Pregnancy and birth complications associations with long-term adverse maternal mental health outcomes: a systematic review and meta-analysis protocol

Background Existing studies have established an association between pregnancy, birth complications, and mental health in the first few weeks postpartum. However, there is no clear understanding of whether pregnancy and birth complications increase the risk of adverse maternal mental outcomes in the longer term. Research on maternal adverse mental health outcomes following pregnancy and birth complications beyond 12 months postpartum is scarce, and findings are inconsistent. Objective This systematic review and meta-analysis will examine the available evidence on the association between pregnancy and birth complications and long-term adverse maternal mental health outcomes. Methods and analysis We will include cohort, cross-sectional, and case-control studies in which a diagnosis of pregnancy and/or birth complication (preeclampsia, pregnancy loss, caesarean section, preterm birth, perineal laceration, neonatal intensive care unit admission, major obstetric haemorrhage, and birth injury/trauma) was reported and maternal mental disorders (depression, anxiety disorders, bipolar disorders, psychosis, and schizophrenia) after 12 months postpartum were the outcomes. A systematic search of PubMed, Embase, CINAHL, PsycINFO, and Web of Science will be conducted following a detailed search strategy until August 2022. Three authors will independently review titles and abstracts of all eligible studies, extract data using pre-defined standardised data extraction and assess the quality of each study using the Newcastle-Ottawa Scale. We will use random-effects meta-analysis for each exposure and outcome variable to calculate overall pooled estimates using the generic inverse variance method. This systematic review will follow the Preferred Reporting Items for Systematic reviews and Meta-Analyses guidelines. Ethical consideration The proposed systematic review and meta-analysis is based on published data; ethics approval is not required. The results will be presented at scientific meetings and publish in a peer-reviewed journal. PROSPERO registration CRD42022359017


Methods and analysis
We will include cohort, cross-sectional, and case-control studies in which a diagnosis of pregnancy and/or birth complication (preeclampsia, pregnancy loss, caesarean section, preterm birth, perineal laceration, neonatal intensive care unit admission, major obstetric haemorrhage, and birth injury/trauma) was reported and maternal mental disorders (depression, anxiety disorders, bipolar disorders, psychosis, and schizophrenia) after 12 months postpartum were the outcomes.A systematic search of PubMed, Embase, CINAHL, PsycINFO, and Web of Science will be conducted following a detailed search strategy until August 2022.Three authors will independently review titles and abstracts of all eligible studies, extract data using pre-defined standardised data extraction and assess the quality of each study using the Newcastle-Ottawa Scale.We will use randomeffects meta-analysis for each exposure and outcome variable to calculate overall pooled estimates using the generic inverse variance method.This systematic review will follow the Preferred Reporting Items for Systematic reviews and Meta-Analyses guidelines.

Ethical consideration
The proposed systematic review and meta-analysis is based on published data; ethics approval is not required.The results will be presented at scientific meetings and publish in a peer-reviewed journal.

Introduction
Pregnancy and childbirth complications are known to cause substantial morbidity and psychological distress in mothers 1,2 .Preterm birth, preeclampsia, preterm labour, prenatal haemorrhage, and gestational hypertension are among the significant pregnancy problems and results in maternal and neonatal morbidity and mortality 3,4 .According to the World Health Organization, in 15% of all pregnancies, a spectrum of pregnancy and birth complications may occur 5 .Every year more than one and a half million women suffer from pregnancy-related complications during pregnancy and birth 6 .Association between obstetric complications and chronic psychiatric and medical conditions in later life is becoming recognised 7 .It has been established that these complications can lead to the emergence of stress and trauma, both of which can affect a woman's mental state 8 .
Several studies have explored short-term maternal mental health problems following pregnancy and birth complications with a focus on maternal postpartum stress 9,10 .Pregnancy and birth are potential triggers for new psychiatric illness, particularly after unexpected events, caesarean sections, miscarriages and, perception of negative or traumatic birth 11 .Preterm birth is associated with an increased risk for depression, anxiety, and stress in the immediate postpartum period [12][13][14][15][16] .Other studies reported that spontaneous abortion and miscarriage during pregnancy puts women at higher risk for posttraumatic stress disorder (PTSD) and bipolar disorder at six to eight weeks postpartum 15,16 .Some studies suggested that having preeclampsia comorbidities resulted in the highest risk of psychiatric episodes 17,18 .A Nigerian study reported independent factors such as hospital admission, emergency caesarean section, and the poor maternal experience of control during childbirth to be associated with PTSD at six weeks postpartum 19 .Several systematic reviews and meta-analyses have also suggested that adverse pregnancy and birth outcomes such as preeclampsia, preterm birth, and mode of delivery were risk factors for postpartum mental disorders [20][21][22] .
Neiger et al. 2017, reported that these obstetrical problems continue to impact on maternal health years after the index pregnancy 23 .Postpartum stress and depression have frequently been investigated, and predictors that have been most associated are pre-existing psychiatric comorbidities, stress levels in pregnancy, and poor social support 11 .Only a small number of studies have reported on maternal mental outcomes after pregnancy and birth complications, and most are restricted to the first few months of life [24][25][26][27] .Two studies with an average of seven years of follow-up showed inconsistent findings; when compared to a control group, Gaugler-Senden et al. reported PTSD symptoms in women who experienced early preeclampsia but no difference in depression and anxiety.Whereas Postma et al. found that women with early preeclampsia reported higher depressive and anxiety symptoms 28,29 .
Despite the psychological implications of adverse pregnancy and birth complications, the plausibility of associations with long-term adverse maternal mental health outcomes is yet to be systematically evaluated in existing literature, highlighting the need for further study in this area.Examining the association between pregnancy and birth complications and mental outcomes beyond the immediate postpartum period is an essential contribution to obstetric care and public health.The findings of this review will provide an overview of the current state of knowledge regarding whether having a complicated pregnancy or birth is a separate risk factor for adverse maternal mental health outcomes beyond the first year following childbirth.Therefore, this systematic review aims to synthesize the available evidence assessing the association between pregnancy and childbirth complications and long-term adverse maternal mental health outcomes.

Review question
Do pregnancy and birth complications increase the risk of adverse maternal mental health outcomes after 12 months postpartum?

Methods
The following PICO requirements will guide this systematic review.

Population
Women who have had at least one pregnancy.

Exposures
We will consider any of the following pregnancy and birth complication as exposures of interest: preeclampsia, pregnancy loss (miscarriage, stillbirth, and spontaneous abortion), caesarean section (elective, and emergency), preterm birth (defined as birth <37 weeks gestation), third/fourth perineal laceration, neonatal intensive care unit (NICU) admission >72 hours, major obstetric haemorrhage, birth injury/trauma.It should be noted that some of these complications such as elective caesarean section maybe at the request of the pregnant women and therefore may not be considered a complication.We plan to have a separate meta-analysis for each complication as we explained later.

Amendments from Version 2
There are several changes to version 2 of our article.We acknowledge the additional limitations of our study.First, an important limitation in our study is the use of observational/ administrative data in measuring an increased risk of mental illnesses beyond 12 months postpartum.Second, we incorporated and highlighted other potential confounders that may be associated with postpartum mental health disorders including adverse life events, first parity, family's socioeconomic status, maternal age, body mass index (BMI), maternal smoking, alcohol, and substance use, preexisting mental health disorders, social support, maternal self-efficacy, co-morbidities/ longstanding illness, ethnicity, employment-related factors, poor current health, breastfeeding, and child's health problem.Third, we acknowledged that for some exposure-outcomes associations, a meta-analysis may not be feasible due to the small number of studies.In such instances, we will conduct a narrative synthesis and present results descriptively in a table.

Comparison
Women who never had corresponding pregnancy and birth complications.For instance, we will compare women who experienced an emergency caesarean section to those who never experienced an emergency caesarean section.

Outcomes
Any of the following adverse maternal mental health outcomes diagnosed or reported after the first year following childbirth will be considered an outcome of interest.

Protocol and registration
This study adheres to the guidelines in the Preferred Reporting Items for Systematic Reviews and Meta-Analysis Protocols (PRISMA-P) statement 30 .Under the guidelines, this systematic review protocol was registered with the International Prospective Register of Systematic Reviews (PROSPERO) on 11 September 2022 with registration number CRD42022359017.

Search strategy
1.One reviewer (E.O.B) will systematically search the literature in the following electronic databases: PubMed, CINAHL, EMBASE, PsycINFO and Web of Science, including all years from the inception of the electronic databases until August 2022.A detailed search strategy has been compiled and these terms will be searched according to the principles of Boolean Logic (AND, OR NOT) and using Medical Subject Headings (MeSH).The search strategy is included in the Extended data 31 .
2. The reference lists of the included studies will be manually searched to find additional potentially eligible research as a supplement to the electronic database searches.

Criteria for considering studies for the review Inclusion criteria
• Cohort, case-control, and cross-sectional studies in which a complication of pregnancy or childbirth was reported, and maternal mental health beyond the first year following childbirth is the outcome of interest.
• Data must be from an original study.If more than one study were based on the same dataset, the study with the longest follow-up period will be included.We may perform sensitivity analyses for different scenarios.Such analyses will be highlighted as post-hoc.
• A complication of pregnancy or childbirth and maternal mental health may be confirmed through medical records, doctor-diagnosed self-reporting, or validated questionnaires.
• We will include studies published in English only.
• Peer-reviewed literature only will be included.

Exclusion criteria
• Systematic reviews, case reports, case series, letters, commentaries, notes, editorials, conference abstracts and dissertations.
• Studies that are not published in English.
• Studies on women with a pre-existing mental illness or mental illnesses prior to 12 months postpartum.

Selection of studies for inclusion in the review
Titles and abstracts of studies retrieved from each database search will be stored and managed in the EndNote reference manager and de-duplicated.Three review authors (E.O.B, E.O and D.B) will independently review the titles and abstracts of the studies.Full texts will be obtained where necessary to screen for eligibility in the systematic review and meta-analysis following the pre-defined inclusion/exclusion criteria.Where consensus on eligibility cannot be achieved, a fourth review author (A.S.K) will be involved in the discussion to reach a consensus.In the case of an eligible study, where more data is needed, the corresponding author will be contacted via email.If the corresponding author does not reply, a reminder will be sent two weeks later.

Data extraction and management
Three reviewers (E.O.B, E.O, and D.B) will independently extract data from the eligible studies using a standardised data extraction form.We will extract data including the author and year of publication, study design, country and setting of study, sample size, definition or assessment of the exposures and outcome(s) of interest, comparison group, length of follow up, confounders adjusted for (if any), crude and adjusted estimates.Where necessary, we will contact corresponding authors of published studies to obtain relevant information about effect estimates.Discrepancies will be discussed between reviewers and where necessary, a fourth reviewer (A.S.K) will be consulted to achieve a consensus.

Quality appraisal of included studies
Quality assessment of the included studies will be conducted by three reviewers (E.O.B, E.O, and D.B) independently and agreed upon subsequently using the Newcastle Ottawa Scale 32 .This scale uses a "star system," in which stars are assigned to show the quality of studies based on the following three criteria: selection of the study groups, comparability of the groups, and the ascertainment of the exposure and outcome of interest (the total score ranged from 0-9).We will consider 0 to 3 stars low quality, 4 to 6 stars moderate quality, and 7 to 9 stars high quality.The overall likelihood of bias will be assessed and reported for each study.Discrepancies will be discussed between reviewers and where necessary, a fourth reviewer (A.S.K) will be consulted.

Data synthesis, including assessment of heterogeneity
We will undertake separate meta-analyses for each exposureoutcome association.Random effects meta-analyses will be performed to calculate overall pooled estimates where data allow.For example, for preeclampsia as an exposure of interest, a meta-analysis will be undertaken to investigate the association between (1) preeclampsia and anxiety disorders, (2) preeclampsia and bipolar disorders, (3) preeclampsia and schizophrenia.We will repeat this for all exposures.The generic inverse variance method will be used to display crude and adjusted results where possible.We will base the adjustment on the definition outlined in each identified study.We will also perform the following subgroup/sensitivity analyses where the data allow, using RevMan 5.4: 1) According to study design (cohort vs case-control vs cross-sectional).
2) According to the study quality (minimal/low versus moderate/high).
3) According to the measurement of outcome data (medical records versus doctor-diagnosed self-reported versus validated questionnaires).
4) According to the length of follow-up.
Some outcomes and exposures may report small number of studies and a meta-analysis may not be feasible.In such instance, we will conduct a narrative synthesis and present results descriptively in a table.Publication bias will be assessed using a funnel plot, provided at least 10 or more studies are included in the meta-analysis.Where any other subgroup/sensitivity analyses are identified in the metaanalysis, such as analyses to explore potential high heterogeneity, these will be clearly labelled as post-hoc analyses.

Presenting and reporting the results
A PRISMA flow diagram will be included to outline the step-by-step study selection process, and a rationale provided for excluded studies at full-text screening.The characteristics and quality assessment of the included studies will be presented in tables, and pooled estimates will be presented using forest plots.If raw data cannot be obtained for inclusion in meta-analyses, the findings will be included individually in a separate table.Where data is unsuitable for meta-analysis, study findings will be narratively synthesized and presented in tables.

Conclusions
This systematic review and meta-analysis will summarise the existing literature examining the association between pregnancy and birth complications and long-term adverse maternal mental outcomes based on a prespecified study protocol.
The high prevalence of pregnancy and birth complications suggests that any potential association would have important public health implications.

Potential strengths and limitations of this study
The strength of this systematic review and meta-analysis includes providing updated knowledge on the associations between common pregnancy and birth complications and the risk of adverse maternal mental health outcomes in the long term.The use of a comprehensive search strategy, a prospectively registered protocol, and adherence to the PRISMA guidelines are further strengths of this review.In addition, three reviewers will screen for study eligibility and perform data extraction and quality appraisal of included studies, minimising the likelihood of reviewer-based bias in the systematic review.
We acknowledge that there are limitations with this review.The use of administrative health data may not accurately reflect an increased risk for mental health disorders beyond 12 months postpartum.As a result, we also included papers that described mental health problems that were both self-reported and physician-diagnosed using validated questionnaires.We anticipate that publication bias may be a limitation in this review.If possible, a funnel plot will be used to assess the presence of publication bias.Some studies may report more than one complication as an exposure, where exposure cannot be determined, we will narratively synthesize results and provide summary of results in a table.Furthermore, the presence of confounding is a major concern in observational studies.Potential confounders that may be associated with postpartum mental health disorders include adverse life events, first parity, family's socio-economic status, maternal age, body mass index (BMI), maternal smoking, alcohol, and substance use, preexisting mental health disorders, social support, maternal self-efficacy, co-morbidities/longstanding illness, ethnicity, employment related factors, poor current health, breastfeeding, and child's health problem 33 .As mentioned above, our meta-analyses will display both crude and adjusted results where possible using the generic inverse variance method, basing adjustment on the definition outlined in each identified study.For specific exposure-outcomes association, there may not be enough studies to conduct a meta-analysis.

Extended data
Figshare: Search strategy-Pregnancy and birth complications and long-term adverse maternal mental outcomes: a systematic review and meta-analysis protocol, https://doi.org/10.6084/m9.figshare.21572304) 31porting guidelines Figshare: Preferred Reporting Items for Systematic review and Meta-analysis protocol (PRISMA-P) checklist and flow diagram.https://doi.org/10.6084/m9.figshare.21568716)30 Data are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).by pregnancy and childbirth complications, the systematic review has potential to contribute to improving preventive maternal mental health.
The major challenge in achieving the aim of the systematic review is identifying increased risk of mental health disorders 12 months after pregnancy and childbirth complications by reviewing observational studies that used medical records.Mental Health diagnoses identified through medical records do not reflect the exact onset of mental disorders for women with delayed help seeking and treatment.Thus, definitions of onset of mental health disorders identified through medical records will be arbitrary and can lead to inaccurate detection of mental health disorders 12 months after pregnancy and childbirth complications.Additionally, mental health diagnoses identified through administrative data such as health claims usually include a lag time.Lastly, studies based on using medical records will include a limitation of not knowing pre-existing mental health disorders, unless the studies retrospectively observe multiple years of data on mental health diagnoses prior to pregnancy.Please elaborate how you will handle the difficulties of identifying the increased risk of mental health disorders 12 months after pregnancy and childbirth complications, given these limitations of observational studies using medical records.
There are other factors (other than the confounders authors listed in the protocol) that are associated with postpartum mental health disorders.For example, maternal self-efficacy, support by the partner, breastfeeding, a negative experience of the first week postpartum, and poor current health of the mother have been identified as significant factors associated with developing postpartum depression and/or anxiety.Refer to the following reference: If there is not a sufficient number of studies published on each pregnancy and childbirth complication outcome, conducting meta-analysis for each outcome, adjusting for the confounding factors identified in the literature, is not feasible.Please elaborate how you will handle this.

Not applicable
Competing Interests: No competing interests were disclosed.
Reviewer Expertise: Mental health services research I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above.This article is a proposal for a systematic review of the published scientific literature on pregnancy and birth complications and their association with long-term mental health outcomes.The stated aim is to look at each specified pregnancy complication, and each mental health outcome, and examine what support there is from the published literature for any association.The protocol is generally well-written, and uses an appropriate methodology.The research question is important, and I support their comments that this is an area that is under-researched and not well understood.I have four questions/comments that may help the authors in making some minor revisions to their protocol.
It is always interesting to discuss what is a pregnancy and birth complication, and whether some of the very common sequela are really complications or should be considered to be within the sphere of 'normal' outcomes.The list given includes some devastating outcomes such as stillbirth, but also includes elective caesarean section (which for some women may not be considered a complication but the only rational option).Perineal tears can vary from minor to very severe with life-long consequences.Have you considered refining the list of complications to only include severe, unexpected maternal and/or perinatal outcomes of pregnancy and birth? 1.
Many women in the reported studies will have experienced more than one complication.For example, someone with pre-eclampsia, who has an emergency caesarean section, and whose baby is admitted to the NICU for 2 weeks.This begs the question as to which complication was causative, or is it the combination that counts?How will you be able to deal with this issue in your meta-analysis? 2.
The list of mental health conditions includes a number which are very common and for many women a diagnosis will predate the first pregnancy.Are you only interested in women with a new diagnosis and no pre-existing mental health conditions?

3.
A few minor points are that data is a plural noun, and birth is a better description than the 4.
term 'delivery'.Also, I found the opening paragraph a bit contradictory.If only 5-15% of women experience a complication, but some of those in the list to be studied are much more common than that, it sounds like the study population is potentially a very large proportion of the birthing population.Reviewer Expertise: Clinical academic practice in obstetrics/maternal-fetal medicine, with extensive research interests in severe complications of pregnancy (especially perinatal death), and post-partum recovery including physical and emotional outcomes.
I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above.

Reviewer Report 03 1 Reviewer
May 2023 https://doi.org/10.21956/hrbopenres.15021.r33663© 2023 Ellwood D. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.David Ellwood 1 School of Medicine and Dentistry, Gold Coast University Hospital, Griffith University, Gold Coast, Qld, Australia 2 Maternal-fetal Medicine, Gold Coast University Hospital, Gold Coast, Qld, Australia I am happy with the responses of the authors to my previous comments, and the resulting revisions to the manuscript and I have no further comments or questions.Is the rationale for, and objectives of, the study clearly described?Not applicableIs the study design appropriate for the research question?Not applicableAre sufficient details of the methods provided to allow replication by others?Not applicableAre the datasets clearly presented in a useable and accessible format?Not applicableCompeting Interests: No competing interests were disclosed.Reviewer Expertise: Clinical academic practice in obstetrics/maternal-fetal medicine, with extensive research interests in severe complications of pregnancy (especially perinatal death), and post-partum recovery including physical and emotional outcomes.I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard.VersionReport 31 January 2023 https://doi.org/10.21956/hrbopenres.14938.r33322© 2023 Ellwood D. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.David Ellwood 1 School of Medicine and Dentistry, Gold Coast University Hospital, Griffith University, Gold Coast, Qld, Australia 2 Maternal-fetal Medicine, Gold Coast University Hospital, Gold Coast, Qld, Australia Is the rationale for, and objectives of, the study clearly described?YesIs the study design appropriate for the research question?YesAre sufficient details of the methods provided to allow replication by others?PartlyAre the datasets clearly presented in a useable and accessible format?Not applicableCompeting Interests: No competing interests were disclosed.