A diagnosis of coronavirus disease 2019 (COVID-19) is made on the basis of epidemiological and clinical history, as well as the results of severe acute respiratory syndrome coronavirus 2 real-time reverse transcriptase polymerase chain reaction (RT-PCR) testing. Chest computed tomography (CT) has been proposed as a useful alternative investigation method for COVID-19 diagnosis or triage, particularly in healthcare settings with restricted access to RT-PCR testing and in the context of lower RT-PCR sensitivity during early stages of the disease; it may also be useful for imaging-mediated evaluation of disease severity and progression.1 2 The most common CT findings in early-stage COVID-19 pneumonia (illness days 0-5) are pure ground-glass opacities (GGOs); the second most common finding is consolidation.3 4 In the later stages (illness days 6-17), findings usually evolve to a combination of GGOs, consolidation, and reticular opacities with architectural distortion.4 These imaging features are not specific to COVID-19 pneumonia; they can overlap with other types of viral or bacterial pneumonia, particularly influenza pneumonia, as well as other non-infectious inflammatory lung diseases.5 6 Influenza, one of the most common causes of viral pneumonia,7 and bacterial pneumonia, historically the most common type of community-acquired pneumonia worldwide,8 maintained high incidences during the early COVID-19 pandemic when this study was conducted; thus, they had the potential to substantially contribute to hospitalisations in this period. However, COVID-19 pneumonia and other types of viral or bacterial pneumonia distinctly differ in terms of their disease course, temporal progression, and available therapeutics9 10 11; thus, there is a need for early and accurate differentiation among these entities.

Studies in 2020 revealed several CT imaging features that can aid in differential diagnosis. Compared with influenza pneumonia, patients with COVID-19 pneumonia are more likely to exhibit a peripheral distribution,12 13 14 patchy combination of GGOs and consolidation,15 fine reticular opacities,16 and vascular thickening or enlargement16 17; patients with influenza pneumonia are more likely to exhibit nodules,18 tree-in-bud sign,18 bronchial wall thickening,15 lymphadenopathy,16 and pleural effusions.12 In the past, diffuse airspace consolidation, centrilobular nodules, bronchial wall thickening, and mucous impaction19 have been identified as typical signs of bacterial pneumonia. Nevertheless, CT assessment of COVID-19 generally remains challenging, with reported accuracies for radiologists ranging from 60 to 83%16 in terms of differentiating patients with COVID-19 pneumonia from patients with influenza pneumonia; considering these rates, further studies of relevant imaging findings are needed.

A report by Wu et al20 highlighted the arched bridge sign, which may be a distinct CT feature of COVID-19 pneumonia. In their analysis of 11 patients with COVID-19 pneumonia, the sign was present in 72.7%.20 The arched bridge sign refers to a specific pattern of GGOs or consolidation, commonly in a subpleural location, which forms an arched contour with a smooth concave margin towards the pleural side. The arched margin outlines the spared parenchyma between the GGOs or consolidation and the pleural surface. Another reported sign, regarded as the vacuole sign,21 22 23 24 is presumably based on the morphological pattern of parenchymal sparing in areas of affected lung. The vacuole sign refers to a focal oval or round lucent area (typically <5 mm) that is observed within GGOs or sites of consolidation. In clinical practice, we often observed these two novel signs on CT scans of patients with COVID-19 pneumonia. We hypothesised that these two signs are common in patients with COVID-19 pneumonia and thus could be used to differentiate such pneumonia from other types of infection-related pneumonia. However, considering the limited prior evidence (solely from small retrospective studies20 21 22 23 24) regarding the prevalence of the vacuole sign in COVID-19 pneumonia, and because the arched bridge sign has—to our knowledge—only been reported in a single previous publication,20 additional assessments of these signs are needed. The utilities of the arched bridge and vacuole signs in COVID-19 pneumonia have not been directly assessed in prior reports, nor have they been compared between COVID-19 pneumonia and other types of infection-related pneumonia. In this study, we evaluated the arched bridge and vacuole signs in patients with COVID-19 pneumonia, then examined whether these signs could be used to differentiate such pneumonia from influenza pneumonia or bacterial pneumonia.

This retrospective study included consecutive patients who were admitted to two hospitals in Hong Kong (Prince of Wales Hospital and Princess Margaret Hospital) with RT-PCR–confirmed COVID-19, along with positive CT findings, from 24 January 2020 to 16 April 2020. These patients represent most patients with COVID-19 in Hong Kong during the study period, when all patients with confirmed COVID-19 were hospitalised regardless of clinical status; moreover, Princess Margaret Hospital also served as a centralised treatment centre for patients with COVID-19. The study recruitment period reflects the early days of the COVID-19 pandemic in Hong Kong, during which CT examinations were commonly performed during the diagnosis and treatment of patients with COVID-19. All patients with COVID-19 underwent complete PCR-based assessment of multiple respiratory pathogens on admission; patients with COVID-19 were excluded from the present study if they exhibited evidence of other concomitant viral or bacterial respiratory infections.

The influenza pneumonia and bacterial pneumonia comparison groups comprised consecutive patients who were admitted to Prince of Wales Hospital in Hong Kong, with pure influenza pneumonia or pure bacterial pneumonia and positive CT findings from 20 February 2018 to 13 January 2020. The diagnosis of pure influenza pneumonia was determined by RT-PCR–mediated detection of influenza A or B viral RNA, in the absence of evidence (eg, respiratory or blood cultures, PCR tests, or serological tests) suggesting concomitant infection with other viral or bacterial pathogens. The diagnosis of pure bacterial pneumonia was determined by positive bacterial culture on sputum or bronchoalveolar lavage, in the absence of evidence suggesting concomitant infection with other viral or bacterial pathogens. Patients with pre-existing lung parenchymal disease (eg, interstitial lung disease) or known lung malignancy were excluded from the study.

Computed tomography scans were performed using 64-section multidetector scanners (LightSpeed VCT or LightSpeed Pro 32, GE Medical Systems, Milwaukee [WI], United States). The following scan parameters were used: voltage, 120 kV; tube current, 50-502 mA; and slice thickness, 0.625 mm or 1.25 mm. Scans were performed with the patient in the supine position during end-inspiration.

All CT images were reviewed in random order by two trained radiologists (TY So and YX Wang) with 7 and 5 years of experience in diagnostic chest imaging, respectively, using a dedicated picture archiving and communication system workstation. Each radiologist was blinded to demographic and clinical information for all patients. The images were independently reviewed by each radiologist, and the consensus findings for any discrepancies from discussion are reported.

Each CT image was initially subjected to broad assessment of abnormalities. Subsequently, the arched bridge and vacuole signs were specifically assessed; the presence or absence of each sign was recorded. The arched bridge sign was defined as the presence of GGOs or consolidation with an arched concave margin outlining a region of spared lung; the vacuole sign was defined as the presence of a vacuole-like region of normal lung (<5 mm) within GGOs or sites of consolidation.21

For patients with COVID-19 pneumonia and patients with influenza pneumonia, CT findings of GGOs (hazy areas of parenchymal opacities that did not conceal underlying vessels), consolidation (parenchymal opacities that concealed underlying vessels), reticular opacities (coarse linear or curvilinear opacities, interlobular septal thickening, or subpleural reticulation), and crazy paving pattern (GGOs with interlobular and intralobular septal thickening) were recorded. Other signs such as air bronchograms (air-filled bronchi on a background of opaque lung), nodules (small rounded focal opacities <3 cm), cavitation (gas-filled spaces within sites of pulmonary consolidation), bronchiectasis, pleural retraction or thickening, pleural effusion, pericardial effusion, pneumothorax, and mediastinal lymphadenopathy (lymph nodes >1 cm in short-axis diameter) were also recorded. The distributions of pulmonary abnormalities were classified as unilateral or bilateral, and peripheral (involving mainly the peripheral one-third of the lung), central (involving mainly the central two-thirds of the lung), or diffuse (involving both peripheral and central regions). Lobar involvement was also recorded (right upper lobe, right middle lobe, right lower lobe, left upper lobe, and/or left lower lobe). For patients with bacterial pneumonia, only the arched bridge and vacuole signs were recorded. Other CT changes and their distributions were not individually recorded. This component of the analysis was determined based on reports that it is easier to differentiate COVID-19 pneumonia from bacterial pneumonia, whereas it is more difficult to differentiate COVID-19 pneumonia from other types of viral pneumonia.6 25 26 This manuscript was written in accordance with the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines for reporting observational studies.

Imaging findings were compared using the Chi squared test or Fisher’s exact test, as appropriate, followed by Bonferroni correction. Comparisons of disease stage, severity, and clinical course among patients with COVID-19 who had the arched bridge and/or vacuole signs were performed using the non-parametric Mann-Whitney U test. P values <0.05 were considered indicative of statistical significance. For the arched bridge and vacuole signs, the sensitivity, specificity, positive predictive value, and negative predictive value were calculated, along with the respective 95% confidence intervals. All analyses were conducted using SPSS software (Windows version 25.0; IBM Corp, Armonk [NY], United States).

Among 76 patients with bacterial pneumonia who were admitted for treatment during the study period, five patients with pre-existing lung parenchymal disease were excluded from the analysis: organising pneumonia (n=2), non-specific interstitial pneumonia (n=1), and idiopathic interstitial pneumonia of uncertain subtype (n=2). No patients with COVID-19 required exclusion because of concomitant viral or bacterial infections. The final study population comprised 187 patients: 66 patients with COVID-19 pneumonia, 50 patients with influenza pneumonia, and 71 patients with bacterial pneumonia. The following organisms were detected in patients with bacterial pneumonia: Streptococcus pneumoniae, Staphylococcus aureus, Haemophilus influenzae, Enterococcus spp., Klebsiella pneumoniae, Pseudomonas aeruginosa, Escherichia coli, Stenotrophomonas spp., Serratia spp., Acinetobacter spp., and Moraxella catarrhalis. Demographic and clinical characteristics of the study population are shown in Table 1. Compared with patients in the influenza pneumonia and bacterial pneumonia groups, patients with COVID-19 pneumonia tended to be younger and healthier.

The arched bridge and vacuole signs were present in 42 (63.6%) and 14 (21.2%) of 66 patients with COVID-19 pneumonia, respectively (Table 2). The arched bridge sign was commonly in a subpleural location, and there was a smooth arched margin outlining the underside of the GGO or consolidation in all cases (Fig a and b). The vacuole sign was present with GGOs or sites of consolidation in various locations (Fig c and d). The arched bridge sign was much more common in patients with COVID-19 pneumonia than in patients with influenza pneumonia (63.6% vs 8.0%) or bacterial pneumonia (63.6% vs 5.6%, P<0.001). Similarly, the vacuole sign was much more common in patients with COVID-19 pneumonia than in patients with influenza pneumonia (21.2% vs 2.0%, P=0.005) or bacterial pneumonia (21.2% vs 1.4%, P<0.001).

The arched bridge and vacuole signs occurred together in 11 (16.7%) of 66 patients with COVID-19 pneumonia, but they did not occur together in any patients with influenza pneumonia or bacterial pneumonia. Additionally, a review of the five excluded patients with bacterial pneumonia and concurrent pre-existing lung parenchymal disease revealed that none of those patients exhibited the arched bridge sign or the vacuole sign.

In this study, the arched bridge and vacuole signs exhibited high specificities (93.4% and 98.4%, respectively) in terms of identifying COVID-19 pneumonia (Table 3), with moderate or low sensitivities (63.6% and 21.2%, respectively). They also exhibited high positive predictive values (84.0% and 87.5%, respectively) and high or moderate negative predictive values (82.5% and 69.6%, respectively).

The relationships of the arched bridge and vacuole signs with disease course are shown in Table 4. Computed tomography was mainly performed during admission, at a mean of 5.3 days after admission, suggesting these two signs generally appeared at an early stage. Comparisons of patients with COVID-19 pneumonia who had and did not have these two signs revealed that the arched bridge sign was associated with more extensive lung involvement (diseased lobes: 4.0 [present] vs 2.4 [absent], P<0.001). This trend was not evident for the vacuole sign (diseased lobes: 3.8 [present] vs 3.3 [absent]). There was no significant difference in the duration of total hospitalisation between patients with COVID-19 who had and did not have these two signs, suggesting they were not associated with a better or worse prognosis if appropriate treatment was administered.

Table 5 shows the comparison of other CT findings between COVID-19 pneumonia and influenza pneumonia. No significant differences were observed in the incidences of GGOs, consolidation, reticular opacities, or crazy paving between patients with COVID-19 and patients with influenza pneumonia (all P>0.05). Air bronchograms (P=0.003), nodules (P=0.009), cavitation (P=0.004), bronchiectasis (P<0.001), pleural effusion (P<0.001), pericardial effusion (P=0.032), and mediastinal lymphadenopathy (P<0.001) were significantly more common in patients with influenza pneumonia.

Abnormalities were more commonly bilateral in patients with COVID-19 pneumonia (77.3%) and patients with influenza pneumonia (96%). The distribution was more likely to be peripheral in patients with COVID-19 pneumonia (51.5% vs 2.0%, P<0.001), and was more likely to be diffuse in patients with influenza pneumonia (98% vs 48.5%, P<0.001). The right upper lobe (P<0.001), right middle lobe (P<0.001), and left upper lobe (P<0.001) were less commonly involved in patients with COVID-19 pneumonia than in patients with influenza pneumonia.

This study evaluated the incidences and diagnostic values of the arched bridge and vacuole signs among patients with COVID-19 pneumonia in a Hong Kong Chinese population. Since the initial description of Wu et al20 in a series of 11 patients with COVID-19, our study is the first to validate the arched bridge sign in patients with COVID-19. To our knowledge, this is also the first study to evaluate the vacuole sign in non–COVID-19–related pneumonia. The arched bridge sign was significantly more common in COVID-19 pneumonia than in influenza pneumonia or bacterial pneumonia. Additionally, the incidences of the vacuole sign and both signs observed in combination were higher (or tended to be higher) in patients with COVID-19 pneumonia than in patients with influenza pneumonia or bacterial pneumonia. Our results imply that these two signs generally appeared at an early stage; the arched bridge sign is more likely to be observed in patients with more severe lung pathology. These results suggest that the arched bridge and vacuole signs can be used in CT-based identification of COVID-19 pneumonia, as well as efforts to differentiate COVID-19 pneumonia from other types of infection-related pneumonia. Currently, chest CT is not recommended for the screening or diagnosis of COVID-19 pneumonia when RT-PCR tests are available. In selected cases, CT can be used to monitor clinical progress and identify complications of the disease. In some scenarios, CT can be a useful alternative investigation method for COVID-19 diagnosis or triage, such as healthcare settings with restricted access to RT-PCR tests.27 28 When these two signs are observed on CTs performed for COVID-19 pneumonia or other indications during the COVID-19 pandemic, physicians should carefully consider a diagnosis of COVID-19 pneumonia. However, our findings indicated there was no significant difference in the duration of total hospitalisation between patients with COVID-19 pneumonia who had and did not have these two signs, suggesting that they are not indicative of a better or worse prognosis if appropriate treatments are administered.

The underlying pathophysiological mechanisms behind these signs remain unclear. However, the morphological appearances of the arched bridge and vacuole signs may indicate different pathophysiological mechanisms of lung sparing that occur during infection-related pneumonia. Histopathological examinations of lung biopsy tissues from patients with COVID-19 pneumonia have provided evidence of variations in diffuse alveolar damage.29 30 The curved concave margin in the arched bridge sign may be the result of secondary pulmonary lobule sparing, with the interlobular septum of the secondary pulmonary nodule forming some resistance to the spread of infection among lobules.20 In contrast, the vacuole sign (ie, a very small focal lucent area) may reflect a spared alveolar cluster or dilated alveolar sac within an area of otherwise involved lung.21 23 Zhang et al23 reported that the vacuole sign was often present in patients with advanced COVID-19 pneumonia, where alveolar sac dilation could result from damage to the alveolar wall.

The incidence of the arched bridge sign in patients with COVID-19 (63.6%) was similar to the incidence reported by Wu et al20 (72.7%). The incidence of the vacuole sign (21.2%) in patients with COVID-19 pneumonia is also within the range reported in prior studies describing this sign (17-66%).21 22 23 24 Notably, three additional case series have revealed spared airspaces in patients with COVID-19 pneumonia, comprising ‘round cystic changes’31, ‘cystic air spaces’32 and ‘cavity signs’,33 with prevalences of 10 to 30%; these phenomena may include the vacuole sign. However, these case series did not include formal definitions of the findings. The differences in definitions of the vacuole sign (and phenomena that include the sign) may also explain the disparate prevalences (17%-66%, as noted above) reported in the literature.

The arched bridge and vacuole signs differentiated COVID-19 pneumonia from influenza pneumonia and bacterial pneumonia with high specificities and high positive predictive values, suggesting that these signs can help to provide a specific imaging diagnosis of COVID-19 pneumonia. When encountering inconclusive CT features of COVID-19 pneumonia, these signs can be identified with minimal additional effort; their presence may be sufficient to increase suspicion or add to the evidence confirming a diagnosis of COVID-19 pneumonia. The respective sensitivities of the arched bridge and vacuole signs were moderate (63.6%) and low (21.2%); the arched bridge sign may be more useful in this context. Our findings suggest that the combined presence of the arched bridge and vacuole signs strongly supports a diagnosis of COVID-19 pneumonia.

Consistent with previous studies, the presence of nodules, cavitations, bronchiectasis, pleural effusion, pericardial effusion, and/or mediastinal lymphadenopathy was uncommon in patients with COVID-19 pneumonia; these features were more common in patients with influenza pneumonia.12 16 17 18 34 35 Our results indicated that COVID-19-related abnormalities on CT were generally bilateral and peripheral, compatible with the findings in prior studies.12 13 14

This study had several limitations. First, it used a retrospective design, and patients were imaged in a cross-sectional manner at various time intervals after symptom onset. Computed tomography was not regularly performed, which hindered the monitoring or analysis of imaging signs over time. Second, CT was not routinely performed for patients with influenza pneumonia or bacterial pneumonia; it was performed based on clinical judgement, generally because of patient deterioration or poor response to treatment. We did not assess differences in the clinical features of patients with influenza pneumonia and patients with bacterial pneumonia between patients who did and did not undergo CT. Third, we attempted to implement diversity in our analysis of COVID-19 pneumonia by comparisons with influenza pneumonia and bacterial pneumonia, whereas prior studies have generally been limited to comparisons of COVID-19 pneumonia with influenza pneumonia. However, we did not examine other types of viral pneumonia; we also did not conduct subgroup analysis according to influenza subtype. Additionally, we did not systematically compare the prognoses of patients with non–COVID-19 pneumonia who had and did not have the arched bridge or vacuole signs. This comparison was hindered by the sample size, because these two signs were very uncommon in patients with non–COVID-19 pneumonia. However, additional analysis did not reveal a clear pattern whereby these two signs would be predictive for clinical prognosis in patients with non–COVID-19 pneumonia. Finally, the sample size in this study was moderate. Although the prevalences of the arched bridge and vacuole signs in our patients with COVID-19 pneumonia were consistent with findings in the literature, their diagnostic specificities should be validated in other types of pneumonia. Despite these limitations, the high diagnostic specificities of these CT signs provide insights that will be useful in future studies. Additional work is needed regarding the relationships of these CT signs with clinical status, and our findings require validation in larger and more diverse patient populations.

In conclusion, two morphological patterns of lung sparing, namely the arched bridge and vacuole signs, are much more common in patients with COVID-19 pneumonia; they have the potential to differentiate COVID-19 pneumonia from influenza pneumonia and bacterial pneumonia. In this study, these signs had high specificities and positive predictive values for COVID-19 pneumonia. The identification of these signs in clinical practice may be useful for increasing suspicion or providing confirmatory evidence to support a diagnosis of COVID-19 pneumonia.

Concept and design: TY So, SCH Yu, JYX Wang.
Acquisition of data: All authors.
Analysis and interpretation of data: All authors.
Drafting of the manuscript: TY So, S Yu, JYX Wang.
Critical revision of the manuscript for important intellectual content: All authors.

All authors had full access to the data, contributed to the study, approved the final version for publication, and take responsibility for its accuracy and integrity.

The authors have no conflicts of interest to disclose.

The authors thank Ms Apurva Sawhney, Department of Imaging and Interventional Radiology, The Chinese University of Hong Kong, for assistance with data collection.

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

This study was approved by the Joint Chinese University of Hong Kong–New Territories East Cluster Clinical Research Ethics Committee (REC Ref. No.: 2020.232), which waived the requirement for informed consent due to the retrospective nature of the study. The study was conducted in compliance with the established ethical standards and principles of the Declaration of Helsinki.

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Appropriate optical correction after cataract extraction in infants is important for efforts to avoid amblyopia. Primary intraocular lens (IOL) implantation allows constant in situ optical correction during the critical years of visual development, while avoiding the expenses and compliance issues associated with contact lenses.1 Disadvantages include increased rates of surgical complications and re-operations,2 as well as the inability to modify IOL power during ocular growth. A recent report by the American Academy of Ophthalmology suggested that IOL implantation can be safely conducted in children aged >6 months.3 However, because of the unpredictable nature of ocular growth, it remains challenging to select a target refraction in infants that allows achievement of optimal long-term visual and refractive outcomes.

Surgeons target various initial hyperopia values, ranging from +5.00 dioptres (D) to +10.50 D,4 5 6 7 8 9 to compensate for the rapid myopic shift that occurs during infancy. However, prediction of the myopic shift remains difficult; significant hyperopia in infants requires stringent optical correction to prevent amblyopia, and some studies have linked high initial hyperopia to worse visual acuity.10 11 This retrospective study aimed to clarify the relationships of initial postoperative refraction with 10-year spherical equivalent refraction (SER) and long-term best-corrected visual acuity (BCVA) after IOL implantation in infants.

This retrospective study included patients who underwent unilateral or bilateral congenital cataract extraction and primary IOL implantation before the age of 1 year between 1997 and 2009 at a single secondary and tertiary referral eye centre. Only patients with ≥10 years of follow-up were included. Eyes with associated ocular co-morbidities (eg, persistent foetal vasculature and glaucoma) were excluded.

The patients’ baseline characteristics (eg, age, axial length [determined by applanation A-scan biometry], and keratometry) were recorded. Intraocular lens powers were calculated using the Sanders–Retzlaff–Kraff II formula. The operating surgeon selected the target refraction and IOL power, considering the patient’s age (all cases) and refractive error in the fellow eye (unilateral cases). All operations were performed using similar techniques, including the creation of a 3.0-mm scleral tunnel, anterior continuous curvilinear capsulorhexis, and lens removal by automated irrigation and aspiration. Heparin-surface-modified polymethyl methacrylate IOLs or acrylic foldable IOLs were implanted. The IOL was placed in the capsular bag or in the sulcus. All wounds were sutured. In some cases, primary posterior curvilinear capsulorhexis and anterior vitrectomy were performed. Because of reports that a significant number of eyes in young infants required secondary posterior capsule opening despite primary posterior capsulotomy,12 13 this procedure was omitted in some eyes to increase the likelihood of achieving capsular IOL implantation. Postoperatively, all eyes were treated with intensive topical steroid and antibiotic medication. Patients were assessed on postoperative day 1, week 1, week 2, and week 4; they were then assessed every 3 to 6 months. When clinically significant posterior capsular opacification developed, secondary posterior capsulotomy was performed promptly. Glasses were used for postoperative optical correction; in some cases, contact lenses were also used. Amblyopia treatment by patching was performed as necessary.

Spherical equivalent refraction at 2 weeks postoperatively was regarded as immediate postoperative refraction. Serial refractions at each year of postoperative follow-up were recorded, and SERs were calculated as the algebraic sum of the sphere and half the cylindrical power. Postoperative axial length was measured using non-contact optical biometry, which was less invasive than applanation biometry.

Statistical analysis was performed using Microsoft Excel and SPSS (Windows version 21.0; IBM Corp, Armonk [NY], United States). Best-corrected visual acuities were converted to logarithm of the minimum angle of resolution (logMAR) values for statistical analysis. Correlations between continuous variables were assessed by Spearman correlation. Differences between groups were analysed by the Mann–Whitney U test. Preoperative axial length and keratometry were compared with values at the last follow-up using the paired-samples Wilcoxon signed-rank test. The independent-sample Kruskal–Wallis test was used to compare 10-year SER and BCVA values among groups with immediate postoperative refraction ≤+3.50 D, +3.50 to +7.00 D, and ≥+7.00 D. Partial correlation analysis was performed to detect correlations of immediate postoperative refraction with spherical refraction at 1 year and 10 years after adjustment for age at operation. Multiple linear regression was performed for multivariate analysis of statistically significant factors identified during univariate analysis. P values <0.05 were considered statistically significant.

Twenty-two eyes of 14 patients were included in this study. One eye in one patient with bilateral cataract was excluded because it was surgically treated after the patient reached 1 year of age. One eye in another patient with bilateral cataract was excluded because it exhibited secondary glaucoma. During surgery, heparin-surface-modified polymethyl methacrylate IOLs were implanted in three eyes, whereas acrylic foldable IOLs were implanted in 19 eyes. The IOL was placed in the capsular bag in 18 eyes and in the sulcus in four eyes. Additionally, primary posterior curvilinear capsulorhexis and anterior vitrectomy were performed in 13 eyes. For postoperative optical correction, all 14 patients wore glasses; four patients (including two with unilateral cataract) also wore contact lenses. Thirteen patients underwent amblyopia treatment by patching.

The Table summarises the baseline characteristics, refractive outcomes, and visual outcomes of eyes included in this study. All 22 eyes exhibited myopic shift, ranging from -21.88 to -3.75 D at 10 years. Figures 1 and 2 show the amounts of myopic shift and SER, respectively, at 1 to 10 years postoperatively and at last follow-up. The greatest myopic shift occurred in the first postoperative year, but smaller shifts continued beyond the tenth year. Ninety percent of eyes exhibited myopic shift >-2.00 D between the third postoperative year and last follow-up (mean myopic shift: -6.40 ± +3.29 D; range, -12.00 to -1.63 D). These proportions were 82% between the sixth postoperative year and last follow-up (mean myopic shift: -4.14 ± +2.35 D; range, -9.38 to -1.13 D), and 50% between the tenth postoperative year and last follow-up (mean myopic shift: -2.64 ± +2.02 D; range, -0.125 to -6.75 D).

In univariate analysis, a larger myopic shift at 1 year postoperatively was correlated with younger age at operation (R²=0.585, P=0.004), more hyperopic immediate postoperative refraction (R²=-0.533, P=0.011), and a need for secondary posterior capsulotomy (U=20, z=-2.066, P=0.04). One-year myopic shift was not correlated with initial axial length (R²=0.038, P=0.878), and it did not differ between unilateral (median=-5.81 D) and bilateral cases (median=-4.38 D) [U=41.5, z=0.469, P=0.652]. Multiple linear regression was performed for statistically significant factors identified during univariate analysis. Only age at operation remained statistically significant (P=0.025); immediate postoperative refraction (P=0.191) and a need for secondary posterior capsulotomy (P=0.781) were not significant in multivariate analysis.

The total amount of myopic shift at 10 years postoperatively was correlated with age at operation (R²=0.579, P=0.006), but it was not correlated with immediate postoperative refraction (R²=-0.339, P=0.133) or initial axial length (R²=0.291, P=0.241). There was no difference in the amount of myopic shift at 10 years between unilateral (median=-14.62 D) and bilateral cases (median=-10.50 D) [U=40.5, z=1.357, P=0.185] or between eyes that required secondary posterior capsulotomy (median=-11.25 D) and eyes that did not (median = -6.19 D) [U=24, z=-1.645, P=0.112].

Spherical equivalent refraction at 1 year did not significantly differ between unilateral (median=-2.69 D) and bilateral cases (median=+1.13 D) [U=59, z=1.959, P=0.053] or between eyes that required secondary capsulotomy (median=+0.31 D) and eyes that did not (median=+1.42 D) [U=32.5, z=-1.143, P=0.261]. Partial correlation analysis showed that after adjustment for age at operation, immediate postoperative refraction (R²=0.522, P=0.015) was a statistically significant predictor of SER at 1 year.

In contrast, SER at 10 years postoperatively was significantly more myopic in unilateral cases (median=-10.63 D) than in bilateral cases (median=-4.81 D) [U=49.5, z=2.264, P=0.017]. This finding may be related to surgeon preference for less hyperopic target refractions in unilateral cases, which can match the refraction of the fellow eye and potentially prevent significant postoperative anisometropia. Indeed, after adjustment for age, immediate postoperative SER was significantly less hyperopic in unilateral cases than in bilateral cases (P=0.025). A need for secondary posterior capsulotomy (U=28, z=-1.325, P=0.205) was not correlated with SER at 10 years. After adjustment for laterality, both age at operation (P=0.066) and immediate postoperative refraction (P=0.116) were not statistically significant predictors of SER at 10 years. There was no significant difference in 10-year SER among eyes with immediate postoperative refraction ≤+3.50 D, +3.50 to +7.00 D, and ≥+7.00 D (P=0.439), as shown in Figure 3.

Subgroup analysis was performed for bilateral cases only. Multiple regression analysis showed that at 1 year, both age at operation (P=0.014) and immediate postoperative refraction (P=0.024) remained significant predictors of SER after unilateral cases had been excluded. At 10 years postoperatively, age at operation was a significant predictor of SER (P=0.015), whereas immediate postoperative refraction was not (P=0.135).

Mean preoperative axial length was 19.12 mm, whereas mean axial length at 10 years was 24.82 mm. There were no differences in initial axial length (U=32, z=0.894, P=0.421) or total axial length change (U=22, z=-0.224, P=0.875) between unilateral and bilateral cases. Final axial length was significantly greater than preoperative axial length (z=3.823, P<0.0005). Total axial length change was strongly correlated with total myopic shift (R²=-0.791, P<0.0005). There was no difference between preoperative and final keratometry values (z=0.081, P=0.936). The total change in the mean keratometry value was not correlated with total myopic shift (R2=-0.168, P=0.490).

At the last follow-up, 11 eyes (50%) had a final BCVA of 0.18 logMAR or better, six eyes (27%) had moderate amblyopia with BCVA of 0.3 to 0.6 logMAR, and five eyes (23%) had severe amblyopia with BCVA of 0.7 to 1.0 logMAR. There was a statistically significant correlation between immediate postoperative refraction and final BCVA (R²=0.440, P=0.041). Best-corrected visual acuity was worse in eyes that required secondary capsulotomy (U=74.5, z=1.995, P=0.049). Multiple regression revealed that a need for secondary capsulotomy was no longer a significant predictor for BCVA (P=0.299), whereas immediate postoperative refraction remained a significant predictor for BCVA (P=0.018). Best-corrected visual acuity was significantly worse in eyes with immediate postoperative refraction of +7.00 D or higher than in eyes with lower levels of immediate postoperative hyperopia (P=0.029) [Fig 4]. There were no significant correlations of final BCVA with age at operation (R²=-0.041, P=0.856), SER at 10 years (R²=0.011, P=0.963), SER at last follow-up (R²=-0.122, P=0.589), or laterality (U=48.5, z=-1.087, P=0.300).

Seventeen eyes underwent 21 re-operations in total, 17 of which were secondary posterior capsulotomies. All nine eyes that did not undergo primary posterior capsulorhexis and anterior vitrectomy required secondary capsulotomy; one of the nine eyes required secondary capsulotomy twice. Seven of 13 eyes with primary posterior capsulorhexis and anterior vitrectomy required secondary capsulotomy. Three eyes underwent injection of intracameral tissue plasminogen activator, one eye underwent dissection of fibrinous membrane, and one eye required removal of anterior capsular phimosis. Notably, anterior capsular phimosis did not develop in any other eyes. One eye developed secondary glaucoma and was excluded from this study.

Two important goals in the management of congenital cataract include achievement of good long-term visual acuity and minimisation of refractive error in adulthood. This study focused on long-term outcomes after primary IOL implantation in infants, all of whom had ≥10 years of follow-up. Myopic shift was present in all eyes, and its magnitude considerably varied. Immediate postoperative refraction was not a statistically significant predictor of SER at 10 years. Moreover, there was a statistically significant negative correlation between immediate postoperative refraction and final BCVA. Finally, immediate postoperative refraction of +7.00 D or higher was correlated with worse final BCVA.

Refractive change in a normal growing eye involves a complex interaction among axial length elongation, corneal curvature flattening, and the reduction of crystalline lens power.14 Additional effects on ocular growth (eg, related to the presence or laterality of congenital cataract, age at corrective surgery, initial axial length, postoperative visual input, and compliance with postoperative amblyopia therapy) remain uncertain.15 The presence of an intraocular lens magnifies myopic shift in a growing eye—the intraocular lens exhibits constant power and moves anteriorly away from the retina during ocular growth, hindering the extrapolation of data from phakic eyes.5 Figure 5 shows the mean SER during the first decade of life in pseudophakic eyes from patients in the present study, compared with normal eyes from the ongoing population-based Hong Kong Children Eye Study.16 At 10 years after corrective surgery, the mean SER was -6.48 D in pseudophakic eyes, whereas it was -0.72 D in normal eyes of age-matched children. The mean axial length at 10 years was 24.82 mm in pseudophakic eyes, whereas it was 23.79 mm in normal eyes of age-matched children.16 These data imply the presence of a greater myopic shift and greater increase in axial length among pseudophakic eyes which continues beyond the first 2 years of life; notably, these increases are relative to the mean growth of normal eyes in Hong Kong children, who exhibit a higher prevalence of myopia compared with other populations.16

Several other studies of myopic shift have revealed considerable refractive change after primary IOL implantation in infants aged <1 year. At 5 years postoperatively, the Infant Aphakia Treatment Study revealed a mean myopic shift of -8.97 D for infants surgically treated at the age of 1 month and -7.22 D for infants surgically treated at the age of 6 months,9 whereas Negalur et al17 found a median myopic shift of -8.43 D after the same duration of follow-up in infants operated before the age of 6 months. Fan et al18 reported a mean myopic shift of -7.11 D at 3 years postoperatively in infants operated before the age of 1 year; Lu et al19 reported a mean myopic shift of -6.46 D at 2 years in 22 eyes, as well as a mean myopic shift of -8.67 D at 6 years in three eyes, among infants operated between the age of 6 and 12 months. In our study, which had a longer follow-up period, the mean 10-year myopic shift was -11.62 ± 5.14 D and myopic progression continued beyond 10 years postoperatively. These findings highlight the importance of using long-term data to guide management decisions, including the selection of target refraction and the determination of appropriate timing for enhancement procedures (eg, IOL exchange).

Our results showed that myopic shift was greatest in the first postoperative year and was correlated with age at operation, which is consistent with findings in the literature.9 10 17 18 19 20 21 Because age at operation is most frequently associated with the magnitude of refractive change, many surgeons prefer to adjust initial hyperopia according to age. McClatchey et al22 recommended targets of +5.00 to +8.00 D in infants aged <1 year, whereas Valera Cornejo et al4 selected targets of +7.00 to +9.00 D in infants of the same age-group. The results of the Infant Aphakia Treatment Study suggested that, to achieve emmetropia at 5 years, immediate postoperative hyperopia should be +10.50 D from 4 to 6 weeks of age and +8.50 D from 7 weeks to 6 months of age.9 However, our results showed considerable variation in myopic shift at 10 years (range, -21.88 to -3.75 D); after adjustment for age, immediate postoperative refraction was not a statistically significant predictor of SER at 10 years. Other studies have shown that initial refraction and IOL undercorrection were not significantly associated with the magnitude or rate of myopic shift9 18 22 23; they also revealed large and unpredictable variations in refractive outcomes after IOL implantation in young infants.10 20 21 22 24 25 At the 3-year follow-up, refractive change ranged from +2.00 to -15.50 D in a study by Gouws et al26 and from -0.47 to -10.69 D in a study by Fan et al.18 Although we observed a trend towards more myopic 10-year refractions in groups with lower initial postoperative hyperopia, there were no significant differences because of substantial variability in the data (Fig 3). The Infant Aphakia Treatment Study showed that the actual and expected amounts of myopic shift differed in a large percentage of patients; 50% of patients exhibited differences of +3.00 to +14.00 D from expected values.9 Therefore, age-adjusted suggested targets only compensate for the mean expected myopic shift; large interpatient variability will often result in unanticipated long-term outcomes for individual patients. Correlation analysis in our study revealed that age at operation only explained 58% of the variance in myopic shift at 10 years. This correlation is presumably influenced by other factors that contribute to myopic progression, such as genetics, ethnicity, outdoor exposure, education level, and extent of near work.27

The achievement of optimal long-term BCVA is another important goal of surgical treatment for congenital cataract. In our study, immediate postoperative refraction of ≥+7.00 D was correlated with worse BCVA. Similarly, in a study of infants who underwent surgery between the ages of 2 and 21 months, with ≥4 years of follow-up, Magli et al10 found that BCVA was higher in infants with initial spherical refraction between +1.00 and +3.00 D than in infants with initial spherical refraction >+3.00 D. In a study that included older children who underwent surgery at or before the age of 8.5 years, Lowery et al11 found that low early postoperative hyperopia (+1.75 to +5.00 D) yielded better longterm BCVA, compared with refractions <+1.75 or >+5.00 D in unilateral cases; no difference was observed in bilateral cases. Another study of older children (surgically treated between the ages of 2 and 6 years) revealed no difference in BCVA between initial postoperative refractive errors of near emmetropia versus undercorrection of +2.00 to +5.50 D23; no patients had initial refraction values >+5.50 D. High initial postoperative hyperopia requires good compliance with refractive correction; in infants, such hyperopia also requires amblyopia treatment because younger children are at higher risk of developing amblyopia. Hyperopia is more amblyogenic than myopia because young children have higher demands for near vision28; moreover, hyperopia causes defocusing in both distance and near vision, particularly among patients who exhibit pseudophakia related to accommodation loss. Studies have shown variable compliance with optical correction and amblyopia treatment after congenital cataract surgery19 29; the use of high-plus spectacles is associated with various optical aberrations. Additionally, contact lenses are suboptimal because one of the original aims of intraocular lens implantation is to avoid the need for contact lens. Myopia is comparatively less amblyogenic because it allows retention of near vision, particularly if the amount of myopia remains low until later in childhood when visual development is more mature.30 Therefore, parental motivation and the likelihood of compliance should be included in decisions regarding postoperative refraction. Ideally, high myopia in adulthood should be minimised. However, this goal should be balanced with the risks of amblyopia and long-term poor vision. Therefore, the selection of high hyperopia (>+7.00 D) as an initial postoperative target refraction should be avoided when possible.

A major strength of our study was the long follow-up period. Additionally, it only included infants who underwent IOL implantation before the age of 1 year because the refractive change in this group exhibits the greatest variability and is most challenging to predict.5

There were some limitations in this study. First, it used a retrospective design and included a small number of patients. Second, there was no objective monitoring of compliance with optical correction or amblyopia treatment. Third, few unilateral cases were included, which may have hindered the detection of larger myopic shifts in post–IOL implantation in unilateral cases. Notably, some previous studies revealed larger myopic shifts after IOL implantation in such cases.4 17 21 22

In conclusion, the large and variable refractive change after IOL implantation in infants aged <1 year hinders the prediction of long-term refractive outcomes in individual patients. When selecting target refraction in infants, low to moderate hyperopia (<+7.00 D) should be considered to balance the avoidance of high myopia in adulthood with the risk of worse long-term visual acuity related to high postoperative hyperopia

Concept or design: All authors.
Acquisition of data: JJT Chan.
Analysis or interpretation of data: JJT Chan.
Drafting of the manuscript: JJT Chan.
Critical revision of the manuscript for important intellectual content: All authors.

All authors had full access to the data, contributed to the study, approved the final version for publication, and take responsibility for its accuracy and integrity.

As an editor of the journal, JC Yam was not involved in the peer review process. Other authors have disclosed no conflicts of interest.

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Ethics approval was granted by the Research Ethics Committee (Kowloon Central/Kowloon East), Hospital Authority (Ref No.: KC/KE-19-0059/ER-4). The requirement for patient consent was waived by the ethics board due to the retrospective nature of the study. The study is conducted in accordance with the ethical principles of the Declaration of Helsinki.

1. Kumar P, Lambert SR. Evaluating the evidence for and against the use of IOLs in infants and young children. Expert Rev Med Devices 2016;13:381-9. Crossref

2. Infant Aphakia Treatment Study Group; Lambert SR, Lynn MJ, et al. Comparison of contact lens and intraocular lens correction of monocular aphakia during infancy: a randomized clinical trial of HOTV optotype acuity at age 4.5 years and clinical findings at age 5 years. JAMA Ophthalmol 2014;132:676-82. Crossref

3. Lambert SR, Aakalu VK, Hutchinson AK, et al. Intraocular lens implantation during early childhood: a report by the American Academy of Ophthalmology. Ophthalmology 2019;126:1454-61. Crossref

4. Valera Cornejo DA, Flores Boza A. Relationship between preoperative axial length and myopic shift over 3 years after congenital cataract surgery with primary intraocular lens implantation at the National Institute of Ophthalmology of Peru, 2007-2011. Clin Ophthalmol 2018;12:395-9. Crossref

5. McClatchey SK, Parks MM. Theoretic refractive changes after lens implantation in childhood. Ophthalmology 1997;104:1744-51. Crossref

6. Enyedi LB, Peterseim MW, Freedman SF, Buckley EG. Refractive changes after pediatric intraocular lens implantation. Am J Ophthalmol 1998;126:772-81. Crossref

7. Astle WF, Ingram AD, Isaza GM, Echeverri P. Paediatric pseudophakia: analysis of intraocular lens power and myopic shift. Clin Experiment Ophthalmol 2007;35:244-51. Crossref

8. Yam JC, Wu PK, Ko ST, Wong US, Chan CW. Refractive changes after pediatric intraocular lens implantation in Hong Kong children. J Pediatr Ophthalmol Strabismus 2012;49:308-13.

9. Weakley DR Jr, Lynn MJ, Dubois L, et al. Myopic shift 5 years after intraocular lens implantation in the Infant Aphakia Treatment Study. Ophthalmology 2017;124:822-7. Crossref

10. Magli A, Forte R, Carelli R, Rombetto L, Magli G. Long-term outcomes of primary intraocular lens implantation for unilateral congenital cataract. Semin Ophthalmol 2015;31:1-6. Crossref

11. Lowery RS, Nick TG, Shelton JB, Warner D, Green T. Long-term visual acuity and initial postoperative refractive error in pediatric pseudophakia. Can J Ophthalmol 2011;46:143-7. Crossref

12. Vasavada A, Chauhan H. Intraocular lens implantation in infants with congenital cataracts. J Cataract Refract Surg 1994;20:592-8. Crossref

13. Plager DA, Yang S, Neely D, Sprunger D, Sondhi N. Complications in the first year following cataract surgery with and without IOL in infants and older children. J AAPOS 2002;6:9-14. Crossref

14. Gordon RA, Donzis PB. Refractive development of the human eye. Arch Ophthalmol 1985;103:785-9. Crossref

15. Indaram M, VanderVeen DK. Postoperative refractive errors following pediatric cataract extraction with intraocular lens implantation. Semin Ophthalmol 2018;33:51-8. Crossref

16. Yam JC, Tang SM, Kam KW, et al. High prevalence of myopia in children and their parents in Hong Kong Chinese population: the Hong Kong Children Eye Study. Acta Ophthalmol 2020;98:e639-48. Crossref

17. Negalur M, Sachdeva V, Neriyanuri S, Ali M, Kekunnaya R. Long-term outcomes following primary intraocular lens implantation in infants younger than 6 months. Indian J Ophthalmol 2018;66:1088-93. Crossref

18. Fan DS, Rao SK, Yu CB, Wong CY, Lam DS. Changes in refraction and ocular dimensions after cataract surgery and primary intraocular lens implantation in infants. J Cataract Refract Surg 2006;32:1104-8. Crossref

19. Lu Y, Ji YH, Luo Y, Jiang YX, Wang M, Chen X. Visual results and complications of primary intraocular lens implantation in infants aged 6 to 12 months. Graefes Arch Clin Exp Ophthalmol 2010;248:681-6. Crossref

20. O’Keefe M, Fenton S, Lanigan B. Visual outcomes and complications of posterior chamber intraocular lens implantation in the first year of life. J Cataract Refract Surg 2001;27:2006-11. Crossref

21. Hoevenaars NE, Polling JR, Wolfs RC. Prediction error and myopic shift after intraocular lens implantation in paediatric cataract patients. Br J Ophthalmol 2011;95:1082-5. Crossref

22. McClatchey SK, Dahan E, Maselli E, et al. A comparison of the rate of refractive growth in pediatric aphakic and pseudophakic eyes. Ophthalmology 2000;107:118-22. Crossref

23. Lambert SR, Archer SM, Wilson ME, Trivedi RH, del Monte MA, Lynn M. Long-term outcomes of undercorrection versus full correction after unilateral intraocular lens implantation in children. Am J Ophthalmol 2012;153:602-8.e1. Crossref

24. Barry JS, Ewings P, Gibbon C, Quinn AG. Refractive outcomes after cataract surgery with primary lens implantation in infants. Br J Ophthalmol 2006;90:1386-9. Crossref

25. Plager DA, Kipfer H, Sprunger DT, Sondhi N, Neely DE. Refractive change in pediatric pseudophakia: 6-year follow-up. J Cataract Refract Surg 2002;28:810-5. Crossref

26. Gouws P, Hussin HM, Markham RH. Long term results of primary posterior chamber intraocular lens implantation for congenital cataract in the first year of life. Br J Ophthalmol 2006;90:975-8. Crossref

27. Morgan IG, French AN, Ashby RS, et al. The epidemics of myopia: aetiology and prevention. Prog Retin Eye Res 2018;62:134-49. Crossref

28. Pascual M, Huang J, Maguire MG, et al. Risk factors for amblyopia in the vision in preschoolers study. Ophthalmology 2014;121:622-9.e1. Crossref

29. Drews-Botsch CD, Hartmann EE, Celano M, Infant Aphakia Treatment Study Group. Predictors of adherence to occlusion therapy 3 months after cataract extraction in the Infant Aphakia Treatment Study. J AAPOS 2012;16:150-5. Crossref

30. O’Hara MA. Pediatric intraocular lens power calculations. Curr Opin Ophthalmol 2012;23:388-93. Crossref

In 2017, breast cancer was the most common cancer and third leading cause of cancer death among women in Hong Kong.1 Additionally, an estimated 20% of breast cancers in Hong Kong were human epidermal growth factor receptor-2 (HER2)-positive.2 3

Intravenous (IV) trastuzumab, in combination with chemotherapy, is licensed for the treatment of HER2-positive early-stage breast cancer and metastatic breast cancer. It must be reconstituted into solution for loading dose infusion over a duration of 90 minutes, followed by maintenance dose infusion over a duration of 30 minutes.4 Additionally, IV trastuzumab is dosed according to each patient’s body weight, with a loading dose of 8 mg/kg followed by a maintenance dose of 6 mg/kg every 3 weeks.4 This regimen consumes considerable healthcare resources, including drug preparation and administration time, clinic and chair time, and physician time dedicated to patient interaction.5

A fixed-dose subcutaneous (SC) formulation of trastuzumab was developed to allow drug administration over approximately 5 minutes, which is much shorter than the duration of IV infusion. The 600-mg dose of SC trastuzumab every 3 weeks is non-dinferior to the IV formulation with respect to efficacy and tolerability.6 7 Furthermore, approximately 90% of patients preferred SC over IV administration of trastuzumab in the PrefHer (Preference for subcutaneous or intravenous administration of trastuzumab in patients with HER2-positive early breast cancer) randomised crossover trials,8 9 which were designed to assess patient preference and healthcare professional satisfaction with both treatment options.

Data from other countries have demonstrated that for SC formulation of trastuzumab, less time is required for drug preparation and administration; moreover, fewer consumables are used.10 11 12 13 A cost-minimisation analysis (CMA) study in Greece demonstrated that the total cost of therapy per patient was 21 870 euros (€) when using the SC formulation of trastuzumab, whereas it was €23 118 when using the IV formation of trastuzumab. The investigators concluded that use of the SC formulation of trastuzumab would provide cost savings for the Greek healthcare system.10 A study in Spain revealed similar findings: the use of the SC formulation of trastuzumab led to a 19.4 to 28.8% cost savings in the hospital.11 Additionally, a time-and-motion study in New Zealand compared medical resource utilisation between the IV and SC formulations of trastuzumab in patients with HER2-positive breast cancer. The potential cost saving was NZ$96.94 per patient per cycle.12 Furthermore, a time-and-motion sub-study13 from the PrefHer trials involving eight countries (Canada, France, Switzerland, Denmark, Italy, Russia, Spain, and Turkey) demonstrated time savings for patient chair, administration by healthcare professionals, and drug preparation.

The SC formulation of trastuzumab is expected to provide cost savings in other countries. However, healthcare systems and modes of clinical services differ between Hong Kong and other countries. Therefore, this study was conducted to investigate cost differences between IV and SC trastuzumab regimens in Hong Kong medical settings, using medical resources utilisation data from other countries.

A CMA model was developed to compare the cost of total care. The CMA approach was used because the clinical efficacy and safety profiles of IV and SC trastuzumab regimens are similar, as demonstrated in the previous studies7 14 15; this fulfils the CMA requirement for two treatments to demonstrate similar efficacy. The following steps were followed in the CMA. We compared direct medical costs related to the IV and SC trastuzumab regimens that produced equivalent health outcomes. The CMA solely focuses on selection of the least costly option. In this study, the CMA was conducted from a hospital perspective. All direct medical costs and full-time equivalent (FTE) hours were included in this study. Drugs, clinic visits for drug administration, specialist out-patient clinic visits, and consumables were regarded as direct medical costs. The time horizon was 18 cycles of treatment, which mimics the duration of treatment for early-stage HER2-positive breast cancer. Drug acquisition cost data were obtained from the manufacturer, whereas costs for hospitalisation and clinic visits were acquired from the 2017 Hong Kong Gazette.16 The drug acquisition cost was based on the dose used in previous clinical trials: IV loading dose of 8 mg/kg and maintenance dose of 6 mg/kg every 3 weeks versus SC fixed dose of 600 mg every 3 weeks. A mean body weight of 57.3 kg was used, based on data from the 2016 Hong Kong Cancer Registry.3

Estimated FTE hour values were obtained from previous literature. These values were regarded as the time (in hours) required for drug preparation and administration, divided by 44 hours, the weekly average working hours for such tasks. The FTE hour values were then converted to monetary values, calculated as the median hourly rate received by individuals in each position. In Hong Kong, nurses and pharmacists are mainly involved in drug preparation and administration; thus, the salaries of these positions were used for estimation of FTE hour values.

All costs were expressed in US dollars (US$1 = HK$7.8), using 2016 as the fiscal year. Because of the short time horizon in the study, no costs were discounted.

Medical resources and FTE hour values were determined by literature review in Embase and MEDLINE, using the key words ‘subcutaneous’, ‘trastuzumab’, ‘time’, ‘cost’, and ‘medical resources’.

The CMA was conducted from the healthcare payer perspective. All continuous variables were described as means ± standard deviations and medians with ranges.

A drug budget impact forecast analysis was performed to determine how changes in the total cost of treatment regimens, including direct medical costs and FTE hours, would impact healthcare expenditures in Hong Kong. Each individual parameter, namely drug acquisition cost for each formulation (±20%), patient body weight (±20%), and time and consumables reported in the literature (based on confidence intervals reported) were analysed independently within specified ranges, whereas other factors were fixed at base-case values. The analysis parameters were chosen based on the findings in previous cost-effectiveness studies.17 A simulation model was used to run 10 000 iterations of the forecast model; for each iteration, model parameters were input as shown in Table 1. We assumed that cost changes were consistent with the beta distribution around the mean. One-way deterministic sensitivity analysis was also performed to evaluate the extent to which the total cost would be affected by changes in the drug acquisition cost for each formulation (±20%), changes in times and consumables obtained from literature (based on confidence intervals reported), and changes in body weight (±20%); this approach is consistent with the methodology used in another cost-effectiveness analysis focused on trastuzumab.17 Figure 1 summarises the analysis process of this study.

In total, 11 studies were identified, eight of which were eligible for analysis.12 18 19 20 21 22 23 24 Three studies were excluded because they did not report the time required for administration or preparation. There are a total of six studies with information on pharmacist time on preparation and nursing time on administration for IV and SC trastuzumab; the remaining two only reported time differences between the two formulations. Among the six studies that reported the time for preparation, four reported the total drug preparation time required for IV and SC trastuzumab, whereas the remaining two only reported time differences. If the SC formulation was used, 0.18 FTE hour of nursing time (7.9 hours) and 0.14 FTE hour of pharmacist time (6.2 hours) could be saved each week. Table 2 summarises the findings from these studies.

After 18 cycles of treatment with SC trastuzumab, the drug acquisition and healthcare professional time costs were reduced by US$9451.28 and US$566.16, respectively, compared with IV trastuzumab. Therefore, US$10 017.44 could be saved for each patient who completed 18 cycles of treatment. The cost of consumables was excluded because only two studies reported this information, and the contributions to overall costs were minimal (NZ$15.2712 and GBP0.6421, respectively). Table 3 summarises the direct medical costs of IV and SC formulations.

The drug budget impact forecast model was most affected by body weight and drug acquisition cost. Cost differences between the IV and SC formulations were reduced by decreases in body weight and IV trastuzumab cost, as well as an increase in SC trastuzumab cost. The effects of changes in nursing time and pharmacist time were smaller. Table 1 summarises the model parameters, and Figure 2 illustrates the effects of each variable on cost differences.

In 2017, 4373 women were diagnosed with invasive breast cancer,1 and approximately 20% of them were HER2-positive.2 3 Furthermore, trastuzumab was the most commonly used targeted therapy (95.3%).3 Assuming that the SC formulation was used (instead of the IV formulation) for all HER2-positive patients receiving trastuzumab and using the 2017 data stated here, an annual saving of over US$8.3 million could be achieved in Hong Kong.

The results of this study suggest that SC trastuzumab would be more cost-effective than its IV counterpart in Hong Kong. Even if lower-cost biosimilar trastuzumab becomes available, the SC formulation will remain less expensive unless there is a substantial reduction in the acquisition cost of IV trastuzumab.

As body weight decreases, the necessary dosage and corresponding expenditures are expected to decrease. Paradoxically, ≤20% increases in body weight had a neutral effect in the analysis. This result could be related to a substantial amount of drug wastage when using weight-based IV trastuzumab, which is consistent with previous findings.19 25 Therefore, further studies are needed to determine the optimal route of administration for patients who are underweight or do not require full doses of trastuzumab because of their clinical conditions.

Although the SC formulation is expected to save time for healthcare professionals,26 27 28 the present analysis suggests that its contribution to the total cost of care is minimal. The cost of drug acquisition has the greatest effect on financial burden.

The use of data from previous time-and-motion studies in other countries may not be appropriate for medical settings in Hong Kong. Further studies should be conducted in Hong Kong to estimate the actual cost savings with respect to healthcare professional time, although theoretical time savings may not accurately represent actual time savings because of clinical activities conducted during administration of trastuzumab.29 Furthermore, data from other countries exhibited wide distributions in terms of standard deviation and range. Nevertheless, the influence of the SC formulation on the total cost-saving effect may be limited, as demonstrated in the sensitivity analysis.

Although the costs of clinic visits and chemotherapy were assumed to be identical throughout 18 cycles of treatment between the two formulations, some patients can receive SC trastuzumab in ambulatory care settings. Thus, the mean savings may have been underestimated in our model.

There were several limitations in this study. First, because of the small number of studies identified in the literature review, consumables could not be included in the CMA. Second, societal cost and patient preferences were not considered because such information is unavailable in Hong Kong. A more patient-centred approach would provide greater insights. Third, time-and-motion analysis and waste handling in Hong Kong were not considered; these factors may have specific impact on drug preparation time and administration time and costs. Fourth, costs for adverse drug reactions were not included because these costs were assumed to be equal for IV and SC trastuzumab regimens. However, this assumption may be incorrect, particularly with regard to infusion-related reactions.

The results of this study suggest that the SC formulation of trastuzumab would be a cost-saving therapy for HER2-positive breast cancer patients in Hong Kong. The drug acquisition cost was the parameter with the greatest effect on the total cost of treatment.

Concept or design: VWY Lee.
Acquisition of data: FWT Cheng.
Analysis or interpretation of data: Both authors.
Drafting of the manuscript: FWT Cheng.
Critical revision of the manuscript for important intellectual content: VWY Lee.

Both authors had full access to the data, contributed to the study, approved the final version for publication, and take responsibility for its accuracy and integrity.

Both authors disclosed no conflicts of interest.

The datasets generated and/or analysed in this study are available from the corresponding author on reasonable request.

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Not applicable because this study did not involve human participants.

1. Hong Kong Cancer Registry, Hospital Authority, Hong Kong SAR Government. Female breast cancer in 2017. Available from: https://www3.ha.org.hk/cancereg/pdf/factsheet/2017/breast_2017.pdf. Accessed 11 May 2020.

2. Yau TK, Sze H, Soong IS, Hioe F, Khoo US, Lee AW. HER2 overexpression of breast cancers in Hong Kong: prevalence and concordance between immunohistochemistry and in-situ hybridisation assays. Hong Kong Med J 2008;14:130-5.

3. Hong Kong Breast Cancer Foundation. Hong Kong Breast Cancer Registry Report No. 8. 2016. Available from: http://www.hkbcf.org/download/bcr_report8/hkbcf_report_2016_full_report.pdf. Accessed 21 May 2017.

4. Genentech. Highlights of prescribing information. 2016. Available from: http://www.gene.com/download/pdf/herceptin_prescribing.pdf. Accessed 8 Aug 2016.

5. Kruse GB, Amonkar MM, Smith G, Skonieczny DC, Stavrakas S. Analysis of costs associated with administration of intravenous single-drug therapies in metastatic breast cancer in a U.S. population. J Manag Care Pharm 2008;14:844-57. Crossref

6. Ismael G, Hegg R, Muehlbauer S, et al. Subcutaneous versus intravenous administration of (neo)adjuvant trastuzumab in patients with HER2-positive, clinical stage I-III breast cancer (Hannah study): a phase 3, open-label, multicentre, randomised trial. Lancet Oncol 2012;13:869-78. Crossref

7. Jackisch C, Kim SB, Semiglazov V, et al. Subcutaneous versus intravenous formulation of trastuzumab for HER2-positive early breast cancer: updated results from the phase III HannaH study. Ann Oncol 2015;26:320-5. Crossref

8. Pivot X, Gligorov J, Müller V, et al. Preference for subcutaneous or intravenous administration of trastuzumab in patients with HER2-positive early breast cancer (PrefHer): an open-label randomised study. Lancet Oncol 2013;14:962-70. Crossref

9. Pivot X, Gligorov J, Müller V, et al. Patients’ preferences for subcutaneous trastuzumab versus conventional intravenous infusion for the adjuvant treatment of HER2- positive early breast cancer: final analysis of 488 patients in the international, randomized, two-cohort PrefHer study. Ann Oncol 2014;25:1979-87. Crossref

10. Mylonas C, Kourlaba G, Fountzilas G, Skroumpelos A, Maniadakis N. Cost-minimization analysis of trastuzumab intravenous versus trastuzumab subcutaneous for the treatment of patients with HER2+ early breast cancer and metastatic breast cancer in Greece. Value Health 2014;17:A640-1. Crossref

11. Gutierrez F, Nazco G, Viña M, Bullejos M, Gonzalez I, Valcarcel C. Economic impact of using subcutaneous trastuzumab. Value Health 2014;17:A641. Crossref

12. North RT, Harvey VJ, Cox LC, Ryan SN. Medical resource utilization for administration of trastuzumab in a New Zealand oncology outpatient setting: a time and motion study. Clinicoecon Outcomes Res 2015;7:423-30. Crossref

13. De Cock E, Pivot X, Hauser N, et al. A time and motion study of subcutaneous versus intravenous trastuzumab in patients with HER2-positive early breast cancer. Cancer Med 2016;5:389-97. Crossref

14. Van den Nest M, Glechner A, Gold M, Gartlehner G. The comparative efficacy and risk of harms of the intravenous and subcutaneous formulations of trastuzumab in patients with HER2-positive breast cancer: a rapid review. Syst Rev 2019;8:321. Crossref

15. Jackisch C, Stroyakovskiy D, Pivot X, et al. Subcutaneous vs intravenous trastuzumab for patients with ERBB2-positive early breast cancer: final analysis of the HannaH phase 3 randomized clinical trial. JAMA Oncol 2019;5:e190339. Crossref

16. Government Logistics Department, Hong Kong SAR Government. Hospital Authority Ordinance (Chapter 113). Revisions to list of charges. Available from: https://www.gld.gov.hk/egazette/pdf/20172124/egn201721243884.pdf. Accessed 30 May 2017.

17. Kurian AW, Thompson RN, Gaw AF, Arai S, Ortiz R, Garber AM. A cost-effectiveness analysis of adjuvant trastuzumab regimens in early HER2/neu-positive breast cancer. J Clin Oncol 2007;25:634-41. Crossref

18. Olofsson S, Norrlid H, Karlsson E, Wilking U, Ragnarson Tennvall G. Societal cost of subcutaneous and intravenous trastuzumab for HER2-positive breast cancer—an observational study prospectively recording resource utilization in a Swedish healthcare setting. Breast 2016;29:140-6. Crossref

19. Ponzetti C, Canciani M, Farina M, Era S, Walzer S. Potential resource and cost saving analysis of subcutaneous versus intravenous administration for rituximab in non-Hodgkin’s lymphoma and for trastuzumab in breast cancer in 17 Italian hospitals based on a systematic survey. Clinicoecon Outcomes Res 2016;8:227-33. Crossref

20. De Cock E, Pan YI, Tao S, Baidin P. Time savings with trastuzumab subcutaneous (SC) injection verse trastuzumab intravenous (IV) infusion: a time and motion study in 3 Russian centers. Value Health 2014;17:A653. Crossref

21. Nawaz S, Samanta K, Lord S, Diment V, Mcnamara S. Cost savings with Herceptin® (trastuzumab) SC vs IV administration: a time & motion study. Breast 2013;22(S1):S112.

22. De Cock E, Tao S, Alexa U, Pivot X, Knoop A. Abstract P5- 15-07: Time savings with trastuzumab subcutaneous (SC) injection vs. trastuzumab intravenous (IV) infusion: first results from a Time-and-Motion study (T&M). Cancer Res 2014;72(24 Suppl):P5-15-07. Crossref

23. De Cock E, Tao S DM-P, Millar D CN. Time savings with trastuzumab subcutaneous (SC) injection vs. trastuzumab intravenous (IV) infusion: a time and motion study in 5 Canadian centres. Proceedings of the Canadian Association for Population Therapeutics (CAPT) Annual Conference; 2013 Nov 17-19; Toronto, Canada.

24. Samanta K, Moore L, Jones G, Evason J, Owen G. PCN39 potential time and cost savings with herceptin (trastuzumab) subcutaneous (SC) injection versus herceptin intravenous (IV) infusion: results from three different English patient settings. Value Health 2012;15:A415. Crossref

25. Nestorovska A, Naumoska Z, Grozdanova A, et al. Subcutaneous vs intravenous administration of trastuzumab in HER2+ breast cancer patients: a Macedonian cost-minimization analysis. Value Health 2015;18:A463. Crossref

26. Rojas L, Muñiz S, Medina L, et al. Cost-minimization analysis of subcutaneous versus intravenous trastuzumab administration in Chilean patients with HER2-positive early breast cancer. PLoS One 2020;15:e0227961. Crossref

27. O’Brien GL, O’Mahony C, Cooke K, et al. Cost minimization analysis of intravenous or subcutaneous trastuzumab treatment in patients with HER2-positive breast cancer in Ireland. Clin Breast Cancer 2019;19:e440-51. Crossref

28. Lopez-Vivanco G, Salvador J, Diez R, et al. Cost minimization analysis of treatment with intravenous or subcutaneous trastuzumab in patients with HER2-positive breast cancer in Spain. Clin Transl Oncol 2017;19:1454-61. Crossref

29. Papadmitriou K, Trinh XB, Altintas S, Van Dam PA, Huizing MT, Tjalma WA. The socio-economical impact of intravenous (IV) versus subcutaneous (SC) administration of trastuzumab: future prospectives. Facts Views Vis Obgyn 2015;7:176-80.

Osteosarcoma arises from primitive bone-forming mesenchymal cells.1 It is the most common primary malignant bone tumour worldwide,1 2 with an annual incidence of 4.8 per million population in the US.2 Moreover, it was one of the most common types of childhood malignancy in Hong Kong in 2017 to 2019.3

In Hong Kong, paediatric patients with high-grade osteosarcoma are treated in accordance with the Hong Kong Paediatric Haematology and Oncology Study Group Treatment Protocol for High-Grade Osteosarcoma (Fig 1), which consists of neoadjuvant chemotherapy, followed by tumour resection and subsequent adjuvant chemotherapy. Histological response to neoadjuvant chemotherapy, defined as tumour chemonecrosis according to the Huvos system,4 is used to stratify patients into good responders (patients with ≥90% tumour chemonecrosis) and poor responders (patients with <90% tumour chemonecrosis). These two groups receive different chemotherapy regimens.

A few prognostic factors for survival have been recognised; these factors include the presence of metastasis at diagnosis5 6 7 and poor tumour chemonecrosis.5 6 7 8 9 However, no specific studies have examined the validity of these factors for patients with osteosarcoma in Hong Kong. Moreover, the presence of lung nodules in computed tomography (CT) scans is a common finding at diagnosis and reassessment. In this study, we reviewed paediatric patients with osteosarcoma at two of the largest paediatric oncology centres in Hong Kong. We sought prognostic factors for event-free survival (EFS) and overall survival (OS), and we assessed lung nodules and metastasis in these patients.

This study included paediatric patients (aged <19 years at diagnosis) with biopsy-proven high-grade osteosarcoma, who were diagnosed from 1 January 2009 to 31 December 2018 at Queen Elizabeth Hospital and Prince of Wales Hospital. The patients’ medical records were reviewed and the following information was collected: demographic data (sex, age at diagnosis, ethnicity, and time from symptom onset to presentation), clinical characteristics (location of tumour, largest dimension of tumour, staging, maximal alkaline phosphatase [ALP] level, calcium and phosphate levels before the start of treatment, and presence of pathological fracture), treatment-related characteristics (time from diagnosis to start of chemotherapy, surgical treatment approach, and histological results of the resected tumour [including tumour chemonecrosis and surgical margin]), and details of metastasis (timing, location, size, and treatment). Radiological reports for the primary tumour were reviewed to determine the presence of local anatomical aggressiveness, which was defined as intra-articular tumour involvement or neurovascular bundle involvement. These risk factors made surgical resection with a negative tumour margin difficult or impossible. Thus, amputation was expected to provide the best local control. There were three indications for limb-salvage surgery (ie, tumour resection and reconstruction). First, clinical and radiological responses were observed during neoadjuvant chemotherapy. Clinical responses were reduction or stabilisation of tumour size and a significant decrease in pain. Radiological responses were an increase in consolidated calcification of the tumour on plain radiographs, reduction or stabilisation of tumour size, and decreased peritumoral oedema on magnetic resonance images. Second, magnetic resonance images showed no neurovascular involvement. Third, there was no need for extensive muscle resection that would render the limb non-functional. Amputation was considered when patients did not meet the above criteria for limb-salvage surgery. It was also considered as a palliative treatment for patients who had large painful tumours with metastatic disease.

The characteristics of lung nodules identified in chest CT scans were recorded from CT reports. The initial and final sizes, laterality, timing of appearance, and mediastinal lymph node involvement were analysed to determine whether their characteristics were sufficiently different for clear distinction. Non-specific lung nodules were either small or remained stable in subsequent scans; they were not biopsied or surgically excised for histological diagnosis. Lung metastases were either large when first observed, had radiological features of metastasis, or demonstrated enlargement in subsequent follow-up scans.

Descriptive data were expressed as median (interquartile range) or frequency (percentage). The Pearson Chi squared test or Fisher’s exact test was used for comparisons of categorical variables. The Mann-Whitney U test was used for comparisons of continuous variables.

The primary outcomes were OS and EFS. Overall survival was defined as the time from diagnosis to death. Event-free survival was defined as the time from diagnosis to the appearance of a new metastasis, progression of an existing metastasis, or death (whichever occurred first). The study end date was 31 December 2020. Patients who had no events were censored at the time of the last follow-up (if they had been lost to follow-up) or at the study end date. Kaplan-Meier curves and log-rank tests were used for survival analysis. To identify prognostic factors for OS and EFS, unadjusted hazard ratios (with 95% confidence intervals) were determined for each potential factor by using Cox proportional hazards models. Significant factors in univariate analyses were included in subsequent multivariate analyses; adjusted hazard ratios (with 95% confidence intervals) were generated in the multivariate analyses.

The secondary outcome was the differentiation of lung nodules. Their initial and final sizes, initial and final lateralities, timing of appearance, and mediastinal lymph node involvement were compared to identify statistical differences.

The SPSS software (Windows version 23.0; IBM Corp, Armonk [NY], US) was used for statistical analysis. P values <0.05 were considered statistically significant.

In total, 52 paediatric patients (22 girls and 30 boys; age 5-18 years) with high-grade osteosarcoma were included in this study. Their baseline demographics are shown in Table 1. Two patients (3.8%) had a predisposing condition: one had Rothmund–Thomson syndrome and the other had osteofibrous dysplasia, from which the high-grade osteosarcoma developed.

For the histological diagnosis, 45 patients (86.5%) had conventional high-grade osteosarcomas. The other subtypes of osteosarcoma were: two giant cell-rich osteosarcomas, one telangiectatic osteosarcoma, one chondrosarcomatous-predominant osteosarcoma, one osteoblastoma-like osteosarcoma, and one chondroblastic osteosarcoma. One patient had features suggestive of small round-cell sarcoma; the tumour was subsequently treated as a conventional high-grade osteosarcoma.

All patients received neoadjuvant chemotherapy with doxorubicin, cisplatin, and high-dose methotrexate (Fig 1). After two courses of chemotherapy, the patients underwent surgical resection of tumours. Almost all patients (n=50, 96.2%) underwent resections of primary tumours. Most patients (n=44, 84.6%) completed the whole course of treatment with adjuvant chemotherapy. Five patients (9.6%) experienced disease progression during treatment. They had terminated chemotherapy early, received palliative care, and eventually died. One patient (1.9%) had disease progression and left Hong Kong to seek a second opinion. In one patient (1.9%), the last course of chemotherapy was omitted because previous chemotherapy had induced clinically significant renal impairment. In one patient (1.9%), the last course of chemotherapy was omitted because of disease progression while receiving treatment.

The lung was the most common site of distant metastasis, both synchronous (n=10, 90.9%) and metachronous (n=12, 80.0%) [Table 2]. Lung nodules in chest CT scans were observed in 39 patients (75.0%). Seventeen nodules (43.6%) were non-specific, while 22 nodules (56.4%) were lung metastases. Factors that could potentially be used to differentiate lung metastases from non-specific lung nodules included laterality of nodules in serial follow-up scans (P=0.004), number of initial nodules (P=0.006), maximal number of nodules (P<0.001), size of initial nodule (P<0.001), and size of the largest nodule (P<0.001) [Table 3].

For the 15 patients who had no lung nodules throughout the course of treatment, OS was very good (93%) [Fig 2]. Only one patient died of local recurrence. For the 17 patients with non-specific lung nodules (Figs 2 and 3), OS was excellent (100%), regardless of the timing of nodule appearance (ie, at diagnosis or later). Among these 17 patients, survival ranged from 2 years 4 months to 11 years 9 months from diagnosis. For the 10 patients with synchronous lung metastasis (Fig 3), OS was 60%, whereas for the 12 patients with metachronous lung metastasis (Fig 2), OS was 33.3%. This difference was not statistically significant (P=0.666).

All patients were followed up until 31 December 2020; thus, the follow-up interval for the last recruited patient was 2 years from diagnosis. The median follow-up interval for all patients was 53 months from diagnosis (range, 4 months to 11 years 11 months). The EFS and OS were 55.8% and 71.2%, respectively. The EFS for patients with localised disease at diagnosis was significantly better than the EFS for patients with metastatic disease at diagnosis (65.9% vs 18.2%; P=0.007). The OS for patients with localised disease was better than the OS for patients with metastatic disease (75.6% vs 54.5%), but the difference was not statistically significant (P=0.26). Similarly, patients with good tumour chemonecrosis had better EFS and OS, compared with poor responders. These values were 78.3% versus 42.3% (P=0.019) and 82.6% versus 65.4% (P=0.209), respectively. Notably, patients with localised disease and good tumour chemonecrosis had very good outcomes, with EFS of 80% and OS of 86.7%. All deaths in this study were caused by disease progression. No patients died of treatment complications or other causes.

The prognostic factors identified for both EFS and OS included the presence of metastasis at diagnosis and throughout, as well as the need for amputation to manage the primary tumour. Local aggressiveness and a larger tumour dimension contributed to OS, while poor tumour chemonecrosis contributed to EFS (Table 4). The following factors did not have a statistically significant impact on EFS or OS: sex, age at diagnosis, primary tumour location in the femur, the presence of a pathological fracture, time from symptom onset to presentation, time from diagnosis to start of chemotherapy, and the histological subtype of the primary tumour.

Multivariate analysis (Table 5) revealed that the presence of metastasis at diagnosis, the need for amputation, and poor tumour chemonecrosis were prognostic factors independently associated with poor EFS, while the presence of metastasis at diagnosis and the need for amputation were prognostic factors independently associated with poor OS. Figure 4 shows the Kaplan-Meier analysis of the effects of the above three independent prognostic factors on EFS.

To our knowledge, this is the first multicentre review of the demographic characteristics and prognostic factors of paediatric high-grade osteosarcoma in Hong Kong. The number of patients included in the study constituted 76.5% of children with osteosarcoma diagnosed in Hong Kong during the study period (unpublished data). Thus, our findings are likely to be representative of the courses of disease and treatment for children with osteosarcoma in Hong Kong. In this study, slightly more patients with high-grade osteosarcoma were boys, the median age at diagnosis was 13.5 years, and the femur was the most common site of involvement. All of these results are comparable to findings in western countries.1 10 Only one patient had a high-grade osteosarcoma in the humerus; no patients had a primary nodule in the axial skeleton, demonstrating the rarity of such nodules. Although our study was limited by a short follow-up interval in some patients, the EFS and OS were comparable to the findings of large studies conducted in other countries,6 8 10 11 as well as the results of a study performed in Hong Kong in 2009.12 The shortest follow-up interval was 2 years from diagnosis. Most events occurred in the first 2 to 3 years, but some poor responders experienced late relapse at 4 to 5 years after initial diagnosis. Thus, a longer follow-up interval is necessary to better determine patient outcomes and more comprehensively assess the incidence of late toxicity.

In terms of prognostic factors, our findings in a cohort of Hong Kong patients confirm the validity of some important prognostic factors recognised in studies performed elsewhere, including the largest dimension of the primary tumour,8 13 14 presence of metastasis at diagnosis,6 8 9 11 and poor tumour chemonecrosis.6 8 9 13 14 15 Additionally, our study identified the need for amputation as an independent prognostic factor for EFS and OS. With respect to mortality, the prognostic effect of the need for amputation has varied among studies.6 13 14 15 16 This variation is presumably because the decision to amputate depends on many factors, including the opinions of orthopaedic surgeons and parental acceptance. In our study, 10 patients underwent amputation; in two of these patients, the procedure was performed with palliative intent to achieve symptomatic control. Both of those patients had metastatic disease at diagnosis, which involved large and painful primary tumours. Thus, risk stratification of patients according to the need for amputation may enable the selection of patients with more advanced disease. Nonetheless, in our cohort, all surgical margins were negative in both limb-salvage surgery and amputation groups. Moreover, local recurrence was uncommon. Thus, our findings may provide insights that can be used to update risk stratification protocols for paediatric patients with osteosarcoma. In the current treatment protocol, there is a considerable delay between initial diagnosis and risk stratification (at week 16), which is performed after tumour resection and when tumour chemonecrosis data are available. However, the surgical approach is usually determined after approximately 4 to 5 weeks of treatment, when reassessment imaging is conducted. If aggressive features are observed at diagnosis (eg, a massive tumour, early intra-articular tumour involvement, or early neurovascular bundle involvement), the discussion of possible amputation may have already begun. Thus, the presence of such features, or the early recognition of the need for amputation, may be suitable for risk stratification after validation in larger-scale studies.

In recent decades, there has been extensive research into surrogate markers for aggressiveness in osteosarcoma. In some studies, the levels of ALP8 9 14 15 17 and lactate dehydrogenase18 19 20 were identified as significant prognostic factors. Although the maximal ALP level was not associated with EFS or OS in our study, some studies have demonstrated a positive association between the serum ALP level and tumour volume.21 This association is presumably related to the increased rate of bone remodelling in the tumour. However, the serum ALP level is also elevated in teenagers because of increased bone remodelling during periods of rapid growth. Thus, a universal cut-off for all paediatric patients may not provide the greatest prognostic accuracy.22 Some studies23 have explored methods to increase the age specificity of serum ALP levels. However, more validation and larger-scale studies are required before these methods can be widely adopted. Whereas the serum lactate dehydrogenase level showed a weaker association with tumour volume,21 a change in this level is more likely to be associated with a non-specific increase in tumour metabolism. Currently, the serum lactate dehydrogenase level is not included in pretreatment staging and investigation protocols; thus, it is not routinely checked. For investigation purposes, it should also be included in baseline investigations.

Because most biochemical parameters are not accurate surrogate markers for the aggressiveness of osteosarcoma, technological advancements have enabled molecular and genetic profiling of osteosarcomas to become the focus of research in the past 10 to 15 years.22 24 25 These studies may provide insights concerning the ‘non-conforming’ behaviour of certain tumours in our patients; examples include locally aggressive primary tumours that warrant amputation but demonstrate good tumour chemonecrosis, or tumours that show disease progression despite good tumour chemonecrosis. The current literature suggests that paediatric osteosarcoma is a heterogeneous disease,21 26 although general knowledge of the disease remains incomplete. Despite advancements in surgical techniques for primary tumour resection,27 improvements in the accuracy of staging imaging, and enhancements of supportive care, further revisions are needed concerning the medical treatment of paediatric osteosarcoma. Thus, molecular and genetic studies are essential and may facilitate further stratification of patients with osteosarcoma into different risk groups, which may require tailored treatment regimens for better outcomes. Future studies may also enable the identification of molecular nodules for targeted therapy or immunotherapy, which lead to considerable advances in the treatment of osteosarcoma.

Lung nodules were common in the initial staging and serial follow-up CT scans of our patients. The small size of some nodules hindered characterisation. They might represent benign lung pathologies. However, they may also represent micro-metastases which were responsive to chemotherapy. Thus, they remained stable in size and number on subsequent scans, suggesting that they persisted as scars. Patients with non-specific lung nodules had an excellent prognosis, with an OS rate of 100% in our study. However, repeated scans are needed for the follow-up and characterisation of such lung nodules. Additionally, the appearance of any new lung nodules on CT scans creates a considerable psychological burden for patients and their families. Our study identified parameters that can help to differentiate true lung metastases from non-specific nodules, including the number of initial nodules, maximal number of nodules, initial nodule size, and largest nodule size. A study in Hong Kong in 201128 also identified number (≤5 vs >5), size, and laterality of lung nodules as important prognostic factors for survival, whereas a study in the US in 201129 found that survival was worse for central lung metastases than for peripherally located lung metastasis. Additional larger-scale risk stratification studies are needed to clearly delineate the cut-offs for size, number, laterality, and location of initial lung nodules. The establishment of a scoring system that considers parameters of lung nodules observed in chest CT scans may enable prediction of the risk of malignancy, thus improving early detection of lung metastasis and reducing unnecessary anxiety for patients and their families. Furthermore, standardised reviews of CT scans will help to ensure more uniform classification of lung nodules, particularly when the nodules are small.

With respect to confirmed lung metastasis, the situation becomes increasingly complicated. For a single synchronous or metachronous lung metastasis, metastasectomy was conducted whenever surgically feasible because it has been regarded as the primary treatment approach in multiple studies.30 31 32 However, given the diversity of treatments, there was no consensus regarding treatment strategies for multiple metastases or local recurrence. This is presumably because the effects of different chemotherapy regimens and targeted therapies remain under investigation.11 33 34 35 36 In our study, surgical resection of lung metastasis whenever possible, together with zoledronic acid, generally achieved durable clinical remission for >5 years. Long-term randomised controlled trials of different chemotherapy or targeted therapy regimens should be conducted to determine the most cost-effective regimens that improve survival for relapsed paediatric patients with high-grade osteosarcoma. Many centres in other nations are performing karyotyping and genetic analysis of osteosarcoma tumour cells to identify targetable mutations.11 24 37 However, these tests are not routinely conducted for standard care in Hong Kong. Collaborations with centres in other nations should be pursued to facilitate the implementation of international standards in Hong Kong.

To our knowledge, this represents the first multicentre review of paediatric high-grade osteosarcoma in Hong Kong. Important prognostic factors, including metastatic disease at diagnosis and poor tumour chemonecrosis, were validated. The need for amputation may reflect local aggressiveness, which influences OS. Larger-scale studies of high-grade osteosarcoma in paediatric patients should be conducted over a longer period of time to better understand the characteristics, patterns, and prognostic factors.

Concept or design: GPY Tong, CK Li.
Acquisition of data: GPY Tong.
Analysis or interpretation of data: GPY Tong, WF Hui, CK Li.
Drafting of the manuscript: GPY Tong, WF Hui, KC Wong, CK Li.
Critical revision of the manuscript for important intellectual content: All authors.

All authors had full access to the data, contributed to the study, approved the final version for publication, and take responsibility for its accuracy and integrity.

The authors have no conflicts of interest to disclose.

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

This study was approved by the Research Ethics Committee (Kowloon Central/Kowloon East Cluster and New Territories East Cluster), Hospital Authority Hong Kong (Ref: KC/KE-19-0301/ER-1, 2019.712). The requirement for patient informed consent was waived.

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23. Shimose S, Kubo T, Fujimori J, Furuta T, Ochi M. A novel assessment method of serum alkaline phosphatase for the diagnosis of osteosarcoma in children and adolescents. J Orthop Sci 2014;19:997-1003.Crossref

24. de Nigris F, Zanella L, Cacciatore F, et al. YY1 overexpression is associated with poor prognosis and metastasis-free survival in patients suffering osteosarcoma. BMC Cancer 2011;11:472. Crossref

25. Morrow JJ, Khanna C. Osteosarcoma genetics and epigenetics: emerging biology and candidate therapies. Crit Rev Oncog 2015;20:173-97. Crossref

26. Poos K, Smida J, Maugg D, et al. Genomic heterogeneity of osteosarcoma–shift from single candidates to functional modules. PLoS One 2015;10:e0123082. Crossref

27. Wong KC, Kumta SM. Use of computer navigation in orthopedic oncology. Curr Surg Rep 2014;2:47. Crossref

28. Rasalkar DD, Chu WC, Lee V, Paunipagar BK, Cheng FW, Li CK. Pulmonary metastases in children with osteosarcoma: characteristics and impact on patient survival. Pediatr Radiol 2011;41:227-36. Crossref

29. Letourneau PA, Xiao L, Harting MT, et al. Location of pulmonary metastasis in pediatric osteosarcoma is predictive of outcome. J Pediatr Surg 2011;46:1333-7. Crossref

30. Daw NC, Chou AJ, Jaffe N, et al. Recurrent osteosarcoma with a single pulmonary metastasis: a multi-institutional review. Br J Cancer 2015;112:278-82. Crossref

31. Matsubara E, Mori T, Koga T, et al. Metastasectomy of pulmonary metastases from osteosarcoma: prognostic factors and indication for repeat metastasectomy. J Respir Med 2015;2015:1-5. Crossref

32. de Bree E, Drositis I, Michelakis D, Mavroudis D. Resection of pulmonary metastases in osteosarcoma. Is it justified? Hellenic J Surg 2018;90:293-8. Crossref

33. Geller DS, Gorlick R. Osteosarcoma: a review of diagnosis, management, and treatment strategies. Clin Adv Hematol Oncol 2010;8:705-18.

34. Warwick AB, Malempati S, Krailo M, et al. Phase 2 trial of pemetrexed in children and adolescents with refractory solid tumors: a Children’s Oncology Group study. Pediatr Blood Cancer 2013;60:237-41. Crossref

35. Jacobs S, Fox E, Krailo M, et al. Phase II trial of ixabepilone administered daily for five days in children and young adults with refractory solid tumors: a report from the children’s oncology group. Clin Cancer Res 2010;16:750-4. Crossref

36. Geoerger B, Chisholm J, Le Deley MC, et al. Phase II study of gemcitabine combined with oxaliplatin in relapsed or refractory paediatric solid malignancies: an innovative therapy for children with Cancer European Consortium Study. Eur J Cancer 2011;47:230-8. Crossref

37. Saraf AJ, Fenger JM, Roberts RD. Osteosarcoma: accelerating progress makes for a hopeful future. Front Oncol 2018;8:4. Crossref

Perinatal and neonatal mortality rates are important measures of the quality of medical care during pregnancy, childbirth, and the neonatal period. Although the global neonatal death (NND) rate has demonstrated a decreasing trend over the past 30 years, from 37/1000 livebirths to 17/1000 livebirths between 1990 and 2020,1 NND rates considerably vary among regions. According to the 2020 report by the World Health Organization, the NND rates were the highest in Africa (27/1000 livebirths), Eastern Mediterranean (25/1000 livebirths) and South-East Asia (18/1000 livebirths); the NND rates were the lowest in Americas (7/1000 livebirths), Western Pacific (5/1000 livebirths) and Europe (4/1000 livebirths).1 In Hong Kong, territory-wide statistics indicated NND rates of 1.2/1000 and 1.0/1000 livebirths in 2004 and 2014, respectively2; these rates are lower than the rates in most regions, according to the above report by the World Health Organization. However, there have been few in-depth studies concerning the trends and underlying causes of NND in Hong Kong. Our group recently published two epidemiological studies regarding singleton pregnancies in Hong Kong, which revealed a decreasing trend in the rate of stillbirths among singleton pregnancies from 3.61/1000 in 2000-2009 to 3.09/1000 in 2010-2019.3 The rate of perinatal mortality in multiple pregnancies also decreased from 5.52/1000 to 4.59/1000 during the same period.4 These improvements in mortality rates have mainly occurred because of advances in the prenatal diagnosis and management of fetal malformations and genetic diseases, as well as improvements in the antenatal management of multiple pregnancies. The present study investigated the trends of NNDs among singleton pregnancies in the largest tertiary perinatal centre in Hong Kong, as well as changes in the characteristics and aetiologies of NND over the past two decades, with the goal of improving perinatal care in Hong Kong.

This retrospective study included all singleton pregnancies that delivered at the Prince of Wales Hospital from 1 January 2000 to 31 December 2019. The STROBE reporting guideline was followed when writing this manuscript. The Prince of Wales Hospital is affiliated with The Chinese University of Hong Kong and serves a large population of 1.7 million in the New Territories East region of Hong Kong; the hospital’s annual delivery rate is 6000 to 7000 (approximately one-sixth of the total births in all public hospitals in Hong Kong, and one-ninth of the total births in Hong Kong). Both the obstetric unit and the neonatal unit are the largest in Hong Kong. The neonatal unit is a Level III centre that consists of a 22-bed neonatal intensive care unit (NICU). The staff of the neonatal unit worked closely with the staff of the obstetric unit to manage high-risk deliveries from complicated pregnancies, as well as pregnancies that required fetal intervention after referral from other hospitals.

Complicated pregnancies were discussed in weekly perinatal meetings attended by the staff of both the obstetric unit and the neonatal unit; discussions of these pregnancies focused on management plans and the optimal timing of delivery. Relevant disciplines (eg, paediatric surgery, cardiology, neurosurgery, radiology, or otolaryngology) were included as appropriate. In cases where a specialist service outside of Prince of Wales Hospital (eg, cardiothoracic surgery) was anticipated after delivery, specialists from other centres were invited to participate in management planning. Active resuscitation was provided for all viable neonates delivered at ≥24 weeks. For extremely premature neonates with borderline viability (ie, delivered at 22-23 weeks of gestation), considering the high risks of mortality and long-term morbidity, comprehensive counselling was provided to affected families, which allowed them to select active resuscitation or no resuscitation at birth. In accordance with the departmental protocol, the paediatric unit was requested to prepare for rapid management of deliveries that involved specific maternal or fetal conditions (eg, prematurity, fetal distress, instrumental deliveries, and antenatally diagnosed severe congenital abnormalities). Neonates were managed in the NICU in accordance with the standard unit protocols and guidelines. These protocols were updated regularly according to the latest evidence-based consensus guidelines and recommendations established by clinicians in Hong Kong and other nations. In accordance with departmental guidelines, comprehensive investigations were performed to determine the cause of death in all cases of NND. All NNDs were referred for autopsy unless the cause of death was clearly identified (eg, trisomy 13 or 18 confirmed by genetic tests). If the cause of NND could not be identified, the case was reported to the coroner. If NND was caused by multiple pathologies, the most clinically significant pathology that contributed to death was selected for analysis.

All cases of NND in livebirths of singleton pregnancies during the study period were retrieved using the Hospital Authority’s Clinical Data Analysis and Reporting System. Cases of NND in livebirths of multiple pregnancies were excluded. The included cases of NND were divided into two groups according to the decade of birth. The first group (ie, first decade) included cases of NND among singleton pregnancies that delivered between 1 January 2000 and 31 December 2009. The second group (ie, second decade) included cases of NND among singleton pregnancies that delivered between 1 January 2010 and 31 December 2019. Obstetric data including maternal demographics (maternal age, maternal illnesses, antenatal complications, and treatment) and birth history (gestation, mode of delivery, sex, birth weight, Apgar scores, and neonatal resuscitation) were collected from the Obstetric Specialty Clinical Information System. Neonatal data comprising neonatal diagnoses, interventions, and length of survival were retrieved from the Hospital Authority’s Clinical Management System. When further details were needed, individual case records were retrieved for analysis.

All NNDs were categorised as early NND (within 7 days after birth) or late NND (within 8-28 days after birth). Early, late, and total rates of NND, as well as baseline demographics, were compared between the two groups. Causes of death were divided into four main categories: prematurity, hypoxic-ischaemic encephalopathy (HIE), congenital abnormalities, and sepsis. Congenital abnormalities were defined by characteristic features on physical examination, confirmed by either genetic tests, diagnostic investigations, or autopsy. Sepsis was defined on the basis of positive cultures established using samples of blood, urine, cerebrospinal fluid, or tissue from the affected neonate. Hypoxic-ischaemic encephalopathy was diagnosed in accordance with criteria derived from international guidelines.5

The analysis was performed using data that overlapped with a previous study.3 Categorical variables were compared by the Chi squared test or Fisher’s exact test. The threshold of statistical significance was defined as a two-sided P value of <0.05. Data analysis was performed with the SPSS software (Windows version 22.0; IBM Corp, Armonk [NY], United States).

There were 124 281 livebirths from singleton pregnancies between 2000 and 2019 (Table 1). The number of livebirths increased by 12.7% from 58 442 in the first decade (2000-2009) to 65 839 in the second decade (2010-2019). There were 184 NNDs (1.48/1000 livebirths) between 2000 and 2019, including 97 in the first decade (1.66/1000 livebirths) and 87 in the second decade (1.32/1000 livebirths). Overall, there were 136 cases (73.9%) of early NND and 48 cases (26.1%) of late NND.

The maternal demographic characteristics of all singleton pregnancies during the study period were reported in our previous paper.3 The distribution of gestational age among all livebirths did not differ between the two decades (P=0.237) [Table 2]. The highest rate of NND (195.12/1000 livebirths) was observed in extremely preterm neonates (≤27 weeks of gestation) [Table 3]. The rate of NND decreased with increasing gestational age, such that NND rates were 48.42/1000, 20.13/1000, 4.98/1000, and 0.37/1000 for neonates delivered at gestational ages of 28-30 weeks, 31-33 weeks, 34-36 weeks, and ≥37 weeks, respectively. Compared with the first decade, there was a significant reduction (75.2%) in the rate of NND among neonates delivered at 31-33 weeks of gestation during the second decade (34.73/1000 vs 8.63/1000; P=0.001); however, there were no significant differences in the rates of NND among neonates in other gestational groups.

The primary causes of NND in the two decades are shown in Table 4. Congenital or genetic abnormalities was the most common cause of NND (82 of 184; 44.6%) during the 20-year study period. Other common causes of NND were prematurity (69 cases; 37.5%), sepsis (16 cases; 8.7%), and HIE (15 cases; 8.2%) [Supplementary Fig].

Chromosomal abnormalities caused 18.3% (15 of 82) of NNDs related to congenital or genetic abnormalities; all of these abnormalities were trisomy 13 or 18. Structural abnormalities caused 63.4% (52 of 82) of NNDs related to congenital or genetic abnormalities, and respiratory system abnormalities were the most common causes in both decades (22 cases). These respiratory system abnormalities included congenital diaphragmatic hernia (13 cases), pulmonary hypoplasia (5 cases), alveolar capillary dysplasia (2 cases), and tracheal stenosis or atresia (2 cases). The next most common causes were congenital cardiac abnormalities (8 cases), including transposition of the great arteries (2 cases), total anomalous pulmonary venous drainage (2 cases), endocardial cushion defect (2 cases), hypoplastic left heart syndrome (1 case), and congenital heart block (1 case); central nervous system abnormalities (8 cases), including anencephaly (3 cases), central nervous system malformation (4 cases), and brain tumour (1 case); and musculoskeletal abnormalities (7 cases), including fetal akinesia syndrome with arthrogryposis (3 cases), spinal muscular atrophy (2 cases), and skeletal dysplasia (2 cases). There were two cases of gastrointestinal abnormalities (volvulus and bowel atresia with meconium peritonitis), two cases of sacrococcygeal teratoma, two cases of multiple abnormalities, and one case of bilateral renal agenesis (a urogenital abnormality). There were also nine cases of haemoglobin Barts disease and six cases of idiopathic hydrops. There was a statistically significant decline in the rate of NND caused by congenital or genetic abnormalities, from 0.82/1000 livebirths in the first decade to 0.52/1000 livebirths in the second decade (P=0.037).

There were no significant differences in the rates of NND caused by prematurity, sepsis, or HIE between the two decades. Cases of NND due to sepsis were mainly caused by Group B Streptococcus in the first decade and Escherichia coli in the second decade. The majority of HIE cases (67.7%) were related to acute intrapartum events, including placenta abruption (5 cases), uterine rupture (2 cases), vasa praevia (1 case), cord accident (1 case), and chorioamnionitis (1 case).

The NND rate in our tertiary centre is consistent with the rate of 1.2/1000 livebirths in the territory-wide report2 and lower than the rates in many developed countries (eg, the United States, Australia, and nations located in Europe; neonatal mortality rates of 2-3/1000 livebirths).1 2 The global NND rate has been decreasing over the past two decades because of advances in perinatal care.2 Our overall NND rate decreased by 20%, from 1.66/1000 in the first decade to 1.32/1000 in the second decade. This decrease is mainly the result of a decrease in NNDs related to congenital or genetic disorders, as well as a decrease in NNDs among neonates delivered at 31-33 weeks of gestation.

Similar to our previous report, which showed a reduction in the rate of congenital or genetic abnormality-related stillbirths,3 the present study showed that the rate of congenital or genetic abnormality-related NNDs decreased from 0.82/1000 livebirths in the first decade to 0.52/1000 livebirths in the second decade. This decline was presumably because of improvements in antenatal screening and the early detection of lethal congenital abnormalities, which resulted in termination of pregnancy before 24 weeks of gestation. Universal first trimester combined screening for Down syndrome was implemented by the Hospital Authority in 2010.6 In 2011, non-invasive cell-free fetal DNA tests for common trisomies, as well as chromosomal microarrays for the diagnosis of chromosomal microdeletion syndromes, became available in the private sector.7 8 Expanded antenatal screening of inborn errors of metabolism was launched in the private sector in 2013; this expanded screening has gradually become available in the public sector since 2018.9 Although we expected a decline in the rate of trisomy-related NNDs after universal aneuploidy screening became available in 2011, there was an increase in the rate of trisomy 18–related NNDs (from 2 cases to 7 cases). A review of the individual cases revealed that the rate of trisomy 13–related NNDs decreased from six cases in the first decade to none in the second decade. Conversely, five of the seven cases of trisomy 18–related NND in the second decade were in pregnancies that had not received any screening; all of these five cases occurred during the period from 2010 to 2013. The other two cases of trisomy 18–related NND were diagnosed during prenatal screening, but the parents chose conservative management rather than termination of pregnancy. To further reduce mortality associated with hereditary genetic disorders such as spinal muscular atrophy and fetal akinesia syndrome (which caused NND in 5 cases), there is a need for expanded carrier screening of parents, particularly in families with a history of consanguineous marriage.10 11

The other main congenital abnormalities that caused NND in our cohort were cardiorespiratory and neuromusculoskeletal disorders, among which congenital diaphragmatic hernia was the most common. Although survival was common among neonates with mild to moderate congenital diaphragmatic hernia, neonates with severe congenital diaphragmatic hernia had a survival rate of 10% to 20% because of pulmonary hypoplasia. A recent large randomised controlled trial showed that fetoscopic endoluminal tracheal occlusion can improve the survival rate to 40% to 50%.12 In our unit, a baby survived after treatment with fetoscopic endoluminal tracheal occlusion in 2020.13 Pulmonary hypoplasia caused by hydrothorax or lung tumours can also be effectively and safely treated before birth with newly designed instruments such as the Somatex^® shunt for pleuro-amniotic shunting, and radiofrequency ablation of the tumour feeding artery, respectively.14 15 Fetal tumours such as sacrococcygeal teratoma, placental chorioangioma, and lung tumours remain challenging to manage because the rapid growth of tumours in utero increases the risk of preterm birth and leads to impaired neonatal cardiac function. We have demonstrated improvements in survival after in utero embolisation of chorioangioma using cyanoacrylate, and after in utero radiofrequency ablation of lung sequestration.15 16 Although spinal muscular atrophy has no cure, it can be prevented by accurate parental carrier screening using genomic technology and prenatal diagnosis.10

The rate of idiopathic hydrops fetalis–related NND decreased from 5.2% in the first decade to 1.1% in the second decade. Advances in antenatal diagnostic techniques in recent years have identified the underlying causes of many conditions which may have previously been regarded as ‘idiopathic hydrops fetalis’.17 The early diagnosis of treatable conditions in the antenatal period can prevent the development of severe hydrops fetalis and subsequent NND.17 18 Intrauterine blood transfusion for fetal anaemia and anti-arrhythmic treatment19 has significantly reduced the rate of hydrops fetalis, resulting in improved survival and long-term outcomes.

Our study showed a significant (75.2%) decrease in the rate of NND among moderately preterm neonates (31-33 weeks of gestation) from 34.73/1000 in 2000-2009 to 8.63/1000 in 2010-2019; however, the rate of NND did not change in other gestational groups (Table 3). The decrease in mortality among moderately preterm neonates could be attributed to the implementation of multiple approaches for the management of such neonates since 2010, including improved ventilation strategies with early extubation to non-invasive ventilation, new methods for surfactant administration (eg, the ‘less invasive surfactant administration’ method), and improvements in NICU care through continuous quality improvement programmes. The rate of NND among extremely preterm neonates (24-27 weeks of gestation) was 175-211/1000, which is comparable with the rates in other developed countries (139-326/1000).20 It is difficult to reduce the rate of NND among extremely preterm neonates. Research is ongoing regarding artificial placenta and womb technology, and the results may improve the survival of extremely preterm neonates in the future.21

The rate of prematurity-related NND can be reduced by preventing preterm delivery; however, this prevention remains a challenging goal. Although our overall preterm delivery rate of 7% is lower than the rates in other developed countries,1 22 it has remained at this level for the past two decades, and there has been no variations in gestation age-specific neonatal mortality among preterm categories. In a previous study, we demonstrated that measurements of cervical length can help to identify pregnant women who are at higher risk of preterm delivery, although the risk prediction values for Chinese women in Hong Kong are lower than the corresponding values for women in non-Asian countries.23 Additional methods to predict the onset of labour (eg, cervical elastography, immune markers, and genetic markers) should be explored to improve accuracy.24 25 Prophylactic progesterone is effective in reducing the risk of preterm delivery among women who have a short cervix.26 Although the use of a cervical ring pessary reportedly had a similar effect in a Spanish study,27 this result was not confirmed by a randomised controlled trial in Hong Kong28 or by subsequent meta-analysis.29 Pre-eclampsia is a common complication that requires medically induced preterm delivery. First trimester screening of pre-eclampsia, followed by prophylactic aspirin treatment in high-risk cases, is a proven strategy to effectively delay the onset of pre-eclampsia and the associated preterm births.29 Our recent study confirmed the accuracy of a screening programme for pre-eclampsia.30 Reductions in pre-eclampsia–related preterm births and mortality may be achieved by the implementation of a universal screening programme in the future.

Despite advances in NICU management of HIE and the use of therapeutic hypothermia since 2011, the rate of HIE-related NND did not improve during the study period. Approximately 67% of HIE-related NNDs were caused by acute and unpredictable perinatal events such as cord prolapse, uterine rupture, vasa praevia, or placental abruption. We previously reported an infant death secondary to severe cerebral palsy as a result of prolonged shoulder dystocia, which occurred during the first study decade.31 Therefore, team-based training for the above perinatal events is needed to ensure that the obstetric team can respond appropriately and efficiently so that the risk of HIE and associated perinatal mortality can be reduced. During these situations that involved irreversible peripartum hypoxia, we showed that umbilical cord arterial pH decreased as the length of the bradycardia-to-delivery interval increased.31 32 33 With appropriate training, we were able to achieve a median bradycardia-to-delivery interval of 10 minutes and a median decision-to-delivery interval of 11 minutes,32 which was effective in preventing peripartum mortality. Furthermore, we showed that during umbilical cord prolapse, the knee-chest position is the most effective approach for relieving fetal compression of the prolapsed cord34; we also formulated an algorithm for acute resolution of cord prolapse.35 Shoulder dystocia is associated with macrosomia, but the optimal fetal weight cut-off for prophylactic elective caesarean delivery has not been established. Our previous study suggested a cut-off of 4.2 kg may help to prevent shoulder dystocia.36 With effective training and correct use of manoeuvres such as posterior arm delivery, we recently showed that the head-to-delivery interval can be shortened and the Apgar scores can be improved.37 38 We also proposed a modified posterior axillary sling technique to relieve severe shoulder dystocia.39

The rate of severe sepsis-related NND is low and has been decreasing over the past two decades. Since the implementation of universal Group B Streptococcus screening and peripartum antibiotic prophylaxis in 2012, the rate of early onset Group B Streptococcus infection has significantly decreased from 1/1000 to 0.24/1000 births.40 Despite the reduced risk of neonatal Group B Streptococcus infection, recent reports have shown an increase in Escherichia coli–related early-onset neonatal sepsis.41 Clinicians should remain vigilant concerning the presence of chorioamnionitis and risk factors for sepsis.

To our knowledge, this is the largest and most comprehensive analysis of neonatal mortality during a 20-year period in Hong Kong. Nevertheless, there were a few limitations in this study. First, it was performed in a single large centre, rather than in a large segment of the population. Because the Prince of Wales Hospital is the main centre for fetal intervention in Hong Kong, many high-risk pregnancies are referred from adjacent hospitals, which may have led to an over-representation of complex cases and a bias towards worse outcomes. Second, some case details were not available for analysis because of the retrospective nature of the study. Third, our study excluded cases of NND among neonates with borderline viability (gestational age: 22-23 weeks and 6 days) because such NNDs are regarded as miscarriages based on the legal definition in Hong Kong. Although some parents of neonates with borderline viability requested resuscitation, the survival rate in this small group was zero according to a recent study in our centre.42 Finally, because the rate of NND is very low in Hong Kong, this study could have been strengthened by including data regarding the rates of major morbidities (eg, cerebral palsy). Nonetheless, our findings provide a basis for future territory-wide reviews of perinatal outcomes.

Hong Kong has one of the lowest rates of NND worldwide. The neonatal mortality in our centre has decreased from 1.66/1000 livebirths to 1.32/1000 livebirths over the past two decades, mainly because of improvements in the prenatal diagnosis and treatment of congenital or genetic abnormalities, as well as an improved survival rate among moderately preterm neonates. Future improvements should focus on in utero treatment, expanded carrier screening for genetic abnormalities, and the prevention of preterm birth and pre-eclampsia.

Concept or design: GPG Fung, TY Leung.
Acquisition of data: All authors.
Analysis or interpretation of data: GPG Fung, TY Leung.
Drafting of the manuscript: GPG Fung, TY Leung.
Critical revision of the manuscript for important intellectual content: All authors.

All authors had full access to the data, contributed to the study, approved the final version for publication, and take responsibility for its accuracy and integrity.

All authors have disclosed no conflicts of interest.

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Ethical approval was obtained from the Joint Chinese University of Hong Kong–New Territories East Cluster Clinical Research Ethics Committee (Ref No.: CRE 2017.442).

1. World Health Organization. Neonatal mortality rate (0 to 27 days per 1000 live births) (SDG 3.2.2). Available from: https://www.who.int/data/gho/indicator-metadata-registry/imr-details/67. Accessed 5 Oct 2022.

2. Hong Kong College of Obstetricians & Gynaecologists. Territory-wide audit in obstetrics & gynaecology 2014. Available from: https://www.hkcog.org.hk/hkcog/Download/Territory-wide_Audit_in_Obstetrics_Gynaecology_2014.pdf. Accessed 15 Jun 2022.

3. Wong ST, Tse WT, Lau SL, Sahota DS, Leung TY. Stillbirth rate in singleton pregnancies: a 20-year retrospective study from a public obstetric unit in Hong Kong. Hong Kong Med J 2022;28:285-3. Crossref

4. Lau SL, Wong ST, Tse WT, et al. Perinatal mortality rate in multiple pregnancies: a 20-year retrospective study from a tertiary obstetric unit in Hong Kong. Hong Kong Med J 2022;28:347-56. Crossref

5. Executive summary: Neonatal encephalopathy and neurologic outcome, second edition. Report of the American College of Obstetricians and Gynecologists’ Task Force on Neonatal Encephalopathy [editorial]. Obstet Gynecol 2014;123:896-901. Crossref

6. Sahota DS, Leung WC, Chan WP, To WW, Lau ET, Leung TY. Prospective assessment of the Hong Kong Hospital Authority universal Down syndrome screening programme. Hong Kong Med J 2013;19:101-8.

7. Chan YK, Leung WC, Leung TY, et al. Women’s preference for non-invasive prenatal DNA testing versus chromosomal microarray after screening for Down syndrome: a prospective study. BJOG 2018;125:451-9. Crossref

8. Hui AS, Chau MH, Chan YM, et al. The role of chromosomal microarray analysis among fetuses with normal karyotype and single system anomaly or nonspecific sonographic findings. Acta Obstet Gynecol Scand 2021;100:235-43. Crossref

9. Chong SC, Law LK, Hui J, Lai CY, Leung TY, Yuen YP. Expanded newborn metabolic screening programme in Hong Kong: a three-year journey. Hong Kong Med J 2017;23:489-96. Crossref

10. Chan OY, Leung TY, Cao Y, et al. Expanded carrier screening using next-generation sequencing of 123 Hong Kong Chinese families: a pilot study. Hong Kong Med J 2021;27:177-83. Crossref

11. Siong KH, Au Yeung SK, Leung TY. Parental consanguinity in Hong Kong. Hong Kong Med J 2019;25:192-200. Crossref

12. Deprest JA, Nicolaides KH, Benachi A, et al. Randomized trial of fetal surgery for severe left diaphragmatic hernia. N Engl J Med 2021;385:107-18. Crossref

13. TOPick. 3次流產40歲婦終懷孕胎兒27周時橫膈膜穿洞威爾斯婦產科團隊施宮內手術力保胎兒順利出世. Available from: https://topick.hket.com/article/2757416. Accessed 15 Jun 2022.

14. Chung MY, Leung WC, Tse WT, et al. The use of Somatex Shunt for fetal pleural effusion: a cohort of 8 procedures. Fetal Diagn Ther 2021;48:440-7. Crossref

15. Tse WT, Poon LC, Wah YM, Hui AS, Ting YH, Leung TY. Bronchopulmonary sequestration successfully treated with prenatal radiofrequency ablation of the feeding artery. Ultrasound Obstet Gynecol 2021;58:325-7. Crossref

16. Cheng YK, Yu SC, So PL, Leung TY. Ultrasound-guided percutaneous embolisation of placental chorioangioma using cyanoacrylate. Fetal Diagn Ther 2017;41:76-9. Crossref

17. Swearingen C, Colvin ZA, Leuthner SR. Nonimmune hydrops fetalis. Clin Perinatol 2020;47:105-21. Crossref

18. Songdej D, Babbs C, Higgs DR; BHFS International Consortium. An international registry of survivors with Hb Bart’s hydrops fetalis syndrome. Blood 2017;129:1251-9. Crossref

19. Donofrio MT, Moon-Grady AJ, Hornberger LK, et al. Diagnosis and treatment of fetal cardiac disease: a scientific statement from the American Heart Association. Circulation 2014;129:2183-242. Crossref

20. Ancel PY, Goffinet F; EPIPAGE-2 Writing Group, et al. Survival and morbidity of preterm children born at 22 through 34 weeks’ gestation in France in 2011: results of the EPIPAGE-2 cohort study. JAMA Pediatr 2015;169:230-8. Crossref

21. De Bie FR, Davey MG, Larson AC, Deprest J, Flake AW. Artificial placenta and womb technology: past, current, and future challenges towards clinical translation. Prenat Diagn 2021;41:145-58. Crossref

22. Hui AS, Lao TT, Leung TY, Schaaf JM, Sahota DS. Trends in preterm birth in singleton deliveries in a Hong Kong population. Int J Gynaecol Obstet 2014;127:248-53. Crossref

23. Leung TN, Pang MW, Leung TY, Poon CF, Wong SM, Lau TK. Cervical length at 18-22 weeks of gestation for the prediction of spontaneous preterm delivery in Hong Kong Chinese women. Ultrasound Obstet Gynecol 2005;25:713-7. Crossref

24. Feng Q, Chaemsaithong P, Duan H, et al. Screening for spontaneous preterm birth by cervical length and shear-wave elastography in the first trimester of pregnancy. Am J Obstet Gynecol 2022;227:500.e1-14. Crossref

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26. Romero R, Nicolaides KH, Conde-Agudelo A, et al. Vaginal progesterone decreases preterm birth ≤34 weeks of gestation in women with a singleton pregnancy and a short cervix: an updated meta-analysis including data from the OPPTIMUM study. Ultrasound Obstet Gynecol 2016;48:308-17. Crossref

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29. Conde-Agudelo A, Romero R, Nicolaides KH. Cervical pessary to prevent preterm birth in asymptomatic high-risk women: a systematic review and meta-analysis. Am J Obstet Gynecol 2020;223:42-65.e2. Crossref

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31. Leung TY, Stuart O, Sahota DS, Suen SS, Lau TK, Lao TT. Head-to-body delivery interval and risk of fetal acidosis and hypoxic ischaemic encephalopathy in shoulder dystocia: a retrospective review. BJOG 2011;118:474-9. Crossref

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33. Wong L, Tse WT, Lai CY et al. Bradycardia-to-delivery interval and fetal outcomes in umbilical cord prolapse. Acta Obstet Gynecol Scand 2021;100:170-7. Crossref

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