On 14 December 2016, the US Food and Drug Administration (FDA) issued a warning that the repeated or lengthy use of general anaesthetic and sedative drugs in children under 3 years old and in pregnant women in their third trimester may affect the development of children’s brains. Warning labels were required to be added to general anaesthetic and sedative drugs.1

Data from published studies in pregnant and young animals have shown that the use of general anaesthetics increases the chance of apoptosis and neurodegeneration in the developing brain. Persistent memory and learning disabilities have been demonstrated2 3 as well as increased severity with increasing duration of anaesthesia.4 Certain human studies suggest an association between anaesthesia and subsequent behaviour or learning issues such as autism, attention-deficit disorder, and language deficits.5 6 7 Some researchers postulate that even relatively simple anaesthesia of babies and young children can pose a risk of neurotoxicity. The question is whether or not we can translate such animal data to humans and to what extent we should interpret the animal findings.8

For many years well-designed human studies were lacking. Data were mainly observational and retrospective, and with too many confounding factors. There were often conflicting results in different studies.9 10 Recently, however, more robust human studies have been published such as General Anaesthesia compared to Spinal anaesthesia (GAS) study11 and Pediatric Anesthesia NeuroDevelopment Assessment (PANDA).12 13 The GAS study, which compares children less than 60 weeks’ post-gestational age (but older than 26 weeks’ post gestation) undergoing hernia surgery under either general anaesthesia or awake regional anaesthesia, has shown that at the 2-year mark (secondary outcome), there is no increase in risk of learning disability. This study is ongoing with its primary outcome being the Wechsler Preschool and Primary Scale of Intelligence Third Edition Full Scale Intelligence Quotient score at 5 years old. The PANDA study was a sibling-matched cohort observational study that examined whether anaesthesia exposure in healthy children younger than 3 years old is associated with an increased risk of impaired global cognitive function as the primary outcome. Their secondary outcome was abnormal domain-specific neurocognitive function and behaviour at the ages of 8 to 15 years. The study found no significant difference between the exposed and unexposed in terms of both primary and secondary outcomes. Both studies point towards a slightly more reassuring outlook for short-duration exposure to anaesthesia in children.

Although a FDA warning on anaesthesia and exposure to anaesthetic drugs in paediatric, neonatal, and third-trimester pregnant women has been long expected, the timing of this warning came as a surprise to many in the paediatric anaesthesia community, particularly in light of the recent findings of the more sanguine and robust human studies and no new evidence of detrimental effects of anaesthesia.

Moreover, the FDA uses a cut-off age of 3 years old. This age limit is highly debatable since there is currently no evidence to support the use of 3 years as a cut-off or that anaesthesia in infants older than 3 years will not be harmful; and vice versa. Some use 3 years as a cut-off for the period of rapid neurodevelopment in a child; nonetheless a few retrospective cohort studies point towards anaesthesia affecting children of an older age-group.14 15 Many of these concerns are likely to be applicable to all patients undergoing surgery with those at the extremes of age being more vulnerable. Duration of surgery and the extent of tissue trauma, need for blood transfusion, and the choice of anaesthetic agent are also important variables.

Data from the American Society of Anesthesiologists (ASA) Closed Claims Project were analysed and revealed that children under 1 year of age with associated disease were at increased risk of major and minor morbidity.16 Cardiac arrests related to anaesthesia most often occurred in infants who were ASA status 3 to 5 and undergoing emergency procedures. Paediatric anaesthesiologists should therefore collaborate with surgeons to determine the best time for surgery in a child.17 Often, children need anaesthesia for operations or procedures that should not be delayed. In these cases, it is easier to balance the detrimental effects of not having the surgery against the potential risk of anaesthesia. In non-urgent surgeries that will not affect the child or the outcome of the operation if postponed until later in life, it is reasonable to discuss with all parties involved, including their parents or guardians, as to whether deferring the surgery can be considered in very young children. Given that perioperative complications are more common in the very young,18 this is a good general principle that has always been advocated by those involved in perioperative paediatric care, notwithstanding this FDA warning.

1. FDA Drug Safety Communication: FDA review results in new warnings about using general anesthetics and sedation drugs in young children and pregnant women. Available from: https://www.fda.gov/Drugs/DrugSafety/ucm532356.htm. Accessed Jul 2017.

2. Jevtovic-Todorovic V, Hartman RE, Izumi Y, et al. Early exposure to common anesthetic agents causes widespread neurodegeneration in the developing rat brain and persistent learning deficits. J Neurosci 2003;23:876-82. Crossref

3. Vutskits L, Xie Z. Lasting impact of general anaesthesia on the brain: mechanisms and relevance. Nat Rev Neurosci 2016;17:705-17. Crossref

4. Zou X, Patterson TA, Divine RL, et al. Prolonged exposure to ketamine increases neurodegeneration in the developing monkey brain. Int J Dev Neurosci 2009;27:727-31. Crossref

5. Hansen TG. Anesthesia-related neurotoxicity and the developing animal brain is not a significant problem in children. Paediatr Anaesth 2015;25:65-72. Crossref

6. Ing C, DiMaggio C, Whitehouse A, et al. Long-term differences in language and cognitive function after childhood exposure to anesthesia. Pediatrics 2012;130:e476-85. Crossref

7. Ing CH, DiMaggio CJ, Malacova E, et al. Comparative analysis of outcome measures used in examining neurodevelopmental effects of early childhood anesthesia exposure. Anesthesiology 2014;120:1319-32. Crossref

8. Todd MM. Anesthetic neurotoxicity: the collision between laboratory neuroscience and clinical medicine. Anesthesiology 2004;101:272-3. Crossref

9. Hansen TG, Pedersen JK, Henneberg SW, et al. Academic performance in adolescence after inguinal hernia repair in infancy: a nationwide cohort study. Anesthesiology 2011;114:1076-85. Crossref

10. Hansen TG, Pedersen JK, Henneberg SW, Morton NS, Christensen K. Educational outcome in adolescence following pyloric stenosis repair before 3 months of age: a nationwide cohort study. Paediatr Anaesth 2013;23:883-90. Crossref

11. Davidson AJ, Disma N, de Graaff JC, et al. Neurodevelopmental outcome at 2 years of age after general anaesthesia and awake-regional anaesthesia in infancy (GAS): an international multicentre, randomised controlled trial. Lancet 2016;387:239-50. Crossref

12. Sun LS, Li G, Miller TL, et al. Association between a single general anesthesia exposure before age 36 months and neurocognitive outcomes in later childhood. JAMA 2016;315:2312-20. Crossref

13. Chinn GA, Sasaki Russell JM, Sall JW. Is a short anesthetic exposure in children safe? Time will tell: a focused commentary of the GAS and PANDA trials. Ann Transl Med 2016;4:408. Crossref

14. Graham MR, Brownell M, Chateau DG, Dragan RD, Burchill C, Fransoo RR. Neurodevelopmental assessment in kindergarten in children exposed to general anesthesia before the age of 4 years: a retrospective matched cohort study. Anesthesiology 2016;125:667-77. Crossref

15. O’Leary JD, Janus M, Duku E, et al. A population-based study evaluating the association between surgery in early life and children development at primary school entry. Anesthesiology 2016;125:272-9. Crossref

16. Jimenez N, Posner KL, Cheney FW, Caplan RA, Lee LA, Domino KB. An update on pediatric anesthesia liability: a closed claims analysis. Anesth Analg 2007;104:147-53. Crossref

17. Paterson N, Waterhouse P. Risk in paediatric anesthesia. Pediatr Anaesth 2011;21:848-57. Crossref

18. Weiss M, Hansen TG, Engelhardt T. Ensuring safe anaesthesia for neonates, infants and young children: what really matters. Arch Dis Child 2016;101:650-2. Crossref

Historically, the introduction of caesarean section (CS) was associated with an improvement in maternal and perinatal health outcomes. In 1985, the World Health Organization (WHO) recommended that CS should not account for more than 10% to 15% of all births.1 The WHO has recently revised their position and stated that “every effort should be made to provide a CS to women in need, rather than striving to achieve a specific rate.”2 The effect of CS rates on other outcomes—such as maternal and perinatal morbidity, paediatric outcomes, and psychological or social well-being—are still unclear.2 Of note, CS carries its own risks for maternal and infant morbidity and for subsequent pregnancies. At some point, these risks will outweigh the potential benefits associated with lowering the threshold at which the procedure becomes indicated.

In recent decades, there has been a rising tide in CS worldwide with a wide variation in CS rate among various countries from approximately 16% to more than 60%.3 The reasons for the increase in CS rates are multiple and complex, but have been attributed to the increasing prevalence of older mothers, rising rates of maternal obesity and medical co-morbidities, and changing medical practice including a relative increased safety of CS itself.4 5 6 7 In addition, there is substantial evidence that this increase is more prevalent among women with privately funded deliveries.8 9 Nevertheless, the dramatic rise in CS rate has not been shown to be accompanied by any substantial decrease in maternal or perinatal morbidity or mortality.10 Malpractice litigation pressure has been suggested as one of the attributes for the rise because associations have been demonstrated between CS rates and malpractice premiums.11

In Hong Kong, the annual CS rate rose steadily from 16.6% to 27.4% from 1987 to 1999, with the rate in private institutions of 27.4% higher than the public sector.9 Published in this issue of the Hong Kong Medical Journal, a retrospective review of CS rates from 1995 to 2014 at a local public hospital by Chung et al12 shows that the overall rate increased modestly from 15.4% to 24.6%. Nonetheless, it is well known by women in Hong Kong that government-funded units under the Hospital Authority do not perform elective CS for non-clinical indications. Those with a strong preference for elective CS might seek private maternity care. The territory-wide audit conducted by the Hong Kong College of Obstetricians and Gynaecologists has documented an increase in overall CS rates in Hong Kong from 27.1% in 1999 to 30.4% in 2004 and 42.1% in 2009.13 The latest annual obstetric report of the Hospital Authority in 2015 showed CS rates in the eight public hospitals in Hong Kong varying from 21.7% to 30.4%.14

The WHO recently adopted the Robson’s classification system as a global standard for assessing, monitoring, and comparing CS rates.2 Robson’s system classifies women into 10 groups based on five obstetric characteristics that are routinely documented: parity, onset of labour, gestational age, fetal presentation, and number of fetuses. The actual indication for CS is not needed for categorisation. The categories in Robson’s system are mutually exclusive, totally inclusive, and can be applied prospectively.15 It allows comparison of clinically meaningful maternity population subgroups and their associated CS rates across institutions, country development groups, and time. The Robson’s classification has been used to analyse trends and determinants of CS rates in high- and low-income countries, such as the data analysis of 21 countries included in the WHO survey.16 The retrospective review by Chung et al12 used the Robson’s classification system to categorise a 20-year database up to 2014. It showed dramatic and statistically significant increases (P<0.001) in CS rate in those with previous CS (rising from 29% to 61%), breech presentation at delivery (primiparous from 72% to 97% and multiparous from 69% to 96%), and multiple pregnancies (from 35% to 86%). The authors suggested that the rise in the previous CS group was secondary to a more liberal policy to allow patients to choose CS after abandonment of pelvimetry to predict successful trial of labour. The increased CS rate in breech presentation group may be due to publication of the Term Breech Trial in 2000, whereas the increase in the multiple pregnancy group was attributed to the liberal policy that accommodated patient expectations. Nonetheless, a significant fall from 14% to 11% was noted in the group of primiparous patients with term spontaneous labour. Such progressive drop in CS rate was a result of the adoption of evidence-based active management of labour protocols, and regular audits in CS rates and indications within the unit.

A local cross-sectional survey of 660 Chinese pregnant women in a government-funded obstetric unit in Hong Kong found that previous CS and conception by in-vitro fertilisation were significant determinants of a preference for elective CS.17 In another local retrospective cohort study of twin pregnancies, conception by assisted reproduction was also a statistically significant factor that affected maternal preference for elective CS.18 Non-cephalic presentation of the second twin was another statistically significant factor in the study, indicating women’s concern for their babies when considering mode of delivery. The survey also showed that women who preferred elective CS were concerned about safety of the baby, and feared a vaginal birth and the pain associated with the delivery.

Two randomised controlled trials aimed to determine whether interventions were useful to reduce the number of women seeking CS. One focused on using an individualised prenatal educational programme in women with previous CS19 and the other used cognitive treatment in women who were fearful of a vaginal birth.20 Both showed no significant difference between intervention and control groups with respect to the women’s request for elective CS. These results may imply that once fear is established, treatment is not of significant clinical benefit.

To reduce the overall CS rate, reducing the proportion of first deliveries by CS appears pertinent. Public and prenatal education may play an important role in shaping expectations. Obstetric management protocols, skills, and clinical audits can be targeted at reducing first birth by CS, eg external cephalic version in term-breech pregnancies, safe vaginal twin delivery techniques, standardised fetal heart rate tracing interpretation and management, and increasing women’s access to non-medical interventions during labour such as labour and delivery support. More drastic attempts to curb primary CS rates in primiparous women can be considered, such as redefining labour dystocia, postponing the cut-off for active labour at 6-cm dilatation, allowing adequate time for the second stage of labour, or encouraging operative vaginal delivery.10 Last but not least, obstetricians should fully discuss the risks and benefits of a vaginal birth versus CS, especially when CS is requested without a clinical indication. In such cases it is important to explore, discuss, and record the specific reasons for the request, and to include a discussion with other members of the obstetric team (including obstetrician, midwife, and anaesthetist) if necessary to explore the reasons for the request and ensure the woman has accurate information.21 The skill needed to make a balanced clinical decision for an individual woman may perhaps be greater than that required to undertake the procedure.

1. Appropriate technology for birth. Lancet 1985;2:436-7.

2. World Health Organization. WHO statement on caesarean section rates. April 2015. Available from: http://apps.who.int/iris/bitstream/10665/161442/1/WHO_RHR_15.02_eng.pdf?ua=1. Accessed Jun 2017.

3. Visser GH. Women are designed to deliver vaginally and not by caesarean section: an obstetrician’s view. Neonatalogy 2015;107:8-13. Crossref

4. O’Dwyer V, Farah N, Fattah C, O’Connor N, Kennelly MM, Turner MJ. The risk of caesarean section in obese women analysed by parity. Eur J Obstet Gynecol Reprod Biol 2011;158:28-32. Crossref

5. Brick A, Layte R. Recent trends in the caesarean section rate in Ireland 1999-2006. ESRI Working Paper No. 309. August 2009. Available from: https://www.esri.ie/pubs/WP309.pdf. Accessed Jun 2017.

6. Brick A, Layte R. Exploring trends in the rate of caesarean section in Ireland 1999-2007. Econ Soc Rev (Irel) 2011;42:383-406.

7. Bayrampour H, Heaman M. Advanced maternal age and the risk of cesarean birth: a systematic review. Birth 2010;37:219-26. Crossref

8. Lipkind HS, Duzyj C, Rosenberg TJ, Funai EF, Chavkin W, Ciasson MA. Disparities in caesarean delivery rates and associated adverse neonatal outcomes in New York City hospitals. Obstet Gynecol 2009;113:1239-47. Crossref

9. Leung GM, Lam TH, Thach TQ, Wan S, Ho LM. Rates of cesarean births in Hong Kong: 1987-1999. Birth 2001;28:166-72. Crossref

10. American College of Obstetricians and Gynecologists (College); Society for Maternal-Fetal Medicine; Caughey AG, Cahill AG, Guise JM, Rouse DJ. Safe prevention of the primary caesarean delivery. Am J Obstet Gynecol 2014;210:179-93. Crossref

11. Yang YT, Mello MM, Subramanian SV, Studdert DM. Relationship between malpractice litigation pressure and rates of cesarean section and vaginal birth after caesarean section. Med Care 2009;47:234-42. Crossref

12. Chung WH, Kong CW, To WW. Secular trends in caesarean section rates over 20 years in a regional obstetric unit in Hong Kong. Hong Kong Med J 2017;23:340-8. Crossref

13. Territory-wide audit in obstetrics and gynaecology. Hong Kong: The Hong Kong College of Obstetricians and Gynaecologists; 2014.

14. Hospital Authority Obstetric Annual Report 2015. Hong Kong: Hospital Authority; 2016.

15. Torloni MR, Betran AP, Souza JP, et al. Classifications for cesarean section: a systematic review. PLoS One 2011;6:e14566. Crossref

16. Vogel JP, Betrán AP, Vindevoghel N, et al. Use of the Robson classification to assess caesarean section trends in 21 countries: a secondary analysis of two WHO multicountry surveys. Lancet Glob Health 2015;3:e260-70. Crossref

17. Pang SM, Leung DT, Leung TY, Lai CY, Lau TK, Chung TK. Determinants of preference for elective caesarean section in Hong Kong Chinese pregnant women. Hong Kong Med J 2007;13:100-5.

18. Liu AL, Yung WK, Yeung HN, et al. Factors influencing the mode of delivery and associated pregnancy outcomes for twins: a retrospective cohort study in a public hospital. Hong Kong Med J 2012;18:99-107.

19. Fraser W, Maunsell E, Hodnett E, Moutquin JM. Randomized controlled trial of a prenatal vaginal birth after cesarean section education and support program. Childbirth Alternatives Post-Cesarean Study Group. Am J Obstet Gynecol 1997;176:419-25. Crossref

20. Saisto T, Salmela-Aro K, Nurmi JE, Könönen T, Halmesmäki E. A randomized controlled trial of intervention in fear of childbirth. Obstet Gynecol 2001;98(5 Pt 1):820-6. Crossref

21. National Institute for Health and Care Excellence. NICE Clinical guideline: Caesarean section (CG132). 2012. Available from: https://www.nice.org.uk/guidance/cg132. Accessed Jun 2017.

Dementia affects 47 million people worldwide.1 Persons with dementia require appropriate diagnostic investigations, treatments, and long-term care. The economic impact of dementia is huge. Globally, the total estimated worldwide cost of dementia is US$818 billion.1 In Hong Kong, the estimated number of persons with dementia was 103 433 among those aged 60 years or above in 2009, and this number is projected to increase to 332 688 by 2039.2 Dementia is a clinical syndrome due to a variety of causes. The most common is Alzheimer’s disease (AD) followed by vascular dementia.3 Other causes include dementia with Lewy bodies (DLB), Parkinson’s disease dementia (PDD), and frontotemporal dementia. Clinical diagnosis is often based on clinical features, with reference to the clinical criteria.4 5 6 7 Overlap of the clinical features of different dementias is common and may result in an incorrect clinical diagnosis. Notably, recent studies have confirmed the role of structural (magnetic resonance imaging [MRI]), functional ([¹⁸F]-2-fluoro-2-deoxy-D-glucose positron emission tomography [¹⁸FDG-PET] or single-photon emission computed tomography [SPECT]), and amyloid pathology (carbon 11–labelled Pittsburgh compound B) brain imaging in improving the accuracy of clinical differential diagnosis of AD versus other dementia subtypes.4 8 9 For example, volumetric MRI hippocampal volumes differentiate AD from healthy elderly adults with over 80% accuracy. Recently, this has been applied in clinical practice and is preferred to the semiquantitative visual hippocampal assessment that has only 81% sensitivity and 67% specificity for AD diagnosis.4 Furthermore, new amyloid and tau PET neuroimaging for preclinical AD diagnosis will also be available soon for clinical application.9

Compared with AD, DLB and PDD are much less prevalent in Chinese than in Caucasian populations. In this issue of the Hong Kong Medical Journal, Shea et al10 reports a Chinese case series of 16 DLB and seven PDD patients from a memory clinic in Hong Kong. In contrast with the first reported series of 31 DLB and four PDD Chinese patients from Mainland China, which employed clinical assessment only,11 Shea et al10 included functional brain imaging with ¹⁸FDG-PET or technetium-99m hexamethylpropylene amine oxime SPECT in the diagnostic assessment, with hypometabolism or hypoperfusion of occipital lobes, respectively as positive evidence of DLB/PDD. With these tools, they studied the diagnostic inaccuracy of clinical assessment alone. Pre-imaging accuracy of clinical diagnosis was only 52%, confirming the clinical utility of adding these imaging investigations to improve diagnostic accuracy in clinical practice.10 The spectrum of disorders with Lewy body embraces a spectrum of neurodegenerative diseases, including Parkinson’s disease, PDD and DLB, that are due to the abnormal neuronal accumulation of the protein α-synucleinopathies in the brainstem, limbic, and neocortical regions. In the diagnostic criteria, a ‘1-year’ duration between the onset of Parkinsonism and dementia symptoms is an arbitrary criterion to clinically distinguish PDD and DLB.9 12 This is being reviewed by the International Parkinson and Movement Disorder Society and may be deleted in the future.9

In elderly patients, multiple co-morbidities are common: AD may coexist with DLB and PDD in the same patient. Shea et al10 found that 52% (12 out of 23) of patients with DLB/PDD had an AD pattern of functional imaging abnormalities (ie bilateral temporoparietal lobes hypometabolism/hypoperfusion), showing that AD actually coexisted in approximately 50% of their DLB/PDD patients. This finding also explained why 38% of them were initially diagnosed with AD.10 The presence of AD in these patients represented additional co-morbid disease and was not a ‘misdiagnosis’.

Clinically, confirming the diagnosis of DLB or PDD in these patients had an important bearing on subsequent treatments. First, clinicians should avoid the use of neuroleptic drugs in these patients, owing to a high risk of neuroleptic syndrome in DLB/PDD. Second, cholinesterase inhibitors should be tried as they are beneficial in alleviating cognitive symptoms in DLB and PDD patients. Third, levodopa/carbidopa treatment of Parkinsonism motor symptoms may be complicated by a worsening of hallucinations.13 With progressive neuronal degeneration, both dementia and Parkinsonism motor symptoms will deteriorate with time. For their DLB and PDD patients, Shea et al10 reported a 30% mortality on follow-up (mean, 3.1 years), and 70%, 26%, 52%, and 26% of patients had falls, pressure sores, dysphagia, and aspiration pneumonia, respectively.

In general, most dementias are neurodegenerative in nature. The disease pathology may start in the brain 10 to 20 years before onset of dementia symptoms. With increasing dementia severity over the years, loss of self-care ability and eventually the ability to eat will occur in the final stage of the dementia illness. Feeding problems lead to weight loss, malnutrition, impaired immunity to infection, and poor wound healing. In the current issue of this Journal, Luk et al14 reviewed the clinical and ethical issues related to feeding problems in advanced dementia patients in Hong Kong. As emphasised by the authors, the key issue was the high prevalence of tube feeding: 53% among advanced dementia persons living in old-age homes.14 15 The reasons for giving tube feeding included dysphagia, inadequate eating, and malnutrition. Tube feeding, however, did not prevent aspiration pneumonia, nor did it yield any benefit for survival. Nasogastric tube feeding also induced nasal discomfort in these demented persons and prompted attempts to self-remove the tube. The latter might lead to an increased chance of being restrained, as well as repeated hospital visits for replacement of the nasogastric tube. Some of these patients might not need a feeding tube,14 and ‘careful hand feeding’ could offer a viable alternative. This may work well for patients who have lost their motivation to eat but still retain their ability to swallow. Formal assessment by the speech therapist should be carried out to confirm this ability. In these patients, careful hand feeding should be tried first. A trial of antidepressants may be given if depressive mood is also present. It should be noted that careful hand feeding is not effective for advanced demented patients with genuine dysphagia in whom the risk of aspiration and aspiration pneumonia is high. Withholding feeding is another option for these patients. Obviously, the harm of withholding feeding includes dehydration, malnutrition, and eventually death. The dilemma of whether to start tube feeding or to stop feeding remains a clinical and ethical challenge for both the physician and family. In this context, the presence of an advance directive of the patient will help guide clinical treatment and care decisions. With an advance directive, a mentally competent person can indicate the form of health care he or she would like to receive in the future. In this regard, the directive must include the use or non-use of tube feeding.16 It should be noted that several local studies have previously confirmed the acceptability and feasibility of advance directives among Chinese adult and elderly patients in Hong Kong.17 18 19 Most demented patients, however, do not have written advance directives before becoming mentally incompetent. Our current challenge now lies in the promotion of the use of advance directives among Hong Kong citizens, while they are still mentally competent, and encouragement to formulate one.

1. World Alzheimer Report 2016. Improving healthcare for people living with dementia. Coverage, quality and costs now and in the future. Alzheimer’s Disease International. Available from: https://www.alz.co.uk/research/WorldAlzheimerReport2016.pdf. Accessed 10 Apr 2017.

2. Yu R, Chau PH, McGhee SM, et al. Trends in prevalence and mortality of dementia in elderly Hong Kong population: projections, disease burden, and implications for long-term care. Int J Alzheimers Dis 2012;2012:406852. Crossref

3. Chiu HF, Lam LC, Chi I, et al. Prevalence of dementia in Chinese elderly in Hong Kong. Neurology 1998;50:1002-9. Crossref

4. Chu LW. Alzheimer’s disease: early diagnosis and treatment. Hong Kong Med J 2012;18:228-37.

5. McKhann GM, Knopman DS, Chertkow H, et al. The diagnosis of dementia due to Alzheimer’s disease: recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement 2011;7:263-9. Crossref

6. McKeith IG, Dickson DW, Lowe J, et al. Diagnosis and management of dementia with Lewy bodies: third report of the DLB Consortium. Neurology 2005;65:1863-72. Erratum in: Neurology 2005;65:1992. Crossref

7. Rascovsky K, Hodges JR, Knopman D, et al. Sensitivity of revised diagnostic criteria for the behavioural variant of frontotemporal dementia. Brain 2011;134:2456-77. Crossref

8. Shea YF, Ha J, Lee SC, Chu LW. Impact of (18)FDG PET and (11)C-PIB PET brain imaging on the diagnosis of Alzheimer’s disease and other dementias in a regional memory clinic in Hong Kong. Hong Kong Med J 2016;22:327-33. Crossref

9. Saeed U, Compagnone J, Aviv RI, et al. Imaging biomarkers in Parkinson’s disease and Parkinsonian syndromes: current and emerging concepts. Transl Neurodegener 2017;6:8. Crossref

10. Shea YF, Chu LW, Lee SC. A descriptive study of Lewy body dementia with functional imaging support in a Chinese population: a preliminary study. Hong Kong Med J 2017;23:222-30. Crossref

11. Han D, Wang Q, Gao Z, Chen T, Wang Z. Clinical features of dementia with lewy bodies in 35 Chinese patients. Transl Neurodegener 2014;3:1. Crossref

12. Walker Z, Possin KL, Boeve BF, Aarsland D. Lewy body dementias. Lancet 2015;386:1683-97. Crossref

13. O’Brien JT, Holmes C, Jones M, et al. Clinical practice with anti-dementia drugs: A revised (third) consensus statement from the British Association for Psychopharmacology. J Psychopharmacol 2017;31:147-68. Crossref

14. Luk JK, Chan FH, Hui E, Tse CY. The feeding paradox in advanced dementia: a local perspective. Hong Kong Med J 2017;23:306-10. Crossref

15. Luk JK, Chan WK, Ng WC, et al. Mortality and health services utilisation among older people with advanced cognitive impairment living in residential care homes. Hong Kong Med J 2013;19:518-24. Crossref

16. Chu LW. One step forward for advance directives in Hong Kong. Hong Kong Med J 2012;18:176-7.

17. Wong SY, Lo SH, Chan CH, Chui HS, Sze WK, Tung Y. Is it feasible to discuss an advance directive with a Chinese patient with advanced malignancy? A prospective cohort study. Hong Kong Med J 2012;18:178-85.

18. Ting FH, Mok E. Advance directives and life-sustaining treatment: attitudes of Hong Kong Chinese elders with chronic disease. Hong Kong Med J 2011;17:105-11.

19. Chu LW, Luk JK, Hui E, et al. Advance directive and end-of-life care preferences among Chinese nursing home residents in Hong Kong. J Am Med Dir Assoc 2011;12:143-52. Crossref

Fragile X syndrome (FXS) is the most frequent cause of intellectual disability after Down syndrome. It is caused by the expansion of an unstable cysteine-guanine-guanine (CGG) trinucleotide repeat on the 5’ untranslated region of the fragile X mental retardation-1 (FMR1) gene. In full mutation (FM), the expansion is >200 CGG repeats with aberrant methylation of the promoter region causing loss of the gene expression. Affected individuals display a spectrum of neurological, psychiatric, and developmental problems, as well as abnormal ophthalmological and facial features.

Fragile X syndrome is an X-linked, dominant disorder. Although all males with a FM have FXS, only half of the females with a FM are clinically affected because of X-chromosome inactivation. The inheritance pattern of FXS is distinctive because a healthy woman who carries a pre-mutation (PM) or a mild expansion of 55-200 CGG repeats can pass on a FM to a child through mitotic expansion of the unstable PM allele. In Cheng et al’s article,1 two PM carriers (1 in 1325) and one FM carrier (1 in 2650) were detected in a sample of 2650 Hong Kong Chinese pregnant women. In Chinese children with unknown intellectual developmental disorder, the prevalence of FXS has been reported to be 0.93%.2 It would appear that FXS is not rare in the Chinese population.

To predict the birth of a FXS-affected children, PM carriers can be identified through screening. According to the American College of Obstetricians and Gynecologists (ACOG), prenatal screening and genetic counselling for FXS should be offered to women with a family or personal history of FXS, unexplained mental retardation or developmental delay, or premature ovarian insufficiency.3 The Society of Obstetricians and Gynaecologists of Canada also suggest that fragile X testing is indicated in a woman who has at least one male relative with autism, mental retardation, or developmental delay of an unknown aetiology within a three-generation pedigree.4 Such screening should also be offered to all women who request it after appropriate genetic counselling.3 It is controversial, however, to offer universal screening to all pregnant women. In Hong Kong, this screening is self-financed.

Conventionally, analysis of maternal blood samples by Southern blot is performed to identify PM carriers. Recently, polymerase chain reaction (PCR)–based approaches have enabled more rapid and easy testing, and can be relied upon to characterise CGG repeat size. Nonetheless, amplification of large CG-rich fragments and the study of the methylation pattern can be difficult. Cheng’s team used a specific FMR1 PCR-based assay that could detect CGG repeat numbers up to 1000, allowing the identification of PM and FM.1 The sensitivity of this PCR test was reported to be high (99%) and the false-positive rate was approximately 1.3% although this was probably overestimated.1 The cost of the test is US$44, which is not high.1

Although obtaining a maternal blood test for FXS carrier screening is relatively simple, genetic counselling is not, as rightly pointed out by Cheng et al.1 In their study, pre-test counselling was given by a research assistant with a bachelor’s and master’s degree in human genetics, supplemented by written information.1 Pre-test counselling for FXS is more difficult than for Down syndrome screening. First, an extensive multigenerational family history must be taken to assess whether FXS, developmental, neurodegenerative, or reproductive disability is present in the mother or any of her family members. Taking such a history is not easy because most patients are not familiar with FXS, and typical phenotypic features of FXS often are not apparent until later childhood.5

Second, the inheritance pattern of FXS is complex. Women should be informed about the various outcomes possible and the implications of detecting FM, PM, and intermediate-sized allele (ie 45-54 CGG repeats) results. Prenatal diagnosis should be offered to all pregnant women who are FM or PM carriers.6 For a female PM carrier, the risk of expanding to a FM in offspring is dependent on the size of the PM, and is above 98% for alleles with >100 repeats.7 For PM carriers with <69 repeats, the number of AGG (adenine-guanine-guanine) interruptions within the CGG repeat tract (eg occurrence of one AGG interruption after nine uninterrupted CGG repeats is described as: [(CGG)9AGG(CGG)9AGG(CGG)9]) may predict the risk.8 The latter risk is higher when there is a positive family history of FXS.

The prevalence of intermediate-sized allele carriers was shown to be 1.1% in a local study.1 It is difficult to counsel these carriers because the risk for CGG expansion, although very low, is uncertain. Thus, prenatal diagnosis may be offered on a case-by-case basis. Expansion of an intermediate-sized allele into FM may occur in two generations. The European Molecular Genetics Quality Network recommends genetic counselling be offered to family members of intermediate carriers with 50-54 CGG repeats because they may carry a PM.9

Prenatal diagnosis can be achieved by determination of CGG expansion and methylation status using a combination of PCR and Southern blot analysis on a sample from chorionic villus sampling (CVS) or amniocentesis. Methylation results from CVS must be interpreted with caution because methylation of a FM is not always present before 14 weeks of gestation,10 and the FMR1 gene is not methylated on the inactive X chromosome in a female fetus. A follow-up amniocentesis may be required if (a) determination of the methylation status is required to differentiate a large PM from a small FM, or (b) exclusion of somatic mosaicism with FM is required in PM. In all cases, maternal contamination should be excluded, and the gender of the fetus determined to interpret the results of the mutation study.

If a female FM carrier fetus is identified through prenatal diagnosis, there is no way to tell whether the fetus is affected by FXS. Their parents will face uncertainty and anxiety about the resulting phenotype, and have a difficult choice to make. Termination of such pregnancy was reported previously and in the study by Cheng et al.1 On the contrary, in the same study, a woman with PM declined prenatal diagnosis owing to the unpredictable phenotype in a FM female.1

Pre-mutation carriers are at risk of developing fragile X–associated tremor/ataxia syndrome (FXTAS) and fragile X–associated primary ovarian insufficiency (FXPOI). Onset of FXTAS is typically in the sixth decade of life, and older males are at high risk.11 Approximately 20% of female PM carriers may suffer from early menopause below the age of 40 years,12 and thus appropriate reproductive interventions should be informed.

Sufficient time should be allowed for women to review and consider the information given, including the complex inheritance pattern and implications of FXS. Women generally know little about FXS prior to counselling. Adequate psychosocial support should be given to the mutation carriers who may become anxious when they know the uncertain inheritance risk of expansion from PM to FM, the uncertain phenotype of a female FM carrier, or the future risks of FXPOI and FXTAS. Family dynamics must also be considered. Although screening for FXS should be offered to other at-risk family members, such extended or cascade screening may be declined as in Cheng et al’s study.1

In summary, ACOG recommends offering prenatal screening and genetic counselling for FXS to all at-risk women.3 Risk factors can be identified by taking an extensive multigenerational family history although this may be difficult. The provision of appropriate counselling is a challenge in view of the time and knowledge required to discuss the screening process, the complex inheritance pattern and heterogeneous phenotype of FXS, and its potential impact on psychosocial status and family members. Providing medical education to obstetricians, midwives and genetic counsellors, and targeted education materials to pregnant women may help.13

1. Cheng YK, Lin CS, Kwok YK, et al. Identification of fragile X pre-mutation carriers in the Chinese obstetric population using a robust FMR1 polymerase chain reaction assay: implications for screening and prenatal diagnosis. Hong Kong Med J 2017;23:110-6. Crossref

2. Chen X, Wang J, Xie H, et al. Fragile X syndrome screening in Chinese children with unknown intellectual developmental disorder. BMC Pediatr 2015;15:77. Crossref

3. American College of Obstetricians and Gynecologists Committee on Genetics. ACOG Committee Opinion No. 469: Carrier screening for fragile X syndrome. Obstet Gynecol 2010;116:1008-10. Crossref

4. Genetics Committee of the Society of Obstetricians and Gynaecologists of Canada (SOGC); Prenatal Diagnosis Committee of the Canadian College of Medical Geneticists (CCMG), Chitayat D, et al. Fragile X testing in obstetrics and gynaecology in Canada. J Obstet Gynaecol Can 2008;30:837-46. Crossref

5. Bailey DB Jr, Raspa M, Bishop E, Holiday D. No change in the age of diagnosis for fragile X syndrome: findings from a national parent survey. Pediatrics 2009;124:527-33. Crossref

6. Ram KT, Klugman SD. Best practices: antenatal screening for common genetic conditions other than aneuploidy. Curr Opin Obstet Gynecol 2010;22:139-45. Crossref

7. Nolin SL, Glicksman A, Ding X, et al. Fragile X analysis of 1112 prenatal samples from 1991 to 2010. Prenat Diagn 2011;31:925-31. Crossref

8. Nolin SL, Sah S, Glicksman A, et al. Fragile X AGG analysis provides new risk predictions for 45-69 repeat alleles. Am J Med Genet A 2013;161A:771-8. Crossref

9. Biancalana V, Glaeser D, McQuaid S, Steinbach P. EMQN best practice guidelines for the molecular genetic testing and reporting of fragile X syndrome and other fragile X–associated disorders. Eur J Hum Genet 2015;23:417-25. Crossref

10. Devys D, Biancalana V, Rousseau F, Boué J, Mandel JL, Oberlé I. Analysis of full fragile X mutations in fetal tissues and monozygotic twins indicate that abnormal methylation and somatic heterogeneity are established early in development. Am J Med Genet 1992;43:208-16. Crossref

11. Jacquemont S, Hagerman RJ, Leehey MA, et al. Penetrance of the fragile X–associated tremor/ataxia syndrome in a premutation carrier population. JAMA 2004;291:460-9. Crossref

12. Sherman SL. Premature ovarian failure in the fragile X syndrome. Am J Med Genet 2000;97:189-94. Crossref

13. Espinel W, Charen K, Huddleston L, Visootsak J, Sherman S. Improving health education for women who carry an FMR1 premutation. J Genet Couns 2016;25:228-38. Crossref

Six years ago, the Hong Kong Medical Journal (HKMJ) vowed to improve the impact of papers published in the Journal, “We publish not for the sake of publication, but to have an impact on medical practice”, by ensuring “that the medical information that we are providing (what we publish) is basically correct and valid”.1

Greater emphasis was to be placed on methodology to produce valid results. A process of methodological review by clinical epidemiologists for all original articles was introduced.1

To improve our capacity to assess the validity of research results, we introduced a series of 12 workshops on Clinical Epidemiology in HKMJ that ran from August 2011 to June 2013 (http://www.hkmj.org/clinical-epidemiology-workshop-series). Their aim was to facilitate authors and reviewers in adopting a more important role in the process of publishing work of a high standard.

The new Editorial Board also introduced a new requirement for original articles to include two boxes of text: ‘New Knowledge Added by This Study’ and ‘Implications for Clinical Practice or Policy’.2 This was intended to improve and emphasise the potential impact of our published original research papers.

During every Editorial Board meeting, it has been the practice for a number of years to identify papers in each issue of HKMJ that are suitable for continuing medical education (CME). A Senior Editor then works with the authors to prepare questions and answers suitable for CME purposes. We also select papers that may be of public interest and the Editorial Office works with the authors to produce Issue Digests that are released to the local media. These have been widely cited and the impact of local medical research published in HKMJ on improving medical knowledge of the public is now evident.

To further enhance the educational role of HKMJ for doctors and its impact on medical practice, two Senior Editors have taken leading roles to plan and solicit high-quality review papers and contributions to the Medical Practice section.3

In August 2012, we introduced the section ‘Doctor for Society’ to report the activities and achievements of medical doctors who contribute substantially to society on a voluntary basis. We wished to disseminate the message that medical doctors can have a significant impact in the community, outside of their clinic or hospital practice.4 The impact has been further extended to the next generation of doctors by engaging medical students from the two local medical schools to interview the nominated interviewee doctors and write a comprehensive report.

In 2013, we began to phase in ahead-of-print versions with DOIs (Online First) for original articles and review articles that had already been accepted and copy-edited.5 This has helped to advance the formal release of information available in those articles by months and maximise the impact on medical practice.

Improving accessibility to papers published in HKMJ should help improve its impact. All papers are freely available on the HKMJ website (http://www.hkmj.org), and the ‘mobile website’ that was introduced in 2015. This re-styled website is based on ‘responsive web’ technology that can automatically adjust a website according to the device that is browsing, thus making the content user-friendly and easily accessible.6

As a result of open recruitment and invitation, the Editorial Board now has 55 members, including the Editor-in-Chief and five Senior Editors, representing all the 15 Colleges of the Hong Kong Academy of Medicine. This ensures that all aspects of medical and dental practice are adequately covered and impacted by the content in HKMJ.

With the joint efforts of all authors, reviewers, advisors in Biostatistics and Clinical Epidemiology, International Editorial Advisory Board members, Editorial Board members, and the Editorial Office, HKMJ received its first official impact factor in the 2014 version of Journal Citation Reports of Thomson Reuters. The impact factor, however, should not be the only parameter to measure the impact of HKMJ. Papers published in the journal attract much media attention and some local journalists use HKMJ as their prime source to identify new developments in medical practice in Hong Kong.6

How much is HKMJ actually influencing medical practice? It will be for you readers to inform us.

The current Editorial Board will be stepping down in mid-December this year, and HKMJ will appoint a new Editorial Board under the capable leadership of Prof Martin Wong (currently Senior Editor). He will expand on his vision for the further development of HKMJ in the coming issue.

I would like to close by taking this opportunity to give a big ‘Thank You’ to all of you! Do not forget to continue your love and support for HKMJ and help the journal to further advance its impact on medical practice!

1. Yu IT. Calling on your continued love and support [editorial]. Hong Kong Med J 2011;17:4.

2. Yu IT. New blood, new initiatives [editorial]. Hong Kong Med J 2011;17:88.

3. Yu IT. Taking stock [editorial]. Hong Kong Med J 2012;18:2.

4. Wong M, Chan KS, Chu LW, Wong TW. Doctor for Society: a corner to showcase exemplary models and promote volunteerism [editorial]. Hong Kong Med J 2012;18:268-9.

5. Yu IT. From strength to strength [editorial]. Hong Kong Med J 2013;19:100.

6. Yu IT. The Third Term [editorial]. Hong Kong Med J 2015;21:4. Crossref