Supplemental Screening With MRI in Women With Dense Breasts: The European Perspective

Abstract

Breast cancer is the most prevalent cancer in women in Europe, and while all European countries have some form of screening for breast cancer, disparities in organization and implementation exist. Breast density is a well-established risk factor for breast cancer; however, most countries in Europe do not have recommendations in place for notification of breast density or additional supplementary imaging for women with dense breasts. Various supplemental screening modalities have been investigated in Europe, and when comparing modalities, MRI has been shown to be superior in cancer detection rate and in detecting small invasive disease that may impact long-term survival, as demonstrated in the Dense Tissue and Early Breast Neoplasm Screening (DENSE) trial in the Netherlands. Based on convincing evidence, the European Society of Breast Imaging issued recommendations that women with category D density undergo breast MRI from ages 50 to 70 years at least every 4 years and preferably every 2 to 3 years. However, currently no countries in Europe routinely offer women with BI-RADS category D density breasts MRI as supplemental imaging. The reasons for lack of implementation of MRI screening are multifactorial. Concerns regarding increased recalls have been cited, as have cost and lack of resources. However, studies have demonstrated breast MRI in women with BI-RADS category D density breasts to be cost-effective compared with the current breast cancer screening standard of biannual mammography. Furthermore, abbreviated MRI protocols could facilitate more widespread use of affordable MRI screening. Women’s perception on breast density notification and supplemental imaging is key to successful implementation.

breast cancer, breast density, MRI, screening

Key Messages

• The sensitivity of mammography is reduced in women with dense breasts. Supplemental screening is variable across Europe, with limited breast density notification.

• Supplemental MRI improves early diagnosis of breast cancer and is superior to other modalities in detecting small invasive disease that may impact long-term survival.

• Barriers to implementation of supplemental MRI in Europe include cost and availability; however, cost-effectiveness analyses for MRI are favorable, and abbreviated protocols may improve this further.

Introduction

Breast cancer is the most prevalent cancer in women in Europe and ranks as the third leading cause of cancer-related deaths in Europe.¹ All European countries have some form of screening for breast cancer, with mammography as the screening test employed. However, disparities exist in terms of the extent to which screening programs are organized, the coexistence with opportunistic screening activity, and the attendance to screening.^2,3 In most countries, women are invited for screening between 50 and 69 years of age, with some countries expanding screening to a range of 45 to 74 years.⁴ The interval between screening rounds is 2 years for most countries, with a 3-year screening interval in Malta and the UK. There is wide variation in breast cancer screening uptake rates across the European Union (EU). Data from 2021 indicate that screening rates were <40.0 % in 6 EU Member States, with a low of 20.6 % in Bulgaria (2017 data). At the other end of the range, Denmark and Finland reported very high uptake rates for screening, peaking at 83.0% in Denmark, while Sweden, Malta, and Slovenia had rates within the range of 77.2% to 80.0 %.⁵

While most countries also implement some form of high-risk screening, usually for genetic mutation carriers such as individuals with BRCA or those with a strong family history, there are currently very few countries in Europe that offer supplemental imaging for women with dense breasts (Table 1). Approximately 40% of women >40 years of age have Breast Imaging Reporting and Data System (BI-RADS) category C and D density in Europe, reducing the effectiveness of mammography and increasing the risk of developing breast cancer.^6,7 Women with BI-RADS category D density are 4 to 6 times more likely to develop breast cancer than women with BI-RADS category A density breasts and about twice as likely as those with BI-RADS category B and C density breasts.^8,9 In addition, the cancers that are found in women with denser breasts are larger, of higher stage, and more likely to be lymph node positive.^10,11 Sensitivity of screening mammography is also significantly reduced in women with BI-RADS category D density breasts (51.3%) compared with women with BI-RADS category A density (75%) (Figure 1, A-D).⁶ As a result, women with dense breasts are at higher risk of interval cancers—up to 17 times more likely when comparing BI-RADS categories D and A.^8,12 Interval cancers are larger and more aggressive than screen-detected cancers, tend to present at a later stage, and are associated with a poorer prognosis.¹³ The European Breast Cancer Screening Network reported that interval cancers represented 28% of cancers detected in the screening program of 6 European countries. Interval cancers are an important measure of the success of a screening program and are a surrogate measure of mortality benefit. When introducing changes to a screening system, the size and biological attributes of cancers detected and found in the rounds between screens need to be assessed so that modeling of mortality benefit can be made. In Europe, many countries are able to monitor interval cancers from cancer registries.

Table 1.

Comparison of European Countries Current Average/Population Risk Screening Programs, Notification of Breast Density, and Guidance for Supplemental Imaging in Dense Breasts

Country	Screening ages, y	Screening interval	Is breast density recorded in mammogram reports?	Do screening guidelines recommend supplemental imaging in dense breasts?
Austria	45-69	Biannual	Yes	Yes—US is recommended
Belgium	50-69	Biannual	No	No
Denmark	50-69	Biannual	No	No
France	50-74	Biannual	Yes	Yes—US is recommended
Germany	50-69	Biannual	No	No
Hungary	45-65	Biannual	Yes	Yes—US is recommended
Iceland	40-69	Biannual	No	No
Republic of Ireland	50-69	Biannual	No	No
The Netherlands	50-75	Biannual	No	No
Norway	50-69	Biannual	No	No
Portugal	50-69	Biannual	No	No
Spain	50-69	Biannual	No	No
Sweden	40-74	18-24 mo	No	No
Switzerland	50-74	Biannual	No	No
UK	50-69	Triennial	No	No

Figure 1.

Fifty-one-year-old woman, asymptomatic. A: Mediolateral and craniocaudal views of both breasts demonstrating dense breast tissue—BI-RADS C, with no mammographic abnormality. B-D: T1 fat-saturated postcontrast MRI, subtracted T1 fat-saturated postcontrast MRI and maximum-intensity projection, respectively, demonstrating 15-mm enhancing lesion in the posterior central lower left breast (lower arrow) with additional anterior lesions measuring up to 8 mm (higher arrow). Second-look US and biopsy confirmation of grade 3 triple-negative cancer.

The aim of this article is to review the evidence behind supplemental imaging with MRI for women with dense breasts, examine the current status of density notification and supplemental screening guidelines in European countries, and consider the factors affecting implementation of supplemental MRI in Europe.

Current European guidance on breast density notification and supplemental imaging for women with dense breasts

Europe has lagged behind the United States in terms of legislation for notification of women with dense breasts. Many countries in Europe have not explicitly stated that breast density should be recorded or that women should be informed of their breast density. This is due to several factors, including the heterogeneity of screening programs that exists in Europe and the doubt as to the value of informing women that they are at higher risk of breast cancer without offering any solution. The UK government released an advisory in 2023, stating that breast density is not assessed or recorded as part of the UK screening program, and they await further evidence for benefit and resource implication for collecting such information.¹⁴

As a result, most countries do not have recommendations in place for offering supplementary imaging for women with dense breasts. The purpose of adding supplemental screening to mammography is to detect cancers earlier, resulting in a shift to earlier-stage cancers, fewer interval cancers, fewer cancers having delayed detection in a subsequent screening round, and potentially reduced mortality from breast cancer. The major concern with introducing supplemental imaging for women with dense breasts has been the lack of definitive evidence of benefit or cost-effectiveness. An additional worry is that the risks of supplemental imaging, including more benign biopsies, increased cost, and patient anxiety, may outweigh the benefit. The key question with additional imaging is whether it improves health outcomes regardless of increased rates of cancer detection.

Evidence for supplemental imaging in women with dense breasts

Various supplemental screening modalities have been investigated in Europe, including digital breast tomosynthesis (DBT), US, contrast-enhanced mammography, and MRI. Although several studies have shown an improvement in cancer detection with DBT, there is limited evidence that DBT reduces interval cancer rates, and there is no evidence that DBT demonstrates any additional benefit in women with dense breasts.^15,16 A large German multicenter screening trial using DBT found a 2.3 per 1000 incremental cancer detection rate (CDR) compared with mammography, which was 2.7 per 1000 in women with BI-RADS category C and D density. However, these figures are considerably lower than the CDR for MRI, with a similar proportion of recalls.¹⁷ Recall rates from DBT varied from 2.1% in BI-RADS category A density women to 7.7% in category D density women, which is comparable to the 9.4% recall rates in category D density in the Dense Tissue and Early Breast Neoplasm Screening (DENSE) trial and substantially higher than the recall rates in the second round of the DENSE trial (3.2%).^18,19

Supplemental screening with handheld US is used in some European countries for women with dense breasts, including Austria, where it is performed for women with BI-RADS C and D density. This is largely due to the proven increase in CDRs and ease of use.²⁰ Handheld US increases the detection of small node-negative breast cancers in women with dense breasts, with an incremental cancer detection of 2.7 out of 1000 screenings.²¹ However, despite its use across Europe, there are several downsides with handheld US, including time to perform the examination, high recall rates, and false-positive results.²² While automated breast US (ABUS) may overcome some of the issues with handheld US and has been shown to be cost-effective in women with dense breasts, interpretation time is high, and second-look handheld US is still required for indeterminate findings.^23,24

Contrast-enhanced mammography (CEM) has been shown to be superior to mammography in women with dense breasts with similar sensitivity to MRI.^25,26 However, CEM has been predominantly used in the diagnostic setting, with more limited studies on its use in screening.²⁷ Most of the screening studies to date have been retrospective,²⁸ demonstrating similar overall CDRs to MRI (15.5/1000 women in Sung et al’s study).²⁹ More recently, larger prospective studies are emerging with promising supplemental CDRs.³⁰ Contrast-enhanced mammography has the benefit over MRI in being is less expensive, more accessible, and potentially better tolerated by patients.³¹ However, there are concerns in an asymptomatic screening population about the relative safety regarding risks of contrast reactions using iodine-based contrast media compared with MRI. In a systematic review of 84 articles, Zanardo et al reported that the pooled reaction rate to CEM was 0.82%, ranging from mild to fatal hypersensitivity reactions. In comparison, MRI reaction rates are reported to be much lower at approximately 0.15%, with fatal reactions being extremely rare.^32,33 Safety concerns have been previously raised regarding evidence that gadolinium-based contrast agents used in MRI are retained and deposited in tissues; however, to date there is no evidence of clinical symptoms nor harm associated with gadolinium deposition in the brain and body.³⁴

Molecular breast imaging uses a radiopharmaceutical 99mTc-sestamibi to detect breast tumors resulting from increased mitochondrial density and increased blood flow. It has demonstrated an incremental CDR of 8.8 per 1000 examinations on the first MBI screening, with favorable false-positive rates; however, disadvantages for its implementation in screening include an examination time of up to 40 minutes, the need for medical licensing, and higher whole-body radiation exposure than for other supplemental screening options.³⁵ Dedicated breast CT systems have also been recently introduced in the market, and the 2 commercially available systems are the cone-beam breast CT and spiral breast CT using photon-counting detectors. While limited studies on small numbers of women have been undertaken, they may show potential as a screening tool especially in women who cannot undergo mammography due to compression.³⁶

Evidence for MRI in women with dense breasts

MRI has long been known to be the most sensitive tool breast radiologists have for breast cancer detection. MRI is recommended in most European countries for supplemental annual screening in women who are at high risk of breast cancer, usually due to genetic mutations such as BRCA1 and 2.³⁷ It has also shown impact in average risk women or in those with a personal history of breast cancer (incremental CDR 15.5/1000 screenings).³⁸ More recently, in women with dense breasts, the Dutch demonstrated MRI to be very sensitive in women of population risk in the DENSE trial.¹⁸ This large multicenter trial in the Netherlands randomized women with BI-RADS category D density and normal mammographic screening to supplemental MRI. Of the women invited, 59% agreed to MRI with resultant detection of an additional 16.5 cancers per 1000 screens in the first round. The interval cancer rate was reduced by 84% in the MRI group (0.8/1000 vs 5/1000), with the significance of this being that a reduction in interval cancers is the most useful surrogate for mortality data.³⁹

The subsequent screening round for the DENSE trial at 2 years was key because it better reflected the actual potential benefit of ongoing screening with breast MRI.¹⁹ This second subsequent MRI yielded a supplemental detection rate of 5.8 per 1000. This lower incident round detection rate is to be expected, with results consistent with the only other MRI screening study of population-risk women with negative mammograms and/or US (the initial MRI round found 22.6/1000 with MRI compared with 6.9/1000 in the subsequent round).³⁸

A recent systematic review and meta-analysis including 22 studies compared the different modalities of supplemental imaging for women with dense breasts and negative mammography, demonstrating that MRI was the best supplemental imaging modality in women with dense breasts considered to be at average or intermediate risk of breast cancer.⁴⁰ MRI was superior to other modalities in CDR and in detecting small invasive disease that may impact long-term survival.⁴¹ Importantly, in the DENSE trial, MRI-detected tumors were small (median 9.5 mm) and node negative (89%), and in the subsequent round, all tumors were early stage (0/1) and node negative.^18,19

A further systematic review and meta-analysis of breast MRI in women with dense breasts following negative mammography included 18 articles (24 studies), of which density was BI-RADS C or D in 15 of 18 and D in 3 of 18. They reported an overall breast CDR of 16.6 per 1000 at prevalent round and 6.8 per 1000 at incident round in women at both high risk and average risk, approximately triple the CDR compared with mammography alone, demonstrating supplemental MRI is an extremely sensitive tool in women with dense breasts regardless of risk category.⁴²

Factors affecting implementation of MRI for supplemental imaging in Europe

The level 1 evidence that MRI screening increases CDR while reducing interval cancers and reducing underdiagnosis in women with BI-RADS category D density breasts resulted in the European Society of Breast Imaging issuing recommendations that women with category D density undergo breast MRI from ages 50 to 70 years at least every 4 years, and preferably every 2 to 3 years.⁴³ However, despite publication in 2022, no countries in Europe currently offer women with BI-RADS category D density breasts MRI as supplemental imaging. Furthermore, guidance is conflicting. The European Commission Initiative on Breast Cancer, a European group that aims to review the latest scientific evidence and provide independent European-wide guidance, proposes DBT rather than MRI in women of screening age with dense breasts, albeit stating conditional evidence with very low certainty.⁴⁴

The reasons for conflicting guidance and lack of implementation of MRI screening are multifactorial. Concerns regarding increased recalls have been cited; however, in the DENSE trial, recalls from MRI in the prevalent round were not dissimilar to mammography (80/1000) and, importantly, were reduced by 65% in the subsequent round (28/1000).¹⁹ This substantial reduction in false-positive results from prevalent to incident round is in line with prior studies that have demonstrated similar findings for MRI screening studies in high-risk women across multiple rounds.⁴⁵ In a recent meta-analysis, there was heterogeneity associated with the positive predictive value (PPV) from supplemental breast MRI, but more recent studies using modern MRI protocols had higher PPVs, highlighting the importance of standardizing equipment and protocols.⁴²

Cost and lack of resources have also been cited as one of the major reasons preventing implementation of MRI screening for increased breast density in Europe. Women with BI-RADS category D density represent approximately 10% of the female population, which equates to 6 to 7 million women in Europe, a substantially greater number than the 0.2% of the population with BRCA mutations currently offered MRI screening.⁴⁶ However, a cost-effectiveness analysis of the data from the DENSE trial determined that performing breast MRI with biannual mammogram would save an additional 8.6 lives per 1000 women invited for screening at a cost of 150 000 euro per life saved for 22 500 per quality-adjusted life year (QALY).⁴⁷ If MRI were used alone as a screening tool in the cohort of women with dense breasts, it would save an additional 7.6 lives per 1000 women screened at a cost of 75 000 euro per life saved or 11 500 euro per QALY. The study concluded that screening at 3- to 4-year intervals with breast MRI in women with BI-RADS category D density breasts on mammography is considered cost-effective compared with the current breast cancer screening standard of biannual mammography.

Abbreviated MRI for supplemental imaging in women with dense breasts

The cost of MRI screening has the potential to be substantially reduced by using MRI with shorter scan protocols. Abbreviated breast (AB)-MRI protocols typically involve an unenhanced T1-weighted (T1W) sequence and at least 1 contrast-enhanced T1W examination (Figure 2, A-C). These protocols are designed to generate subtraction and 3D maximum-intensity projection (MIP) images. The key mechanism of this technique relies on the high-intensity signal difference between the enhancing tumor and the background, which is highest in the early postcontrast phase—that is, within the first 60 seconds after intravenous contrast administration. Kuhl et al⁴⁸ conducted the first prospective reader study evaluating AB-MRI for screening asymptomatic women with mild to moderate breast cancer risk. The study found a sensitivity of 91% and a negative predictive value (NPV) of 99% using MIP images alone, with a reading time averaging 3 seconds. When T1W contrast-enhanced images were included, sensitivity and NPV both increased to 100%, with a reading time of approximately 30 seconds.

Figure 2.

Sixty-six-year-old, asymptomatic, underwent abbreviated MRI following normal mammography demonstrating dense breast tissue, BI-RADS D. A-C: Maximum-intensity projection, T1 fat-saturated postcontrast MRI, and subtracted T1 fat-saturated postcontrast MRI, respectively, demonstrating 9-mm enhancing lesion in the lateral left breast (arrow). Second-look US and biopsy confirmed 8-mm grade 2 invasive carcinoma no special type, with high-grade ductal carcinoma in situ.

Numerous studies have since investigated AB-MRI, although the protocols vary across institutions, highlighting the need for standardization.^49,50 Three major studies, including the prospective EA1141 multicenter trial, have investigated AB-MRI’s clinical performance in screening (Table 2).^51-53 The EA1141 study, which included 1444 participants with BI-RADS C and D density breasts, found a 2.45-fold–higher CDR using AB-MRI (15.2/1000) compared with DBT (6.2/1000). These results align with the DENSE trial’s findings, in which full-protocol MRI detected 16.5 cancers per 1000 in women with BI-RADS category D density breasts and normal mammograms. The EA1141 study demonstrated a sensitivity of 100% for invasive cancer and 95.7% for overall cancer detection, although AB-MRI had a lower specificity (87%) compared with DBT (97%). Despite this, the specificity of AB-MRI met the Breast Imaging Reporting and Data System performance benchmarks for full-protocol MRI.

Table 2.

Recent Published Studies Using Abbreviated MRI in a Screening Setting

Study	Design	Cohort type	Number of patients	CDR per 1000	Sensitivity	Specificity	PPV
Comstock et al 51	Prospective multicenter	Screening women of intermediate risk, BI-RADS C and D	1444	15.2	96%	87%	19.6%
Weinstein et al 52	Retrospective single center	Screening women at intermediate risk with dense breasts	475	27.4	NR	NR	28.6%
Kwon et al 53	Retrospective single center	High to intermediate risk	1975	6.9-10.7 (year 1 to year 3)	75%-80%	93.5%-94.1%	31.6%-63.2%

Abbreviations:

CDR, cancer detection rate; PPV, positive predictive value; NR, not reported.

A meta-analysis of 5 studies, including 2588 patients and 62 cancers, compared AB-MRI and full diagnostic protocol (FDP)-MRI in screening settings.⁴⁹ The analysis found comparable diagnostic performance (areas under the curve [AUCs] of 0.94 and 0.97, respectively) and no significant differences in sensitivity and specificity between the 2 protocols. Pooling analysis of 8 studies with enriched cohorts (1432 patients and 540 cancers) also demonstrated diagnostic equivalence between AB-MRI and FDP-MRI (AUCs of 0.94 and 0.95, respectively).⁴⁹ However, these enriched cohorts do not fully reflect typical clinical settings, necessitating cautious interpretation of the outcome measures. Abbreviated breast MRI offers a promising alternative to traditional FDP-MRI, particularly for women with dense breasts and those at moderate risk of breast cancer. Its shorter examination and interpretation times combined with comparable diagnostic performance could facilitate more widespread use of affordable MRI screening.

Solutions for implementation of MRI for supplemental imaging in Europe

Mammographic screening has been shown to be effective in reducing breast cancer mortality by at least 20%.⁵⁴ According to epidemiological modeling of the DENSE trial results, screening with MRI every other year provides a mortality reduction of double this—approximately ~40%.⁵⁵ Despite convincing evidence of clinical importance, a number of factors will need to be addressed to allow widespread implementation of MRI screening in women with dense breasts across Europe.

High recall rates will hamper implementation, and while the majority of MRI-detected lesions can be identified by second-look US, MRI-guided biopsy will be required for some lesions, which is not available in many centers in Europe. Novel developments in artificial intelligence (AI) may help reduce recalls with AI tools demonstrating downgrade of MRI recalls by >40%.⁵⁶

Artificial intelligence will likely also be helpful with breast density assessment. Visual assessment is known to have a high intra- and interreader variability, and multiple automated methods are currently in use.⁵⁷ This may be helpful in better defining cutoff values for the benefit of MRI according to density. While the DENSE trial only included women with BI-RADS category D density, a number of studies are currently underway to assess the benefit in less-dense breast tissue (BI-RADS C), which has implications for an even greater percentage of the European population. The early results of the German MA-DETECT study looking at additional breast cancer yield with MRI in women with BI-RADS category C and D density breasts show similar additional CDRs to the DENSE trial, albeit small initial numbers, with a CDR of 20 per 1000 screenings in women undergoing MRI, comparable with the 16.5 per 1000 in the DENSE trial.⁵⁸ The results of the Breast Screening - Risk Adaptive Imaging for Density (BRAID; Clinicaltrials.gov identifier: NCT04097366) study are awaited with interest.⁵⁹ This is a prospective, randomized controlled UK-based trial looking at the role of additional supplemental imaging in women with BI-RADS category C and D density breasts on mammography undergoing population-based breast cancer screening. Women with a negative mammogram are randomized to 1 of the following 4 arms: standard of care (3 yearly mammography from age 50 years) or supplemental imaging of either abbreviated MRI, CEM, or ABUS following their normal screening mammogram and again at 18 months.

In the future, a more personalized approach to breast cancer screening may be adopted, incorporating relevant patient clinical information, such as family history, breast density, and information including genetic factors, such as single-nucleotide polymorphisms. This is the basis of the My Personalised Breast Cancer Screening study (MyPEBS study; Clinicaltrials.gov identifier: NCT03672331).⁶⁰ This study also incorporates supplemental imaging with DBT, US, or MRI in some women based on risk assessment. The study has an estimated completion date in 2027.

Artificial intelligence tools are now being used to identify women with a negative mammogram at short-term increased risk of developing breast cancer to offer supplemental imaging. The Swedish randomized controlled ScreenTrust MRI trial used a combination of 3 AI algorithms (risk prediction, masking, and feature identification) to select women with a negative mammogram at population risk for an MRI examination. The first round reported a CDR of 64 out of 1000, >4 times higher than using a density measure.⁶¹ The results of the subsequent rounds are important to determine the CDR and how frequently MRI should be offered.

Women’s perspectives on supplemental imaging

Finally, the key factor to address when formulating policy on breast density and supplemental imaging is what women want and what is deemed acceptable to them. Supplemental imaging for dense breasts will never become widespread in Europe if women decide not to take it up. Little is known about the perceptions and beliefs of the European population in terms of breast density and potential implications, and, thus, we must rely on U.S.-based studies. In a study of 2329 women, those with dense breasts indicated a lower confidence in breast screening irrespective of modality of imaging employed.⁶² Women, regardless of breast density, expressed higher confidence in imaging with breast MRI. This study includes U.S. patients, who are expressly communicated their breast density as per Food and Drug Administration recommendations, which was previously done by state law. Despite long-term individual knowledge of breast density and its associated implications in the United States, a systematic review illustrated that there is a paucity of studies evaluating patient perceptions and knowledge of breast density.⁶³ The authors conclude that there is particularly limited awareness of breast density and implications for women—in particular, in more socioeconomic disadvantaged communities. A recent qualitative study of 2306 women determined that few women identified breast density as a strong personal risk factor for breast cancer and identified obesity and family history as higher risk.⁶⁴

In the DENSE trial in the Netherlands, only 59% of women accepted the invitation to MRI, citing MRI-specific concerns, including claustrophobia and anxiety regarding supplemental screening.⁶⁵ However, reattendance rates in the second (81.3%) and third (85.2%) rounds were much higher.⁶⁶ Improving women’s MRI experience may therefore help with increasing acceptance of MRI. Abbreviated MRI and wide-bore scanners may be helpful approaches for a more optimal experience.⁶⁷ While false-positive results may be considered a reason for low attendance, it has been shown that women value the possibility of an earlier diagnosis over the risks of a false-positive result or overdiagnosis.⁶⁸

Conclusion

The evidence for the benefit of supplemental imaging with MRI in women with dense breasts is now well established with increased cancer detection, reduced interval cancers, and, importantly, detection of clinically relevant cancers. Despite this, European countries lack legislation for notification of breast density and recommendations for additional supplementary imaging. While there are barriers to implementation, solutions are available. It is hoped that with the results of further trials, as well as increased awareness that breast density is a risk factor for breast cancer, governments in Europe may be encouraged to change policy and practice in the near future.

Acknowledgments

Cambridge Biomedical Research Centre, UK is acknowledged for its contributions.

Funding

None declared.

Conflict of interest statement

The authors have no conflict of interest in relation to this paper. Please see individual International Committee of Medical Journal Editors (ICMJE) disclosure forms.

Author contributions

Fleur Kilburn-Toppin (Conceptualization, Writing - original draft, Writing - review & editing), Iris Allajbeu (Writing - original draft, Writing - review & editing), Nuala Healy (Writing - original draft, Writing - review & editing), and Fiona J. Gilbert (Writing - original draft, Writing - review & editing)