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Dr Julia Marcello

“Be patient with yourself… nothing in Nature blooms all year.” One of my favourite quotes regarding perinatal depression and anxiety which affects 10-16% of all new parents. The importance of perinatal mental health cannot be overstated. Research has shown that an untreated perinatal mental health condition can lead to substance misuse, poor antenatal attendance as well as poor self-care. There is also a risk of poor attachment to the infant, and a long-term risk of poor child development outcomes through neglect. Suicide is the final risk. The government have recently supported our concerns regarding this important topic by changing the MBS item numbers (16590, 16591, 16407) to include a mental health assessment. We have a duty of care to our patients to know what is safe to prescribe or continue to use in pregnancy- remembering that pregnancy is not protective against mental illness. Did you know that more than half of all women abruptly discontinue antidepressant medication upon confirming a pregnancy? Almost 70% of these women suffer a relapse of depression. Currently the recommendations for a woman on an antidepressant who has been euthymic for at least 12 months include cease the medication in pregnancy, continue the current medication, change to an alternative, safer medication or cease the medication and then reintroduce it if a relapse occurs. Antidepressant medications can cross the placenta, meaning the fetus is exposed. There are also potential pregnancy complications, but the risks to the fetus and the pregnancy are very low. Congenital malformation may occur from exposure to some antidepressants in the first trimester. Growth restriction and neurobehavioural problems may result from exposure in the second trimester. And congenital cardiac defects have been associated with paroxetine use in pregnancy. Postpartum haemorrhage is the only significant potential obstetric complication associated with SSRI and SNRI use. There is also a small increased risk of persistent pulmonary hypertension of the newborn associated with SSRI, SNRI and TCA use in late pregnancy. Antidepressants taken in late pregnancy, may also cause poor neonatal adaptation syndrome (PNAS). This manifests as hypotonia, respiratory distress, hypoglycaemia, seizures and most commonly ‘jittery-ness’ in the infant. Paroxetine has the highest risk of PNAS. Despite this, it is NOT recommended that the dose of medication be reduced in late pregnancy. Because the fetus may not clear the medication in the same way the mother does, lowering the dose might simply risk a relapse of depression in the mother while gaining little or no benefit to the infant. RANZCOG states that SSRIs are generally considered low risk and safe to prescribe in pregnancy and breastfeeding. It is important to know that sertraline has the lowest placental exposure and the lowest excretion into breastmilk. Other medications are listed in the table below as a quick reference guide:

Table 1. ANTIDEPRESSANT CATEGORIES FOR PREGNANCY AND BREASTFEEDING:

Medication Pregnancy Category Breastfeeding
TCAs * avoid doxepin during breastfeeding C Compatible
Citalopram C Compatible
Escitalopram *preferred to citalopram in breastfeeding C Compatible
Fluoxetine C Compatible
Mirtazapine C Compatible
Paroxetine *can cause cardiac defects with high dose first trimester but safest for breastfeeding along with sertraline D Compatible
Sertraline B Compatible
Venlafaxine C Compatible
Compatible- an acceptably low relative infant dose or no significant plasma concentrations or no adverse effects in breastfed infants. When managing perinatal depression is it important to consider potential risk against the known benefits of the medications and the potential detrimental effects of mental illness on the development of the infant and other children in the home.

Key References:

  1. The Royal Australian and New Zealand College of Obstetricians and Gynaecologists.  Perinatal Depression and Anxiety: C-Obs 48. East Melbourne (AU): RANZCOG; Mar 2015. 16 p. RANZCOG Cat. No.: C-Obs 48. Available from: https://www.ranzcog.edu.au/RANZCOG_SITE/media/RANZCOG-MEDIA/Women%27s%20Health/Statement%20and%20guidelines/Clinical-Obstetrics/Mental-health-care-in-the-perinatal-period-(C-Obs-48).pdf?ext=.pdf
  2. White L. Antidepressants in Pregnancy. O&G Magazine. 2018; 20(3): 24-25. Available from: https://www.ogmagazine.org.au/20/3-20/antidepressants-in-pregnancy/
  3. Galbally M, Lewis AJ, Snellen M. Introduction Pharmacological management of major depression in pregnancy. In: Gabally M, Snellen M, Lewis AJ, editors. Psychopharmacology and Pregnancy. Berlin: Springer; 2014. p. 67-85.
  Dr Julia Marcello works at Bentley Maternity Unit which provides maternity services to low risk women in WA. The unit is staffed by GP obstetricians, specialist obstetricians and gynaecologists and midwives and offers the option of private care within a public setting. The midwife service is available to low risk women and includes antenatal care, birthing services and postnatal care through the visiting midwifery service and lactation consultant support.  GP shared care services are also available. The Unit also provides a gynaecology service led by Dr Aseel Alkiaat and specialists from King Edward Hospital.  For further information go to www.bhs.health.wa.gov.auFor-health-professionals
Dr Linda Calabresi

Australian research has found an increased risk of intellectual disability with some forms of Assisted Reproductive Technology (ART). The WA study published in Pediatrics found that one in 48 children conceived using ART were diagnosed with an intellectual disability, compared with only one in 59 children conceived naturally. And the risk was even greater for certain subgroups within the ART cohort. “The risk was more than doubled for those born very preterm, for severe [intellectual disability] and after intracytoplasmic sperm injection (ICSI) treatments,” said the researchers from the Telethon Kids Institute. To conduct the study, researchers analysed population registers of over 200,000 live births occurring between 1994 and 2002 in Western Australia and examined data on ART and diagnoses of intellectual disability occurring within eight years of follow-up. The fact that the study findings were based on analyses of statistics from almost 20 years ago was acknowledged by the authors, especially since ART practices have changed greatly since then. “Our study included children born from 1994 to 2002 when multiple embryo transfer was common practice in Western Australia,” they said. This increased the likelihood of a multiple pregnancy and preterm birth. However even when the analyses are restricted to singleton births the small increased risk of intellectual disability persisted but was not as great. The link between ICSI-conceived children and intellectual disability was also of interest. At the time, this technique was restricted to couples with severe male-factor subfertility and was often associated with older aged males. “Genetic abnormalities occur more frequently in men who are infertile, so ICSI (which bypasses natural selection barriers) may allow for the transmission of chromosomal anomalies in the offspring,” the authors said. According to the study, one in 32 children conceived using ICSI were diagnosed with an intellectual disability. ICSI is now used more broadly, prompting concerns. As lead author, Dr Michele Hansen said, “[ICSI] is currently used in 63 per cent of treatment cycles.” “Our findings show an urgent need for more recent data to establish whether the increased risks of intellectual disability seen in children conceived using ICSI are solely related to severe male subfertility and older paternal age, or if there are other risks associated with the technique itself.” Overall the study findings provide supportive evidence for Australia’s current IVF policy of single embryo transfer unlike many other countries where multiple embryo transfers are still routinely performed. The researchers also point out the study has implications for the use of ICSI, or more exactly restricting the use of ICSI and recognising the increased risk of genetic anomalies that might occur in children conceived in this way. “These couples may opt to use preimplantation genetic testing to maximise the transfer of chromosomally normal embryos,” they suggest.  

Reference

Hansen M, Greenop KR, Bourke J, Baynam G, Hart RJ, Leonard H. Intellectual Disability in Children Conceived Using Assisted Reproductive Technology. Pediatrics. 2018; 142(6): e20181269. DOI 10.1542/peds.2018-1269
Dr Ian Chambers

Each year, around late winter to spring, we see an increase in the number of serologically-confirmed infections with parvovirus B19. These infections are usually trivial in nature and benign in outcome, but there are important exceptions to this rule. This article will review the typical presentation and course of infection with parvovirus B19, discuss its potential adverse outcomes and in whom that potential is greatest. Parvovirus B19 was discovered and named in 1975 by virologists working at the University of Sydney. It is the predominant genotype (of three) which are pathogenic for humans. Infection is common, occurring sporadically and in clusters, it has a clear seasonality (late winter through to spring) and also has an epidemic cycle with a 4–5 year periodicity. While 50–80% of adults have parvovirus IgG and are regarded as immune, there remains a significant proportion of the adult population who are susceptible to infection.

Infection and its complications

Humans are the only known host for parvovirus B19. The anaemia and thrombocytopenia which are usually subclinical in a normal individual may, in those with increased red blood cell turnover (for example, sickle-cell disease, haemoglobinopathies), lead to significant falls in haemoglobin and, potentially, aplastic crisis. Because B19 is cytotoxic to fetal red blood cell precursors, fetal infection may cause severe anaemia, high cardiac output failure and non-immune hydrops. Unlike rubella, which has a similar presentation and with which it can cross-react in serological assays, B19 has no association with congenital malformations.

Clinical presentation

The clinical presentation of infection is highly variable; Fifth disease, slapped cheek disease and erythema infectiosum all refer to the same febrile exanthem, without significant sequelae, occurring in young children, while an adult frequently presents with fever and arthralgia/arthritis but with no rash at all. However, the same adult with sickle-cell disease may present in aplastic crisis and, in pregnancy, there is a risk of hydrops fetalis, myocarditis and fetal death. In general, the typical presentation of B19 infection in children and its benign outcome require laboratory confirmation relatively infrequent. By contrast, the more variable and dramatic clinical presentation in adults, the absence of any rash rather than the presence of a typical one and, in women, the threat of adverse pregnancy outcomes lead to a much greater reliance on laboratory diagnosis.

Laboratory diagnosis

Generally, diagnosis of parvovirus B19 infection is serological. IgM is usually detectable from just before the onset of symptoms and present in >90% of people by the time of onset of the rash. Detectable IgM is suggestive of infection but not conclusive, unless an IgG seroconversion is also demonstrated or (if IgG was also present at the time IgM was detected) there has been a significant rise when testing is repeated after two weeks. When infection has been diagnosed in a pregnant woman, there is little reason to attempt definitive diagnosis in the fetus. Parvovirus PCR can provide that confirmation however it requires amniocentesis to obtain the required specimen.

Erythema infectiosum (Fifth disease, slapped cheek disease)

These terms all refer to the same presentation of parvovirus B19 infection in childhood. After an incubation period of 4–14 days, and a non-specific prodrome of fever, malaise and rhinorrhoea, a red, macular rash appears on the cheeks, fading to become more lacy and erythematous after a few days. There is no such typical presentation in an adult (see above), with rash being variable or absent. Joint pain and swelling, however, are almost as typical of adult infection as a slapped-cheek rash is in childhood.

Parvovirus B19 infection in pregnancy

Around 40% of women of child-bearing age are susceptible to parvovirus infection. The highest infection rates are seen in school teachers, day-care workers and women with school-aged children in the home. The obvious common factor is their greater likelihood of being exposed to children with erythema infectiosum and that exposure being sustained for longer. Transmission is thought to be through respiratory droplets, with infectivity lasting from one week prior to the rash until the time of onset of the rash. Between 25 and 50% of susceptible household contacts of a case will acquire infection, of whom up to 50% will do so asymptomatically. Therefore, unless women are aware of their potential exposure there is a significant risk of acquisition going undetected. The incidence of parvovirus infection in pregnancy is approximately 1–2% and vertical transmission occurs in about 50%. The risk of hydrops is low (estimated incidence, 3–6%) but there is an overall excess fetal loss of 10% for infection acquired in the first 20 weeks of pregnancy. The fetus is particularly susceptible to hydrops in the second trimester when haematopoiesis is occurring in the liver. During this time, there is a 34-fold increase in red cell mass and a reduction in the life span of the red blood cells. In pregnant women with proven recent infection, the overall fetal death rate of hydrops or its treatment is 0.6% according to ASID guideline.

Management of proven parvovirus B19 infection in pregnancy

When maternal infection is proven or is highly likely, it is not necessary to prove that vertical transmission has occurred, but the fetus should be monitored by frequent ultrasonography. This allows the early detection and assessment of both myocardial dysfunction and fetal hydrops, but more importantly, it makes possible the early detection of fetal anaemia, prior to the development of hydrops. The peak systolic velocity (PSV) of the waveform in the middle cerebral artery can detect moderate to severe fetal anaemia with a sensitivity of 100%, followed by intra-uterine transfusion.   General Practice Pathology is a regular column each authored by an Australian expert pathologist on a topic of particular relevance and interest to practising GPs. The authors provide this editorial free of charge as part of an educational initiative developed and coordinated by Sonic Pathology.
Dr Michelle H Lim

One in four Australians are lonely, our new report has found, and it’s not just a problem among older Australians – it affects both genders and almost all age groups. The Australian Loneliness Report, released today by my colleagues and I at the Australian Psychological Society and Swinburne University, found one in two (50.5%) Australians feel lonely for at least one day in a week, while more than one in four (27.6%) feel lonely for three or more days. Our results come from a survey of 1,678 Australians from across the nation. We used a comprehensive measure of loneliness to assess how it relates to mental health and physical health outcomes. We found nearly 55% of the population feel they lack companionship at least sometime. Perhaps unsurprisingly, Australians who are married or in a de facto relationship are the least lonely, compared to those who are single, separated or divorced. While Australians are reasonably connected to their friends and families, they don’t have the same relationships with their neighbours. Almost half of Australians (47%) reported not having neighbours to call on for help, which suggests many of us feel disengaged in our neighbourhoods.

Impact on mental and physical health

Lonely Australians, when compared with their less lonely counterparts, reported higher social anxiety and depression, poorer psychological health and quality of life, and fewer meaningful relationships and social interactions. Loneliness increases a person’s likelihood of experiencing depression by 15.2% and the likelihood of social anxiety increases by 13.1%. Those who are lonelier also report being more socially anxious during social interactions. This fits with previous research, including a study of more than 1,000 Americans which found lonelier people reported more severe social anxiety, depression, and paranoia when followed up after three months. Interestingly, Australians over 65 were less lonely, less socially anxious, and less depressed than younger Australians. This is consistent with previous studies that show older people fare better on particular mental health and well-being indicators. (Though it’s unclear whether this is the case for adults over 75, as few participants in our study were aged in the late 70s and over). Younger adults, on the other hand, reported significantly more social anxiety than older Australians. The evidence outlining the negative effects of loneliness on physical health is also growing. Past research has found loneliness increases the likelihood of an earlier death by 26% and has negative consequences on the health of your heart, your sleep, and levels of inflammation. Our study adds to this body of research, finding people with higher rates of loneliness are more likely to have more headaches, stomach problems, and physical pain. This is not surprising as loneliness is associated with increased inflammatory responses.

What can we do about it?

Researchers are just beginning to understand the detrimental effects of loneliness on our health, social lives and communities but many people – including service providers – are unaware. There are no guidelines or training for service providers. So, even caring and highly trained staff at emergency departments may trivialise the needs of lonely people presenting repeatedly and direct them to resources that aren’t right. Increasing awareness, formalised training, and policies are all steps in the right direction to reduce this poor care. For some people, simple solutions such as joining shared interest groups (such as book clubs) or shared experienced groups (such as bereavement or carers groups) may help alleviate their loneliness. But for others, there are more barriers to overcome, such as stigma, discrimination, and poverty. Many community programs and social services focus on improving well-being and quality of life for lonely people. By tackling loneliness, they may also improve the health of Australians. But without rigorous evaluation of these health outcomes, it’s difficult to determine their impact. We know predictors of loneliness can include genetics, brain functioning, mental health, physical health, community, work, and social factors. And we know predictors can differ between groups – for example, young versus old. But we need to better measure and understand these different predictors and how they influence each other over time. Only with Australian data can we predict who is at risk and develop effective solutions. There are some things we can do in the meantime. We need a campaign to end loneliness for all Australians. Campaigns can raise awareness, reduce stigma, and empower not just the lonely person but also those around them. Loneliness campaigns have been successfully piloted in the United Kingdom and Denmark. These campaigns don’t just raise awareness of loneliness; they also empower lonely and un-lonely people to change their social behaviours. A great example of action arising from increased awareness comes from the Royal College of General Practitioners, which developed action plans to assist lonely patients presenting in primary care. The college encouraged GPs to tackle loneliness with more than just medicine; it prompted them to ask what matters to the lonely person rather than what is the matter with the lonely person. Australia lags behind other countries but loneliness is on the agenda. Multiple Australian organisations have come together after identifying a need to generate Australian-specific data, increase advocacy, and develop an awareness campaign. But only significant, sustained government investment and bipartisan support will ensure this promising work results in better outcomes for lonely Australians.
Dr Linda Calabresi

No one wants to miss ovarian cancer especially in its early stages when you have a chance of successful treatment. But should we be regularly monitoring women who have had a simple ovarian cyst detected on ultrasound, as most guidelines recommend to avoid missing this particularly deadly cancer? That is what US researchers investigated in a nested case controlled study, recently published in JAMA. The study was based on a cohort of adult women from the Kaiser Permanente Washington health care system who had had a pelvic ultrasound at some stage over a 12-year period starting in 1997, and looked at the association of the ultrasound finding with the risk of being diagnosed with ovarian cancer within three years. On analysing the data from the 72,000 women who underwent the investigation, the first finding was that ovarian cysts were very common, particularly simple ovarian cysts, occurring in more than 15,000 women. Simple cysts were detected in almost one in four women aged younger than 50, and just over one in 12 women aged 50 and over. Complex cyst structures were far less common, which is fortunate as the study also confirmed that most of the 212 women who were eventually diagnosed with ovarian cancer had a complex cyst structure on ultrasound. According to their analysis, the detection of a complex cystic ovarian mass on ultrasound increased the likelihood of cancer eight-fold, and if they were 50 or over and found to have ascites as well, the finding was practically diagnostic with the likelihood of having ovarian cancer being over 70 times greater than normal. Ultrasound detection of solid masses was not as dangerous a finding, but the one in ten association with ovarian cancer certainly warranted further investigation. But what of the women found to have a simple cyst on ultrasound? How many of them went on to be diagnosed with ovarian cancer? Well, among those aged under 50 – none! And among the older women only one – and the researchers suspect that the simple cyst found in this case was, in fact an incidental finding. As the study authors point out, this finding shouldn’t be surprising as it is well-known that ‘simple cysts are almost universally benign.’ But the majority of guidelines still recommend on-going surveillance, mainly because of a reluctance to make a definitive diagnosis on the basis of the ultrasound appearance or interpretation alone. “One of the justifications for the surveillance of simple cysts is that imaging may be inaccurate and might miss complex features,” the researchers explain. But such concerns are not warranted according to this study. What’s more, the authors suggest the constant monitoring of these benign cysts may in fact not only be useless but may cause harm. “While surveillance may not seem harmful, there is a growing realisation across all areas of medicine that unnecessary imaging is associated with morbidity, including wasted time, false-positive results, over diagnosis, unnecessary surgery and anxiety,” the study authors concluded.  

Reference

Smith-Bindman R, Poder L, Johnson E, Miglioretti DL. Risk of Malignant Ovarian Cancer Based on Ultrasonography Findings in a Large Unselected Population. JAMA Intern Med. Published online November 12, 2018. doi:10.1001/jamainternmed.2018.5113.
Dr Nelson Chong

A stressful event, such as the death of a loved one, really can break your heart. In medicine, the condition is known as broken heart syndrome or takotsubo syndrome. It is characterised by a temporary disruption of the heart’s normal pumping function, which puts the sufferer at increased risk of death. It’s believed to be the reason many elderly couples die within a short time of each other. Broken heart syndrome has similar symptoms to a heart attack, including chest pain and difficulty breathing. During an attack, which can be triggered by a bereavement, divorce, surgery or other stressful event, the heart muscle weakens to the extent that it can no longer pump blood effectively. In about one in ten cases, people with broken heart syndrome develop a condition called cardiogenic shock where the heart can’t pump enough blood to meet the body’s needs. This can result in death.

Physical damage

It has long been thought that, unlike a heart attack, damage caused by broken heart syndrome was temporary, lasting days or weeks, but recent research suggest that this is not the case. A study by researchers at the University of Aberdeen provided the first evidence that broken heart syndrome results in permanent physiological changes to the heart. The researchers followed 52 patients with the condition for four months, using ultrasound and cardiac imaging scans to look at how the patients’ hearts were functioning in minute detail. They discovered that the disease permanently affected the heart’s pumping motion. They also found that parts of the heart muscle were replaced by fine scars, which reduced the elasticity of the heart and prevented it from contracting properly. In a recent follow-up study, the same research team reported that people with the broken heart syndrome have persistent impaired heart function and reduced exercise capacity, resembling heart failure, for more than 12 months after being discharged from hospital.

Long-term risk

A new study on the condition, published in Circulation, now shows that the risk of death remains high for many years after the initial attack. In this study, researchers in Switzerland compared 198 patients with broken heart syndrome who developed cardiogenic shock with 1,880 patients who did not. They found that patients who experienced cardiogenic shock were more likely to have had the syndrome triggered by physical stress, such as surgery or an asthma attack, and they were also significantly more likely to have died five years after the initial event. People with major heart disease risk factors, such as diabetes and smoking, were also much more likely to experience cardiogenic shock, as were people with atrial fibrillation (a type of heart arrythmia). A second study from Spain found similar results among 711 people with broken heart syndrome, 11% of whom developed cardiogenic shock. Over the course of a year, cardiogenic shock was the strongest predictor of death in this group of patients. These studies show that cardiogenic shock is not an uncommon risk factor in broken heart syndrome patients, and it is a strong predictor of death. They shed light on a condition that was previously thought to be less serious than it is. The evidence now clearly shows that the condition is not temporary and it highlights an urgent need to establish new and more effective treatments and careful monitoring of people with this condition.
Dr Linda Calabresi

It appears we might still be failing some of our poorer migrant women, with new study finding that they have higher rates of stillbirth compared to Australian-born mothers. Analysing data from stillbirths that occurred in Western Australia over the period 2005 to 2013, researchers found that while stillbirth rates overall were low and often much lower than in these migrant women’s country of birth, they were higher in non-Australian born women, especially in those women who were born in Africa. Published recently in The Medical Journal of Australia, the study also took note of whether the deaths occurred in the antepartum period (between 20 weeks gestation up to before labour commences) or the intrapartum period (which is the period after labour has started), in an attempt to determine when and in whom intervention might be warranted. Researchers found the key factor was the woman’s country of birth rather than her ethnic origin, as there appeared no difference in stillbirth rates among white and non-white Australian-born women. However, women born in Africa were twice as likely to have a stillbirth in the weeks before going into labour compared with Australian-born women. And Indian-born women were 70% more likely. Migrant women born in other countries collectively had an increased risk of about 40% of an antepartum stillbirth. And frighteningly, it appeared the rates of stillbirth occurring once labour had started were also much higher than that which occurs in Australian born women. Almost twice the risk for most migrant women, and more than double that again for African-born women. “That the rate intrapartum stillbirth was twice as high among African women is especially worrying, as intrapartum stillbirth is regarded as preventable and indicative of inadequate quality of care,” the study authors wrote. So why is this happening, the researchers asked. Why is it, that, despite access to the same standard of healthcare as the rest of the Australian population, these women are more at risk of losing their babies, especially African-born women and especially so late in the pregnancy? The study authors suggest cultural issues may play a major role. They point to statistics that show African-born women are more likely to have pregnancies lasting 42 weeks or more, a well-recognised risk factor for stillbirth. Qualitative studies have also determined there is often, particularly among African-born women, a deeply-held suspicion of interventions in pregnancy believing them to interfere with the natural process of childbirth and possibly having long-term repercussions. Consequently, there is not only a poorer attention to antenatal care but also a resistance to procedures such as induction of labour and caesarean section. “More in-depth investigation of the patterns of health service use, pregnancy, and labour care for migrant women, particularly African migrants, is warranted,” the researchers said. They suggest education is the most likely solution, but the changing of what is likely to be long-held and culturally-associated attitudes will need both sensitivity and intelligence. “Culturally appropriate antenatal engagement and educational programs about the risk of stillbirth and the indications for and the safety of induction and related interventions may be useful preventive strategies,” they concluded.  

Reference

Mozooni M, Preen DB, Pennell CE. Stillbirth in Western Australia, 2005–2013: the influence of maternal migration and ethnic origin. Med J Aust. 2018; 209(9): 394-400. DOI 10.5694/mja18.00362
A/Prof Ken Sikaris

Vitamin B12 testing remains the most common vitamin investigation in clinical practice and is often included in the investigation of common problems such as anaemia and dementia. The assessment of Vitamin B12 status using blood tests is imperfect and although a variety of other tests can be used to improve assessment, this can lead to complexity and confusion. In this discussion I hope to share the insights from thousands of analyses and hundreds of clinician’s questions.

Sources of Vitamin B12

Vitamin B12 is a unique cobalt-containing molecule naturally synthesised by bacteria. Some animals, especially herbivores, absorb it from their intestinal microbiome, and build up a store. Other animals, particularly carnivores, can obtain B12 by eating animals that store B12, or animal-based products such as eggs and milk. Vegetarians consuming milk products and eggs may have low B12 levels, as the B12 content of milk is often low (1mg/L) and even lower if ultra-heat treated. Non-animal sources of B12 are extremely limited, with Nori seaweed containing small amounts and B12 levels in mushrooms and most other plant-based sources reflecting bacterial exposure (eg manure/compost).(1) Only strict vegetarians are considered at serious risk of dietary B12 deficiency, and even then only after some years. However, vegetarian and vegan diets are becoming increasingly popular. Similarly, breast-fed infants of vegan mothers, if not supplemented, may also be at risk of B12 deficiency.

How common is B12 deficiency?

Vitamin B12 deficiency is relatively common (4- 26%) but difficult to define accurately because of varying definitions.(2) It is more common in the elderly and significant deficiency is present in up to 23% of elderly Australian populations.(3) Iron deficiency is similarly common, especially in young women, and since low consumption of iron from meat sources correlates with lower B12 intake, B12 deficiency should always be considered when dietary iron deficiency exists. While pernicious anaemia is often considered as a cause of B12 deficiency, this autoimmune illness has a relatively low prevalence compared to B12 deficiency. In our experience, only 4% of our Intrinsic Factor antibody requests are positive which is a similar result to that described by others.(4) Higher prevalence has been reported when using the less specific parietal antibody test, but even then, less than 20% of B12 deficiency can be attributed to pernicious anaemia.(5) Less than one in eight patients with positive parietal cell antibodies have pernicious anaemia and this lack of specificity increases in the elderly when the test should be avoided.

Clinical issues

Unexplained anaemia and/or macrocytosis have traditionally been the indications used for suspicion of B12 deficiency. But there are other common reasons for anaemia such as iron deficiency and the anaemia of chronic disease. There are also other common reasons for macrocytosis including liver disease and alcoholism. Vitamin B12 levels are more likely to be low in a vegetarian (or vegan) than in a patient with anaemia or macrocytosis.(6) We also find that symptoms of confusion and dementia are just as likely to be associated with low B12 levels as anaemia. And while this may be partly associative due to the higher prevalence of B12 deficiency, it should be concerning because of the neurological sequelae of B12 deficiency that may arise prior to anaemia. Neurological symptoms of B12 deficiency include paraesthesia of the hands and feet, diminished perception of vibration and position, absence of reflexes, and unsteady gait and balance (ataxia). But the range of symptoms is broad and may include irritability, tiredness, and mild memory and cognitive impairment. Severe deficiency causes subacute combined degeneration of the spinal cord. In pregnancy, B12 deficiency is associated with some increase in the risk of neural tube defects and in childhood is associated with developmental delay and failure to thrive.

Why is testing so complicated?

Cobalamine is a precious vitamin that is captured and chaperoned around the body. Saliva contains a protein that will capture B12. In the stomach, intrinsic factor is produced to capture B12 released by digestion and transport it into the body. Within the bloodstream, there are two proteins that bind B12; haptocorrin and transcobalamin. These two proteins seem to have different functions with transcobalamin delivering B12 to the cells whereas haptocorrin correlates with storage. (This is similar to iron where transferrin transports iron to the cells and ferritin reflects storage.)

How to interpret B12 and HoloTC levels.

The amount of B12 attached to transcobalamin (ie holo-transcobalamin or HoloTC) therefore reflects the Vitamin B12 level available to cells. When there is a cellular deficiency of B12, the reactions dependent on B12 are obstructed and precursors such as homocysteine and methyl-malonic acid (MMA) build up and can be measured as indicators of functional B12 deficiency. HoloTC correlates better with homocysteine and MMA than the total B12 level of the blood. When total B12 levels are low or equivocal, it is appropriate to follow up with the more specific HoloTC test to help ascertain if there is a functional deficiency. Pregnant women often deplete their B12 stores during pregnancy, but they uncommonly have B12 deficiency evidenced by their normal HoloTC levels. Conversely, patients with some haematological malignancies may have high B12 stores (eg by tumours producing haptocorrin) but may not mobilise those stores evidenced by a low HoloTC and macrocytic anaemia.

Summary

Vitamin B12 deficiency is common and can be associated with neurological symptoms and haematological signs especially in vegetarians, and uncommonly in pernicious anaemia. HoloTC is more specific for clinical B12 deficiency than total B12 and that is why laboratories reflex test for HoloTC whenever the total B12 is low or equivocal.   General Practice Pathology is a new regular column each authored by an Australian expert pathologist on a topic of particular relevance and interest to practising GPs. The authors provide this editorial free of charge as part of an educational initiative developed and coordinated by Sonic Pathology.  

References

  1. Watanabe F, Yabuta Y, Bito T, Teng F. Vitamin B12-Containing Plant Food Sources for Vegetarians. Nutrients. 2014 May; 6(5): 1861-73.
  2. Moore E, Pasco J, Mander A, Sanders K, Carne R, Jenkins N, et al. The prevalence of vitamin B12 deficiency in a random sample from the Australian population. Journal of Investigational Biochemistry. 2014 Oct 2; 3(3): 95-100.
  3. Flood VM, Smith WT, Webb KL, Rochtchina E, Anderson VE, Mitchell P. Prevalence of low serum folate and vitamin B12 in an older Australian population. Aust N Z J Public Health. 2006 Feb; 30(1): 38-41.
  4. Aa A, Ah A, Ap S, Fh A, Pernicious anemia in patients with macrocytic anemia and low serum B12.  Pak J Med Sci. 2014 Nov-Dec; 30(6): 1218-22.
  5. Sun A, Chang JY, Wang YP, Cheng SJ, Chen HM, Chiang CP. Do all the patients with vitamin B12 deficiency have pernicious anemia? J Oral Pathol Med. 2016 Jan; 45(1): 23-7.
  6. Botros M, Lu ZX, McNeil AM, Sikaris KA. Clinical notes as indicators for Vitamin B12 levels via text data mining. Pathology. 2014; 46 Suppl 1: S84.
Dr Linda Calabresi

New NHMRC guidelines put age and family history up front and centre in determining who should be screened for bowel cancer with colonoscopy and who needs iFOBT. It has been known for some time that family history can influence the risk of developing bowel cancer, Australia’s second most common cause of cancer death. But it is also known that specific, identified genetic mutations causing conditions such as Lynch syndrome or familial adenomatous polyposis are rare, accounting for less than 5% of all bowel cancers diagnosed. At most, the researchers say, this only explains half of the reasons why family history is a risk factor for bowel cancer. “The remainder of the observed increases in familial risk could be due in part to mutations in yet to be discovered colorectal cancer susceptibility genes, polygenic factors such as single-nucleotide polymorphisms, or dietary and other lifestyle factors shared by family members,” the guideline authors said in the Medical Journal of Australia. Therefore, the researchers, led by Professor Mark Jenkins, director of the Centre for Epidemiology and Biostatistics, in the University of Melbourne’s School of Population and Global Health, analysed all the available cohort studies to determine the risk of developing colorectal cancer based on age and family history. They categorised cohorts into one of three levels of risk and this determined at what age screening would be worthwhile starting and which screening method was most appropriate. The screening guidelines exclude people with a known or suspected cancer-causing genetic syndrome, as these people require much more intensive screening and should be managed in a family cancer clinic. The majority of Australians (90%) fall into the lowest risk category, category 1, which puts their risk at age 40 of developing colorectal cancer in the next 10 years at about 0.25% (one in 400). As with most other cancers age is a risk factor, so it is unsurprising that at age 50 the risk of developing this cancer has risen to 0.9%. Screening for this category 1 group should be the two-yearly iFOBT test that is currently available via the National Bowel Screening program for adults between the ages of 50 and 74 years. Interestingly, people aged 75 and older still develop bowel cancer but there have been no studies to determine the cost-effectiveness or benefit vs risk analysis of screening in this age group which is why the program and the guideline recommendations stop at 74 years. One of the differences in these new guidelines, a revision from the previous ones published back in 2005, is that people with a first degree relative who has had or has a bowel cancer at age 55 or older are still considered at average risk (category 1). However, people with this history might consider starting the iFOBT screening at a younger age (45 years), the guideline authors suggest. Category 2 includes people with a moderately increased risk of developing colorectal cancer, 3-6 times higher than average. This will mean having a first degree relative diagnosed with a bowel cancer before the age of 55 or having two first degree relatives who developed bowel cancer at any age (or one first degree and two second degree relatives). Category 2 people are recommended to have iFOBT every two years for the decade between ages 40 and 50 and then switch to five yearly colonoscopies until the age of 75. Finally, the high risk, category 3 is for all those patients without a genetic syndrome whose family history is even stronger than those people in category 2. Their risk is between 7-10 times higher than average. This includes people with at least three first-degree relatives who have been diagnosed with colorectal cancer at any age or people who have multiple relatives with the cancer including at least one diagnosed before aged 55. These high-risk people need to start screening earlier, with the guidelines recommending iFOBT every two years starting at age 35 and continuing for 10 years and then having a colonoscopy every five years between the ages of 45 and 75. Of note is that the revised guidelines have deleted the reference in the previous guidelines to starting screening 10 years before the earliest age colorectal cancer was diagnosed in a first degree relative. “There have been no studies conducted to determine the utility of beginning screening 10 years before the earliest diagnosis in the family, which was a recommendation in the 2005 guidelines and, therefore, it is not included in these guidelines,” they said. The new guidelines aim not only to more strongly define risk based on the latest evidence, but also to determine the most appropriate screening method based on that risk, taking into consideration cost-effectiveness and rationalisation of available services, in particular, colonoscopies.   Reference Jenkins MA, Ouakrim DA, Boussioutas A, Hopper JL, Ee HC, Emery JD, et al. Revised Australian national guidelines for colorectal cancer screening: family history. Med J Aust. 2018 Oct 29. doi: 10.5694/mja18.00142. [epub ahead of print]

Healthed

There are new changes to Medicare from November 1, 2018, which will affect how GPs can order sleep studies and how they follow up the results. These changes have been introduced by the MBS Review Taskforce and Government to improve doctor assessment and management of a patient having a sleep study.

What are the new Medicare changes?

From November 1 2018:
  • GPs will need to administer screening questionnaires before directly ordering a Medicare rebatable sleep study.
  • Only if these screening questionnaires are positive, can GPs refer directly for a Medicare rebatable sleep study test.
  • The screening questionnaires restrict testing to patients with a “high probability for symptomatic, moderate to severe obstructive sleep apnoea”.
  • Following sleep study testing, “the results and treatment options following any diagnostic sleep study should be discussed during a professional attendance with a medical practitioner before the initiation of any therapy”.
If the screening questionnaires are not positive, patients will need to be referred to Sleep or Respiratory Physicians for assessment and testing. Diagnostic sleep studies can only be rebated once a year.  

Why were the changes made?

 The MBS Review Taskforce noted a very large growth in sleep study testing, especially home sleep study testing, and were concerned that better access to testing has been associated with less appropriate referrals for testing. The Taskforce noted a lack of Sleep or Respiratory Physician review of patients for advice regarding the diagnosis and treatment of OSA. Related to this was a concern that some models of care were promoting home sleep study testing and then advising patients to proceed to CPAP “at lower apnoea-hypopnoea index (AHI) thresholds than is conventionally recommended as indicative of OSA requiring treatment.” The Taskforce commented that there may be a “commencement on CPAP which in some cases is not clinically indicated and does not address their sleep related problem. In this (later) scenario, patients purchase CPAP devices that may deliver little benefit, often based on advice from non-health professionals, and with no medical consultation involved.”  

What do GPs need to do differently?

For adult sleep disorders, GPs can refer to a Sleep or Respiratory Physician for further testing and management (unchanged). This is particularly relevant and important if the patient has atypical symptoms of OSA; have a BMI > 30 and obesity hypoventilation is suspected; or they have symptoms of non-OSA sleep disorders that require management (e.g. insomnia, parasomnias, restless legs syndrome, primary hypersomnolence, etc.) OR GPs can refer directly for a sleep study to investigate OSA (subject to the new specific rules below) Direct referral for a sleep study by a GP should be for patients who have a high probability for symptomatic, moderate to severe obstructive sleep apnoea using the following screening tools:
  • An Epworth Sleepiness Scale score of 8 or more; AND
  • One of the following
    • A STOP-BANG score of 4 or more; or
    • An OSA-50 score of 5 or more; or
    • A high risk score on the Berlin Questionnaire.
The screening questionnaires must be administered by the referring practitionerUnattended (home) sleep studies are suitable for many patients with suspected OSA but patients with other sleep disorders should undergo an attended (laboratory) study.  If GPs refer direct for sleep study testing, a doctor (GP or Sleep/Respiratory Physician) should see the patient after the test to discuss the results and advise on the best management for the patient’s sleep condition.  

The future for primary care and sleep disorders

GPs and Sleep Specialists need to work closely together to co-manage the range and high prevalence of sleep disorders. The new Medicare rules place a greater emphasis on medical assessment, before and after sleep study testing, and emphasise the important role that doctors need to take in managing these conditions.

Summary:

  1. For a GP to refer directly for a sleep study, the relevant questionnaires need to be attached to the referral for it to be valid.
  2. Sleep or Respiratory Physician referrals do not need the questionnaires to be filled in.
  3. Patients must be seen by a doctor before the study for the questionnaires to be filled, and after the study,before any treatment is initiated.
  4. The number of Medicare rebatable sleep studies per patient per year has been limited.

Screening questionnaires:

See link: http://www.sleepcentres.com.au/tl_files/PDF/referral_form_PDF.pdf See tables attached.  

Epworth Sleepiness Scale

               

OSA-50 Questionnaire

         

STOP-BANG Questionnaire

       

Berlin Questionnaire

Loubaba Mamluk

While heavy drinking is clearly harmful to the unborn baby, often leading to miscarriage, premature birth and foetal alcohol syndrome, the possible effects of light drinking have been less clear. High quality data on this issue is lacking due to ethical and methodological issues. On the one hand, experiments (clinical trials) in this area are impossible to conduct. Clinical trials would include randomising a group of pregnant women to drinking alcohol, which is clearly unethical. On the other hand, in observational studies we can never be sure whether the results are due to alcohol or other factors, such as wealth or education.

‘One glass is OK, isn’t it?’

Women often ask about “safe” levels of drinking during pregnancy. The distinction between light drinking and abstinence is indeed the point of most tension and confusion for health professionals and pregnant women, and public health guidance varies worldwide. Our new review of the evidence, published in BMJ Open, shows that this specific question is not being researched thoroughly enough. As there can be no clinical trial research carried out on this topic, we systematically reviewed all the data from a wide range of high quality observational studies. These studies involved pregnant women, or women trying to conceive, who reported on their alcohol use before the baby was born. The researchers assessed the impact of light drinking, compared with no alcohol at all.   >> Read More Source: The Conversation
Allison Sigmund

In Australia 12-14% of pregnancies are affected by gestational diabetes. Despite its prevalence, most people aren’t aware the risks don’t end when the pregnancy does. Diabetes occurs when the level of glucose (sugar) in the blood is higher than normal. Cells in the pancreas control blood glucose levels by producing insulin. When these cells are destroyed, type 1 diabetes results. When the body becomes resistant to the action of insulin and not enough insulin can be made, this is known as type 2 diabetes. Resistance to insulin action occurs for many reasons, including increasing age and body fat, low physical activity, hormone changes, and genetic makeup. Gestational diabetes occurs when high blood glucose levels are detected for the first time during pregnancy. Infrequently, this is due to previously undiagnosed diabetes. More commonly, the diabetes is only related to pregnancy. Pregnancy hormones reduce insulin action and increase insulin demand, in a similar way to type 2 diabetes, but usually after the baby is born, hormones and blood glucose levels go back to normal. Read more: Weight gain during pregnancy: how much is too much?

Who gets gestational diabetes?

Factors that increase the risk of gestational diabetes include:
  • a strong family history of diabetes
  • weight above the healthy range
  • non Anglo-European ethnicity
  • being an older mum.
Weight is the major risk factor that can be changed. But in some cases, gestational diabetes may develop without any of these risk factors. Rates of gestational diabetes in Australia have approximately doubled in the last decade. Increased testing for gestational diabetes, changing population characteristics, and higher rates of overweight and obesity may have contributed to this. There are likely to be other factors we do not fully understand.   >> Read More Source: The Conversation