Creating an evidence map of the safety profile of spironolactone across all clinical indications to establish whether it may be a safe treatment in female adolescent acne: a protocol for a scoping review

Abstract

Introduction

Spironolactone is a useful and effective acne treatment option for adult female patients. We aim to establish whether spironolactone could be a safe treatment for the management of acne in the female adolescent population as well. The objective of this scoping review is to provide an evidence map of the safety profile of spironolactone in the paediatric population aged 0–17 across all clinical indications.

Methods and analysis

This scoping review will be conducted according to the Joanna Briggs Institute scoping review protocol. Relevant publications will be searched on the MEDLINE, Embase and Web of Science databases from inception until July 2025. The authors of included studies will be contacted using contact details provided in the manuscript to check for any further published or unpublished data on the review question. An initial search will be conducted using keywords to identify relevant articles. After identifying the research strategy, articles will be extracted into a reference management tool, and a two-part study selection process will be systematically applied by two reviewers. The first part consists of screening titles and abstracts to define the eligibility of each article. In the second part, the full texts will be screened and only relevant articles will be kept. All articles related to the safety of spironolactone in children and adolescents across all clinical indications will be included. Data will be extracted using a scoping review management software such as Covidence, collated and charted to summarise all the relevant methods, outcomes and key findings in the articles.

Ethics and dissemination

This scoping review will provide an extensive overview of the available safety evidence for the use of spironolactone in children and teenagers. Since the scoping review methodology consists of reviewing and collecting data from publicly available materials, this study does not require ethics approval. The results will be disseminated in a peer-reviewed publication.

STRENGTHS AND LIMITATIONS OF THIS STUDY.

• Our scoping review will conform to the rigorous methodology set out by the Joanna Briggs Institute.

• We acknowledge the limitation that comes with the nature of a scoping review and narrowing down the research questions to very specific inclusion criteria, in turn, reducing the number of included articles.

• The identification and synthesis of data will be limited to published articles found on the MEDLINE, Embase and Web of Science databases and snowball references.

• Studies will be limited to those published in the English language or those able to be translated into English using artificial intelligence software, for practical purposes.

Introduction

Acne vulgaris is one of the most common inflammatory dermatosis worldwide and can cause significant physical morbidity, resulting in permanent scarring.¹ Psychological sequelae are common, with one UK survey reporting that 54% of people who have ever had acne say it impacted their self-confidence.² In some cases, the psychological burden for those living with acne has been identified as a contributing factor to those who have died by suicide.³ According to the National Health Service (NHS) website, around 95% of the population between the ages of 11 and 30 years are affected by acne to some degree.⁴ Acne is most common in female adolescents of the age range 14–17.⁵

Current National Institute for Health and Care Excellence (NICE) guidelines for the treatment of acne recommend a stepwise treatment approach starting with topical treatment, escalating to oral antibiotics and finally isotretinoin, an oral vitamin A derivative.⁶ Some of the reported challenges with the current treatment options for acne include the following:

• Daily application of topical acne treatments may not be sufficiently effective. Topical treatments may cause side effects such as skin irritation, photosensitivity and bleaching of hair and fabrics.^{6 7}

• Oral antibiotics such as lymecycline, doxycycline and trimethoprim may cause unwanted side effects, such as gastrointestinal upset, leading to poor treatment adherence. Additionally, increased use can lead to antibiotic resistance, reducing their effectiveness against other infections.^{8 9}

• Isotretinoin is licensed only for severe acne at risk of scarring, meaning that some people do not qualify for this medication and are prescribed recurrent courses of antibiotics.⁶

• Isotretinoin can be harmful to a developing fetus, so there are strict guidelines around its use in females of childbearing potential.⁶

• There have been reports of psychological and psychosexual side effects with isotretinoin, which may particularly concern adolescent patients and/or their parents. Other potential side effects (eg, photosensitivity, myalgia) may make isotretinoin unacceptable as a choice for some.^{6 10}

• New sebaceous glands are continuing to develop during puberty; therefore, sebum production can increase again after a course of isotretinoin, leading to the recurrence of acne.¹¹

Spironolactone has been found to have a useful role in the treatment of adult female acne, as an alternative to both antibiotics and isotretinoin. It blocks the effects of some hormones on the skin (including testosterone) that would otherwise increase sebum production and contribute to acne.¹² Spironolactone was recently studied in a trial of 410 women and was shown to be safe and effective for the treatment of acne.¹³ An improvement in acne was seen after 12 weeks, with further improvement at 24 weeks. It is generally avoided in males as it can increase breast tissue development, lead to sexual dysfunction and decrease libido.^{14 15}

Spironolactone has been used safely in children since the 1960s as part of combination diuretic regimens used in the management of paediatric cardiac and pulmonary disease, including ventricular septal defect, atrial septal defect, hypoplastic heart syndrome, transposition of the great arteries, tetralogy of Fallot, cardiomyopathy, pulmonary stenosis, pulmonary hypertension, Ebstein’s anomaly, nephrotic syndrome, pulmonary oedema and portal hypertension to name but a few.¹⁶ It has, to date, only been used in small numbers for acne and is not licensed for this indication.¹⁷ Small studies of children treated for acne have shown it to be safe and effective, but there are no randomised controlled trials available.

Severe hyperkalaemia with spironolactone has not been frequently reported in children, despite it being a well-recognised concern.¹⁶ In one observational study, the most common adverse effects with spironolactone use in children were alterations in serum potassium concentrations, resulting from the combined effects of spironolactone with other diuretics, aspirin or angiotensin-converting enzyme inhibitors.¹⁶ While hyperkalaemia was more common initially, hypokalaemia was a more significant problem with long-term diuretic use.¹⁶ The European Medicines Agency lists the following as contraindications to spironolactone therapy: acute renal insufficiency, significant renal compromise (estimated glomerular filtration rate (eGFR) <30 mL/min), anuria, Addison’s disease and hyperkalaemia (>5.5 mEq/L).¹⁸

Acne is not only a burden for individuals affected, but also creates a significant workload for the NHS, with 3.5 million primary care visits reportedly related to acne.¹⁹ Robust assessment of the cost savings related to using oral spironolactone as a treatment for acne in this age group depends on where in the treatment algorithm it would sit (before oral antibiotics or before isotretinoin) and the healthcare setting in which it is used (primary or secondary care).

In summary, acne is common, and its effects can be severe. Current treatment options are not always effective and have side effects or contraindications that may limit their use. Spironolactone could be a safe and effective treatment option for acne management in adolescent females.

Methods and analysis

Patient and public involvement

Members of the research team attended a UK Dermatology Clinical Trials Network patient involvement focus group in June 2024, consisting of a range of patients with skin conditions, some of whom have had experience managing acne. These discussions aided us in the development of the research question and outcome measures. Patients were consulted on the acceptability and feasibility of the intervention.

Searches

An electronic search of online databases (MEDLINE, Embase and Web of Science) will be performed from inception until July 2025. The search strategy is built around three key terms: ‘spironolactone’, ‘paediatric’ and ‘safety’ and uses subject headings and free text words. The search will include synonyms of these terms. The search strategy is inclusive of all languages, but studies will only be able to be included if local or artificial intelligence translation to English is available. The reference lists of included studies will be hand-searched. The authors of included studies will be contacted using contact details provided in the manuscript to check for any further published or unpublished data on the review question. A grey literature search will be undertaken of published online abstracts presented at the British Association of Dermatology annual scientific meeting, American Academy of Dermatology annual scientific meeting, European Academy of Dermatology and Venerology biannual Scientific meeting, European Academy of Paediatrics annual scientific meeting, American Academy of Pediatrics annual scientific meeting and Royal College of Paediatrics and Child Health annual conference. National regulatory authorities’ (Medicines and Healthcare products Regulatory Agency (MHRA), U.S. Food and Drug Administration (FDA), etc) data on spironolactone, yellow card reporting and spironolactone manufacturers' pharmacovigilance data will be requested if available.

Draft search strategy

(Aldactone OR spironolactone) AND (paediatric OR pediatric OR child OR adolescent OR infant OR newborn OR neonate OR young adult) AND (side effect OR adverse effect OR adverse reaction OR adverse drug reaction OR safety OR safety profile).

Types of studies to be included

Experimental and epidemiological study designs including randomised controlled trials, cohort, case–control, cross-sectional and case series.

Condition or domain being studied

The domain being studied is the safety profile (adverse effect profile, toxicity profile, tolerability, etc) of spironolactone in the paediatric population (children aged 0–17 years old) across all clinical indications. There is very limited data on the safety of spironolactone specifically in the female adolescent population for acne, which necessitates expansion of the search to include all clinical indications. We will also aim to describe dosing regimens of spironolactone in the paediatric population for different indications.

Participants or population

• Children aged 0–17 years old.

• All geographical areas.

• Both hospital and community settings.

Intervention(s), exposure(s)

To assess the safety profile of spironolactone in the paediatric population across all clinical indications in order to establish whether spironolactone could be used safely as a treatment option for acne in adolescent females.

Comparator(s)/control

None.

Primary outcome

To assess the safety of spironolactone as a treatment option for acne in the adolescent female population by extrapolating data on the incidence and severity of adverse events with spironolactone in the paediatric population across all clinical indications. We will list the frequency of adverse effects and use the Hartwig Scale to assess the severity of an adverse drug reaction.

Secondary outcome

To describe dosing regimens of spironolactone in the paediatric population for different indications.

To collect data on the tolerability of spironolactone in the paediatric population.

To assess the safety, tolerability and clinical efficacy of spironolactone in the management of acne in the female adolescent population.

Risk of bias

Joanna Briggs Institute critical appraisal tools will be used to assess the quality and the risk of bias in the case–control, cohort, cross-sectional and case series studies chosen for the review. The Cochrane Risk of Bias tool will be used to assess risk of bias in randomised controlled trials.

Inclusion/exclusion criteria

Inclusion

• Studies which include children aged 0–17 years old.

• Taking spironolactone for any clinical indication, either as monotherapy or in combination with other medications.

Exclusion

• Studies which include combined data on children and adults using spironolactone, unless the data can be separated.

• Studies that have no English language translation available.

Study selection

Two authors will independently screen all abstracts and titles. If either author considers an article relevant for inclusion, then the full-text paper will be requested. Two authors will independently check the eligibility of all full-text papers. Any disagreements will be solved by consensus or by the decision of a third reviewer.

Data extraction

Two authors will independently chart the data; discrepancies between entries will be checked against the original manuscript. Where possible, studies not reported in English will be checked for eligibility and data extracted using AI translation technology. Any further information required will be requested from the original author by written correspondence.

The data will be charted using scoping review management software such as Covidence as follows:

1. Author(s).

2. Year of publication.

3. Origin/country of origin (where the source was published or conducted).

4. Aims/purpose.

5. Population demographics and sample size within the source of evidence (if applicable).

6. Methodology/methods.

7. Intervention type, comparator and intervention details (eg, duration of the intervention) (if applicable).

8. Outcomes and outcome details (eg, how measured) (if applicable).

9. Key findings that relate to the scoping review question, including indication of spironolactone use, comorbidities, side effects identified and dose/duration of spironolactone use.

Data extraction is an iterative process, with any modifications identified and reported in the final scoping review.

Data synthesis

Selected articles will be analysed, identifying characteristics of the studies and extracting results. Data will be presented in narrative form and mapped using charting, including tables. The focus of this scoping review is on the breadth of evidence, not on synthesising the findings of individual studies to draw conclusions. Therefore, assessing the quality of each study is not a goal of this review.

Analysis of subgroups

Subgroup analysis will be conducted if sufficient data are available to explore heterogeneity of the studies. Subgroups may include spironolactone indication and dosing. Data on adverse effect profile/side effects in the paediatric population with polypharmacy, which cannot be directly attributable to spironolactone, may under-report adverse effects. We will consider these as ‘possible’ side effects.

Ethics and dissemination

The results of this scoping review will be disseminated in a peer-reviewed medical journal. Since the scoping review methodology consists of reviewing and collecting data from publicly available materials, this study does not require ethics approval.