Cardiovascular diseases are a major burden to healthcare globally and a leading cause of death in industrialised countries.1 In 2015, cardiovascular disorders accounted for 77 600 inpatient discharges in Hong Kong, including 6190 deaths, making them the third most common cause of death. The prevalence of cardiovascular disease is increasing and the age-standardised mortality is decreasing.2 Thus, patients with heart diseases are increasingly likely to present to primary care physicians as their first point of care or for a follow-up examination: up to 15% of coronary heart disease patients are treated exclusively by primary care physicians.3 Furthermore, a long-term follow-up study has proven the viability of general practitioners providing care for low-risk chronic heart failure patients.4 As such, clinical care for patients with heart diseases has become increasingly relevant to primary care physicians.

Echocardiography does not involve any radiation and may be performed as a point-of-care diagnostic tool in both outpatient and inpatient settings. Doppler echocardiography allows haemodynamic assessment of stroke volume, pressure gradients, valvular regurgitations, and intracardiac shunts. The treatment of patients with cardiovascular diseases almost invariably involves the use of echocardiography as a means of initial and follow-up investigation. Many patients undergo cardiac surgery and/or catheter-based interventions guided by perioperative or intraprocedural echocardiography. Point-of-care echocardiography in primary care settings improves outcomes in some patients,5 and may identify otherwise-undiagnosed valvular heart diseases.6

Echocardiographic technologies remain a vibrant field of research. The rapid advancement of echocardiographic technologies requires primary care physicians to have an updated understanding of its appropriate use and referral. According to the American College of Cardiology, appropriate echocardiography “likely contributes to improving patient’s clinical outcomes” and inappropriate echocardiography may be “potentially harmful to patients and generate unwarranted costs to the healthcare system”.7 Recent technological developments have expanded the use of echocardiography dramatically. Therefore, the aim of this study was to review the contemporary literature on clinical indications and emerging technologies of echocardiography and to provide a summary for primary care physicians.

Transthoracic echocardiography (TTE) is non-invasive, readily available, and is generally the initial imaging option. In contrast, transoesophageal echocardiography (TEE) requires insertion of a probe into the oesophagus and thus involves sedation and risks of complications such as major bleeding (<0.01%) and hoarseness of voice (12%).8 However, TEE offers better resolution, especially of the left heart, mitral and aortic valves, and the aorta. A routine echocardiography involves several methods of imaging, including two-dimensional (2D; previously known as B mode), Doppler, and M mode echocardiography. Two-dimensional echocardiography, the most commonly used and intuitive method, is used for visualisation and dimensional measurements of the cardiac structures. Two-dimensional echocardiography is often the initial method of imaging, by which cardiac structures are identified and other methods applied. The left ventricular ejection fraction (LVEF) is also obtainable from 2D echocardiography, with the normal value being 50% to 70%. This is mainly used in the classification of heart failure.

Colour Doppler imaging allows visualisation of the blood flow, the conventional colour scheme being red for flow towards the probe and blue for away. This allows intuitive and easy assessment of valvular assessments, where stenotic valves generally show turbulent flow and often thickened valve leaflets, whereas regurgitating valves show a regurgitant jet. Trace or mild regurgitation is common even in normal, healthy individuals. When an abnormal, turbulent flow is detected by colour Doppler imaging, continuous and pulse wave spectral Doppler techniques should be used to further evaluate the nature and severity of the abnormal flow.

Continuous and pulse wave Doppler imaging provides quantitative measurement of flow velocity, volume, and pressure gradient at operator-defined locations. These allow calculation of stroke volume and haemodynamic assessment of the heart valves. Tissue Doppler provides information about movement of cardiac tissues, such as the diastolic motion of the mitral annulus that reflects left ventricular diastolic function. By means of transmitral flow assessment (ie, E, A, E/A ratio) and tissue Doppler imaging of the mitral annulus (ie, e′, a′, s′, E/e′), filling pressure and diastolic function of the left ventricle can also be assessed.9 Interpretation of these parameters is complex and requires correlation with the clinical picture; in general, the normal E/A ratio is 0.8-2 but may be high in young, fit persons; a E/e′ (medial mitral annulus) ratio <8 generally indicates normal left ventricular filling pressure. Further details may be found in the joint recommendation of the European Association for Cardiovascular Imaging and the American Society of Echocardiography for diastolic echocardiographic assessment.10

Lastly, M mode tracks over time the movement of tissues along a straight line extending from the probe and has the advantage of high temporal resolution. The M mode is most commonly used for the assessment of right ventricular function by means of tricuspid annular plane systolic excursion, which is typically ≥17 mm. The M mode is also useful in the assessment of constrictive pericarditis, pericardial effusion and cardiac tamponade, hypertrophic obstructive cardiomyopathy, pulmonary hypertension, and left ventricular outflow tract obstruction.11 An echocardiographic report thus contains information about dimensions and functions of the heart chambers and the proximal aorta. Table 1 summarises the typical components of an echocardiographic report.12 A set of selected standard echocardiographic images is shown in Figure 1.

The clinical indications for echocardiography are detailed in the appropriate use criteria from the European Association for Cardiovascular Imaging13 and the American College of Cardiology.7 This section summarises the key recommendations for the use of echocardiography in some common chief complaints encountered by clinicians. Key points are summarised in Table 2. In general, echocardiography is indicated for evaluating symptoms or conditions potentially of cardiac aetiology, including chest pain, shortness of breath, palpitations, transient ischaemic attack, stroke, or peripheral embolic event. Echocardiography is also considered appropriate when heart disease or structural abnormality are suspected on prior testing including but not limited to chest X-ray, electrocardiogram (ECG), or cardiac biomarkers, whether the patient is symptomatic or not. As a general principle, echocardiography is accepted as appropriate for initial diagnosis when there is a change in clinical status or when the results of the echocardiography are anticipated to change patient treatment. In contrast, routine testing when there is no change in clinical status or when test results are unlikely to lead to changes in treatment are generally considered inappropriate.

The differential diagnoses of chest pain are broad, and reaching a definitive diagnosis is often difficult when relying on the clinical history and physical examination only. The most important diagnosis in patients presenting with acute chest pain is acute coronary syndrome (ACS). As such, 12-lead ECG and troponin assay are the first-line investigations for acute chest pain suggestive of ACS. Echocardiography aids or confirms ischaemic diagnoses, and is used to screen for non-ischaemic structural, aortic, and pericardial pathology in selected patients. For evaluation of acute chest pain with suspected myocardial ischaemia/infarction and non-diagnostic ECG, resting TTE is appropriate and can be performed while the patent has chest pain. The absence of regional wall motion abnormality on 2D TTE during chest pain virtually excludes acute myocardial infarction, with a sensitivity of 93% for any infarct and 100% for ST-elevation myocardial infarction.14 All patients with chest pain should have initial evaluation of ventricular function by TTE after ACS. After ACS, re-evaluation of ventricular function during the recovery phase is appropriate when results will guide therapy.15 For detecting other causes of chest pain, including acute aortic syndromes, valvular diseases, pulmonary embolism, and pericarditis, TTE is valuable and can be done in emergency settings. Although TTE can be used as a first-line test to assess suspected aortic pathologies, TEE allows clearer and more complete assessment of the thoracic aorta, with diagnostic accuracy equivalent to that of cardiac computed tomography (CT) scans or magnetic resonance imaging (MRI).16 Even though CT is the imaging modality of choice in acute aortic syndromes, TTE and TEE remain valuable for acute assessment and follow-up, with the advantage of not requiring radiation, and especially for hemodynamically unstable patients and situations where CT contrast is contraindicated (eg, severe renal impairment).17

Shortness of breath is a common symptom among patients presenting to primary and emergency care physicians. Differential diagnoses of breathlessness include cardiovascular disease, lung disease, anaemia, obesity, and deconditioning. In any setting, clinical history and examination are the first step in evaluation.13 When heart failure is suspected after initial clinical evaluation, TTE is mandatory to confirm or exclude the diagnosis; to quantify chamber volumes, systolic and diastolic function, and wall thickness; and to identify the aetiology of heart failure (eg, cardiomyopathy, valvular disease, or prior myocardial infarction). The TTE also serves to classify heart failure into heart failure with preserved, mid-range or reduced EF (Fig 2).18 Such classification guides management of the condition. For patients with heart failure with preserved or mid-range EF, assessment of diastolic function is important as diastolic dysfunction is known to be key in the pathogenesis. Although some patients have resting echocardiographic evidence of diastolic dysfunction, left ventricular filling pressure, which is the main haemodynamic parameter that explains exertional dyspnoea, may only be elevated during exertion. This may be demonstrated by diastolic stress echocardiography, providing additional haemodynamic information about the patient and aiding diagnosis and treatment.19

Patients who have undergone chemotherapy or radiotherapy are at risk of developing heart failure, and baseline echocardiography with regular follow-up examinations are required. The precise algorithm depends on the cardiotoxic agent prescribed. Traditionally, LVEF has been used as the main marker of cardiac function and cancer therapeutics- related cardiac dysfunction is defined as a drop in LVEF of ≥5% in symptomatic patients or a drop in LVEF of ≥10% to an LVEF of <53% in asymptomatic patients.20 However, significant damage has occurred when a drop in LVEF is detected. Earlier detection can potentially reverse myocardial dysfunction before irreparable damage occurs.21 Thus, global longitudinal strain assessment is recommended for these patients (see section “Advanced and emerging imaging technologies”).20

In the acute setting of respiratory failure where patients present with acute shortness of breath and hypoxaemia of uncertain aetiology, or with hypotension of uncertain or suspected cardiac aetiology, TTE is useful to confirm or exclude cardiac diseases. However, if pulmonary or other noncardiac causes of respiratory distress are established, TTE is unnecessary. Right ventricular function can be evaluated by TTE to determine prognosis and predict recurrence of pulmonary embolism.7 13 However, CT, ventilation-perfusion imaging, and pulmonary angiography remain the imaging modalities of choice in the diagnosis of patients with suspected pulmonary embolism.22 In particular, the triple-rule-out CT—which uses contrast enhancement to evaluate the coronary arteries, aorta, and pulmonary arteries—may be used reliably to detect or exclude pulmonary embolism.23 24 TTE is not sensitive nor specific for diagnosing acute pulmonary embolism. Conversely, in a haemodynamically compromised patient with high clinical probability of pulmonary embolism, unequivocal signs of right ventricular pressure overload and/or right-heart/pulmonary artery thrombi on bedside TTE may support a presumptive diagnosis of pulmonary embolism and may justify emergency reperfusion treatment if immediate CT angiography is not feasible. Although sudden-onset dyspnoea is the most common presenting complaint in pulmonary embolism (80%), chest pain is also common (49%) and a low threshold of clinical suspicion should be maintained.25

For patients with known chronic pulmonary diseases presenting with acute deterioration, careful physical exam and TTE can identify complicating factors such as pulmonary hypertension and right heart failure (cor pulmonale).

The differential diagnoses for syncope or dizziness include vasovagal and orthostatic syncope, arrhythmias, cardiac structural abnormalities, and neurological causes.26 A TTE is indicated when clinical symptoms, signs, or ECG findings are consistent with a structural cardiac diagnosis known to cause syncope/dizziness, such as aortic stenosis (Fig 2), left ventricular dysfunction, hypertrophic cardiomyopathy, intracardiac tumours, or pericardial effusions. A normal TTE in this setting is still an important finding that helps to direct the clinician in diagnosis and treatment.7 13

In patients with suspected cardioembolic stroke, echocardiography especially TEE is useful for identifying intracardiac thrombi in the left atrial appendage (typically in patients with atrial fibrillation) and aortic atherosclerosis. In younger patients with cryptogenic stroke, patent foramen ovale, right-to-left interatrial shunt, and/ or atrial septal aneurysm should be looked for on echocardiography with agitated saline contrast at rest and on Valsalva manoeuvre. TEE is also indicated in patients with high clinical suspicion of septic emboli associated with infective endocarditis.27

Patients presenting with palpitation should be evaluated with a careful history and physical examination followed by a 12-lead ECG and, where appropriate, ambulatory ECG monitor (eg, Holter, loop recorder). If frequent ventricular premature complexes, atrial fibrillation, supraventricular, or ventricular tachycardia are diagnosed, TTE is appropriate to identify and evaluate underlying structural heart abnormalities.7 13 28 However, it is inappropriate to routinely order TTE for evaluation of infrequent atrial premature complexes, ventricular premature complexes without other evidence of heart disease, or asymptomatic isolated sinus bradycardia.13

Patients with new right bundle branch block should be assessed with a careful history focusing on potential causes of right ventricular strain (eg, pulmonary embolism, pulmonary hypertension, obstructive sleep apnoea). Echocardiographic examination should be performed if there is suspicion of pulmonary disease potentially impacting the right ventricle. Asymptomatic isolated chronic right bundle branch block generally does not require further evaluation or treatment. In contrast, left bundle branch block needs to be assessed carefully, mostly by history taking and physical examination for any associated disorders, including but not limited to hypertension, coronary artery disease, heart failure, myocarditis, valvular heart disease, and cardiomyopathies. Typically, an echocardiographic examination for LVEF is indicated. A subset of patients may be indicated for further evaluation by stress testing with imaging, depending on the clinical contexts.29

Murmur or clicks on auscultation may suggest the presence of valvular or congenital heart diseases. Initial evaluation with TTE is appropriate when there is a reasonable suspicion of valvular (Fig 2) or structural heart disease.7 Conversely, echocardiography is inappropriate for routine evaluation of murmur when there are no other symptoms or signs of valvular or structural heart disease. An innocent murmur is typically a short and soft systolic ejection murmur, with normal S1 and S2, normal cardiac impulse, and no evidence for any haemodynamic abnormality. Hand grip usually decreases the intensity of an innocent murmur but increases that of a regurgitant murmur. Initial evaluation of suspected infective endocarditis with positive blood cultures or a new murmur with TTE is appropriate. Initial evaluation with TEE for suspected endocarditis is appropriate if pretest probability is moderate or high (eg, staphylococcal bacteraemia, fungaemia, prosthetic heart valve, or intracardiac device).30 31 However, echocardiography should not be routinely ordered for evaluation of transient fever without evidence of bacteraemia or a new murmur.

Re-evaluation of known valvular heart disease with echocardiography is considered appropriate where there is any change in clinical status or cardiac examination, or to guide therapy (eg, detecting asymptomatic ventricular dysfunction that would prompt early surgical or transcatheter valve intervention). Routinely repeating echocardiography is inappropriate in patients with no or mild valve disease on prior echocardiography with no change in clinical symptoms or cardiac exam. In patients with exercise-induced symptoms but only moderate valvular dysfunction on resting echocardiography, an exercise or pharmacological stress echocardiography may be necessary to reveal the true severity of valve dysfunction during exertion.28 A TEE is indicated in some patients where TTE is inconclusive, or when intervention is planned.32

This is a complex topic and a full discussion is beyond the scope of this review. Thus, this subsection shall focus on the two most common congenital diseases affecting the heart with the highest inheritability: bicuspid aortic valve (BAV) and Marfan syndrome. Although BAV is not always syndromic, 9% of first-degree relatives of BAV patients also have BAV,33 and echocardiographic screening in these patients detects a substantial number of BAV cases.34 In most cases, a single TTE is sufficient to diagnose BAV. Once diagnosed, the patient should be referred for specialist cardiology treatment and follow-up.

In contrast, Marfan syndrome is an autosomal dominant disorder of the fibrillin gene on chromosome 15. Its main effects on the cardiovascular system include aortic aneurysms (especially thoracic) and aortic regurgitation. The diagnosis of Marfan syndrome is made with the Ghent nosology, a set of diagnostic criteria last revised in 2010 that includes clinical, laboratory, and imaging criteria.35 The imaging criteria includes significant aortic root dilatation (Z score of ≥2). The European Society of Cardiology recommends at-risk relatives without a definite diagnosis of Marfan syndrome to be screened every 5 years until a definitive diagnosis is established or excluded.17 Once diagnosed, yearly echocardiography is required for the stable patient, as well as baseline and at least 5-yearly cardiac MRI scan. If aneurysmal changes are detected beyond the aortic root, MRI scan should be repeated at least yearly.36

This section summarises advanced echocardiographic technologies that are relevant to common cardiovascular diseases, as well as emerging imaging technologies (Table 3).

Stress echocardiography is valuable for evaluation of suspected coronary artery disease. Myocardial ischaemia causes reduced systolic wall thickening and excursion during stress, constituting stress-induced regional wall motion abnormalities (Fig 3). These may precede angina and ST-T changes on ECG. The sensitivity of exercise and dobutamine stress echocardiography for detection of coronary artery disease are 85% and 80% with specificity of 77% and 86%, respectively.37 Using cardiac MRI as reference standard, three-dimensional (3D) echocardiography provides more accurate and reproducible left ventricle volume and ejection fraction measurements than 2D echocardiography.38 39 40 41 42 The American Society of Echocardiography recommends the use of 3D echocardiography in chamber quantification when such technique is available in the echocardiography laboratory.43 Three-dimensional TEE has brought new insights to the mechanisms of mitral regurgitation,44 45 and has become essential in guiding transcatheter structural interventions such as transcatheter edge-to-edge mitral46 or tricuspid47 repair, transcatheter aortic valve implantation,48 and left atrial appendage occlusion (Fig 4).49 50 51 More recently, 3D printing has been used to create 3D models from 3D TEE images for preprocedural simulation.52 53 54 Speckle-tracking echocardiography allows measurement of myocardial strain (deformation; Fig 3).55 56 Assessment of the global longitudinal strain is useful for detection of chemotherapy-related cardiotoxicity in cancer patients, better than the assessment of LVEF.20

More recently, echocardiography has been used to visualise intracardiac blood flow.57 Intracardiac vortex patterns of various pathological conditions have been shown to differ from those of healthy patients, including heart failure,58 dilated and hypertrophic cardiomyopathy,59 coronary heart disease,60 and valvular diseases.61

Echocardiography is essential in a wide range of clinical scenarios. Appropriate use of echocardiography improves clinical outcomes by increasing diagnostic accuracy, providing non-invasive or minimally invasive assessment of disease status and risk stratification, and enabling real-time monitoring and guidance of interventional procedures. Technological advancements have extended echocardiography beyond 2D imaging, allowing advanced structural visualisation and functional measurement of the heart. Echocardiography remains a vibrant field of research, and recent developments are promising clinically. Echocardiography will continue to grow as a core clinical investigation for a wide spectrum of disorders, and its relevance to primary care physicians cannot be overstated.

All authors are responsible for writing the article. APW Lee had critical revision for important intellectual content. 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.

This work was funded by the Hong Kong Special Administrative Region Government Health and Medical Research Fund (Ref 05160976).

APW Lee receives speaker honorarium and research grant from Philips Healthcare.

The incidence of infertility has increased in recent decades, and women are more often delaying marriage and pregnancy. The mean age at which women deliver their first baby has increased from 27.9 years in 1995 to 30.5 years in 2017.1 Owing to the natural decline in fertility with age, more and more couples seek help to conceive through IVF. The number of IVF cycles performed in Europe increased from 203 225 cycles in 1997 to 776 556 in 2014, with 170 163 babies born.2 A similar trend has been observed worldwide.3 The aim of this paper is to review the current situation of IVF in 2019.

Last year in 2018, the first “test tube” baby Louise Brown celebrated her 40th birthday. In vitro fertilisation was pioneered by Patrick Steptoe and Robert Edwards. They first obtained an oocyte in a natural cycle using a laparoscope. After it was fertilised in the laboratory, they transferred the embryo back to the donor’s uterus. The techniques of IVF have progressed rapidly since then. The success rate has also greatly increased from lower than 1% per cycle to around 35% per cycle. The success rate has increased owing to several factors, including ovarian stimulation, assisted fertilisation using intracytoplasmic sperm insemination, improvements in culture conditions, and more advanced embryo transfer techniques.

Modern IVF cycles include ovarian stimulation, oocyte retrieval, fertilisation and culture in vitro, and embryo transfer to the uterus. Ovarian stimulation involves administration of gonadotropin, coupled with suppression of endogenous gonadotropin release by either gonadotropin-releasing hormone (GnRH) agonist or antagonist. The super-physiological doses of gonadotropins enhance growth of multiple follicles, in contrast to the development of a single follicle in a natural cycle. The use of GnRH agonist or antagonist reduces the risk of premature ovulation. Women undergoing ovarian stimulation need close monitoring, with pelvic scanning to determine the number and size of the follicles and hormonal tests to measure the serum oestradiol level. When the leading follicles reach >17 to 18 mm, human chorionic gonadotropin is usually given to the patient to trigger the final maturation of the oocytes.

At 36 to 38 hours after the trigger, oocyte retrieval is typically performed through the transvaginal route under ultrasound guidance. An aspiration needle is used to puncture through the vagina to aspirate the follicular fluid with the oocytes and the follicles are aspirated till complete collapse of the follicles. Oocyte retrieval involves a small risk of bleeding, infection, pain, and risk of injury to visceral organs.

In vitro fertilisation refers to the overnight co-culture of oocytes with sperm. For couples with severe male factor infertility or fertilisation problems in previous IVF cycles, intracytoplasmic sperm insemination involving injection of a single sperm into an oocyte is advised.4 The fertilised embryo is transferred back to the uterine cavity either at cleavage (Day 2 or 3) or blastocyst stage (Day 5). Surplus high quality fertilised embryos can be frozen at the cleavage or blastocyst stage for subsequent transfer by slow freezing or more commonly by vitrification, which involves rapid freezing in liquid nitrogen. Vitrification enables a rapid transition of the liquid form of water to a “glass” status, which avoids crystallisation that can damage the cells.

In vitro fertilisation is not without risks, even in healthy couples. The most common complications of IVF are multiple pregnancy followed by ovarian hyperstimulation syndrome, which can lead to ascites, pleural effusion, venous thromboembolism, or even death. Although severe ovarian hyperstimulation syndrome has a low incidence, it can be potentially life-threatening and is avoidable. In cycles using GnRH antagonists to prevent premature ovulation, agonist can be used instead of human chorionic gonadotropin as a trigger for oocyte final maturation in order to lower the risk of ovarian hyperstimulation syndrome.2 5

Overall, the success of IVF greatly depends on the woman’s age. As shown by the latest data by ESHRE (European Society of Human Reproduction and Embryology),2 in 2014, live birth rates after fresh transfer IVF in women aged <35, 35 to 39, and ≥40 years were 23.8%, 18.8%, and 8.1%, respectively. For women aged <30 years, the cumulative live birth rate after completion of a cycle can be nearly 70%, compared with 17.3% in women aged ≥40 years.4

In Hong Kong, IVF programmes were initiated in the Department of Obstetrics and Gynaecology, The Chinese University of Hong Kong in December 1984, in the Hong Kong Sanatorium & Hospital in January 1986, and in the Department of Obstetrics and Gynaecology, The University of Hong Kong in July 1986.7 The Hong Kong Sanatorium & Hospital programme achieved the first successful IVF pregnancy and delivery in Hong Kong.7

By August 1987, 522 IVF cycles had been initiated in Hong Kong and the overall clinical pregnancy rate was 5.2% per cycle initiated.6 From January 1992 to December 1993, 912 IVF cycles, 158 cycles of gamete intrafallopian transfer, 87 cycles of zygote intrafallopian transfer, and 233 cycles of frozen-thawed embryo transfer (FET) were initiated, with delivery rates per cycle started of 8.4%, 29.1%, 13.8%, and 11.2%, respectively.8

More recently, according to the Council on Human Reproductive Technology (HRT Council) Annual Report,9 the number of women undergoing IVF increased from 2415 in 2009 to 7995 in 2018, with the number of fresh and FET IVF cycles increasing from 2768 to 10 105 over the same period (Table 1). The ongoing pregnancy rate per transfer increased slightly from 29.9% in 2009 to 32.8% in 2015 and remained steady in 2015 to 2018 (Table 2). The ongoing pregnancy rate per transfer was 33.7% in 2018. However, there was no significant increase in live birth rates throughout the years. Both ongoing and live birth rates are markedly reduced in women aged ≥41 years.

The number of embryos transferred has reduced gradually over the years, though double embryo transfer still is the most common. The single embryo transfer rate has increased from 12.9% (321 cycles) in 2009 to 49.2% (3043 cycles) in 2017. As a result, the multiple pregnancy rate per ongoing pregnancy has decreased, but remained high at 15.2% in 2017.

Assisted reproduction in Hong Kong is regulated by the Human Reproductive Technology Ordinance (Cap. 561).10 Centres that provide IVF must obtain a treatment licence from the HRT Council. At the time of writing, there are 18 licensed treatment centres in Hong Kong and of these, 13 provide IVF. Of these 13 treatment centres, 10 are in the private sector and three are in the public sector.11

As stated in the HRT Council Code of Practice,6 in Hong Kong, IVF can be provided only to legally married couples in monogamous relationship. The maximum number of embryos that can be transferred to the woman is three per cycle. Frozen embryos can be stored for up to 10 years from the day of freezing, and gametes can be stored until the patient is aged 55 years. All IVF data must be documented clearly and reported promptly and accurately to the HRT Council. Commercial oocyte donation is not allowed in Hong Kong.11 No payment to the oocyte donor is allowed apart from reimbursing the loss of earnings and the expenses, such as transportation and appointment fee. Sex selection, unless medically indicated, is also prohibited in Hong Kong. Although surrogacy is legal in Hong Kong, none of the centres in Hong Kong has a licence for surrogacy arrangements, and surrogacy agreements have been found to be unenforceable under the law.11

Currently, IVF service is provided in three public hospitals in Hong Kong: Kwong Wah Hospital, Prince of Wales Hospital, and Queen Mary Hospital. Eligible couples can receive partial subsidy funding from the Hong Kong Hospital Authority for up to three IVF cycles. The number of publicly funded cycles has increased to around 1000 cycles in total in 2018. The criteria for funded IVF cycles include women who are permanent Hong Kong residents, aged <40 years, and with no biological children. The waiting time for IVF in public hospitals in Hong Kong is up to 3 years. The provision of IVF in public hospitals is not entirely free of charge. Couples pay approximately HK$20 000 for all medication, procedures, and embryo storage for up to three cycles, but this is lower than the HK$80 000 to HK$100 000 required for just one IVF cycle in the private sector.

Chromosome aneuploidy is an error in cell division that results in the “daughter” cells having the wrong number of chromosomes. Chromosome aneuploidy is a major reason for failure of conception, pregnancy loss, and congenital anomalies following both natural conception and IVF pregnancies and its prevalence increases exponentially with maternal age. The need to assess embryo quality and select those with the highest potential for implantation on the basis of morphology has led to preimplantation genetic testing for aneuploidy (PGT-A).9 This involves biopsy of a few cells from an embryo at the blastocyst stage and assessment of the comprehensive chromosome copy numbers. Although PGT-A cannot create a healthy embryo or improve the health of an embryo, it can provide an accurate method of selecting of embryos with a normal number of chromosomes for transfer. This in turn has the potential to increase the chance of having a healthy live birth per each transfer and to reduce the risk of miscarriage or abnormal fetus caused by an abnormal number of chromosomes.12 However, the potential damage of trophectoderm biopsy on the developing embryos remains unknown. In addition, the concordance of trophectoderm biopsy and blastocyst is questionable especially in those with segmental aneuploidy13 and mosaicism.14 Gene editing may provide a new perspective in future, but there is still a long way ahead. Gene editing technologies are immature and imprecise, and involve unknown long-term risks.

Oocyte freezing by vitrification is no longer considered to be experimental and is offered to women who desire preservation of their fertility potential before chemotherapy or radiotherapy for cancer treatment. In Hong Kong, the indication of oocyte freezing has been extended to single women who wish to delay parenthood for education or career purposes. In general, fertility preservation for cancer patients is underutilised, partly owing to lack of funding in the public sector and inadequate information for patients. Fertility preservation for cancer patients requires a close cooperation between fertility specialists, oncologists, paediatricians, and surgeons. Oocyte or embryo freezing provides more promising results in fertility preservation, but it involves a delay of treatment for at least 2 weeks and it is possible only in postpubertal women. Owing to the lack of funding, patients often need to pay for their own treatment.

There is an international goal aiming to reduce the incidence of multiple pregnancy as a result of IVF to <10%. Multiple pregnancies after IVF create a huge burden on the healthcare system. The chance of multiple pregnancy increases exponentially with the number of embryos transferred. Multiple pregnancies are associated with high risk of prematurity, low birth rate, and tremendous support from neonatal intensive care unit. It has been estimated that one premature baby at 29 weeks can cost up to US$122 000 and prematurity cost a total of US$4567 billion in United Kingdom in 2006.15 Owing to improvements in embryo culture and cryopreservation techniques, with the use of vitrification, the cumulative pregnancy rate is similar in single or double embryo transfer.16 In Kwong Wah Hospital and Queen Mary Hospital, women can have only one embryo transferred at a time unless they are aged ≥38 years, have failed two IVF cycles, and have had no live births. Although single embryo transfer results in a slightly longer interval to pregnancy, it can significantly lower the multiple pregnancy rate to <2%.16

The reasons for Hong Kong residents seeking cross-border reproductive care are multifactorial. Reasons may include the long waiting times for publicly funded IVF, the high cost of private IVF, lack of oocyte donors, and ineligibility for IVF in Hong Kong. Those ineligible for IVF in Hong Kong include unmarried couples, same-sex couples, and those seeking IVF for surrogacy, sex selection, or social reasons. Women seeking IVF overseas face risks including lack of regulations in some centres and lack of medical care or insurance coverage in case of complications.

Other problems include the risks of ovarian hyperstimulation syndrome, the high cost of IVF, and difficulty in getting gamete and embryo donation.

In vitro fertilisation provides hope for infertile couples. However, there are many unresolved issues, especially the high rate of multiple pregnancies and potential risks associated with cross-border reproductive care.

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.

Concept or design: EHY Ng.
Acquisition of data: MW Lui.
Analysis or interpretation of data: MW Lui.
Drafting of the article: MW Lui.
Critical revision for important intellectual content: WSB Yeung, PC Ho, EHY Ng.

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.

1. Organisation for Economic Co-operation and Development. OECD Family Database. SF2.3.B. Age of mothers at childbirth and age-specific fertility. Available from: http://www.oecd.org/els/family/database.htm. Accessed 26 Jul 2019.

2. De Geyter C, Calhaz-Jorge C, Kupka MS, et al. ART in Europe, 2014: results generated from European registries by ESHRE: The European IVF-monitoring Consortium (EIM) for the European Society of Human Reproduction and Embryology (ESHRE). Hum Reprod 2018;33:1586-601. Crossref

3. Chambers GM, Wand H, Macaldowie A, Chapman MG, Farquhar CM, Bowman M, Molloy, D, Ledger W. Population trends and live birth rates associated with common ART treatment strategies. Hum Reprod 2016;31:2632-41. Crossref

4. Babayev SN, Park CW, Bukulmez O. Intracytoplasmic sperm injection indications: how rigorous? Semin Reprod Med 2014;32:283-90. Crossref

5. McLernon DJ, Maheshwari A, Lee AJ, Bhattacharya S. Cumulative live birth rates after one or more complete cycles of IVF: a population-based study of linked cycle data from 178,898 women. Hum Reprod 2016;31:572-81. Crossref

6. Council on Human Reproductive Technology. Code of Practice on Reproductive Technology and Embryo Research. January 2013. Available from: https://www.chrt.org.hk/english/service/service_cod.html. Accessed 26 Jul 2019.

7. Mao KR, Loong EP, Lee HC, et al. Current status of in-vitro fertilization (IVF) in Hong Kong. J Hong Kong Med Assoc 1987;39:144-6.

8. Hong Kong IVF Study Group. Assisted reproduction in Hong Kong: status in the 1990s. Hong Kong Med J 1996;2:253-6.

9. Lehmann L, El-Haddad A, Barr RD. Global approach to hematologic malignancies. Hematol Oncol Clin North Am 2016;30:417-32. Crossref

10. Cap. 561 Human reproductive technology ordinance 2000 (Hong Kong SAR). Available from: https://www.elegislation.gov.hk/hk/cap561. Accessed 26 Jul 2019.

11. Council on Human Reproductive Technology. Available from: https://www.chrt.org.hk/. Accessed 26 Jul 2019.

12. Maxwell SM, Grifo JA. Should every embryo undergo preimplantation genetic testing for aneuploidy? A review of the modern approach to in vitro fertilization. Best Pract Res Clin Obstet Gynaecol 2018;53:38-47. Crossref

13. Victor AR, Griffin DK, Brake AJ, et al. Assessment of aneuploidy concordance between clinical trophectoderm biopsy and blastocyst. Hum Reprod 2019;34:181-92. Crossref

14. Capalbo A, Ubaldi FM, Rienzi L, Scott R, Treff N. Detecting mosaicism in trophectoderm biopsies: current challenges and future possibilities. Hum Reprod 2017;32:492-8. Crossref

15. Saha S, Gerdtham UG. Cost of illness studies on reproductive, maternal, newborn, and child health: a systematic literature review. Health Econ Rev 2013;3:24. Crossref

16. Pandian Z, Marjoribanks J, Ozturk O, Serour G, Bhattacharya S. Number of embryos for transfer following in vitro fertilisation or intra-cytoplasmic sperm injection. Cochrane Database Syst Rev 2013;(7):CD003416. Crossref

The incidence of infertility has increased in recent decades, and women are more often delaying marriage and pregnancy. The mean age at which women deliver their first baby has increased from 27.9 years in 1995 to 30.5 years in 2017.1 Owing to the natural decline in fertility with age, more and more couples seek help to conceive through IVF. The number of IVF cycles performed in Europe increased from 203 225 cycles in 1997 to 776 556 in 2014, with 170 163 babies born.2 A similar trend has been observed worldwide.3 The aim of this paper is to review the current situation of IVF in 2019.

Last year in 2018, the first “test tube” baby Louise Brown celebrated her 40th birthday. In vitro fertilisation was pioneered by Patrick Steptoe and Robert Edwards. They first obtained an oocyte in a natural cycle using a laparoscope. After it was fertilised in the laboratory, they transferred the embryo back to the donor’s uterus. The techniques of IVF have progressed rapidly since then. The success rate has also greatly increased from lower than 1% per cycle to around 35% per cycle. The success rate has increased owing to several factors, including ovarian stimulation, assisted fertilisation using intracytoplasmic sperm insemination, improvements in culture conditions, and more advanced embryo transfer techniques.

Modern IVF cycles include ovarian stimulation, oocyte retrieval, fertilisation and culture in vitro, and embryo transfer to the uterus. Ovarian stimulation involves administration of gonadotropin, coupled with suppression of endogenous gonadotropin release by either gonadotropin-releasing hormone (GnRH) agonist or antagonist. The super-physiological doses of gonadotropins enhance growth of multiple follicles, in contrast to the development of a single follicle in a natural cycle. The use of GnRH agonist or antagonist reduces the risk of premature ovulation. Women undergoing ovarian stimulation need close monitoring, with pelvic scanning to determine the number and size of the follicles and hormonal tests to measure the serum oestradiol level. When the leading follicles reach >17 to 18 mm, human chorionic gonadotropin is usually given to the patient to trigger the final maturation of the oocytes.

At 36 to 38 hours after the trigger, oocyte retrieval is typically performed through the transvaginal route under ultrasound guidance. An aspiration needle is used to puncture through the vagina to aspirate the follicular fluid with the oocytes and the follicles are aspirated till complete collapse of the follicles. Oocyte retrieval involves a small risk of bleeding, infection, pain, and risk of injury to visceral organs.

In vitro fertilisation refers to the overnight co-culture of oocytes with sperm. For couples with severe male factor infertility or fertilisation problems in previous IVF cycles, intracytoplasmic sperm insemination involving injection of a single sperm into an oocyte is advised.4 The fertilised embryo is transferred back to the uterine cavity either at cleavage (Day 2 or 3) or blastocyst stage (Day 5). Surplus high quality fertilised embryos can be frozen at the cleavage or blastocyst stage for subsequent transfer by slow freezing or more commonly by vitrification, which involves rapid freezing in liquid nitrogen. Vitrification enables a rapid transition of the liquid form of water to a “glass” status, which avoids crystallisation that can damage the cells.

In vitro fertilisation is not without risks, even in healthy couples. The most common complications of IVF are multiple pregnancy followed by ovarian hyperstimulation syndrome, which can lead to ascites, pleural effusion, venous thromboembolism, or even death. Although severe ovarian hyperstimulation syndrome has a low incidence, it can be potentially life-threatening and is avoidable. In cycles using GnRH antagonists to prevent premature ovulation, agonist can be used instead of human chorionic gonadotropin as a trigger for oocyte final maturation in order to lower the risk of ovarian hyperstimulation syndrome.2 5

Overall, the success of IVF greatly depends on the woman’s age. As shown by the latest data by ESHRE (European Society of Human Reproduction and Embryology),2 in 2014, live birth rates after fresh transfer IVF in women aged <35, 35 to 39, and ≥40 years were 23.8%, 18.8%, and 8.1%, respectively. For women aged <30 years, the cumulative live birth rate after completion of a cycle can be nearly 70%, compared with 17.3% in women aged ≥40 years.4

In Hong Kong, IVF programmes were initiated in the Department of Obstetrics and Gynaecology, The Chinese University of Hong Kong in December 1984, in the Hong Kong Sanatorium & Hospital in January 1986, and in the Department of Obstetrics and Gynaecology, The University of Hong Kong in July 1986.7 The Hong Kong Sanatorium & Hospital programme achieved the first successful IVF pregnancy and delivery in Hong Kong.7

By August 1987, 522 IVF cycles had been initiated in Hong Kong and the overall clinical pregnancy rate was 5.2% per cycle initiated.6 From January 1992 to December 1993, 912 IVF cycles, 158 cycles of gamete intrafallopian transfer, 87 cycles of zygote intrafallopian transfer, and 233 cycles of frozen-thawed embryo transfer (FET) were initiated, with delivery rates per cycle started of 8.4%, 29.1%, 13.8%, and 11.2%, respectively.8

More recently, according to the Council on Human Reproductive Technology (HRT Council) Annual Report,9 the number of women undergoing IVF increased from 2415 in 2009 to 7995 in 2018, with the number of fresh and FET IVF cycles increasing from 2768 to 10 105 over the same period (Table 1). The ongoing pregnancy rate per transfer increased slightly from 29.9% in 2009 to 32.8% in 2015 and remained steady in 2015 to 2018 (Table 2). The ongoing pregnancy rate per transfer was 33.7% in 2018. However, there was no significant increase in live birth rates throughout the years. Both ongoing and live birth rates are markedly reduced in women aged ≥41 years.

The number of embryos transferred has reduced gradually over the years, though double embryo transfer still is the most common. The single embryo transfer rate has increased from 12.9% (321 cycles) in 2009 to 49.2% (3043 cycles) in 2017. As a result, the multiple pregnancy rate per ongoing pregnancy has decreased, but remained high at 15.2% in 2017.

Assisted reproduction in Hong Kong is regulated by the Human Reproductive Technology Ordinance (Cap. 561).10 Centres that provide IVF must obtain a treatment licence from the HRT Council. At the time of writing, there are 18 licensed treatment centres in Hong Kong and of these, 13 provide IVF. Of these 13 treatment centres, 10 are in the private sector and three are in the public sector.11

As stated in the HRT Council Code of Practice,6 in Hong Kong, IVF can only be provided to legally married couples in monogamous relationship. The maximum number of embryos that can be transferred to the woman is three per cycle. Frozen embryos can be stored for up to 10 years from the day of freezing, and gametes can be stored until the patient is aged 55 years. All IVF data must be documented clearly and reported promptly and accurately to the HRT Council. Commercial oocyte donation is not allowed in Hong Kong.11 No payment to the oocyte donor is allowed apart from reimbursing the loss of earnings and the expenses, such as transportation and appointment fee. Sex selection, unless medically indicated, is also prohibited in Hong Kong. Although surrogacy is legal in Hong Kong, none of the centres in Hong Kong has a licence for surrogacy arrangements, and surrogacy agreements have been found to be unenforceable under the law.11

Currently, IVF service is provided in three public hospitals in Hong Kong: Kwong Wah Hospital, Prince of Wales Hospital, and Queen Mary Hospital. Eligible couples can receive partial subsidy funding from the Hong Kong Hospital Authority for up to three IVF cycles. The number of publicly funded cycles has increased to around 1000 cycles in total in 2018. The criteria for funded IVF cycles include women who are permanent Hong Kong residents, aged <40 years, and with no biological children. The waiting time for IVF in public hospitals in Hong Kong is up to 3 years. The provision of IVF in public hospitals is not entirely free of charge. Couples pay approximately HK$20 000 for all medication, procedures, and embryo storage for up to three cycles, but this is lower than the HK$80 000 to HK$100 000 required for just one IVF cycle in the private sector.

Chromosome aneuploidy is an error in cell division that results in the “daughter” cells having the wrong number of chromosomes. Chromosome aneuploidy is a major reason for failure of conception, pregnancy loss, and congenital anomalies following both natural conception and IVF pregnancies and its prevalence increases exponentially with maternal age. The need to assess embryo quality and select those with the highest potential for implantation on the basis of morphology has led to preimplantation genetic testing for aneuploidy (PGT-A).9 This involves biopsy of a few cells from an embryo at the blastocyst stage and assessment of the comprehensive chromosome copy numbers. Although PGT-A cannot create a healthy embryo or improve the health of an embryo, it can provide an accurate method of selecting of embryos with a normal number of chromosomes for transfer. This in turn has the potential to increase the chance of having a healthy live birth per each transfer and to reduce the risk of miscarriage or abnormal fetus caused by an abnormal number of chromosomes.12 However, the potential damage of trophectoderm biopsy on the developing embryos remains unknown. In addition, the concordance of trophectoderm biopsy and blastocyst is questionable especially in those with segmental aneuploidy13 and mosaicism.14 Gene editing may provide a new perspective in future, but there is still a long way ahead. Gene editing technologies are immature and imprecise, and involve unknown long-term risks.

Oocyte freezing by vitrification is no longer considered to be experimental and is offered to women who desire preservation of their fertility potential before chemotherapy or radiotherapy for cancer treatment. In Hong Kong, the indication of oocyte freezing has been extended to single women who wish to delay parenthood for education or career purposes. In general, fertility preservation for cancer patients is underutilised, partly owing to lack of funding in the public sector and inadequate information for patients. Fertility preservation for cancer patients requires a close cooperation between fertility specialists, oncologists, paediatricians, and surgeons. Oocyte or embryo freezing provides more promising results in fertility preservation, but it involves a delay of treatment for at least 2 weeks and it is only possible in postpubertal women. Owing to the lack of funding, patients often need to pay for their own treatment.

There is an international goal aiming to reduce the incidence of multiple pregnancy as a result of IVF to <10%. Multiple pregnancies after IVF create a huge burden on the healthcare system. The chance of multiple pregnancy increases exponentially with the number of embryos transferred. Multiple pregnancies are associated with high risk of prematurity, low birth rate, and tremendous support from neonatal intensive care unit. It has been estimated that one premature baby at 29 weeks can cost up to US$122 000 and prematurity cost a total of US$4567 billion in United Kingdom in 2006.15 Owing to improvements in embryo culture and cryopreservation techniques, with the use of vitrification, the cumulative pregnancy rate is similar in single or double embryo transfer.16 In Kwong Wah Hospital and Queen Mary Hospital, women can only have one embryo transferred at a time unless they are aged ≥38 years, have failed two IVF cycles, and have had no live births. Although single embryo transfer results in a slightly longer interval to pregnancy, it can significantly lower the multiple pregnancy rate to <2%.16

The reasons for Hong Kong residents seeking cross-border reproductive care are multifactorial. Reasons may include the long waiting times for publicly funded IVF, the high cost of private IVF, lack of oocyte donors, and ineligibility for IVF in Hong Kong. Those ineligible for IVF in Hong Kong include unmarried couples, same-sex couples, and those seeking IVF for surrogacy, sex selection, or social reasons. Women seeking IVF overseas face risks including lack of regulations in some centres and lack of medical care or insurance coverage in case of complications.

Other problems include the risks of ovarian hyperstimulation syndrome, the high cost of IVF, and difficulty in getting gamete and embryo donation.

In vitro fertilisation provides hope for infertile couples. However, there are many unresolved issues, especially the high rate of multiple pregnancies and potential risks associated with cross-border reproductive care.

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.

Concept or design: EHY Ng.
Acquisition of data: MW Lui.
Analysis or interpretation of data: MW Lui.
Drafting of the article: MW Lui.
Critical revision for important intellectual content: WSB Yeung, PC Ho, EHY Ng.

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.

1. Organisation for Economic Co-operation and Development. OECD Family Database. SF2.3.B. Age of mothers at childbirth and age-specific fertility. Available from: http://www.oecd.org/els/family/database.htm. Accessed 26 Jul 2019.

2. De Geyter C, Calhaz-Jorge C, Kupka MS, et al. ART in Europe, 2014: results generated from European registries by ESHRE: The European IVF-monitoring Consortium (EIM) for the European Society of Human Reproduction and Embryology (ESHRE). Hum Reprod 2018;33:1586-601. Crossref

3. Chambers GM, Wand H, Macaldowie A, Chapman MG, Farquhar CM, Bowman M, Molloy, D, Ledger W. Population trends and live birth rates associated with common ART treatment strategies. Hum Reprod 2016;31:2632-41. Crossref

4. Babayev SN, Park CW, Bukulmez O. Intracytoplasmic sperm injection indications: how rigorous? Semin Reprod Med 2014;32:283-90. Crossref

5. McLernon DJ, Maheshwari A, Lee AJ, Bhattacharya S. Cumulative live birth rates after one or more complete cycles of IVF: a population-based study of linked cycle data from 178,898 women. Hum Reprod 2016;31:572-81. Crossref

6. Council on Human Reproductive Technology. Code of Practice on Reproductive Technology and Embryo Research. January 2013. Available from: https://www.chrt.org.hk/english/service/service_cod.html. Accessed 26 Jul 2019.

7. Mao KR, Loong EP, Lee HC, et al. Current status of in-vitro fertilization (IVF) in Hong Kong. J Hong Kong Med Assoc 1987;39:144-6.

8. Hong Kong IVF Study Group. Assisted reproduction in Hong Kong: status in the 1990s. Hong Kong Med J 1996;2:253-6.

9. Lehmann L, El-Haddad A, Barr RD. Global approach to hematologic malignancies. Hematol Oncol Clin North Am 2016;30:417-32. Crossref

10. Cap. 561 Human reproductive technology ordinance 2000 (Hong Kong SAR). Available from: https://www.elegislation.gov.hk/hk/cap561. Accessed 26 Jul 2019.

11. Council on Human Reproductive Technology. Available from: https://www.chrt.org.hk/. Accessed 26 Jul 2019.

12. Maxwell SM, Grifo JA. Should every embryo undergo preimplantation genetic testing for aneuploidy? A review of the modern approach to in vitro fertilization. Best Pract Res Clin Obstet Gynaecol 2018;53:38-47. Crossref

13. Victor AR, Griffin DK, Brake AJ, et al. Assessment of aneuploidy concordance between clinical trophectoderm biopsy and blastocyst. Hum Reprod 2019;34:181-92. Crossref

14. Capalbo A, Ubaldi FM, Rienzi L, Scott R, Treff N. Detecting mosaicism in trophectoderm biopsies: current challenges and future possibilities. Hum Reprod 2017;32:492-8. Crossref

15. Saha S, Gerdtham UG. Cost of illness studies on reproductive, maternal, newborn, and child health: a systematic literature review. Health Econ Rev 2013;3:24. Crossref

16. Pandian Z, Marjoribanks J, Ozturk O, Serour G, Bhattacharya S. Number of embryos for transfer following in vitro fertilisation or intra-cytoplasmic sperm injection. Cochrane Database Syst Rev 2013;(7):CD003416. Crossref

Acute renal failure secondary to contrast-induced acute kidney injury (CI-AKI) is one of the most commonly encountered problems in hospitalised patients.1 2 The CI-AKI is generally defined as an increase of at least 0.5 mg/dL in the plasma creatinine level from the basal value within 24 to 48 hours of contrast exposure.3 The rising incidence of CI-AKI in recent decades is concurrent with the increasing use of diagnostic and therapeutic procedures requiring contrast administration, such as coronary angiography (CAG) and percutaneous coronary intervention (PCI). Recent studies have suggested that CI-AKI may lead to the development of persistent renal disease4 and is thus a cause of significant morbidity and mortality,5 particularly in patients with pre-existing chronic diseases.6 Thus, there is an urgent need to design effective prophylactic regimens for CI-AKI to improve the long-term outcomes in patients undergoing such procedures.

The complex pathways involved in the pathogenesis of CI-AKI are not fully understood. Contrast media are known to cause reduced perfusion of renal medulla, owing to an increase in the release of vasoconstrictive mediators and decrease in the vasodilator substances.7 8 This leads haemodynamic changes in the renal vasculature that contribute to CI-AKI. Other mechanisms include direct tubular injury by contrast agents and free-radical mediated injury.9 Both direct cellular injury and ischaemia act in concert to increase the production of free radicals that can cause cellular injury themselves and thus cause cumulative damage to tubular cells.10

An appropriate preventative strategy is the sole means of lowering the risk of contrast-induced nephropathy in high-risk patients, because no intervention is effective once exposure to the contrast medium has already occurred.3 Despite extensive research, the best prophylactic approach for acute kidney injury is yet to be discovered. The current recommended strategy is adequate hydration and intravascular volume expansion prior to contrast administration.3 Although routinely practised, this strategy has not resulted in substantial reduction of CI-AKI; thus, research on optimal prophylactic regimens for CI-AKI is necessary.

In recent years, there has been increasing interest in statins for prophylaxis of CI-AKI, although the results to date are controversial.11

The aim of the present scoping review was to summarise existing evidence on the efficacy of statins in preventing CI-AKI, to identify discrepancies and gaps in the available literature, and to recommend areas for future research.

We conducted a review of the literature from PubMed for articles published up to May 2018. A variety of keywords were employed including “Statins AND contrast-induced kidney injury”, “3-hydroxy-3-methyl-glutaryl-CoA reductase inhibitors AND contras-induced kidney injury”, “HMG-CoA reductase inhibitors AND contrast-induced kidney injury”, “Statins AND contrast-induced nephropathy”, “3-hydroxy-3-methyl-glutaryl-CoA reductase inhibitors AND contrast-induced nephropathy”, “HMG-CoA reductase inhibitors AND contrast induced nephropathy”, “Statins AND CI-AKI”, “HMG-CoA reductase inhibitors AND CI-AKI”, and “3-hydroxy-3-methyl-glutaryl-CoA reductase inhibitors AND CI-AKI”. No language restriction was placed. The abstracts of all the articles were reviewed to assess their relevance to the aims of our study. Our review was conducted in accordance with the PRISMA Extension for Scoping Reviews.12

In the past decade, there has been growing interest in discovering the renoprotective effects of statins. The cholesterol-lowering properties of statins are well recognised, supporting their widespread use for the prevention of cardiovascular diseases.13 However, studies have also revealed a number of pleiotropic effects of statins which are not directly related to lipid metabolism.14 Though the exact mechanism has not been discovered, it has been speculated that statins act by modulation of immune and inflammatory responses, reduction of oxidative stress, prevention of plaque rupture, and improvement in endothelial function.15 16 Since aberrations in these responses are thought to be responsible for CI-AKI, statins can potentially be used to effectively prevent CI-AKI.

The efficacy of statins in preventing CI-AKI has been demonstrated in various trials; however, results have been contradictory. One of the earliest meta-analyses by Zhang et al17 showed no statistically significant benefits (relative risk [RR]=0.76) of statin pretreatment in preventing CI-AKI. The only significant difference between the treatment arm and the control arm in that study was serum creatinine levels, which were slightly more elevated in patients treated with statins. However, this meta-analysis included only four trials and a total of 752 subjects, increasing the likelihood of bias and rendering the results of the analysis inconclusive. In contrast, several meta-analyses, with greater numbers of trials and patients included, have yielded promising results with pre-procedural statin administration.18 19 20

A recent meta-analysis by Li et al21 that included 21 randomised controlled trials and 7746 patients observed a significant decrease (RR=0.57) in the likelihood of CI-AKI with statin pretreatment in patients undergoing CAG and PCI. This analysis had some major strengths over previous analyses; for example, the risk of bias in all included studies was gauged using Cochrane Collaboration’s tool. This contrasts with earlier analyses22 23 which used the Jadad scoring system.24 The Jadad scoring system has several inherent shortcomings; for example, it does not account for bias arising from the absence of allocation concealment, which limits its reliability for the assessment of methodological quality of trials.

Another major strength of the meta-analysis by Li et al21 was the use of subgroup analysis to discover differences in the effectiveness of statin use with respect to statin type, dosages, duration of therapy, pre-existing diseases, hydration protocols, and definition of CI-AKI. Although the need for better quality trials was emphasised, the authors of that study recommended the use of statins in patients undergoing CAG and PCI, particularly those at high risk of CI-AKI.

The most recent review on statins by Verdoodt et al11 concluded that, although statins are useful for the prevention of cardiovascular diseases, their effectiveness in acute kidney injury and chronic kidney disease (CKD) remains unclear. There is a considerable lack of homogeneity in trials of statin use for preventing CI-AKI, not only in the protocols and methodological designs, but also in the clinical settings in which contrast administration was required. This has limited the validity and reliability of the results of the meta-analyses that have been performed using these trials.

There are inadequate data regarding the differences in the efficacy of different types of statins, mainly because many trials have only compared one type of statin versus placebo. Li et al21 used subgroup analysis to determine discrepancies among different statins and found that the prophylactic effect of statins in CI-AKI was seen irrespective of the type of statin used. Most studies have used one of three statins: rosuvastatin, atorvastatin, or simvastatin. Of these, an appreciable amount of evidence exists for rosuvastatin and atorvastatin, but data on simvastatin are insufficient to draw any reliable conclusions. Liu et al22 did not find any difference in the incidence of CI-AKI between patients treated with rosuvastatin and atorvastatin. However, in another experimental study, rosuvastatin was found to yield better outcomes than simvastatin and atorvastatin.25 Yang et al26 performed a meta-analysis of five randomised controlled trials including a total of 4045 patients that compared the effects of rosuvastatin versus placebo and discovered that rosuvastatin administration prior to cardiac catheterisation caused a notable decrease in the risk of CI-AKI. However, since only one type of statin was used, comparisons could not be made among different types of statins. Current evidence indicates that all statin types have similar effects in the prophylaxis of CI-AKI.

Statins have consistently demonstrated higher efficacy at higher doses. In the meta-analysis by Li et al,21 compared with lower-dose statin, high-dose statins were associated with an absolute risk reduction of 63% although the quality of the evidence was reportedly low. Cheungpasitporn et al23 reported that only three out of 13 trials compared high- versus low-dose statins; however, all trials that showed a decreased risk of CI-AKI with statin pretreatment used moderately high-dose statins. Another meta-analysis that evaluated the statin efficacy in patients undergoing CAG found high-dose statins to be more effective.27 However, significant heterogeneity in the protocols of the trials and differing baseline characteristics of the patients render it difficult to decide on a single-best dosing regimen. This highlights the need to ensure homogeneity in the protocols of the future trials, so that more reliable conclusions can be drawn.

Timing and duration of statin therapy differed markedly across the trials. Most meta-analyses did not perform subgroup analyses based on these parameters. Li et al21 studied the effect of short-term statin treatment on the incidence of CI-AKI, but the duration of therapy that qualified as ‘short-term’ was not specified. This was also the case with the meta-analysis by Ukaigwe et al,27 which had several strengths but did not elaborate on the timing and duration of statin therapy separately. A meta-analysis by Barbieri et al,20 which demonstrated half the risk of CI-AKI in the statin group versus the control group specified the duration of statin therapy (12 hours to 3 days); however, the effect of therapy duration on outcomes was not determined.

Most studies have shown that the combination of hydration with statins yields optimal results. Verdoodt et al11 concluded that adequate intravenous hydration with iso-osmolar crystalloids is the best preventative measure for acute coronary syndrome or for patients undergoing CAG and PCI. The meta-analysis by Barbieri et al20 reported the administration of periprocedural hydration in all but one study, in which hydration was administered only in patients with serum creatinine level <1.5 mg/dL or creatinine clearance >60 mL/min.28 Quintavalle et al29 primarily used sodium bicarbonate solution for hydration. In contrast, most other studies have reported the use of isotonic saline instead of sodium bicarbonate solution for hydration, with30 31 32 or without33 34 35 36 N-acetylcysteine. However, a recent large-scale multi-centre prospective randomised trial (the ‘Acetylcysteine for Contrast-induced nephropathy Trial37’) demonstrated the ineffectiveness of N-acetylcysteine in cases of CI-AKI.38 39

High-volume contrast media (>100 mL) are associated with a particularly high risk of adverse renal events and the current recommendation is the use of low-volume contrast media.40 However, Li et al21 found that the benefit of statin therapy was observed even in patients administered with contrast media volumes as high as ≥140 mL, although the evidence was of moderate quality for this subgroup of patients.

Statins were found to be useful in cases of both low-osmolar (RR=0.42) and iso-osmolar (RR=0.59) contrast media. The quality of evidence for both subgroups was high.21 An earlier meta-analysis by Barbieri et al20 also demonstrated the efficacy of statins in CI-AKI which was independent of the strength of contrast media.

To assess the efficacy of statin use, different studies assessed renal function via different measures. For example, a number of studies28 32 41 42 used an increase in serum creatinine of ≥0.5 mg/dL or >25% from baseline within 48 h after procedure, whereas others31 32 43 used the same criteria but within 72 h. Acikel et al42 and Toso et al44 assessed renal function by an increase in serum creatinine of ≥0.5 mg/dL within 5 days after contrast exposure. Those findings suggest significantly lower postprocedural serum creatinine level among patients in the statin-use group than among those in the control group (P<0.0001).21 A few studies have excluded patients on the criteria of serum creatinine level of >3 mg/dL.28 30 Quintavalle et al29 reported the incidence of CI-AKI on the basis of increases in serum cystatin C ≥10% from baseline within 24 hours after contrast exposure. Creatinine clearance is another parameter used to enrol patients in different studies, for example with a creatinine clearance of <60 mL/min8 21 22 or <70 mL/min.32 A meta-analysis indicated that, in some studies, postprocedural estimated glomerular filtration rate was higher among patients in the statin-use group than among those in the control group (P=0.001).21 However, no restrictions on the basis of renal function were imposed by Li et al.31

Most articles, including meta-analyses and reviews, have not commented on whether different effects of statins were observed in different populations. However, a meta-analysis conducted by Mao and Huang19 included trials consisting of Caucasian and Asian populations. The authors reported that the effect of statins in both groups was equally significant.19 A meta-analysis by Li et al21 was the first to report better outcomes in East Asian and statin-naïve patients. Another meta-analysis that performed subgroup analysis for different populations found that there were no differences in the efficacy of statins among different racial populations, suggesting that genetic polymorphisms may not have an important role in determining the efficacy of statins in CI-AKI.27

Most previous studies recruited patients who already had some underlying disease or precipitating risk factor for CI-AKI. Advanced age, type and volume of contrast, pre-existing disease such as congestive heart failure and CKD, and haemodynamic instability are reportedly more likely to influence the development of CI-AKI.11 Chyou et al45 demonstrated that increased age, diabetes mellitus, acute coronary syndrome, and CKD are the factors responsible for precipitating the hazard for contrast-induced nephropathy. Further, Chung et al46 confirmed that there is a 13% increased risk of developing severe renal failure with statin treatment among the high-risk population. Quintavalle et al29 found lower rates of CI-AKI occurrence in patients with CKD, whereas Toso et al44 did not find decrease in the occurrence of CI-AKI in patients with existing CKD with high-dose atorvastatin; however, high-dose rosuvastatin was effective in these patients.44

The study by Li et al21 was the first to assess the benefits of statin therapy in patients with diabetes mellitus, acute coronary syndrome, CKD, or congestive heart failure and those requiring higher-volume contrast media. The authors observed that statins proved useful regardless of these risk factors, although the quality of evidence varied from low to high. The authors found that the risk of CI-AKI was 4.4% in the diabetes mellitus subgroup compared with 6.5% in control group (RR=0.70).21 The overall risk reduction was 5.0% in the statin pretreatment arm compared with 8.4% in the control arm (RR=0.61).21 Thus, the results of these meta-analysis indicate that statins are effective prophylactic agents for CI-AKI even in patients with risk factors such as CKD and diabetes mellitus.

As most trials reviewed did not have a long-term follow-up, the frequency of adverse events with statin use for prophylaxis of CI-AKI is not accurately known.43 A recent updated review published by Verdoodt et al11 was sceptical of the beneficial effects of statins owing to the wide range of potential adverse effects. A large retrospective cohort study from Taiwan found that high-efficacy statins increased the risk of severe renal failure by 13% compared with low-efficacy statins, such as lovastatin, pravastatin, simvastatin, and fluvastatin.46 Myopathy is a common adverse effect of statin use and its risk is further increased by concomitant CKD. Statin-induced myopathy clinically manifests as a mild increase in creatinine kinase levels, myalgia, myositis, and rhabdomyolysis. The incidences of these effects have not been reported in most trials that have focused on CI-AKI. Thompson et al47 reviewed data from two databases and revealed that the incidence of myalgia ranged from 6% to 14% in one database and from 19% to 25% in the other. However, the clinical trials rarely report on the incidence of myalgia. In almost all trials and meta-analyses that explored the efficacy of statin use for the prevention of CI-AKI, adverse effects of statin use were not documented. This highlights the need for long-term follow-up of patients undergoing statin prophylaxis, so that the potential adverse effects of statin use can be clarified.

Although several studies have implied beneficial therapeutic effects of short-term high-dose statin use in preventing CI-AKI, statin therapy is not yet the standard prophylactic regimen. Widespread heterogeneity in clinical trials has resulted in inconclusive and contradictory findings regarding the efficacy of statin use for preventing CI-AKI. Large and well-designed trials with more homogeneous protocols should be conducted to minimise discrepancies among the results. Statin therapy can be used as an adjunct to usual prophylactic measures such as adequate hydration and use of low-volume contrast media. However, further controlled trials are required to clarify the harmful potential of statin use in the context of CI-AKI, before this treatment is adopted in clinical practice.

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.

Concept and design of study: I Anjum.
Acquisition of data: M Akmal, N Hasnain, M Jahangir.
Analysis or interpretation of data: W Sohail.
Drafting of the manuscript: M Akmal, N Hasnain, M Jahangir.
Critical revision for important intellectual content: I Anjum, W Sohail.

All authors have declared no conflicts of interest.

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

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9. Katzberg RW. Contrast medium-induced nephrotoxicity: which pathway? Radiology 2005;235:752-5. Crossref

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11. Verdoodt A, Honore PM, Jacobs R, et al. Do statins induce or protect from acute kidney injury and chronic kidney disease: an update review in 2018. J Transl Int Med 2018;6:21-5. Crossref

12. Tricco AC, Lillie E, Zarin W, et al. PRISMA Extension for Scoping Reviews (PRISMA-ScR): checklist and explanation. Ann Intern Med 2018;169:467-73. Crossref

13. Davies JT, Delfino SF, Feinberg CE, et al. Current and emerging uses of statins in clinical therapeutics: a review. Lipid Insights 2016;9:13-29. Crossref

14. Liao JK, Laufs U. Pleiotropic effects of statins. Annu Rev Pharmacol Toxicol 2005;45:89-118. Crossref

15. Hernández-Perera O, Pérez-Sala D, Navarro-Antolin J, et al. Effects of the 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors, atorvastatin and simvastatin, on the expression of endothelin-1 and endothelial nitric oxide synthase in vascular endothelial cells. J Clin Invest 1998;101:2711-9. Crossref

16. Al-Otaibi KE, Al Elaiwi AM, Tariq M, Al-Asmari AK. Simvastatin attenuates contrast-induced nephropathy through modulation of oxidative stress, proinflammatory myeloperoxidase, and nitric oxide. Oxid Med Cell Longev 2012;2012:831748. Crossref

17. Zhang L, Zhang L, Lu Y, et al. Efficacy of statin pretreatment for the prevention of contrast-induced nephropathy: a meta-analysis of randomised controlled trials. Int J Clin Pract 2011;65:624-30. Crossref

18. Liu LY, Liu Y, Wu MY, Sun YY, Ma FZ. Efficacy of atorvastatin on the prevention of contrast-induced acute kidney injury: a meta-analysis. Drug Des Devel Ther 2018;12:437-44. Crossref

19. Mao S, Huang S. Statins use and the risk of acute kidney injury: a meta-analysis. Ren Fail 2014;36:651-7. Crossref

20. Barbieri L, Verdoia M, Schaffer A, Nardin M, Marino P, De Luca G. The role of statins in the prevention of contrast induced nephropathy: a meta-analysis of 8 randomized trials. J Thromb Thrombolysis 2014;38:493-502. Crossref

21. Li H, Wang C, Liu C, Li R, Zou M, Cheng G. Efficacy of short-term statin treatment for the prevention of contrast-induced acute kidney injury in patients undergoing coronary angiography/percutaneous coronary intervention: a meta-analysis of 21 randomized controlled trials. Am J Cardiovasc Drugs 2016;16:201-19. Crossref

22. Liu YH, Liu Y, Duan CY, et al. Statins for the prevention of contrast-induced nephropathy after coronary angiography/percutaneous interventions: a meta-analysis of randomized controlled trials. J Cardiovasc Pharmacol Ther 2015;20:181-92. Crossref

23. Cheungpasitporn W, Thongprayoon C, Kittanamongkolchai W, et al. Periprocedural effects of statins on the incidence of contrast-induced acute kidney injury: a systematic review and meta-analysis of randomized controlled trials. Ren Fail 2015;37:664-71. Crossref

24. Jadad AR, Moore RA, Carroll D, et al. Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials 1996;17:1-12. Crossref

25. Ferreira TS, Lanzetti M, Barroso MV, et al. Oxidative stress and inflammation are differentially affected by atorvastatin, pravastatin, rosuvastatin, and simvastatin on lungs from mice exposed to cigarette smoke. Inflammation 2014;37:1355-65. Crossref

26. Yang Y, Wu YX, Hu YZ. Rosuvastatin treatment for preventing contrast-induced acute kidney injury after cardiac catheterization: a meta-analysis of randomized controlled trials. Medicine (Baltimore) 2015;94:e1226. Crossref

27. Ukaigwe A, Karmacharya P, Mahmood M, et al. Meta-analysis on efficacy of statins for prevention of contrast-induced acute kidney injury in patients undergoing coronary angiography. Am J Cardiol 2014;114:1295-302. Crossref

28. Patti G, Ricottini E, Nusca A, et al. Short-term, high-dose atorvastatin pretreatment to prevent contrast-induced nephropathy in patients with acute coronary syndromes undergoing percutaneous coronary intervention (from the ARMYDA-CIN [atorvastatin for reduction of myocardial damage during angioplasty–contrast-induced nephropathy] trial. Am J Cardiol 2011;108:1-7. Crossref

29. Quintavalle C, Fiore D, De Micco F, et al. Impact of a high loading dose of atorvastatin on contrast-induced acute kidney injury. Circulation 2012;126:3008-16. Crossref

30. Leoncini M, Toso A, Maioli M, Tropeano F, Villani S, Bellandi F. Early high-dose rosuvastatin for contrast-induced nephropathy prevention in acute coronary syndrome: Results from the PRATO-ACS Study (Protective Effect of Rosuvastatin and Antiplatelet Therapy On contrast-induced acute kidney injury and myocardial damage in patients with Acute Coronary Syndrome). J Am Coll Cardiol 2014;63:71-9. Crossref

31. Li W, Fu X, Wang Y, et al. Beneficial effects of high-dose atorvastatin pretreatment on renal function in patients with acute ST-segment elevation myocardial infarction undergoing emergency percutaneous coronary intervention. Cardiology 2012;122:195-202. Crossref

32. Özhan H, Erden I, Ordu S, et al. Efficacy of short-term high-dose atorvastatin for prevention of contrast-induced nephropathy in patients undergoing coronary angiography. Angiology 2010;61:711-4. Crossref

33. Jia X, Fu X, Zhang J, et al. Comparison of usefulness of simvastatin 20 mg versus 80 mg in preventing contrast-induced nephropathy in patients with acute coronary syndrome undergoing percutaneous coronary intervention. Am J Cardiol 2009;104:519-24. Crossref

34. Yun KH, Lim JH, Hwang KB, et al. Effect of high dose rosuvastatin loading before percutaneous coronary intervention on contrast-induced nephropathy. Korean Circ J 2014;44:301-6. Crossref

35. Abaci O, Arat Ozkan A, Kocas C, et al. Impact of rosuvastatin on contrast-induced acute kidney injury in patients at high risk for nephropathy undergoing elective angiography. Am J Cardiol 2015;115:867-71. Crossref

36. Qiao B, Deng J, Li Y, Wang X, Han Y. Rosuvastatin attenuated contrast-induced nephropathy in diabetes patients with renal dysfunction. Int J Clin Exp Med 2015;8:2342-9.

37. ACT Investigators. Acetylcysteine for prevention of renal outcomes in patients undergoing coronary and peripheral vascular angiography: main results from the randomized Acetylcysteine for Contrast-induced nephropathy Trial (ACT). Circulation 2011;124:1250-9. Crossref

38. Akyuz S, Yaylak B, Altay S, Kasikcioglu H, Cam N. The role of statins in preventing contrast-induced acute kidney injury: a narrative review. Angiology 2015;66:701-7. Crossref

39. O’Sullivan S, Healy DA, Moloney MC, Grace PA, Walsh SR. The role of N-acetylcysteine in the prevention of contrast-induced nephropathy in patients undergoing peripheral angiography: a structured review and meta-analysis. Angiology 2013;64:576-82. Crossref

40. McCullough PA. Contrast-induced acute kidney injury. J Am Coll Cardiol 2008;51:1419-28. Crossref

41. Jo SH, Koo BK, Park J, et al. Prevention of radiocontrast medium-induced nephropathy using short-term high-dose simvastatin in patients with renal insufficiency undergoing coronary angiography (PROMISS) trial—a randomized controlled study. Am Heart J 2008;155:499.e1-8. Crossref

42. Acikel S, Muderrisoglu H, Yildirir A, et al. Prevention of contrast-induced impairment of renal function by short-term or long-term statin therapy in patients undergoing elective coronary angiography. Blood Coagul Fibrinolysis 2010;21:750-7.

43. Han Y, Zhu G, Han L, et al. Short-term rosuvastatin therapy for prevention of contrast-induced acute kidney injury in patients with diabetes and chronic kidney disease. J Am Coll Cardiol 2014;63:62-70. Crossref

44. Toso A, Maioli M, Leoncini M, et al. Usefulness of atorvastatin (80 mg) in prevention of contrast-induced nephropathy in patients with chronic renal disease. Am J Cardiol 2010;105:288-92. Crossref

45. Chyou AC, Thodge A, Feldman DN, Swaminathan RV. Statins in the prevention of contrast-induced nephropathy. Curr Treat Options Cardiovasc Med 2015;17:375. Crossref

46. Chung YH, Lee YC, Chang CH, Lin MS, Lin JW, Lai MS. Statins of high versus low cholesterol-lowering efficacy and the development of severe renal failure. Pharmacoepidemiol Drug Saf 2013;22:583-92.

47. Thompson PD, Clarkson P, Karas RH. Statin-associated myopathy. JAMA 2003;289:1681-90. Crossref

Rubella, also called German measles, is a communicable viral illness that typically begins with mild fever and lymphadenopathy followed by a characteristic brief appearance of a generalised erythematous, maculopapular rash.1 The disease was described by two German physicians, De Bergen in 1752 and Orlow in 1758, leading to the term “German measles”.2 The term “rubella” was coined by Henry Veale, a Scottish physician in 1866.2 The word “rubella” is derived from the Latin word “rubellus” meaning “reddish” or “little red”. In the absence of pregnancy, rubella is generally a mild, self-limited, and relatively benign infection. However, maternal rubella infection during the first trimester of pregnancy can be catastrophic and can result in fetal death or the birth of an infant with a constellation of congenital anomalies referred to as congenital rubella syndrome.3 This article provides an update on current knowledge about rubella and outlines an approach to its evaluation, prevention, and management.

A PubMed search was conducted in November 2018 using Clinical Queries with the key terms “Rubella” and “German measles”. The search strategy included randomised controlled trials, meta-analyses, observational studies, clinical trials, and reviews. Only papers published in the English literature were included in this review. The information retrieved from the above search was used in the compilation of the present article.

The causative organism is the rubella virus, which is a non-arthropod-borne member of the family Togaviridae and the sole member of the genus Rubivirus.4 5 It is an enveloped, single-stranded, positive sense ribonucleic acid (RNA) virus.6 The virus is easily destroyed by detergents, heat (temperature >56°C), ultraviolet light, and extremes of pH (pH <6.8 or >8.1).4

The rubella virus is spherical, measuring 50 to 85 nm in diameter and shows pleomorphism.5 The viral genome encodes three structural proteins (C, E1, and E2) and two non-structural proteins (p90 and p150).6 7 The nucleocapsid is composed of the capsid protein C which surrounds the single-stranded RNA.6 8 The outer envelope contains two glycosylated lipoproteins E1 and E2 which form transmembrane spikes anchored to the external layer of the membrane.5 The humoral response is induced particularly by these two glycosylated proteins which are important for the virulence of the virus.9 The E1 protein contains antigenic determinants that induce major immune responses.7 The protein is responsible for receptor binding, receptor-mediated endocytosis, and induction of membrane fusion.5 6 The E2 protein forms connections between rows of E1 proteins.5 The two non-structural proteins are related to transcription and replication which take place in the cytoplasm of the host cells.5 6

Humans are the only known reservoir for rubella infection.7 10 Postnatal rubella is transmitted primarily by inhalation of virus-laden airborne droplets or direct contact with infected nasopharyngeal secretions.1 Peak infection rates tend to occur in late winter and early spring.3 4 9

Prior to the introduction of the rubella vaccine, rubella was endemic worldwide, epidemics occurred at 6- to 9-year intervals, and major pandemics occurred every 10 to 30 years.6 11 During the last major pandemic from 1962 to 1965, approximately 10% of pregnant women were infected and 30% of infants born to the infected mothers ultimately manifested features of congenital rubella syndrome.11 In the US alone, there were at least 12.5 million cases of clinically acquired rubella with more than 13 000 fetal or early infant deaths, and 20 000 cases of congenital rubella syndrome during the pandemic from 1962 to 1965.11 Since the introduction of the live attenuated rubella vaccine in 1969, rubella has become increasingly rare in North America and many developed countries.8 From 1969 to 1989, the annual number of reported cases of rubella in the US decreased 99.6% and the annual number of reported cases of congenital rubella syndrome decreased 97.4%.11 From 1998 to 2000, 2001 to 2004, and 2005 to 2011, the median number of reported rubella cases in the US was 272, 13, and 11 per year, respectively.10 On 29 April 2015, the Pan American Health Organization officially declared elimination of rubella from the whole of the American region.12 Nowadays, rubella cases in developed countries are mainly “imported” from those countries where rubella is endemic and occur mostly in incompletely vaccinated or unvaccinated individuals.7 13

Globally, rubella continues to occur, with more than 100 000 cases reported worldwide, especially in countries where routine childhood rubella vaccination is either not available or has just been recently introduced.14 In 2011, the World Health Organization (WHO) updated its guidance on the preferred strategy for introduction of rubella-containing vaccine into the national immunisation schedules and recommended a vaccination campaign, targeting mainly children aged 9 months to 14 years.15 The number of WHO member states that include a rubella-containing vaccine in their routine childhood immunisation schedule has increased from 83 (43%) of 193, to 132 (68%) of 194, to 141 (72.7%) of 194, and to 152 (78.4%) of 194, in 1996, 2012, 2014, and 2016, respectively.16 17 This is encouraging as there was a net increase of 20 countries that introduced the rubella-containing in their routine childhood immunisation schedule from 2012 to 2016. Despite this, intermittent rubella outbreaks continue to occur in some parts of the world, even in countries with a national immunisation if there is a substantial proportion of the population that are susceptible.8 18 The recent outbreak of rubella in Japan can be primarily attributed to susceptible men who were not included in the initial rubella immunisation schedule as the initial immunisation strategy provided rubella vaccine only to adolescent girls.5 8 In 2018, there were 2186 cases of rubella in Japan as of 29 November with more than 70% of cases reported in Tokyo and its surrounding prefectures. This is a significant increase from 1103 cases of rubella reported on 7 October 2018.19 As of 22 October 2018, the Centre for Health Protection of the Department of Health in Hong Kong recorded only six local cases of rubella infection in 2018 affecting two male and four female patients with age ranging from 3 to 65 years.20

In children, rubella affects both sexes equally whereas in adults, rubella affects more women than men. In the pre-vaccine era, rubella was most common in children aged 5 to 9 years.6 7 16 Currently, individuals aged ≥20 years account for most reported cases.11 Risk factors for rubella include partially vaccinated or unvaccinated individuals, travelling to endemic areas, exposure to household members with rubella, and immunodeficiency.21 22

Postnatally acquired rubella is transmitted mainly via inhalation of aerosolised particles from the respiratory tract secretions of an infected individual.8 The virus infects cells in the upper respiratory tract of the susceptible host through receptor-mediated endocytosis.6 23 Initial replication occurs in the nasopharyngeal cells and lymphoid tissue of the nasopharynx and upper respiratory tract.6 8 23 Infected individuals may shed virus from the oropharynx and are contagious before the infection becomes clinically evident.8 Viraemia occurs 5 to 7 days after inoculation, disseminating the virus to multiple organs including the skin, lymph nodes, and, in a gravid patient, the placenta.8 9 The maculopapular rash occurs 2 to 8 days after the onset of viraemia and resolves as the humoral immune response develops and at this stage, the viraemia is terminated.6 23

Maternal immunity, either naturally derived or after vaccination, is generally protective against intrauterine rubella infection.24 In a susceptible gravid patient, after infecting the placenta, the virus may cross the placenta, and spread through the vascular system of the developing fetus.6 14 25 Fetal damage may result from necrosis in the epithelium of chorionic villi, direct viral damage of infected cells by apoptosis, viral inhibition of mitosis and restricted development of precursor cells, and cytopathic damage to endothelial cells of blood vessels with resultant ischaemia in developing organs.14 23 24 25 Maternal rubella infection during pregnancy does not always result in vertical transmission of the virus to the fetus.9 The risk of fetal infection varies depending upon the time of maternal infection.11 25 Fetal infection rates are approximately 80% in the first trimester, 25% in the late second trimester, 35% at 27 to 30 weeks’ gestation, and close to 100% beyond 36 weeks’ gestation.10 11 24 It is important to note that although a fetus becomes infected, fetal malformation may not necessarily develop.11 The estimated risk for fetal malformation is approximately 90%, 33%, 11%, 24% and 0% when maternal infection occurs before 11 weeks, at 11 to 12 weeks, at 13 to 14 weeks, at 15 to 16 weeks, and after 20 weeks of gestation, respectively.10 24 25 This can be explained by passive transfer of maternal antibodies and by development of fetal humoral and cell-mediated immune responses with time.23

The incubation period for postnatally acquired rubella is approximately 14 to 21 days (usually 16 to 18 days) after exposure to an individual with rubella.1 Approximately 25% to 50% of patients are asymptomatic (subclinical infection).1 4 10 24 The period of infectivity is maximal 7 days before to 7 days after onset of rash, coinciding with peak levels of rubella virus in the respiratory tract and viraemia which facilitate transmission.1 6 24

Prodromal symptoms typically precede the rash by 1 to 5 days.6 24 The symptoms, though common in adolescents and adults, are unusual in young children.3 6 8 The prodromal illness is characterised by low-grade fever, anorexia, nausea, malaise, lethargy, coryza, cough, headaches, non-exudative conjunctivitis, sore throat, myalgia, and tender lymph nodes.4 The lymphadenopathy typically involves retroauricular, suboccipital, and posterior cervical lymph nodes which often become more pronounced with the onset of rash (Fig 1).1 3 8 At times, the lymphadenopathy can be generalised.1 10 In approximately 20% of cases, petechiae can be observed on the soft palate (Forchheimer spots).6 8

The exanthem consists of pinpoint erythematous, maculopapules which classically begin on the face, spread caudally to the trunk and extremities, and become generalised within 24 hours (Fig 2).24 It is not unusual for the rash to be mildly pruritic.24 Occasionally, the rash is scarlatiniform or purpuric.7 The rash usually lasts for 3 days and fades in the same directional pattern as it appears.3 24

Congenital rubella syndrome may result from maternal rubella infection during embryogenesis.14 Cataracts, congenital heart defects, and sensorineural deafness are the classic triad of congenital rubella syndrome and they typically occur if the fetal infection occurs in the first 11 weeks of gestation.7 25 26

Ophthalmic abnormalities including cataracts (Fig 3), pigmentary retinopathy, infantile glaucoma, cloudy cornea, chorioretinitis, iris hypoplasia, lacrimal drainage anomalies, and microphthalmia occur in approximately 40% of cases.4 5 7 25 26 27 28 Cataracts occur in approximately 25% of children with congenital rubella syndrome and they are bilateral in approximately 50% of cases.4 25 Congenital rubella syndrome is the most common cause of congenital cataracts.13 Pigmentary retinopathy is traditionally characterised by a salt and pepper appearance or a mottled, blotchy, irregular pigmentation in the fundus.11 27

Patent ductus arteriosus and peripheral pulmonary artery stenosis occur in approximately 20% and 12% of patients with congenital rubella syndrome, respectively.25 Other cardiovascular defects such as pulmonary artery hypoplasia, pulmonary valvular stenosis, aortic valve stenosis, coarctation of the aorta, atrial septal defect, ventricular septal defect, and tetralogy of Fallot have also been reported.5 14 25

Hearing impairment occurs in approximately 60% of patients and is usually sensorineural and bilateral.7 25 At times, hearing impairment may be the sole manifestation of congenital rubella syndrome.29 The hearing impairment ranges from mild to severe, may not be apparent until the second year of life and beyond, and may progress over time.25

During the neonatal period, congenital rubella may produce a myriad of clinical features and conditions. These include prematurity, intrauterine growth retardation, microcephaly, haemolytic anaemia, thrombocytopenia, purpuric rash, jaundice, hepatitis, hepatomegaly, splenomegaly, “blueberry muffin” spots (sites of dermal erythropoiesis, Figs 4 and 5), hypotonia, bulging anterior fontanelle, constricted maxillary arch, high palate, interstitial pneumonia, myocarditis, myositis, nephritis, meningoencephalitis, and striated radiolucencies in the long bone (“celery stalk” lesions).4 7 25 30 31 32 33 34 35 Many of these features are transient and may resolve spontaneously over days or weeks.25

Delayed manifestations, in addition to sensorineural hearing impairment, include mental retardation, psychomotor retardation, speech delay, attention deficit hyperactivity syndrome, autism, behavioural disorders, progressive encephalopathy, insulin-dependent diabetes mellitus, thyroid dysfunction (hypothyroidism, hyperthyroidism, thyroiditis), Addison disease, growth hormone deficiency, and immunological defects.4 5 25 36 37 38

The most common complication of postnatal rubella is arthralgia/arthritis, which occurs in 60% to 70% of teenagers and adult women about 1 week after the rash.8 23 24 The arthralgia/arthritis usually lasts 3 to 4 days but may persist for 1 month.7 Typically, the wrists, fingers, knees, and ankles are affected symmetrically.8 24 Morning stiffness may also occur.10 Arthralgia/arthritis is uncommon in children and adult men.4 8 Other rare complications include carpal tunnel syndrome, tenosynovitis, thrombocytopenia, purpura, haemolytic anaemia, haemolytic uraemia syndrome, myocarditis, pericarditis, hepatitis, orchitis, retinopathy, uveitis, Guillain-Barré syndrome, and post-infectious encephalopathy.7 23 24 39 40 41 42

In addition to congenital rubella syndrome, maternal rubella, especially during early pregnancy, may lead to miscarriage, intrauterine fetal death, premature labour, and intrauterine growth retardation.14 25 Individuals with congenital rubella syndrome are at risk for deafness, blindness, hypertension, cardiac failure, academic failure, reduced life expectancy and, in female patients, early menopause and osteoporosis.37 The disabilities and financial burden associated with congenital rubella syndrome have an adverse effect on quality of life.

Rubella should be suspected in a patient with fever, erythematous maculopapular (non-vesicular) rash spreading cephalocaudally from the face downwards, and retroauricular/suboccipital/posterior cervical lymphadenopathy, especially in the presence of arthralgia/arthritis. This is especially so if there is a history of exposure to rubella, travel to an endemic area, or during an outbreak of rubella in an individual without immunity to rubella.

Generally, clinical diagnosis of rubella is unreliable because the clinical manifestations can be mild and non-specific especially in young children. In addition, there are many other viral infections having similar clinical features. Laboratory confirmation of rubella virus infection is therefore essential. The diagnosis of a recent postnatal rubella infection can be based on a positive serological test for rubella-specific immunoglobulin M (IgM) antibody in a single sample or a four-fold or greater increase in rubella-specific immunoglobulin (IgG) titres between acute and convalescent sera drawn 2 to 3 weeks apart.5 6 8 24 Among all the serologic tests available, enzyme linked immunoassays (ELISA) are most commonly used to measure rubella-specific IgG and IgM because they are very sensitive, highly specific, technically easy to perform, rapid, and relatively inexpensive.8 10 Rubella-specific IgM antibody is present in approximately 50% of patients on the day of appearance of the rash but in almost all the cases 5 days after the onset of rash; the IgM antibody tends to persist ≥8 weeks.5 8 As such, rubella-specific IgM antibody might be falsely negative if the test is conducted early. In contrast, false positive results may rarely occur in patients with heterophile antibodies, rheumatoid factors, parvovirus B19 infection, and cytomegalovirus infection.1 8 The use of IgM-capture ELISA rather than indirect IgM ELISA may reduce the occurrence of false positive results.1 8 When the first serum sample was collected months after clinical symptoms, avidity (strength of antigen-antibody binding) test of rubella-specific IgG antibody, if available, can be used to differentiate a recent primary infection from a past infection or reinfection.3 5 8 Low avidity anti-rubella IgG suggests recent primary rubella infection while high avidity is consistent with previous rubella vaccination, past rubella infection, or reinfection.3 5 7 8

Although rubella virus can be isolated most consistently from nasopharyngeal and throat specimens, viral culture is generally not necessary because viral culture is expensive, time-consuming, and not readily available. Rubella virus culture is done mainly for academic and epidemiological purposes to facilitate surveillance during outbreaks.10 Rubella virus RNA testing by real-time reverse transcriptase-polymerase chain reaction (RT-PCR), if available, may be performed for diagnosis and genotype identification.1 10

The diagnosis of congenital rubella syndrome can be confirmed by the detection of rubella-specific IgM antibody in the cord blood or in the neonatal serum collected within the first 6 months of life.1 25 In infants older than 3 months, a negative IgM does not exclude a congenital rubella infection although a positive test does support the diagnosis.23 25 Congenital rubella infection can also be confirmed by demonstrating persistent or increasing serum concentrations of rubella-specific IgG over the first 7 to 11 months of life.1 Detection of rubella virus RNA by RT-PCR in nasopharyngeal swab or urine provides laboratory evidence of congenital rubella syndrome.4 6 8 25

The differential diagnosis includes measles, scarlet fever, roseola infantum (exanthem subitum), erythema infectiosum (fifth disease), infectious mononucleosis, mycoplasma infection, rash-associated enteroviral infection, Kawasaki disease, drug eruption, contact dermatitis, dengue, toxoplasmosis, cytomegalovirus infection, Zika virus infection, West Nile fever, Ross River fever, and Chikungunya fever.8 14 21 23 43 44

Treatment of postnatally acquired rubella in a non-gravid individual is mainly symptomatic and consists of the use of non-steroidal anti-inflammatory drugs for severe arthralgia/arthritis.10 In a gravid individual with rubella infection, management depends on the gestation age at the time of infection.7 If the infection occurs before 20 weeks’ gestation, the fetus is at risk for malformation.10 24 25 Termination of pregnancy should be discussed as an option based on local legislation. Immune globulin administered intramuscularly or intravenously should be considered for susceptible women with known rubella exposure in early pregnancy for whom termination of pregnancy is not an option.4 6 24

Treatment of children with congenital rubella syndrome should be symptomatic and organ-specific and directed to improve the patient outcome and quality of life. Children with congenital rubella syndrome often present with a broad range of problems and therefore will benefit from a multidisciplinary approach. Consultations with, among others, a paediatrician, ophthalmologist, cardiologist, otorhinolaryngologist, and speech pathologist should be considered. Because children with congenital rubella syndrome are at risk for delayed manifestations, long-term audiologic, ophthalmic, and neurodevelopmental follow-up is indicated for early identification of these disorders. Early intervention is important to educate the family, organise the most appropriate educational placement, and plan specialist referral and follow-up.

Universal childhood immunisation and vaccination of all susceptible patients with rubella vaccine to decrease circulation of the virus are the cornerstones to prevention of rubella and, more importantly, congenital rubella syndrome. The current strategy is to immunise all children aged 12 to 15 months and again at age 4 to 6 years with rubella vaccine, according to recommendations for routine measles, mumps, rubella, and varicella vaccination.1 One dose of rubella vaccine given at or after age 1 year is 95% effective in protecting against rubella infection whereas two doses given at appropriate intervals is close to 100% effective.4 5 8 14 Women of childbearing age without documentation of rubella immunity should get vaccinated before they become pregnant.1 14 Women receiving rubella vaccine should be advised to avoid pregnancy for 1 month after rubella vaccination.4 10 Routine prenatal screening for immunity to rubella should be performed.1 Rubella susceptible women should receive measles-mumps-rubella (MMR) vaccine in the immediate postpartum period as a significant number of these individuals are also susceptible to measles and/or mumps.10

Globally, the most commonly used rubella vaccines contain a live attenuated RA 27/3 strain grown in human diploid cell cultures.1 8 24 China and Japan use BRD-2 and TO-336 strains, respectively.7 The vaccines, once administered, would replicate within the host to induce both humoral and cellular immunity.1 8 24 Rubella vaccines can be given subcutaneously as a single component (eg, in Russia and some African countries), but more often, as combination vaccines such as measles-mumps-rubella-varicella (MMRV) vaccine and MMR vaccine.8 10 The MMRV vaccine has similar safety profile and immunogenicity as the MMR vaccine except that MMRV vaccine has a two-fold increase in relative risk of febrile seizures.45

Rubella vaccines are generally safe, immunogenic, highly cost-effective, and well tolerated.5 Adverse effects usually occur 5 to 12 days post-vaccination and consist mainly of fever (15%), rash (5%), transient arthralgia/arthritis, and mild lymphadenopathy.1 7 10 24 Rare adverse effects include febrile seizures, parotiditis, thrombocytopenic purpura, anterior uveitis, cataract, anaphylaxis, and encephalitis.7 46

Rubella vaccine given to a nursing mother does not affect the safety of breastfeeding both for the mother and infant.1 As such, breastfeeding is not a contra-indication to rubella immunisation.1 Contra-indications for rubella vaccination include febrile illness, moderate/severe illness, immunodeficiency, hypersensitivity to any component of the vaccine including gelatine and neomycin, confirmed history of an anaphylactic reaction to a previous rubella-containing vaccine, and pregnancy.4 10 However, inadvertent administration of a rubella-containing vaccine to pregnant mothers is not known to cause fetal and/or maternal complications.4 10 24 Rubella vaccination should be deferred for at least 4 weeks in those individuals with recent use of high-dose corticosteroids (>2 mg/kg or 20 mg/day) for ≥14 days or recent administration of immunoglobulin or blood products.1 The rubella vaccine can be given at the same time as other live vaccines, but should be deferred for 3 weeks after another live vaccine has been given.4

Confirmed cases of rubella should be excluded from day care or school for at least 7 days after onset of the rash.1 Proper hand washing technique and droplet precautions should be emphasised.14

Children with congenital rubella syndrome can transmit the disease as long as they are shedding the virus. Approximately 20% of children with congenital rubella syndrome may still be shedding the virus from the pharynx at aged 1 year and therefore are contagious.3 These individuals should be isolated to avoid the spread of the infection until two throat swab or urine cultures obtained at least 1 month apart are negative for the rubella virus.1 Only healthcare providers with immunity to rubella should be involved in the care of these patients.

Postnatally acquired rubella is generally a mild, self-limited, and relatively benign infection without consequences in most cases.35 However, infection in early pregnancy may lead to miscarriage, intrauterine fetal death, premature labour, and congenital rubella syndrome. The prognosis of children with congenital rubella syndrome varies, depending on the severity and number of organs affected. Infants with thrombocytopenia, hepatosplenomegaly, interstitial pneumonia, and pulmonary hypertension have a high risk of mortality.34 47 Of those who develop thrombocytopenia and hepatosplenomegaly in the neonatal period, approximately 15% die within the first year of life.3

Apart from congenital infection, rubella is generally a mild and self-limited disease in children. Rubella when acquired by a pregnant mother in an early stage of the pregnancy can have catastrophic effects on the developing fetus and may result in miscarriage, intrauterine fetal death, premature labour, intrauterine growth retardation, and congenital rubella syndrome. To eliminate rubella from a population, universal childhood immunisation and vaccination of all susceptible individuals with rubella vaccine is required. Although rubella has been eliminated from most developed countries, physicians should remain vigilant in recognising both postnatal rubella and congenital rubella syndrome because rubella cases can be “imported” from those countries where rubella is endemic.

All authors have made substantial contributions to the concept or design of the study, acquisition of data, analysis or interpretation of data, drafting of the manuscript, and critical revision for important intellectual content. 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 conflict of interest.

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

All patients were treated in accordance with the Declaration of Helsinki. The parents of all patients provided written informed consent for photographs to be taken and published.

1. Kimberlin DW, Brady MT, Jackson MA, Long SS, editors. Red Book: 2018 Report of the Committee on Infectious Diseases. 31st ed. Itasca: American Academy of Pediatrics; 2018: 705-11.

2. Veale H. History of an epidemic of Rötheln with observations on its pathology. Edinb Med J 1866;12:404-14.

3. Drutz JE. Rubella. Pediatr Rev 2010;31:129-30. Crossref

4. Best JM. Rubella. Semin Fetal Neonatal Med 2007;12:182-92. Crossref

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