Keywords
Pregnancy, preeclampsia, gestational hypertension, retinal disease, ophthalmic disease
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Barrett P, Carey C, Ding Wu A et al. Hypertensive disorders of pregnancy and the long-term risk of maternal retinal disease: a systematic review protocol [version 1; peer review: awaiting peer review]. HRB Open Res 2025, 8:5 (https://doi.org/10.12688/hrbopenres.14003.1)
NOTE: If applicable, it is important to ensure the information in square brackets after the title is included in all citations of this article.
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Study Protocol
Hypertensive disorders of pregnancy and the long-term risk of maternal retinal disease: a systematic review protocol
[version 1; peer review: awaiting peer review]
PUBLISHED 17 Jan 2025
OPEN PEER REVIEW
REVIEWER STATUS
This article is included in the Maternal and Child Health collection.
Abstract
Corresponding author:
Peter Barrett
Competing interests:
No competing interests were disclosed.
Grant information:
Health Research Board [CSF-2023-006].
The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Copyright:
© 2025 Barrett P et al.
This is an open access article 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.
How to cite: Barrett P, Carey C, Ding Wu A et al. Hypertensive disorders of pregnancy and the long-term risk of maternal retinal disease: a systematic review protocol [version 1; peer review: awaiting peer review]. HRB Open Res 2025, 8:5 (https://doi.org/10.12688/hrbopenres.14003.1)
First published: 17 Jan 2025, 8:5 (https://doi.org/10.12688/hrbopenres.14003.1)
Latest published: 17 Jan 2025, 8:5 (https://doi.org/10.12688/hrbopenres.14003.1)
The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Introduction
Hypertensive disorders of pregnancy (HDP), such as preeclampsia and gestational hypertension, have been strongly linked with maternal vascular disease in later life. Preeclampsia is now established as an independent risk-enhancing factor for cardiovascular disease and renal disease1,2, and it has also been linked to increased risk of maternal stroke, peripheral vascular disease, and vascular dementia1,3,4. Similarly, gestational hypertension is associated with an increased risk of adverse cardiometabolic outcomes in affected women in later life5.
There is comparatively little known about the association between HDP and maternal retinal disease. The retinal circulation is unique compared to other vascular beds in the human body in that it does not have autonomic innervation and is particularly susceptible to changes in blood pressure. Preeclampsia has been associated with long-term risk of microvascular dysfunction6 and thus, it is biologically plausible that HDP may lead to increased risk of retinal vascular disease. However, the evidence for this association remains uncertain at present.
Previous studies have linked HDP to changes in retinal arterial and venular caliber at one year and six years postpartum respectively7,8, but it is unclear whether this leads to more permanent microvascular dysfunction. Retinal vascular disease may manifest as a range of different disorders in later life including retinal vein occlusion, hypertensive retinopathy, and diabetic retinopathy. It is uncertain whether HDP differentially impact on the risk of these disease subtypes, some of which can lead to irreversible vision loss. Furthermore, while chronic hypertension is a recognised risk factor for a range of non-retinal ophthalmic diseases9 it is unclear whether transient, self-resolving HDP may be independently associated with more permanent ophthalmic damage.
Increasingly, HDP are recognised as providing a potential opportunity for sex-specific vascular disease prevention10. Globally, most cases of vision loss are preventable11, but the prevention of long-term retinal and other ophthalmic diseases may only be achieved if underlying risk factors are more fully understood, including the potential role that pregnancy-related complications may play.
Methods
PECO
Population
Women who have had at least one pregnancy
Exposures
Diagnosis of any HDP, such as preeclampsia (including eclampsia or haemolysis, elevated liver enzymes and low platelets syndrome, HELLP), gestational hypertension, or other. These can be defined either using established clinical criteria, hospital records, diagnostic codes, or self-reporting of a doctor diagnosis.
Comparison
Parous women who never had a corresponding HDP. For example, women who experienced preeclampsia in at least one pregnancy will be compared with parous women who never experienced preeclampsia.
Outcome
Primary outcome: We will include maternal retinal disease (undifferentiated) diagnosed at least six months after a pregnancy complicated by HDP. Subtypes of maternal retinal disease will be explored separately where possible: hypertensive retinopathy, diabetic retinopathy, retinal detachment and/or tears, retinal vein occlusion, retinal artery occlusion, macular oedema and associated maculopathies. We will include any diagnoses based on medical reports, objective clinical codes, and clinical tests or self-reporting.
Secondary outcomes: The secondary outcome will be any maternal ophthalmic disease (undifferentiated). Subtypes of anterior and posterior ophthalmic disease will be explored separately where possible: choroidal disease, macular degeneration, cataract and other causes of visual impairment and/or loss.
Protocol and registration
This study protocol adheres to the guidelines in the Preferred Reporting Items for Systematic Reviews and Meta-Analysis Protocols (PRISMA-P) statement12. This systematic review protocol was registered with the International Prospective Register of Systematic Reviews (PROSPERO) on 22 September 2024 with registration number CRD42024589508 If any important protocol amendments arise, these will be made promptly to the PROSPERO record.
Search strategy
Two reviewers (PB, CC) will systematically search the literature in the following electronic databases: PubMed, EMBASE, Web of Science, and the Cochrane Library, from inception of the databases until 30 September 2024 (Table 1). A detailed search strategy has been compiled and these terms will be searched according to the principles of Boolean Logic (AND, OR, NOT). Supplementary searches of the grey literature will be conducted using keyword searches in the Bielefeld Academic Search Engine (BASE), Trip Database, and medRxiv. The reference lists of all included studies will be manually searched to find additional potentially eligible research as a supplement to the electronic database searches.
Table 1. Search Strategy.
Criteria for considering studies for the review
Inclusion criteria
Original cross-sectional, case-control and cohort studies (retrospective and prospective), case series, and existing systematic reviews and meta-analyses.
If more than one study were based on the same dataset, the study with the longest follow-up period will be included.
Studies may be published in any language without restriction
Exclusion criteria
Studies where the retinal/ophthalmic disease is only measured during pregnancy, or less than 6 months postpartum
Studies where there was pre-existing ocular disease prior to pregnancy
Studies where the focus is on retinal or ocular disease in the offspring (not the mothers)
Non-human studies
Individual case reports
Selection of studies for inclusion in the review
We will store all titles and abstracts from each database search in EndNote reference manager, and two review authors will independently review them. Full texts will be obtained to screen for eligibility in the systematic review if required. Pre-defined inclusion/exclusion criteria will be applied. Online translation software will be used to screen non-English articles for eligibility (e.g. Google translate) if necessary. If a situation arises whereby consensus on eligibility cannot be achieved, a third review author will be involved in the decision.
Data extraction and management
Data will be extracted from eligible studies using standardised data collection forms by two review authors independently, including the author and year of publication, study design, country and setting, definition of exposure and outcome used, sample size, follow-up time, confounders adjusted for (if any) as well as crude and adjusted effect estimates. Corresponding authors of published studies will be contacted, if required, to obtain further information relating to effect estimates. If any discrepancies arise, these will be resolved by a third reviewer.
Methodological quality appraisal of included studies
Two reviewers will independently assess the methodological quality of all included studies, using an adapted version of the validated Newcastle-Ottawa Quality Assessment Form. An adapted version of each form will be used depending on the study design, with eight distinct topics spanning selection of study groups; comparability of the groups; ascertainment of exposure/outcome of interest (total score ranges from 0 to 9). These topics will be addressed for all cross-sectional, case-control, and cohort studies. We will consider a total score 0 to 3 to be low quality, total score 4 to 6 to be moderate quality, total score 7 to 9 to be high quality. Discrepancies will be discussed between reviewers and where necessary, a third reviewer will be consulted.
Data synthesis, including assessment of heterogeneity
If the data allow, a pooled estimate of the relationship between HDP and retinal disease will be calculated in the meta-analysis. Both crude and adjusted measures of association will be presented, where adjustment is based on the definition outlined in each of the individual studies. Each study's effect estimates will be weighted accordingly by use of the inverse-variance method. Random-effects models will be used to combine the results of different studies.
For the potential cohort studies included in this review, we expect the incidence of maternal retinal or other ophthalmic disease to be relatively low (affecting <5% of participants), and thus we will apply the rare disease assumption that key measures of effect (odds ratios, risk ratios and, by extension, hazard ratios) may be considered as approximations of each other, and thus grouped together for analysis. However, if we identify studies with longer follow-up periods (and higher incidence of maternal retinal disease), this assumption will not be applied, and we will group analyses by effect measure.
A forest plot will be used to present the findings of any meta-analysis. Study heterogeneity will be explored based on χ2 statistics and I² values. For the former, heterogeneity will be deemed present if the p-value < 0.1, and the latter will be used to quantify the extent of heterogeneity present.
If a meta-analysis includes a minimum of ten studies, a funnel plot will assess the potential issue of publication bias. Firstly, visual inspection will assess asymmetry (performed on RevMan v5.4). Subsequently, an Egger’s test may be used to test for significance wherein a p-value <0.05 is indicative of publication bias. To quantify the magnitude, and attempt to correct this potential publication bias, Duval and Tweedie’s trim and fill method will be used if necessary.
We will perform the following subgroup analyses where the data allow, using RevMan 5.4:
Subgroup analysis of the association between different subsets of HDP (e.g. preeclampsia, gestational hypertension) and maternal retinopathy (e.g. hypertensive retinopathy, diabetic retinopathy) respectively
Subgroup analysis of any HDP and retinal vs non-retinal disease
Subgroup analysis according to the extent of confounding present (unadjusted vs. adjusted risk ratios) and based on the presence of a minimal suite of confounding factors including: age, chronic hypertension, ethnicity, smoking and diabetes.
We will also aim to perform the following subgroup/sensitivity analyses where the data allow: by ethnicity; length of follow-up following index pregnancy; measurement of exposure and outcome data (self-reported vs medical records vs laboratory measurements); study quality (low vs moderate vs high); study design (case-control vs. cohort).
If other relevant subgroup analyses are identified throughout this review and meta-analysis, they will be clearly assigned to 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 will be provided for excluding studies at full-text screening. The characteristics and quality assessment of all included studies will be presented in tables, and pooled estimates will be presented using forest plots. Where data is unsuitable to conduct meta-analysis, study findings will be narratively synthesized and presented in tabular format, and we will adhere to the Synthesis without meta-analysis (SWiM) reporting guideline13
Potential strengths and limitations of this study
This study will summarise and clarify existing knowledge on the associations between HDP and the risk of maternal retinal disease in the long term. Strengths of this study include the use of a comprehensive search strategy and adherence to international reporting guidelines. There will be up to three reviewers involved in screening studies for eligibility, and undertaking data extraction and quality appraisal. These measures will reduce any potential for individual reviewer-based bias in the systematic review.
We acknowledge that there will be some limitations with this review. The use of administrative hospital records may not accurately reflect the true prevalence of HDP or retinal disorders in a population, since some of these issues may be managed in primary care or community settings. Thus, we will include papers that describe HDP and ophthalmic disorders based on self-reported diagnosis, clinical measurement, or diagnostic coding. While this may allow us to provide a more comprehensive summary of the existing literature, it may also introduce heterogeneity to the results. We will consider overall findings in the context of any inherent clinical and methodological diversity between studies, and can do sensitivity analyses if appropriate.
The presence of confounding is a concern in any observational studies and may introduce further heterogeneity between studies. Potential confounders that may be associated with HDP and maternal retinal disease include maternal age, ethnicity, smoking, diabetes and other comorbidities. We will present crude and adjusted pooled odds ratios separately, where adjustment is initially based on the definition outlined in each identified study. Where possible, we will also present adjusted odds ratios which have been controlled for a minimal suite of key confounders (e.g. age, ethnicity, smoking, chronic hypertension, diabetes) to improve comparability of results and to reduce heterogeneity.
For specific exposure-outcome associations, there may not be enough studies to conduct meta-analysis. However, the use of international reporting guidelines will ensure that results are presented in a transparent, accurate, and complete manner. If meta-analysis is feasible, publication bias may remain a limitation. Where possible, funnel plots and statistical tests will be used to evaluate the presence of publication bias.
Conclusions
This systematic review and meta-analysis will summarise the existing literature examining the association between HDP and maternal retinal disease and other long-term ophthalmic outcomes based on a prespecified study protocol. Given the high prevalence of HDP, and the potentially devastating personal consequences of visual impairment for affected individuals and their families, any possible associations may have important implications for preventive efforts.
Ethics and dissemination
This protocol is for a systematic review based on published data, and thus there is no requirement for ethics approval. The results will be disseminated through publication in a peer reviewed journal, and through presentations at conferences aimed at both academic and lay audiences.
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Barrett P, Carey C, Ding Wu A et al. Hypertensive disorders of pregnancy and the long-term risk of maternal retinal disease: a systematic review protocol [version 1; peer review: awaiting peer review]. HRB Open Res 2025, 8:5 (https://doi.org/10.12688/hrbopenres.14003.1)
NOTE: If applicable, it is important to ensure the information in square brackets after the title is included in all citations of this article.
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