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Dr Linda Calabresi

Finally, we’ve got some robust evidence to answer the question - is ondansetron safe to take for morning sickness. Published in JAMA, a very large retrospective study involving over 1.8 million pregnancies, almost 90,000 of which included exposure to ondansetron in the first trimester has found that taking the drug did not increase the risk of cardiac malformations or congenital malformations overall. However, first trimester ondansetron was associated with a very small increased risk of oral clefts (three additional cases per 10,000 women treated). Interestingly the increased risk for oral clefts was confined to cleft palate, there was no evidence for an increased risk of cleft lip. The information will be eagerly received by the thousands of pregnant women who experience severe nausea and vomiting, and the clinicians who care for them many of whom have been prescribing ondansetron because of its effectiveness, despite the lack of detailed safety data. “Although not formally approved for the treatment of nausea and vomiting during pregnancy, ondansetron, a 5-HT receptor antagonist, has rapidly become the most frequently prescribed drug for nausea and vomiting during pregnancy in the United States because of its perceived superior antiemetic effects and improved adverse effect profile compared with treatment alternatives,” the study authors said. “In 2014, an estimated 22% of pregnant women used ondansetron in the United States,” they said. The major strengths of this study lie in the size of the cohort and the fact that the information on ondansetron exposure was based on filled prescriptions, thereby negating any possible recall bias. Both these factors are particularly important given how rare these abnormalities are and how many possible confounders there could be. As for limitations of the study, of course just because a prescription has been filled doesn’t always mean the medication has been taken, but even if the exposure wasn’t as great as calculated, the risk would be only lessened rather than raised. There is also the possibility that there might have been some other unrecognised factor involved especially since all the women in the study were uninsured and treated under Medicaid insurance and therefore included a higher percentage of women from disadvantaged communities. However, given the detailed information collected on these women and their pregnancies, and the multiple analyses conducted on this data, the likelihood of unmeasured confounders affecting the findings was thought to be low. Overall the results of this study should provide reassurance for clinicians and pregnant women, according to an accompanying editorial, written by a US obstetrician and gynaecologist. “As clinicians and pregnant women engage in informed, shared decision-making surrounding treatment for nausea and vomiting, the current information is important for contextualising risks in light of the potential benefits,” he concluded.

References

Huybrechts KF, Hernández-Díaz S, Straub L, Gray KJ, Zhu Y, Patorno E, et al. Association of Maternal First-Trimester Ondansetron Use With Cardiac Malformations and Oral Clefts in Offspring. JAMA. 2018 Dec 18; 320(23): 2429-37. DOI: [10/1001/jama.2018.18307] Haas DM. Helping Pregnant Women and Clinicians Understand the Risk of Ondansetron for Nausea and Vomiting During Pregnancy. JAMA. 2018 Dec 18; 320(23): 2425-6. DOI: [10.1001/jama.2018.19328]
Daryl Efron and Harriet Hiscock

The rate of medications dispensed for attention-deficit hyperactivity disorder (ADHD) in children aged 17 and under increased by 30% between 2013-14 and 2016-17. The Australian Atlas for Healthcare Variation, released today, shows around 14,000 prescriptions were dispensed per 100,000 children aged 17 and under in 2016-17, compared with around 11,000 in 2013-14. The atlas for 2016-17 also showed some areas had a high dispensing rate of around 34,000 per 100,000 while the area with the lowest rate was around 2,000 per 100,000 – a 17-fold difference. This difference is much lower than in 2013-14, when the highest rate was 75 times the lowest. For decades people have been concerned too many children could be diagnosed with ADHD and treated with medications. We are conducting a study called the Children’s Attention Project, following 500 children recruited through Melbourne schools. So far, we have found only one in four children who met full ADHD criteria were taking medication at age ten. So it looks like, if anything, more children with ADHD should be referred for assessment and consideration of management options.

How many kids are medicated?

ADHD is the most common neurodevelopmental disorder of childhood – the prevalence is around 5% in Australia. Children with ADHD have great difficulty staying focused, are easily distracted and have poor self-control. Many are also physically hyperactive, especially when they are young. To be diagnosed, children need to have major problems from their ADHD symptoms both at home and school. These include learning difficulties, behavioural problems and trouble making friends. Young people with ADHD are more likely to fail school, have lower quality of life, experience substance abuse issues and teenage pregnancy, or end up in prison. Medication can make a big difference to these children’s lives. While there are many ways to help children with ADHD, stimulant medication is the most effective treatment. All international clinical guidelines recommend it for children with significant ADHD that persists after non-medication approaches have been offered. Our previous research found that about 80% of children diagnosed with ADHD by a paediatrician (the main medical specialty that manages ADHD) in Australia are treated with medication. The atlas shows the proportion of children and adolescents who had at least one ADHD medication prescription dispensed was 1.5% in 2013-14 and 1.9% in 2016-7. This is similar to the prevalence of stimulant medication prescription in previous Australian studies in the past 15 years. It sits between the US (high) and Europe (low) and is not excessive given the prevalence of the condition. The Children’s Attention Project found those with the most severe symptoms were more likely to be prescribed medications, as were those from families of lower socioeconomic status. Other Australian studies have found similar results. This is not surprising as ADHD does appear to be more common in children from socioeconomically disadvantaged families. Our research suggests that disadvantaged families in Australia appear to be able to access services for ADHD, at least in metropolitan centres.

Why does it vary between areas?

The atlas finding that there is considerable regional variation in prescribing of stimulant medications in Australia has been identified in previous studies and needs to be better understood. Some variation in health care is normal and good, but too much suggests there may be a problem with the quality of care or access to care. For example, greater prescribing in regional areas may reflect lack of timely access to non-pharmacological services. We do need to keep watching this space, monitoring rates and regional variation of medication use. A landmark study in the US, published in 1999, compared medication with intensive parent and teacher behaviour training. The children who received medication had a much greater reduction in ADHD symptoms. But medication is only one consideration in ADHD. Other supports are also important. Behavioural therapies can help reduce anxiety and behaviour problems in children with ADHD and improve relationships with parents and teachers. However, accessing psychologists can be hard for many families. While Medicare rebates are available for up to ten sessions per year, costs can still be a barrier. In our research, Victorian parents reported out-of-pocket costs of up to A$200 per session with a psychologist. ADHD is not considered a disability under the National Disability Insurance Scheme, so families are not eligible for funding packages. Further research is needed to better understand the factors influencing access to care for Australian children with ADHD, and why there is such variation in rates of prescribing between regions. We also need to ensure children across Australia get equitable access to non-medication management. We need evidence-based clinical guidelines relevant to the Australian healthcare system, which is quite different from places such as the UK and US. This work must include adult ADHD, which is an emerging area with a raft of clinical and service system complexities.The Conversation This article is republished from The Conversation under a Creative Commons license. Read the original article.
Dr Linda Calabresi

Women with a normal BMI can no longer tick off weight as breast cancer risk factor, US researchers say. According to their study, published in JAMA Oncology, it’s body fat that increases the risk even if the woman falls into a healthy weight range. The study was in fact a secondary analysis of the Women’s Health Initiative clinical trial along with observational study cohorts involving almost 3500 post-menopausal, healthy BMI women who at baseline had their body fat analysed (by DXA) and were then followed up for a median duration of 16 years. What the researchers discovered was that women in the highest quartile for total body fat and trunk fat mass were about twice as likely to develop ER-positive breast cancer. “In this long-term prospective study of postmenopausal with normal BMI, relatively high body fat levels were associated with an elevated risk of invasive breast cancers,” the study authors spelled. Perhaps less surprisingly, the analysis also found that the breast cancer risk increased incrementally as the body fat levels increased. “We found a 56% increase in the risk of developing ER-positive breast cancer per 5-kg increase in trunk fat, despite a normal BMI,” they said. The proposed mechanism that explains why high body fat levels increases the risk of breast cancer, is much the same as the known mechanism that explains the link between obesity and breast cancer risk. People with high body fat levels tend to have adipocyte hypertrophy and cell death which means the adipose tissue is chronically although sub-clinically inflamed. This inflammation triggers the production of a number of factors including an increased ratio of oestrogens to androgens which is believed to predispose to the development of oestrogen-dependent breast cancer. Basically the study authors believe these women with high body fat but normal BMI, are ‘metabolically obese’ even though they do not fit the standard definition of obese. And while using DXA to determine body fat levels is highly accurate, such an assessment is rarely used in everyday practice. Most doctors look only at BMI measurements or they may also assess waist measurement which has variable sensitivity in terms of diagnosing excess body fat. Consequently, the researchers say, many non-overweight women who are at increased risk of breast cancer because of their high adiposity may be going unrecognised. So where does that leave us? Here the study authors were less definitive. The link between body fat and breast cancer is clear but, they say, more research is needed to determine the most appropriate management for this cohort of women with high body fat levels and normal BMI. “Future studies are needed to determine whether interventions that reduce fat mass, such as diet and exercise programs or medications including aromatase inhibitors, might lower the elevated risk of breast cancer in this population with normal BMI,” they concluded.

Reference

Iyengar NM, Arthur R, Manson JE, Chlebowski RT, Kroenke CH, Peterson L, et al. Association of Body Fat and Risk of Breast Cancer in Postmenopausal Women With Normal Body Mass Index: A Secondary Analysis of a Randomized Clinical Trial and Observational StudyJAMA 2018 Dec 6. DOI: [10.1001/jamaoncol.2018.5327] [Epub ahead of print]
Dr Amanda Henry

Women often wonder what the “right” length of time is after giving birth before getting pregnant again. A recent Canadian study suggests 12-18 months between pregnancies is ideal for most women. But the period between pregnancies, and whether a shorter or longer period poses risks, is still contested, especially when it comes to other factors such as a mother’s age. It’s important to remember that in high-income countries most pregnancies go well regardless of the gap in between.

What is short and long

The time between the end of the first pregnancy and the conception of the next is known as the interpregnancy interval. A short interpregnancy interval is usually defined as less than 18 months to two years. The definition of a long interpregnancy interval varies – with more than two, three or five years all used in different studies. Most studies look at the difference every six months in the interpregnancy interval makes. This means we can see whether there are different risks between a very short period in between (less than six months) versus just a short period (less than 18 months). Most subsequent pregnancies, particularly in high-income countries like Australia, go well regardless of the gap. In the recent Canadian study, the risk of mothers having a severe complication varied between about one in 400 to about one in 100 depending on the interpregnancy interval and the mother’s age. The risk of stillbirth or a severe baby complication varied from just under 2% to about 3%. So overall, at least 97% of babies and 99% of mothers did not have a major issue. Some differences in risk of pregnancy complications do seem to be related to the interpregnancy interval. Studies of the next pregnancy after a birth show that:

What about other factors?

How much of the differences in complications are due to the period between pregnancies versus other factors such as a mother’s age is still contested. On the one hand, there are biological reasons why a short or a long period in between pregnancies could lead to complications. If the gap is too short, mothers may not have had time to recover from the physical stressors of pregnancy and breastfeeding, such as pregnancy weight gain and reduced vitamin and mineral reserves. They may also not have completely recovered emotionally from the previous birth experience and demands of parenthood. If the period between pregnancies is quite long, the body’s helpful adaptations to the previous pregnancy, such as changes in the uterus that are thought to improve the efficiency of labour, might be lost. However, many women who tend to have a short interpregnancy interval also have characteristics that make them more at risk of pregnancy complications to start with – such as being younger or less educated. Studies do attempt to control for these factors. The recent Canadian study took into account the number of previous children, smoking and the previous pregnancy outcomes, among other things. Even so, they concluded that risks of complications were modestly increased with a lower-than-six-month interpregnancy period for older women (over 35 years) compared to a 12-24-month period. Other studies, however, including a 2014 West Australian paper comparing different pregnancies in the same women, have found little evidence of an effect of a short interpregnancy interval.

So, what’s the verdict?

Based on 1990s and early 2000s data, the World Health Organisation recommends an interpregnancy interval of at least 24 months. The more recent studies would suggest that this is overly restrictive in high-resource countries like Australia. Although there may be modestly increased risks to mother and baby of a very short gap (under six months), the absolute risks appear small. For most women, particularly those in good health with a previously uncomplicated pregnancy and birth, their wishes about family spacing should be the major focus of decision-making. In the case of pregnancy after miscarriage, there appears even less need for restrictive recommendations. A 2017 review of more than 1 million pregnancies found that, compared to an interpregnancy interval of six to 12 months or over 12 months, an interpregnancy interval of less than six months had a lower risk of miscarriage and preterm birth, and did not increase the rate of pre-eclampsia or small babies. So, once women feel ready to try again for pregnancy after miscarriage, they can safely be encouraged to do so.
Dr David Kanowski

Short or tall stature is considered to be height below or above the 3rd or 97th percentile respectively. Abnormal growth velocity, showing on serial height measurements, is also an important finding. Growth charts based on the US NHANES study are available from www.cdc.gov/growthcharts/charts.htm. Copies of growth charts, together with height velocity and puberty charts are available at the Australasian Paediatric Endocrine Group (APEG) website, https://apeg.org.au/clinical-resources-links/growth-growth-charts/. Local Australian growth charts are currently not available. The height of the parents should be considered in evaluating the child. Expected final height can be calculated from the parents’ heights as follows: For boys: Expected final height = mean parental height + 6.5cm For girls: Expected final height = mean parental height – 6.5cm Assessment of bone age (hand/wrist) is also useful. With familial short or tall stature, bone age matches chronological age. Conversely, in a child with pathological short stature, bone age is often well behind chronological age, and may continue to fall if the disease is untreated. The stage of puberty is relevant, as it will affect the likely final height. A short child who is still pre-pubertal (with unfused epiphyses) is more likely to achieve an adequate final height than one in late puberty.

Short stature

Causes to consider include:
  • Malnutrition, the commonest cause worldwide
  • Chronic disease, for example, liver/renal failure, chronic inflammatory diseases
  • Growth hormone deficiency, with/without other features of hypopituitarism
  • Other endocrinopathies, for example, hypothyroidism, (rarely) Cushing’s syndrome
  • Genetic/syndromic causes, for example, Down, Turner, Noonan, Prader-Willi syndromes
  • Depression or social deprivation should also be considered
  • Idiopathic short stature is a diagnosis of exclusion
Appropriate initial screening investigations can include liver and renal function tests, blood count, iron studies, thyroid function tests, coeliac disease screen, thyroid function tests, urinalysis (including pH) and karyotype. Other specialised tests may be needed, based on suspicion. In the lower range, IGF-1 shows considerable overlap between normal and abnormal levels, especially in the setting of poor nutrition. Small children tend to have low levels, regardless of whether growth hormone deficiency is the underlying cause. Random growth hormone levels vary widely because of pulsatile secretion and are also not a reliable test. Therefore, unless there is a clear underlying genetic or radiological diagnosis associated with clearly low IGF-1, stimulation testing is typically required to formally diagnose growth hormone deficiency and may be essential for funding of growth hormone treatment.

Tall stature

Causes include:
  • Chromosomal abnormalities, for example, Klinefelter syndrome (qv), XYY syndrome
  • Marfan syndrome
  • Homocystinuria
  • Hyperthyroidism
  • Growth hormone excess (see Acromegaly; Growth hormone; Insulin-like growth factor-1 (IGF-1))
  • Precocious puberty
  • Other syndromic causes, for example, Sotos, Beckwith-Wiedemann syndromes
  • Familial tall stature (predicted final height should match mid-parental height)
Investigation of stature is a specialised area and early discussion with a paediatric endocrinologist is indicated if there is clinical concern, for example, height below the 3rd percentile at age five, slow growth (crossing two percentile lines away from the median), significant height/ weight discrepancy (more than two centile lines), suspected/confirmed metabolic or genetic abnormality, or clinical evidence of malnutrition or marked obesity.

References

  1. Cohen P, Rogol AD, Deal CL, Saenger P, Reiter EO, Ross JL, et al. Consensus statement on the diagnosis and treatment of children with idiopathic short stature: a summary of the Growth Hormone Research Society, the Lawson Wilkins Pediatric Endocrine Society, and the European Society for Paediatric Endocrinology workshop. J Clin Endocrinol Metab. 2008 Nov; 93(11): 4210-7. DOI: [10.1210/jc.2008-0509]
  2. Nwosu BU, Lee MM. Evaluation of short and tall stature in children. Am Fam Physician. 2008 Sep 1; 78(5): 597-604. Available from: www.aafp.org/afp/2008/0901/p597.pdf.
  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 Linda Calabresi

Giving children with acute gastroenteritis probiotics will not help them recover more quickly, according to two large randomised controlled trials. At least if the probiotic includes Lactobacillus rhamnosus. The research, published in the New England Journal of Medicine, provides solid evidence against the adjunctive treatment, which, as the study authors point out, has been recommended by many health professionals and authoritative bodies. “Many experts consider acute infectious diarrhoea to be the main indication for probiotic use,” they said. However, the two studies, both conducted on children aged three months to four years with a less than 72-hour history of acute vomiting and diarrhoea, failed to show any benefit of taking a five-day course of the probiotics. One of the studies conducted across six tertiary paediatric centres in Canada, involved almost 900 children with acute gastroenteritis randomly assigned to receive either a combination probiotic (L. rhamnosus and L. helveticus) or placebo. The other very similar study, this one involving US centres, included 970 children with gastroenteritis and tested the effectiveness of giving the single probiotic Lactobacillus rhamnosus against placebo. The results of the two trials, using almost identical outcome measures were the same – the probiotics did not make a difference. “Neither trial showed a significant difference in the duration of diarrhoea and vomiting, the number of unscheduled visits to a health provider or the duration of day-care absenteeism,” an accompanying editorial concluded. The role of probiotics in the management of gastroenteritis in children has been an area of controversy and contradiction not only among individual specialists but also among different expert bodies, with guideline recommendations varying from “not recommended” by the Centers of Disease Control and Prevention to “strongly recommended” by the European Society for Pediatric Gastroenterology, Hepatology and Nutrition. But now, it appears this grey area has now become very black and white. “Taken together, neither of these large, well-done trials provides support for the use of probiotics containing L. rhamnosus to treat moderate-severe gastroenteritis in children,” the editorial stated. The caveat, of course, is that this evidence while robust only applies to this particular probiotic. There might still be probiotics out there that do make a difference. The editorial author referred to a recent large randomised-controlled trial conducted in rural India that found giving healthy newborns the probiotic, L. planatarum in the first few days of life was associated with a significantly lower risk of sepsis and lower respiratory tract infection in the subsequent two months. So while these studies might appear to be the nail in the coffin for L. rhamnosus -containing probiotics, it is still a case of ‘watch this space’ with regard the role of probiotics more generally.

Reference

Schnadower D, Tarr PI, Casper TC, Gorelick MH, Dean JM, O'Connell KJ, et al. Lactobacillus rhamnosus GG versus Placebo for Acute Gastroenteritis in Children. N Engl J Med. 2018 Nov 22; 379(21): 2002-2014. DOI: 10.1056/NEJMoa1802598 Freedman SB, Williamson-Urquhart S, Farion KJ, Gouin S, Willan AR, Poonai N, et al. Multicenter Trial of a Combination Probiotic for Children with Gastroenteritis. N Engl J Med. 2018 Nov 22; 379(21): 2015-26. DOI: 10.1056/NEJMoa1802597 LaMont JT. Probiotics for Children with Gastroenteritis. N Engl J Med 2018 Noc 22; 379(21): 2076-77. DOI: 10.1056/NEJMe1814089
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.