Review question(s)

1. i. How have previous studies measured the continuation of antidepressant exposure a) prior to, b) during, and c) after pregnancy (i.e., binary exposures, sustained use, measurement of lactation)?
2. ii. What specific characteristics have previous studies measured concerning continued antidepressant exposure prior to, during, and after pregnancy (e.g., indication, dose, duration, timing)?

Ethics approval

This review is part of LT’s doctoral thesis, which has received ethics approval from the Research Ethics Boards of the University of Toronto (HPR-00055550-V0001.0000-O), Aarhus University (REB# 2016-051-000001/810), and the Hospital for Sick Children (REB# REB 1000080862).

Eligibility criteria

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Table 1. Eligibility Criteria.

https://doi.org/10.1371/journal.pone.0335144.t001

Participants

As described in Table 1, we will include studies examining human pregnant individuals who continue to use antidepressants throughout the perinatal period, defined as use during pregnancy as well prior to conception (within 12 months preconception) continuing into pregnancy and after pregnancy (continued use within 12 months post-delivery), with a focus on sustained use throughout pregnancy (i.e., not postpartum initiation of antidepressants). We will exclude studies that focus on non-human populations or only include individuals who are not pregnant, attempting to conceive, or have a history of delivery more than 1 year prior. We will not impose other population restrictions (i.e., we will include individuals with comorbidities or co-existing conditions) [27]. Concerning sex and gender, this review will focus on perinatal antidepressant exposure, meaning only conceiving, pregnant, or previously pregnant individuals of reproductive age (assigned female sex at birth, generally 15–49 years [28, 29]) will inherently be included, although we will not limit the search by sex, gender, or age.

Concept

The main concept of interest for this scoping review is how prior studies have measured and defined continued antidepressant use throughout the preconception, prenatal, and postpartum periods, for all antidepressant classes, particularly concerning continued use throughout the perinatal period and the categorization of continued antidepressant use (i.e., binary, categorical (i.e., ever, never, sometimes)). Since the focus of our concept is the measurement of continued antidepressant use during the perinatal period, we are also interested in specific factors that are measured in relation to antidepressant exposure, such as indication, dose, class, trimester/timing, and/or cumulative duration of use. Therefore, an additional element of our concept of interest will be the characteristics of antidepressant use.

Context

This review will consider all human studies with no restrictions on language or geographic location. As described by Peters et al., the context of a scoping review includes details on location, social-cultural factors, or sex-based factors [27]. We will not restrict based on location or social-cultural contexts (e.g., acute care).

Types of sources

As per Peters et al., reviews can limit study designs based on the research question and when the team believes certain designs are unlikely to contain relevant information [25]. Since we aim to summarize continued perinatal antidepressant exposure, we will include study designs that allow for the analysis of temporal assessment of exposure with longitudinal data prior to, during, or following a pregnancy. We will, therefore, limit our search to peer-reviewed studies that capture patterns or trends in exposure with the following study designs: cohort studies, cross-sectional studies (i.e., where women recall preconception, prenatal, and postpartum use), case-control studies, and descriptive analyses or spontaneous reports that reference use of medications over time. We will exclude studies that lack the ability to measure individual-level longitudinal patterns of antidepressant use throughout the perinatal period across broad populations, as well as those that have insufficient primary data or detail of use (e.g., conference abstracts, case reports/series, editorials, reviews, and opinion pieces). A search of the grey literature will be performed using the first five pages of Google, Google Scholar, and Canada’s Drug Agency Grey Matters tool (formerly the Canadian Agency for Drugs and Technologies in Health (CADTH) Grey Matters Guide) Advisories and Warnings section to examine surveillance data from pharmaceutical or public health agencies [30]. As with peer-reviewed studies, included grey literature must have longitudinal data of individual-level antidepressant exposure to be included.

Study design

The proposed scoping review will be conducted in accordance with the JBI methodology for scoping reviews [31] and the protocol will be reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for protocols (PRISMA-ScR) [27, 32]. As noted by Munn et al. and previously described, scoping reviews are indicated when researchers seek to clarify key concepts/definitions in the literature and identify and analyze knowledge gaps, making the scoping review format the most appropriate for this research question [26]. This protocol has been registered in OSF (https://osf.io/2ewpq).

Search strategy

The search strategy aims to locate published studies. A three-step search strategy will be used in this review as per the JBI Manual for Evidence Synthesis [33]. First, an initial limited search of MEDLINE (PubMed) will be conducted to identify articles on the topic. The text words contained in the titles and abstracts of relevant articles and the index terms used to describe the articles will be used to develop a full search strategy for Ovid MEDLINE(R) and Epub Ahead of Print, In-Process & Other Non-Indexed Citations and Daily; Ovid Embase Classic + Embase; Ovid APA PsycInfo; Ovid EBM Reviews Central Register of Clinical Trials; and Clarivate Web of Science Core Collection (see S1 File. Complete Literature Search Strategy). Grey literature sources will be identified using previously described methods. With guidance from an expert librarian (JC), the search strategy, including all identified keywords and index terms, will be adapted for each included database and/or information source. The reference lists of all included sources of evidence will be screened for additional studies.

While the initial abstract screening will include studies published from 2015 onward to capture a broad range of potentially relevant literature, the full-text review will be limited to studies published from 2022 to 2024. This decision was made to improve feasibility given the high volume of eligible studies and to ensure that the review reflects contemporary patterns of antidepressant use during pregnancy. Over the past two decades, prenatal antidepressant prescribing has shifted, with a decline in the use of older, less selective antidepressants and a rise in the use of more selective agents, such as selective serotonin reuptake inhibitors (SSRIs). Limiting the full-text review to more recent publications ensures a focus on research that aligns with current prescribing practices, safety profiles, and clinical guidelines, thereby increasing the relevance of our findings for contemporary clinical decision-making [34]. This timeframe limitation was chosen pragmatically to manage the volume of literature and ensure relevance to contemporary prescribing patterns, while still capturing a range of exposure measurement approaches. Non-English language articles will be translated when needed, and artificial intelligence software (e.g., Deep-L [35–37] and CUBBITT [37, 38] have been shown to be highly reliable, with CUBBIT exhibiting increased fluency) to translate non-English studies may be used in addition to human translators, as have been used in previous scoping reviews [39].

Study selection

Following the search, all identified citations will be collated and uploaded into Covidence screening software (Veritas Health Innovation, Melbourne, Australia), and duplicates will be removed. All identified titles/abstracts will be screened independently by at least two independent reviewers based on the inclusion criteria for the review. We will conduct a pilot test of 50 titles/abstracts and 10 full-text articles prior to conducting the official screening to ensure that the eligibility criteria are sufficient and clear, with a goal of 75% agreement [25]. The references of included studies will be scanned to identify studies not identified in the original search. All studies identified in the title/abstract screening stage that meet the inclusion criteria will proceed to full-text review. At the full-text review stage, we will apply more detailed eligibility criteria and extract relevant data. Reasons for the exclusion of full-text papers that do not meet the inclusion criteria will be recorded and reported in the scoping review. Any conflicts will be resolved through discussion or by a third independent reviewer. Search results and the study inclusion process will be reported in full in the final scoping review and presented in a PRISMA flow diagram [40].

Data extraction

Relevant information from the studies, including year of publication, country, design, objectives, study population, definition and measurement of continued pre- and perinatal antidepressant use, indication, method of ascertainment of indication, and outcomes examined, will be extracted by two independent reviewers using a data extraction tool developed by the reviewers. Any conflicts will be resolved through discussion or by a third independent reviewer. A risk of bias assessment will not be conducted as per scoping review guidelines [25]. The draft data extraction tool (refer to Table 2) will be modified and revised as necessary during the data extraction process, and all modifications will be detailed in the full scoping review. If appropriate, the authors of included papers will be contacted to request missing or additional data, where required.

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Table 2. Draft data extraction instrument^a.

https://doi.org/10.1371/journal.pone.0335144.t002

Since this study is a scoping review, all data underlying the findings will be derived from published, peer-reviewed articles or grey literature that are already available in the public domain. A complete list of included studies will be provided as a supplementary file with the final manuscript. The extracted data will also be made available as supplementary tables at the time of publication.

Data analysis and presentation

We will use descriptive statistics to summarize the characteristics of included studies (e.g., the number and proportion of studies reporting specific medication classes/types). A summary of the characteristics of antidepressant use (i.e., dose, class, trimester/timing, and duration) will also be displayed in tables. To ascertain how continued antidepressant use has been captured, we will first report the number of studies that consider versus do not consider antidepressant continuation during pregnancy and then will categorize studies based on the robustness of their measurement of continued antidepressant use (considering factors such as timing, duration, adherence, exposure ascertainment, etc.). Study details will be presented as tables or figures (e.g., word heat maps, waffle charts) as described by Pollock et al [41] where appropriate. Tabular or diagrammatic data will be accompanied by a narrative summary to illustrate key findings.

Scoping review timeline

As this is a scoping review of the available literature, no participant recruitment is involved. Title and abstract screening have been completed as of June 18, 2025. Full-text screening has been completed as of July 7, 2025. Data extraction is underway and expected to be completed by October 2025. We anticipate that results will be available by December 2025.