abstract in your revised manuscript. This text is subject to editorial change and should be distinct from the scientific abstract.

We expect to receive your revised manuscript within 1 week. Please email us (plosmedicine@plos.org) if you have any questions or concerns.

We ask every co-author listed on the manuscript to fill in a contributing author statement. If any of the co-authors have not filled in the statement, we will remind them to do so when the paper is revised. If all statements are not completed in a timely fashion this could hold up the re-review process. Should there be a problem getting one of your co-authors to fill in a statement we will be in contact. YOU MUST NOT ADD OR REMOVE AUTHORS UNLESS YOU HAVE ALERTED THE EDITOR HANDLING THE MANUSCRIPT TO THE CHANGE AND THEY SPECIFICALLY HAVE AGREED TO IT.

Please ensure that the paper adheres to the PLOS Data Availability Policy (see http://journals.plos.org/plosmedicine/s/data-availability), which requires that all data underlying the study's findings be provided in a repository or as Supporting Information. For data residing with a third party, authors are required to provide instructions with contact information for obtaining the data. PLOS journals do not allow statements supported by "data not shown" or "unpublished results." For such statements, authors must provide supporting data or cite public sources that include it.

To enhance the reproducibility of your results, we recommend that you deposit your laboratory protocols in protocols.io, where a protocol can be assigned its own identifier (DOI) such that it can be cited independently in the future. Additionally, PLOS ONE offers an option to publish peer-reviewed clinical study protocols. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols

Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript.

Please note, when your manuscript is accepted, an uncorrected proof of your manuscript will be published online ahead of the final version, unless you've already opted out via the online submission form. If, for any reason, you do not want an earlier version of your manuscript published online or are unsure if you have already indicated as such, please let the journal staff know immediately at plosmedicine@plos.org.

If you have any questions in the meantime, please contact me or the journal staff on plosmedicine@plos.org.

We look forward to receiving the revised manuscript by Dec 10 2021 11:59PM.

Sincerely,

Caitlin Moyer, PhD

Associate Editor

PLOS Medicine

plosmedicine.org

------------------------------------------------------------

Requests from Editors:

1. Title: Please capitalize the first word of the subtitle: “Antidepressant discontinuation before or during pregnancy and risk of psychiatric emergency: A population-based propensity score-matched cohort study” and please update this in the manuscript submission system.

2. Data availability statement: Thank you for providing a statement regarding the availability of the data underlying your study. Please add the weblinks and contact email address(es) for the registers used in the study (e.g. https://econ.au.dk/the-national-centre-for-register-based-research/danish-registers/the-danish-civil-registration-system-cpr; https://econ.au.dk/the-national-centre-for-register-based-research/danish-registers/the-national-patient-register; https://econ.au.dk/the-national-centre-for-register-based-research/danish-registers/the-danish-psychiatric-central-research-register; https://econ.au.dk/the-national-centre-for-register-based-research/danish-registers/the-medical-register-of-births-and-deaths if these links are applicable. Please also provide a link and contact information for the Danish National Prescription Registry).

3. Abstract: Methods: Line 34: Please revise to “We carried out a propensity score-matched cohort study of women with singleton live births between…” or similar. Please also note the setting of the study (Denmark) in the first sentence.

4. Abstract: Methods: Line 35-36: Please broadly define the categories of “antidepressants” considered.

5. Abstract: Methods and Findings: Please avoid the use of italics for emphasis.

6. Abstract: Methods and Findings: Please also provide the cumulative incidence for those who discontinued before pregnancy compared to those who did not.

7. Abstract: Conclusions: Please revise to: “In this study, we found that discontinuing antidepressant medication during pregnancy (but not before) is associated with an apparent increased risk of psychiatric emergency compared to continuing treatment across pregnancy.”

8. Author summary: What do these findings mean? We suggest revising to: “Our findings add to the limited evidence on the relationship between continued antidepressant treatment during pregnancy and perinatal psychiatric emergency.”

9. Introduction: Line 97: Please avoid the use of italics for emphasis, here and throughout the text.

10. Methods: Line 105-106: Thank you for your response indicating that there was no prospectively developed protocol for the study. Please include a sentence noting this in the main text, early on in the Methods section, similar to: “There is no documented analysis plan associated with the study. We planned our analyses on a detailed discussion among the authors and agreed on an outline for how the work would be done, as described in the Methods. Changes to the pre-planned analyses include…” and please specifically note the changes to the analyses that were implemented post-hoc, e.g. in response to peer reviewer comments. We ask that you please indicate in the text: (1) the specific hypotheses you intended to test, (2) the analytical methods by which you planned to test them, (3) the analyses you actually performed, and (4) when reported analyses differ from those that were planned, transparent explanations for differences that affect the reliability of the study's results. If a reported analysis was performed based on an interesting but unanticipated pattern in the data, please be clear that the analysis was data-driven.

11. Methods: Line 110-111: Thank you for including the detailed information in the Supporting Information files. In the main text, please do at least mention the names of the registers (e.g. the register from which pregnancies and births were identified, etc).

12. Methods: Line 160: Please briefly explain “mandatory school” in terms of what this indicates.

13. Methods: Line 165-166: Please either list the 19 comorbid conditions here, or provide a supporting information file with the list of conditions.

14. Methods: Line 216: Please list the imbalance covariates adjusted for in the adjusted analyses.

15. Results: Line 249-250: Please add “significantly” to the sentence: “Antidepressant discontinuation before pregnancy was not significantly associated with…”

16. Results: Line 251-253: Please provide the results (for the interaction) in the text that support this statement: “The risk of psychiatric emergency associated with antidepressant discontinuation before pregnancy did not differ between the pregnancy and the postpartum periods.”

17. Results: Line 257: Please clarify to “A total of 202 women who discontinued during pregnancy…” or similar.

18. Results: Line 263: Please clarify to “The risk of psychiatric emergency associated with antidepressant discontinuation during pregnancy…” if accurate.

19. Results: Line 265: We suggest revising to: “There was no statistically significant interaction between antidepressant discontinuation during pregnancy and time of observation of psychiatric emergency (p=0.153).” or similar.

20. Results: Lines 277-279: We suggest revising to “The associations remained similar, though they did not reach statistical significance: the HR was 0.74 (95%CI: 0.47–1.17, p=0.137) for SSRI discontinuation before pregnancy and 1.16 (95%CI: 0.88–1.53, p=0.302) for SSRI discontinuation during pregnancy, compared to women who continued SSRIs.” or similar.

21. Results: Line 281: Please clarify “having admission” in this sentence.

22. Results: Line 282-285: We suggest revising to: “The association between antidepressant discontinuation during pregnancy and risk of psychiatric emergency was greater for women with severe disorders (HR=2.68, 95%CI: 0.91–7.89, p=0.708) than those with moderate disorders (HR=1.38, 95%CI: 1.00–1.89, p=0.050), although associations did not meet statistical significance and the confidence intervals overlapped.”

23. Discussion: Lines 292-294: We suggest revising to: “Conducting a propensity score-matched cohort study, we found that antidepressant discontinuation during pregnancy was associated with an increased risk of psychiatric emergency during the perinatal period.” as there was no significant interaction between psychiatric emergency during pregnancy and the 6 months following pregnancy.

24. Discussion: Line 300: Here and throughout, where multiple references are indicated within brackets, please do not include spaces [6,7,34].

25. Discussion: Lines 306-308: Please revise to “...the point estimate suggests that the increased risk of psychiatric emergencies following antidepressant discontinuation may be more pronounced among women with severe psychiatric disorders…”

26. Discussion: Lines 347-349: It would be helpful to further clarify this sentence, in terms of why the less-restrictive grace period would lead to a reversal of the direction of the association with the 14 day grace period. “It is probable that women who get pregnant after discontinuing antidepressants 30 days may have planned their pregnancy even earlier than those who get pregnant 14 days after discontinuation.”

27. Discussion: Line 359: We suggest removing “(and will likely remain)” from the sentence.

28. Discussion: Line 377: Please use “adherence” rather than “compliance” here and throughout the manuscript.

29. Discussion: Line 399-403: We suggest revising to: “However, we observed that the absolute risk difference of psychiatric emergency is low (cumulative incidence of 5.0% in women who discontinue versus 3.7% in women who continue antidepressants). While causality cannot be determined from this study, if the association we observed indicates a causal relationship, continuing antidepressant treatment across pregnancy may be effective in reducing psychiatric emergency risk.”

30. Line 405: Please remove the “Competing Interests” section from the main text, and please ensure all information is complete and accurate in the Competing Interests section of the manuscript submission system.

31. Lines 405-426: Please remove the Funding, Contributors, and Data Sharing sections from the main text and please ensure all information is completely and accurately entered into the relevant sections of the manuscript submission system.

32. References: Please use the "Vancouver" style for reference formatting, and see our website for other reference guidelines https://journals.plos.org/plosmedicine/s/submission-guidelines#loc-references

Please avoid the use of italics.

33. Figure 1: Please revise to “680,312 women aged 18 years or older” in the first box.

34. Figure 2: For comparison, could the curves also be shown for those who discontinued antidepressant prior to pregnancy? Please provide the number at risk for each relevant time interval.

35. Table 1: Please define all abbreviations used in the table. Please include a definition of “mandatory school” in the legend.

36. Supporting Information file: Please submit a clean version of the file (without tracked changes). Please include both titles and legends for all figures and tables.

37. Supporting Information S2: Please provide a citation or other quantitative support for the sentence “The information is of very high quality.”

38. S1 Figure: Please provide a descriptive legend for the figure, and please provide more information for the y-axis label.

39. S4 Table: Please define all abbreviations used in the table. Please include a definition of “mandatory school” in the legend.

40. STROBE Checklist: Please provide the checklist as a separate file.

Comments from Reviewers:

Reviewer #1: The authors have addressed my concerns and I now recommend publication.

Peter Flom

Reviewer #2: I am satisfied with the revisions and have no additional comments to offer. The work remains important and although it is not possible to control for all confounders, etc, this does add to the field and could be used in helping clinicians/patients determine risk of continuing vs discontinuing medications preconception and during pregnancy.

Reviewer #4: The reviewers responded adequately to my critiques. I believe many of the important criticisms raised by other reviewers have also been adequately addressed in the limitations section and are well-acknowledged by the authors in the revised manuscript.

Any attachments provided with reviews can be seen via the following link:

[LINK]

10 Dec 2021

Submitted filename: Rebuttal letter_3rd.docx

Click here for additional data file.

20 Dec 2021

Dear Dr Liu,

On behalf of my colleagues and the Academic Editor, Mark Tomlinson, I am pleased to inform you that we have agreed to publish your manuscript "Antidepressant discontinuation before or during pregnancy and risk of psychiatric emergency: A population-based propensity score-matched cohort study" (PMEDICINE-D-21-01037R3) in PLOS Medicine.

Before your manuscript can be formally accepted you will need to complete some formatting changes, which you will receive in a follow up email. Please be aware that it may take several days for you to receive this email; during this time no action is required by you. Once you have received these formatting requests, please note that your manuscript will not be scheduled for publication until you have made the required changes.

In the meantime, please log into Editorial Manager at http://www.editorialmanager.com/pmedicine/, click the "Update My Information" link at the top of the page, and update your user information to ensure an efficient production process.

Please also address the following editorial points:

1. Title: We suggest including the study setting: “Antidepressant discontinuation before or during pregnancy and risk of psychiatric emergency in Denmark: A population-based propensity score-matched cohort study” or similar.

2. Supplementary material. In the published article, supporting information files are accessed only through a hyperlink attached to the captions. For this reason, please list captions at the end of your manuscript file. You may include a caption within the supporting information file itself, as long as that caption is also provided in the manuscript file. Please do not submit a separate caption file. The supporting information file name and number are required in a caption, and we highly recommend including a one-line title and a caption as well. We also suggest including each supporting information figure and table as a file.

3. Table 2, S5 Table, S6 Table: Please indicate whether the p values correspond to the unadjusted or adjusted analyses.

4. Acknowledgements: Please note that it is not necessary to remove the acknowledgements section from the manuscript, if including one is preferred, as long as complete funding information is included in the relevant “Funding” section within the manuscript submission system.

PRESS

We frequently collaborate with press offices. If your institution or institutions have a press office, please notify them about your upcoming paper at this point, to enable them to help maximise its impact. If the press office is planning to promote your findings, we would be grateful if they could coordinate with medicinepress@plos.org. If you have not yet opted out of the early version process, we ask that you notify us immediately of any press plans so that we may do so on your behalf.

We also ask that you take this opportunity to read our Embargo Policy regarding the discussion, promotion and media coverage of work that is yet to be published by PLOS. As your manuscript is not yet published, it is bound by the conditions of our Embargo Policy. Please be aware that this policy is in place both to ensure that any press coverage of your article is fully substantiated and to provide a direct link between such coverage and the published work. For full details of our Embargo Policy, please visit http://www.plos.org/about/media-inquiries/embargo-policy/.

To enhance the reproducibility of your results, we recommend that you deposit your laboratory protocols in protocols.io, where a protocol can be assigned its own identifier (DOI) such that it can be cited independently in the future. Additionally, PLOS ONE offers an option to publish peer-reviewed clinical study protocols. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols

Thank you again for submitting to PLOS Medicine. We look forward to publishing your paper.

Sincerely,

Caitlin Moyer, Ph.D.

Associate Editor

PLOS Medicine