Women's health

Difficulty in achieving proper informed consent for a complex screening test and the varying phenotypic outcomes leaves pregnant women in a precarious situation when results are abnormal The combined first trimester screening test for Down syndrome, involving a nuchal translucency scan and biochemistry at 11–13 weeks, improved detection rates to 90% when compared with the sensitivity of screening by age‐related a priori risk of around 30% for a false positive rate of 5%.1 The advent of non‐invasive prenatal testing (NIPT) in 2010 as a screening test for the common trisomies was revolutionary, with sensitivity, specificity and detection rates unmatched by the combined first trimester screening programs. NIPT was found to achieve a detection rate for Down syndrome of 99.7%, with a false positive rate of 0.04%.2 However, some NIPT providers now additionally offer extended panels and low resolution whole genome sequencing (WGS) including sex chromosome aneuploidies, rare autosomal aneuploidies, and subchromosomal deletions, duplications and recurrent microdeletions. This comes at a cost of a higher false positive rate and lower positive predictive value.3 Moreover, the expanded panels and WGS NIPT raise issues of clinical utility and ethical concerns.4,5 Clinical utility Screening not diagnosis NIPT is based on the detection of cell‐free fetal DNA in the maternal circulation. The placental origin of cell‐free fetal DNA means that NIPT can only be a screening test and is not diagnostic.6 NIPT findings can be confounded by confined placental mosaicism, cell‐free fetal DNA from a demised co‐twin placenta, maternal chromosomal changes or malignancy.6,7 Moreover, a NIPT result will be issued even if the fetus is demised. The current NIPT tests available are for specific chromosomal aneuploidy, extended panels of targeted conditions and low resolution WGS. Targeted and low resolution WGS NIPT Targeted NIPTs (Box 1) interrogate specific chromosomes: standard (usually 13, 18, 21, X and Y) or extended (specific recurrent microdeletions associated with known syndromes, such as 22q11.2 microdeletion [DiGeorge syndrome]).8 Many abnormalities that can be detected by targeted NIPT have varying clinical outcomes (eg, sex chromosome abnormalities and DiGeorge syndrome). Each of these conditions has varying sensitivity, specificity and positive predictive value. Other NIPTs interrogate every chromosome (by low resolution WGS). These tests can potentially screen for aneuploidy of every chromosome (all 22 autosomes and the sex chromosomes), and for subchromosomal gains and losses on every chromosome. There is potential utility in detecting rare or novel large subchromosomal imbalances, as they are likely to be associated with abnormal clinical phenotype when present in the fetus, and may indicate a familial balanced rearrangement. The clinical utility of screening for rare autosomal aneuploidies is less certain. Most rare autosomal aneuploidies (95%) are confined to the placenta, and those which are present in the fetus as well as the placenta often result in early fetal demise.9 The resolution of WGS NIPT is likely to increase as deeper sequencing becomes viable and cost‐effective. Whereas prenatal microarray testing of amniotic fluid in Australia is primarily used in the context of a fetal structural abnormality, higher resolution NIPT could become a general screening test. This would, however, increase both the number of variants of uncertain significance and the likelihood that they are detected in an apparently phenotypically normal fetus.3,10 Ethical concerns Respect for maternal autonomy is an important ethical principle in clinical guidelines for prenatal screening. Recommendation 2 of the Royal Australian and New Zealand College of Obstetricians and Gynaecologists guidelines states: “Screening or diagnostic testing for fetal chromosomal and genetic conditions is voluntary and should only be undertaken as an informed decision by the pregnant woman”.11 In light of the issues surrounding clinical utility and complexity of expanded panels and WGS NIPT, care needs to be taken to ensure that autonomy is respected. Moreover, consent alone cannot be expected to do the ethical heavy lifting, because of (i) the challenges in providing adequate information arising from complexity of the tests; (ii) the risk of power imbalances and “normalisation” of testing; (iii) anxiety resulting from complex and potentially unnecessary medical decisions; (iv) the problem of screening for “normality” and genetic reductionism; and (v) the doctor’s responsibility in determining which NIPT test is clinically indicated. Complexity endangers informed consent Respect for autonomy requires that informed consent is obtained. From a medico‐legal perspective, consent must be given voluntarily. The individual must also be sufficiently informed regarding a test or procedure, including the associated risks and benefits. The requisite extent of information provision is generally determined in accordance with what information a reasonable person, in that person’s circumstances, would expect to receive. From an ethical perspective, however, it is the understanding of information that is important, not merely that a person was given the legally required information. Given the complexity of extended panels and WGS NIPT, ensuring understanding means that significant time needs to be invested. Power imbalances and normalisation Two additional factors could ethically undermine consent for all NIPT options. First, the power imbalance between a doctor and patient, whereby a patient simply agrees because “doctor knows best” and, second, the impression that NIPT is a normal part of care that it would be foolish to reject.12 The anxiety caused by uncertain results It is tempting to respect autonomy by being non‐paternalistic and non‐directive in counselling by giving parents all the information from prenatal testing regardless of its nature. However, this shifts the burden of the uncertain results and the resultant anxiety to the parents. Qualitative and quantitative research shows higher levels of decisional regret among parents whose results identified variation of uncertain significance. At least some parents would not have consented to the test if they had known what this would entail. The lack of certainty by clinicians about what these results might actually mean for a future child increased parental distress.13 The meaning of screening and the danger of genetic reductionism According to the synthesis of screening criteria offered by Andermann and colleagues (Box 2), screening should be used to identify an individual who is high risk for a specific disease or need, thereby filling the perceived gap between standard screening and invasive diagnostics.14 Screening is then followed up with diagnostic tests and appropriate treatment. The availability of extended panels and WGS NIPT (Box 1) increases the tendency away from screening for diseases guided by public health screening principles. It is difficult to identify a recognised need or define the objectives of the screening beyond merely looking to see if there is anything abnormal. Even if these principles were met, one may be detecting placental pathology, or clinical conditions with highly variable outcomes for the fetus. As the resolution of WGS NIPT increases, so does the likelihood of detecting variants of uncertain significance. Provision of extended panels and WGS NIPT should be seen in light of the bigger question of how we see genetic information in our society.15 Research shows that many genetic tests are in effect screening for “normality”, which partly explains the anxiety when variants of uncertain significance are reported.13 This approach potentially changes the purpose of screening from screening for a specific disease to screening for normality by identifying any abnormality in the genome. The error in this thinking is that it assumes that genetic variation is abnormal. Just because a genetic anomaly can be identified does not necessarily mean that it would be phenotypically expressed. Similarly, detection of genes associated with adult onset disease does not necessarily equate to disease, and the possible future development of therapies for currently untreatable conditions cannot be ruled out. Consent is not sufficient to justify a procedure of questionable clinical utility Screening should be recommended or chosen only if there is likely to be a proportionate benefit, and there is no disproportionate burden. What is proportionate rests on a number of objective and subjective factors, but the aforementioned public health screening principles provide a good starting point. We agree with national guidelines that recommend against routine screening for recurrent microdeletions, and recommend provision of in‐depth counselling before screening for sex chromosome abnormalities.11 Recommendations The following recommendations may address the clinical and ethical concerns outlined above. Informed consent is required for all NIPT tests, especially in the context of extended panels and WGS NIPT. Clinicians must understand the different abnormalities targeted by extended NIPT panels and be able to assess and communicate the clinical utility of screening in accordance with a particular patient’s needs, desires and circumstances (Box 1). If ordering WGS NIPT, given that there may be significant uncertainty as to the actual phenotypic or functional manifestation of a genetic variation in a particular child, the consent process should include helping to contextualise limitations and risks in the broader context of the human experience of risk and uncertainty. Genuine shared decision‐making models can empower patient autonomy by helping them to understand the implications of their possible decisions in relation to their values.16 Moreover, decision tools and algorithms that align a variety of scenarios with personal values can facilitate a high quality informed consent process. Higher resolution WGS NIPT should only be used for research purposes until we have robust data regarding its clinical utility. Box 1 – Non‐invasive prenatal testing (NIPT) options: current availability and main advantages and disadvantages CPM = confined placental mosaicism; PPV = positive predictive value; WGS = whole genome sequencing. Box 2 – Synthesis of screening criteria12 The screening program should respond to a recognised need. The objectives of screening should be defined at the outset. There should be a defined target population. There should be scientific evidence of screening program effectiveness. The program should integrate education, testing, clinical services and program management. There should be quality assurance, with mechanisms to minimise potential risks of screening. The program should ensure informed choice, confidentiality and respect for autonomy. The program should promote equity and access to screening for the entire target population. Program evaluation should be planned from the outset. The overall benefits of screening should outweigh the harm.

Joseph Thomas · James Harraway · David Kirchhoffer

Although VTE risk in minor gynaecological procedures is low, a systematic approach to prophylaxis is necessary

Esther MC Johns · Alex Ades · Pavitra Nanayakkara

There is more to female sexual function than circulating testosterone, and symptomatic women require a thorough clinical evaluation The 2019 global consensus position statement on the use of testosterone therapy for women1 aims to provide guidance for clinicians managing women with female sexual dysfunction. The recommendations, graded according to levels of evidence, have been developed by an international taskforce with representatives from a range of organisations and societies, headed by Australian endocrinologist Professor Susan Davis, the current President of the International Menopause Society. The position statement bases many of its recommendations on a systematic review and meta‐analysis of randomised controlled trials.2 The meta‐analysis includes data from 36 randomised controlled trials with 8480 participants and includes studies with a testosterone treatment duration of at least 12 weeks. The primary outcome indicates an improvement in satisfying sexual events, measured as a mean increase of one event over 4 weeks with the use of testosterone. There were also improvements in other parameters associated with sexual function, including sexual desire, arousal and self‐image. There were no cognitive, psychological, wellbeing or musculoskeletal (including bone mineral density) benefits. In doses that approximate physiological levels, the main adverse effects of testosterone therapy are significant increases in acne and hair growth but no difference in alopecia, clitoromegaly or voice change. The position statement provides recommendations covering the assessment of women with female sexual dysfunction, laboratory measurement of testosterone, indications for treatment, and ongoing monitoring once treatment is commenced. It emphasises that the only evidence‐based indication for the use of testosterone in women is the treatment of post‐menopausal women who have been diagnosed with hypoactive sexual dysfunction disorder (HSDD) after formal biopsychosocial assessment. Doses that approximate physiological testosterone concentrations in pre‐menopausal women are recommended. At these doses, testosterone therapy is not associated with serious adverse events. Notably there are no safety data for beyond 24 months of treatment. There are insufficient data regarding the use of testosterone therapy in pre‐menopausal women. The position statement does not comment regarding women with premature ovarian insufficiency and recommends caution in women with a breast cancer diagnosis, reflecting the lack of data.3,4 The classification of female sexual disorders has been a source of controversy and debate. In the Diagnostic and Statistical Manual of Mental Health Disorders, 5th Edition, HSDD and female sexual arousal disorder (FSAD) have been amalgamated and classified as a single entity: female sexual interest/arousal disorder. The writing group for the position statement regards HSDD and FSAD to be distinct conditions, a view shared by experts in the field.5,6 Diagnostic criteria for both conditions are outlined in Box 1.7 It is important to understand this clinical distinction as the position statement does not consider FSAD to be an indication for testosterone therapy. Serum testosterone levels decline during the reproductive years and are significantly reduced in women post‐oophorectomy.8 There was no reported correlation between androgen levels and reported sexual function in one study,9 and there is no serum testosterone cut‐off below which women are more likely to experience HSDD. The authors of the position statement comment that the relationship between endogenous androgen concentrations and sexual function remains uncertain because of issues related to androgen assays in some studies. Notwithstanding these factors, it is recommended that a baseline measurement of testosterone be taken to avoid overtreatment.1 Serum total testosterone rather than free testosterone is the recommended biomarker. The significance of free testosterone in the context of female sexual dysfunction has not been evaluated. Most commercial assays in Australia use immunoassays to measure testosterone, while free testosterone and free androgen index are calculated from total testosterone and sex hormone‐binding globulin. However, immunoassays are considered unreliable, particularly for low levels in the female reference range. Liquid and gas chromatography and mass spectrometry, while not yet in common use, are considered far more accurate and efforts are being made to increase availability.10 The position statement does not comment on whether menopausal hormone therapy should be used concurrently with testosterone therapy. However, a biopsychosocial model of treatment of female sexual dysfunction is recommended, which may include menopausal hormone therapy. Multiple studies have looked at the effect of oestrogen therapy alone, testosterone alone and a combination of the two on female sexual function, with variable outcomes. One of the main criticisms of studies demonstrating no improvement with oestrogen (alone or combined with testosterone) is that low therapeutic doses of oestrogen were used and circulating oestradiol levels were either not measured or were low and did not reach pre‐ovulatory levels consistent with those seen in pre‐menopausal women.11 Only one of eight studies included in the meta‐analysis did not include concomitant menopausal hormone therapy.2 Systemic oestrogen therapy is known to improve hot flushes, urogenital symptoms and mood disturbance, while topical vaginal oestrogen is effective in managing vulvovaginal atrophy.12 Both improve wellbeing in menopausal women and may enhance libido such that other therapies are not required,13 although an improvement in absolute terms has not been described. Our view is that menopausal hormone therapy with oestrogen with or without progestogen should be considered initially in all post‐menopausal women who present with low libido before the initiation of testosterone. A significant issue is the clinical meaningfulness of the finding of a mean increase of one satisfying sexual event per month. Many will argue that such an outcome does not justify the use of testosterone therapy in clinical practice. In context, however, the meaningfulness will depend on the individual woman. For example, for a woman experiencing no satisfying sexual events, an extra one per month would equate to twelve extra events per year and could represent a significant improvement in her quality of life. Consumer involvement in the development of the position statement may have provided insight into this question. In the meta‐analysis, testosterone therapy compared with placebo was found to reduce personal distress, a key component of HSDD, in all studies of post‐menopausal women. Perhaps more relevant to the discussion is whether a satisfying sexual event is adequate as the primary measure of efficacy for treatment. The authors address this in the final part of the position statement. Appropriately, recommendations are made for the design of future clinical trials, including the development of a validated instrument for the screening and diagnosis of HSDD that can also be used as a marker of efficacy of treatment. Australian perspective Sexual dysfunction is common among Australian women. The prevalence of low sexual desire and HSDD was 69.3% and 32.2%, respectively, among a sample of community‐based women aged 40–65 years in one study.14 In older women, the prevalence of HSDD was reported to be one in seven women in a population of women aged 65–79 years living in the community.15 The use of testosterone for therapeutic purposes in women has been controversial. Despite this, clinicians in many countries including Australia have been prescribing testosterone off‐label primarily for low sexual desire in women for several years.16 Various formulations have been used, including subcutaneous pellets, transdermal gels and intramuscular injections that are designed for men, with dosing then adjusted for the female population. In this setting, there is greater potential for treatment to result in supraphysiological testosterone levels. The position statement suggests that ‘‘where approved female preparations are unavailable, off‐label prescribing of an approved male formulation is reasonable”.1 Bio‐identical and compounded products are not recommended. In Australia, a 1% transdermal testosterone cream is available, designed specifically for women and indicated for symptoms caused by testosterone deficiency. Although the product is unlicensed in Australia, it has been available on prescription from pharmacies within Western Australia since 1999 due to an exemption under section 6 of the Therapeutic Goods Act 1989 (Cth). Women prescribed this treatment in other states are required to access it by mail order along with a prescription from their clinician. It was submitted for Therapeutic Goods Administration evaluation and inclusion on the Australian Register of Therapeutic Goods as a registered product in 2019 for the proposed indication of treatment of hypoactive sexual desire dysfunction in post‐menopausal women, and a response is expected by the end of 2020 (Michael Buckley, Medical Director, Lawley Pharmaceuticals, personal communications). Although limited by small sample sizes, pharmacokinetic and clinical studies of the recommended 5–10 mg daily dose of this cream demonstrated total and free testosterone levels within or above the pre‐menopausal range.17,18,19 Its availability in Australia overcomes the need to consider male preparations or compounded and bio‐identical products. The publication of the position statement will increase awareness of female sexual dysfunction in the medical community. Clinicians managing these patients will require education in practical terms about assessing such patients for HSDD and safely prescribing and monitoring testosterone therapy when indicated. Based on the authors’ expertise and experience, we propose an algorithm for the assessment of women presenting with female sexual dysfunction and use of testosterone (Box 2), with women initially undergoing a biopsychosocial assessment.6 We recommend information sheets for clinicians and patients written by local experts be made available on the websites of the Australasian Menopause Society, the Endocrine Society of Australia and the Royal Australian and New Zealand College of Obstetricians and Gynaecologists. Conclusion The position statement is a timely addition to the literature regarding testosterone therapy for women. What is clear is that there is more to female sexual function than circulating testosterone and that symptomatic women require a thorough clinical evaluation, assessing for other factors which may be contributing to their presentation. Testosterone therapy is a small piece of the puzzle in the management of female sexual dysfunction. This position statement provides clarification regarding the indication, adverse effects and knowledge gaps. The availability in Australia of a transdermal testosterone preparation designed for women obviates the need to use male preparations, but further research regarding efficacy and safety is necessary. Future studies should address the safety of long term use of testosterone in women, particularly with respect to cardiovascular disease and breast cancer. Box 1 – Definition of hypoactive sexual desire disorder and female sexual arousal disorder7 Disorder Definition Hypoactive sexual desire disorder Any of the following for a minimum of 6 months: lack of motivation for sexual activity as manifest by reduced or absent spontaneous desire (sexual thoughts or fantasies); or reduced or absent responsive desire to erotic cues and stimulation or inability to maintain desire or interest through sexual activity loss of desire to initiate or participate in sexual activity, including behavioural responses such as avoidance of situations that could lead to sexual activity that is not secondary to sexual pain disorder AND is combined with clinically significant personal distress that includes frustration, grief, guilt, incompetence, loss, sadness, sorrow or worry Female sexual arousal disorder* Female cognitive arousal disorder Distressing difficulty or inability to attain or maintain adequate mental excitement associated with sexual activity as manifest by problems with feeling engaged, or mentally turned on or sexually aroused for a minimum of 6 months Female genital arousal disorder Distressing difficulty or inability to attain or maintain adequate genital response associated with sexual activity for a minimum of 6 months, including: vulvovaginal lubrication engorgement of the genitalia sensitivity of the genitalia associated with sexual activity Disorders related to: vascular injury or dysfunction, or neurological injury or dysfunction * Encompasses female cognitive arousal disorder and female genital arousal disorder Box 2 – Testosterone therapy for post‐menopausal women: proposed algorithm CNS = central nervous system; CVD = cardiovascular disease; HSDD = hypoactive sexual desire disorder; IMS = International Menopause Society; VTE = venous thromboembolism. * Simon et al.6 † Jane and Davis.20

Christina Jang · Jacqueline A Boyle · Amanda Vincent

A recently developed national transport and cryopreservation service improves equity of access to fertility care for young people across Australia Loss of fertility, which is a well recognised complication of cancer treatment, has a significant impact on quality of life and is ranked as one of the top survivorship concerns.1 Improvements in survival (> 88% for adolescents and young adults) and expansion of fertility preserving options have stimulated rapid evolution of the fertility preservation landscape, aiming to decrease this devastating impact of cancer therapy.2 In addition to the gonadotoxic burden of cancer treatment, societal trends of delayed fertility mean that there are many young people who have not yet completed or even commenced trying for a family when diagnosed with a life‐threatening illness. Fertility discussion, and provision of services to preserve gametes or tissue, is no longer seen as a distraction or a luxury but is acknowledged as a mandatory part of cancer management.3 However, barriers to provision of fertility preservation care remain. These include the lack of education of health care providers about both the long term fertility consequences of cancer treatment and the clinical value of available options. There is also often a lack of clarity about whose role it is to educate patients about these options. Importantly, there can be significant logistic, geographic and economic barriers for patients, especially outside the major centres, such that only 4–50% of young people take up fertility preservation in a timely fashion.4 Established strategies to preserve fertility for the future include medical therapies to protect the primordial follicle pool, vitrification of oocytes and embryos, and ovarian tissue cryopreservation for females. Mature sperm freezing is undertaken in post‐pubertal males, and testicular tissue cryopreservation, while providing the only opportunity for pre‐pubertal boys, is still considered experimental.3 Gonadal tissue cryopreservation Ovarian tissue cryopreservation is the only option for prepubertal girls and may be the only or best option for women at high risk of infertility from cancer treatment, particularly if there are time constraints or safety concerns with other options. Ovarian tissue cryopreservation is no longer considered experimental by peak bodies,3 and there have been over 140 births worldwide following ovarian tissue grafting, including several in young women whose ovarian tissue was cryopreserved as pre‐pubertal children.5 Testicular tissue cryopreservation provides an experimental option for fertility preservation in pre‐pubertal boys at significant risk of azoospermia from gonadotoxic treatments. As boys do not produce mature sperm that can be frozen, a treatment involving testicular biopsy and cryopreservation of spermatogonial stem cells, followed by transplantation into the testis after treatment, is proposed to allow restoration of fertility.6 Recent publications of in vitro sperm maturation and live birth success using the primate animal model provide optimism, such that the joint international consensus statement of peak fertility bodies in 2015 recommended that testicular tissue cryopreservation should be offered for pre‐pubertal boys,3 despite the currently experimental nature of future use, especially as there are no other options. Testicular biopsy can be safely performed and often coordinated concomitantly with other medically necessary procedures without delaying the start of treatment.7 While cryopreservation of eggs, sperm and embryos is a routine part of assisted reproductive laboratory activity, the technique for cryopreservation of ovarian and testicular tissue is biophysically different, and very few centres nationally and internationally have established tissue cryopreservation laboratories with validated, published protocols and clinical success after thawing.8 Due to distance challenges within Australia and lack of resources to meet the needs of these patients, particularly those who reside in rural and remote areas, ovarian and testicular tissue cryopreservation is not accessible to over 70% of people who would benefit from this opportunity.4 Establishment of the National Ovarian and Testicular Transport and Cryopreservation Service To provide equity of access to fertility care, the Fertility Preservation Service at the Royal Women's Hospital in Melbourne has developed the National Ovarian and Testicular Transport and Cryopreservation Service, allowing collaboration between local units and specialised centres, with professional and patient education as part of the program. There are several successful international models for collaborative care with published protocols and data to support transportation and storage of gonadal tissue or gametes in a specialised centre with expertise, health and safety regulations.9 The live birth rates with and without overnight transportation are comparable.9 The Fertility Preservation Service, a partnership between the Royal Women's Hospital and Melbourne IVF, was established 30 years ago. It is the largest service of its kind in Australia, with clinical expertise in counselling, cryopreservation, testing, storage and transport procedures. It sees about 300 patients per year, managed by a multidisciplinary team of fertility specialists, nurses, research scientists, research managers, laboratory staff, counsellors and administrators. There have been increasing referrals each year, reflecting the increased demand. Eighty percent of these are cancer related, with serious medical conditions and gender dysphoria forming the remainder. The Fertility Preservation Service has built extremely strong relationships with cancer centres, both in Victoria and nationally, and collaborates closely with other fertility preservation units, including the Fertility and Research Centre in NSW and the Royal Children's Hospital Melbourne. It supports data collection for the Australasian Oncofertility Registry.10 Based on a recent Fertility Society of Australia survey,11 we believe that Victoria, possibly because of both the dedicated fertility preservation centre and the well developed collaborative relationships, has the highest rate of patients referred for fertility consultation. The service stores gonadal tissue from over 1000 patients. Ovarian tissue grafting has been performed in 40 patients, with five children born and a live birth rate of 20% per embryo transferred. There are also mature eggs and embryos which have been cryopreserved from ovarian tissue stimulation. Testicular tissue has been cryopreserved for 163 patients. The establishment of a centralised national tissue retrieval and transport program allows gonadal tissue harvesting to take place in a local centre with subsequent transportation to the central laboratory for processing, cryopreservation and storage. Communication with the National Ovarian and Testicular Transport and Cryopreservation Service team occurs via a paging service which is checked daily by a dedicated nurse, with treating clinician and, when appropriate, patient follow‐up by teleconference. Subsequently, ovarian tissue grafting may be performed at the Royal Women's Hospital or the tissue can be transported back to the local centres. The service also provides follow‐up and psychological support for patients, and educational resources to assist with all aspects of fertility preservation, both for patients and health practitioners. Fertility preservation is a mandatory part of cancer care; the National Ovarian and Testicular Transport and Cryopreservation Service program will improve equity of access to fertility preservation for young women and men around Australia.

Genia Rozen · Stephanie Sii · Franca Agresta · Debra Gook · Catharyn Stern

Publicly funded reproductive carrier screening programs must weigh up a number of ethical considerations Reproductive genetic carrier screening (RCS) is undertaken by individuals or couples to determine their likelihood of having a child with particular autosomal recessive or X‐linked genetic conditions. It can be undertaken by anyone of reproductive age who wishes to have it, regardless of their family history or ancestry, and either before or during pregnancy.1 Some forms of RCS are currently available in Australia on a user‐pays basis, costing around $400–$500 per person. It is usually accessed via general practitioners but can also be accessed directly from testing companies.2 People who receive an increased chance result are offered genetic counselling to explore their reproductive options, which might include steps to avoid having a child with a genetic condition. Taking the test before pregnancy gives those with an increased chance result a wider range of reproductive options compared with prenatal testing.3 The Australian Reproductive Genetic Carrier Screening Project (Mackenzie's Mission), announced by federal Health Minister Greg Hunt in 2018, is a research project offering RCS to 10 000 Australian couples. Recruitment via participating health professionals commenced in late 2019. Mackenzie's Mission is gathering evidence — including clinical, laboratory, psychosocial, health economic and ethical aspects — to inform how publicly funded screening could be operationalised in Australia within ten years.4 Here, we reflect on the ethical implications of RCS in Australian health care.5 While the issues raised apply to all types of RCS, we focus on aspects relating to large scale, publicly funded initiatives like Mackenzie's Mission. Ethics and the goals of RCS A central ethical issue for large scale RCS initiatives is how their goals are described. Two main foci for articulating the goals of such programs are (i) outcomes for individuals and their families, such as reproductive autonomy; and (ii) outcomes for populations, such as reduced incidence of certain genetic conditions. It has been argued that a goal of seeking to reduce the population incidence of babies who will develop severe genetic conditions is inappropriate for RCS.6 This line of reasoning draws partly on concerns about perceived coercion; when RCS is offered routinely, couples may perceive that participating is the right thing to do, even if testing is optional.7 Additionally, such a goal might be interpreted as implying that couples who receive an increased chance result are then obliged to take action to avoid the birth of an affected child. Any future national program must be delivered as a genuinely optional intervention, respecting couples’ values and preferences. It has also been argued that the goal of reducing the incidence of certain genetic conditions in the population expresses an unfavourable judgement about the value of the lives of people who currently live with such a condition.8 Therefore, in the case of RCS it is considered more ethically acceptable for a program's stated aim to be aligned with the first set of outcomes mentioned above; namely, to support couples’ reproductive autonomy through provision of relevant information to enable choices that are consistent with their values.1 RCS programs are also motivated, at least in part, by the desire to mitigate harms that couples who have parented a baby or child with a severe or fatal genetic condition experience. These harms include the grief of losing a child or witnessing one's child suffering. RCS might enable some parents to avoid such distressing experiences. Emphasising the severity of a condition included in a screening program arguably lessens any implied negative judgement about people living with genetic conditions screened for. However, ethical debate on what constitutes a severe or serious condition remains ongoing.9 Ethical aspects of gene selection A significant component of designing a publicly funded RCS program is determining which genes warrant inclusion for testing.10 Since screening can be stigmatising for people living with the genetic conditions screened for, it is considered most ethically defensible to screen only for genes associated with severe childhood‐onset conditions.1,3 However, because perceptions surrounding seriousness and severity are not purely objective,9 any RCS program must carefully weigh the diverse ways in which a condition can present, as well as the implications of that condition for the person and their family. There are also ethical aspects regarding the classification of gene variants identified during the testing process.11 There can be a degree of uncertainty as to how strongly a particular variant is associated with a genetic condition, an issue compounded in population screening because there is no index case (proband) to facilitate interpretation. This has ethical implications because reporting a variant as disease‐causing when it is not may mean a couple will experience additional uncertainty and perhaps go through unnecessary tests or interventions. On the other hand, not reporting a variant that does turn out to be disease‐causing means a couple may go on to have a child with a serious condition despite receiving a low chance result from RCS. This issue will remain important for some time, especially as variant databases are still developing. Consent for RCS: enabling meaningful choices Whether and how to gain consent can be contentious in many public health screening programs.12 While both consent and pre‐test education are important for RCS,1 determining how best to do this can be complex. It has been argued that when screening is perceived as routine, people will be less likely to reflect critically on whether it is appropriate for them, or to consider whether the results will be relevant to their decision making.7 Support for pre‐test decision making such as educational videos and decision aids can help couples consider the implications of an increased chance result and their options for reproduction. Mackenzie's Mission is one of several large scale population‐based RCS initiatives globally that have curated large panels of genes to test using a couple‐based model.5,10,13 It is important for participants to understand that RCS is designed to provide the couple with information that might help with decisions about reproduction, rather than to convey genetic risk information for their own health. Participants will also be encouraged and supported to reflect on their values and their goals for testing, to help them decide whether this screening will be useful or important for them.14 Reporting results: ethical implications Results of any genetic test can be complex and might be uncertain.15 As such, results from RCS need to be provided in a way that is meaningful and useful. To optimise the utility of their results, participants will require a basic understanding of key concepts such as what it means to carry a recessive genetic condition, and the implications of an increased chance finding. It is also important to ensure that participating in screening is not interpreted as guaranteeing that someone will have a healthy child. Publicly funded population RCS globally is tending towards reporting couple‐based findings. Evidence suggests that participants understand and accept this approach and that it is feasible as a population screening model.5,13,16 Mackenzie's Mission participants will be informed when they both carry the same disease‐causing variant for an autosomal recessive condition, or when the genetic mother is found to carry one of the X‐linked conditions screened for. Reporting only couple‐based findings is justifiable from an implementation perspective, for both programmatic and pragmatic reasons. Programmatically, RCS aims to inform reproductive choices, so it provides couples with information relevant to those choices. Any potential for false reassurance can be carefully addressed during the pre‐ and post‐test education processes. Pragmatically, publicly funded RCS would be prohibitively expensive to offer if it reported individual carrier results, as the majority of individuals screened are likely to be a carrier for something.16 Each of these people would then need individual follow‐up, despite their future offspring having a very low chance of actually having that autosomal recessive condition, even if they were to re‐partner.17 Moreover, this information has no clinical utility for the individual's own health. It also has the potential to provoke anxiety. As such, it is premature and potentially inequitable to provide individuals with information relating to their individual carrier status without providing further support. Further research will inform considerations of the ethical and psychosocial aspects of using an RCS framework to report individual results, including the possibility of offering individual results for a limited number of the more prevalent conditions on the panel. Public funding How RCS is funded is also ethically relevant, not least due to the perceived endorsement of screening by the state when a program is publicly funded. A formal, publicly funded, screening program may have advantages,18 but public funding might also carry tacit value implications. Experience with antenatal screening suggests that blame and guilt can be associated with declining an offer of screening.19 Funding models can also reinforce routinisation, where a screening offer might be perceived as encouraging or even coercing couples to terminate a pregnancy if a genetic condition is identified in the fetus.7 Within public funding structures, ethical issues also arise from the mode of offer of RCS, either in the context of a formal population screening program (likely to be delivered by centralised, publicly funded entities) or via a Medicare item number. Provision via Medicare will allow any provider who can meet the item number requirements to offer the test, and as such is likely to attract a greater commercial presence in RCS. The resulting fragmentation might constitute a lost opportunity for uniform evaluation of program effectiveness and might also give rise to inconsistencies in aspects of test provision, such as counselling. On the other hand, provision through Medicare may also enable RCS to be rolled out more quickly than establishing a formal population screening program. Cost‐effectiveness of population‐wide RCS has not yet been established conclusively by the existing evidence;11 however, one of the aims of Mackenzie's Mission is to generate such evidence for the Australian health care system. RCS and community values Underlying these ethical considerations is the question of how RCS reflects societal values. While most people are likely to agree on core principles such as respecting couples’ choices about whether to participate in screening, there will also be variations in preferences between communities, families and individuals.20 Future delivery of a national RCS program in Australia will need to recognise and respond to this diversity, while also upholding the values that motivate the program. The central values for RCS in Australia are good health outcomes for families and communities, alongside respect for all Australians, equity in program design and delivery, and reproductive autonomy.

Lisa Dive · Ainsley J Newson

To the Editor: In Australia, gestational diabetes mellitus is diagnosed by 75 g oral glucose tolerance test (OGTT). The diagnostic criteria are fasting plasma glucose (FPG) ≥ 5.1 mmol/L, one‐hour glucose level ≥ 10.0 mmol/L, and/or 2‐hour glucose level ≥ 8.5 mmol/L.1,2 International consensus favours OGTT over single measures of glucose because, in the pivotal Hyperglycaemia and Adverse Pregnancy Outcome (HAPO) study, hyperglycaemia at each time point was independently associated with adverse outcomes, individual measures were not well correlated with one another, and no single measure was clearly superior in predicting adverse outcomes, such as birthweight above the 90th percentile, shoulder dystocia and pre‐eclampsia.2,3 To reduce contact time at pathology collection centres during the coronavirus disease 2019 (COVID‐19) pandemic, measurement of FPG alone has been advocated.4,5 One guideline advised that a result below 4.7 mmol/L may not merit a follow‐up OGTT.4 Another advised diagnosing gestational diabetes mellitus by stand‐alone FPG greater than 5.1 mmol/L.5 To determine the proportion and characteristics of gestational diabetes mellitus cases that would be missed by using alternative criteria, we extracted the results of all obstetrician‐referred OGTTs performed by our private community‐based laboratory between January 2017 and April 2020. The analysis, including determination of Wilson score confidence intervals (CIs), was performed with SAS 9.4 (SAS Institute). Of 16 169 patients, 1790 (11.1%) were diagnosed with gestational diabetes mellitus by OGTT. A rule‐out threshold of FPG below 5.1 mmol/L would have resulted in 1202 cases (67%; 95% CI, 65–69%) being missed, and a threshold below 4.7 mmol/L would have resulted in 831 cases (46%; 95% CI, 44–49%) being missed (Box). Women with gestational diabetes mellitus and normal fasting glucose did not have significantly lower one‐ or 2‐hour concentrations than those with increased fasting glucose (data not shown). Missing the diagnosis of gestational diabetes mellitus exposes women and their newborns to significant risks, including birth weight above the 90th percentile, primary caesarean delivery, neonatal hypoglycaemia, premature delivery, shoulder dystocia or birth injury, intensive neonatal care, hyperbilirubinaemia and pre‐eclampsia. Use of fasting glucose to screen for gestational diabetes mellitus would miss a large proportion of cases, with the potential for significant harm to mothers and their offspring. Clinicians must recognise the substantial limitations of stand‐alone FPG so that pregnant women can be adequately counselled and, if opting out of OGTT, considered for careful monitoring for consequences of undiagnosed gestational diabetes mellitus, such as accelerated growth or polyhydramnios. In regions without significant community spread of COVID‐19, modifying sample collection procedures to ensure strict physical distancing and having dedicated collection centres for vulnerable populations may be better than using deficient diagnostic criteria. Box – Distribution of fasting glucose results at 24–28 weeks’ gestation in patients with (n = 1790) and without (n = 14 379) gestational diabetes mellitus* (GDM) The vertical grey lines denote thresholds below which new guidelines propose that oral glucose tolerance testing is not required during the coronavirus disease 2019 (COVID‐19) pandemic. * Diagnosed using oral glucose tolerance test.

Ranita Siru · Johan H Conradie · Melissa J Gillett · Emily Gianatti · Michael M Page

Objective: To synthesise what is known about women combining motherhood and a career in medicine by examining the published research into their experiences and perspectives. Study design: We reviewed peer‐reviewed articles published or available in English reporting original research into motherhood and medicine and published during 2008–2019. Two researchers screened each abstract and independently reviewed full text articles. Study quality was assessed. Data sources: CINAHL, MEDLINE, PsycINFO, Web of Science, and Scopus abstract databases. Data synthesis: The database search identified 4200 articles; after screening and full text assessment, we undertook an integrative review synthesis of the 35 articles that met our inclusion criteria. Conclusions: Three core themes were identified: Motherhood: the impact of being a doctor on raising children; Medicine: the impact of being a mother on a medical career; and Combining motherhood and medicine: strategies and policies. Several structural and attitudinal barriers to women pursuing both medical careers and motherhood were identified. It was often reported that women prioritise career advancement by delaying starting a family, and that female doctors believed that career progression would be slowed by motherhood. Few evaluations of policies for supporting pregnant doctors, providing maternity leave, and assisting their return to work after giving birth have been published. We did not find any relevant studies undertaken in Australia or New Zealand, nor any studies with a focus on community‐based medicine or intervention studies. Prospective investigations and rigorous evaluations of policies and support mechanisms in different medical specialties would be appropriate. Protocol registration: PROSPERO CRD42019116228.

Rebekah Hoffman · Judy Mullan · Marisa Nguyen · Andrew D Bonney

To the Editor: A recent article highlighted a case where self‐collection enabled detection of an early cervical adenocarcinoma and curative treatment in a previously underscreened woman.1 This case underlines the important benefits from self‐collection making cervical screening more accessible and acceptable to women who have previously declined or delayed screening. Unfortunately, self‐collection is currently very underutilised in Australia. Although it is currently restricted to women aged 30 years and over who are 2 or more years overdue for cervical screening, potentially around a million women are eligible.2 In contrast, data from Medicare, VCS Pathology, and the National Cancer Screening Register suggest that fewer than 6000 self‐collected tests were processed over 2018 and 2019, indicating that less than 1% of eligible women have had a self‐collected test. What drives this discrepancy? Self‐collection is highly acceptable to underscreened Australian women, and very high uptake can be achieved with appropriate clinical support.3 A recent survey reported that many practitioners, especially outside Victoria, do not yet feel comfortable discussing or recommending self‐collection, and lack confidence that self‐collection is a reliable test.4 Potentially, this is due to an initial delay in self‐collection being available, confusion about eligibility, and current restrictions giving the false impression that self‐collection is less sensitive. Self‐collection is now available to eligible women nationally (provided samples are sent to one of two accredited laboratories, which accept samples from anywhere in Australia), and updated evidence demonstrates that polymerase chain reaction‐based human papillomavirus (HPV) testing is equally sensitive for detecting pre‐cancer in self‐collected and clinician‐collected samples.5 Another barrier may be difficulties for providers in checking whether women are eligible. The rollout of the provider portal into the National Cancer Screening Register, allowing providers to view a woman's screening history at the point of care, will be important in addressing this issue. Many screening‐eligible women who have not had their first HPV test are now overdue and could be eligible for self‐collection. Self‐collection is a reliable test now available nationally to eligible women, which can have a transformative effect in the lives of underscreened women, as shown in the recent case study.

Megan Smith · Marion Saville · Karen Canfell

Our new birthweight charts may facilitate more accurate diagnosis and improve care for small-for-gestational age babies

Farmey A Joseph · Jonathan A Hyett · Philip J Schluter · Andrew McLennan · Adrienne Gordon · Georgina M Chambers · Lisa Hilder · Stephanie KY Choi · Bradley Vries

To the Editor: Gestational diabetes mellitus (GDM) is being diagnosed with increasing frequency in Australia, with the greatest prevalence reported in South Asian women.1,2 South Asian women, comprising Indians, Sri Lankans, Bangladeshis, Afghanis and Pakistanis, are more likely to have GDM and develop type 2 diabetes than Caucasian women.1,2 Data from the landmark Mothers after Gestational Diabetes in Australia trial show that about 40% of the 573 women recruited into the trial were from an Asian background.2 Retention rates for the intervention and usual care groups were 73% and 79%, respectively.2 The Royal Australian College of General Practitioners3 and the Australasian Diabetes in Pregnancy Society4 recommend oral glucose tolerance testing 6–12 weeks post partum for women who experienced a GDM‐complicated pregnancy. Repeat testing should be performed every 1–2 years among women with normal glucose tolerance and the potential for further pregnancies. If further pregnancy is not possible, follow‐up testing should be performed every 3 years, with more frequent retesting depending on clinical circumstances.5 Although studies have been conducted to evaluate the implementation of post partum guidelines generally in women with a history of GDM,6 there is no information about the implementation and uptake of guidelines in high risk ethnic populations. Additionally, there is evidence to suggest that culturally specific GDM follow‐up care would increase adherence to diet and lifestyle modifications during the interconception period in high risk ethnic women.7 Therefore, as a high risk group for progression to type 2 diabetes following GDM, South Asian women in Australia should be targeted for testing, and culturally appropriate lifestyle interventions, before conception. General practitioners have a critical role in the post partum, interconception and pre‐pregnancy care of women with previous GDM. This is even more pronounced in high risk populations such as South Asians. More culturally appropriate resources are therefore required to assist with recommended lifestyle modifications to reduce risks for future development of GDM or type 2 diabetes. There is an urgent need for qualitative research to focus on identifying the barriers and enablers to the implementation of the Royal Australian College of General Practitioners guidelines for the management of GDM, with a particular focus on GDM interconception care for South Asian women. Findings may be used to inform the development phase of an intervention aimed at improving the implementation and uptake of GDM guidelines among high risk populations in Australian general practice.

Asvini K Subasinghe · Alison J Nankervis · Jacqueline A Boyle · Danielle Mazza

Caution is needed so that population‐level reductions in the stillbirth rate are not offset by iatrogenic harm to healthy babies The federal Minister for Health the Honourable Greg Hunt MP recently launched the Safer Baby Bundle — a national stillbirth program that aims to reduce stillbirth in Australia by 20% by 2023.1 The program is one of the responses to recommendations arising from the federal Senate's Select Committee on Stillbirth Research and Education.2 It draws from similar bundles of care in the United Kingdom that have been associated with successful reductions in stillbirth.3,4 Undoubtedly, these whole‐of‐population level programs are important and effective. However, because late pregnancy stillbirth can be prevented simply by delivering all babies early, they have the potential for harm. There are five components of the Safer Baby Bundle: supporting women to stop smoking in pregnancy; improving awareness of a safe maternal sleeping position; improving decision making about timing of birth; improving the detection and management of fetal growth restriction (FGR); and raising awareness and improving care for women with decreased fetal movements (DFM). Of these five components, the latter two have the potential to increase early delivery. FGR is the strongest contributor to the burden of stillbirth. If detected and managed, the risk of stillbirth is 20‐fold lower than if FGR remains undetected.5 Improving the detection of FGR is central to any program aiming to reduce stillbirth. But increasing FGR detection may also cause harm. In a French population, half of the babies suspected of FGR antenatally had normal growth.6 In Victoria, a greater focus on improving the detection of FGR quadrupled the number of babies delivered early for suspected FGR, from 741 in 2000 to 2996 in 2017.5 The number and proportion of these babies with a birthweight in the 10th centile or greater increased from 307 (41%) to 1597 (53%).5 Striving to increase the sensitivity of FGR detection decreased specificity. This is a problem because unwarranted early delivery is harmful to both immediate perinatal5,6 and longer term developmental outcomes.7 Similar risks exist for increasing awareness of DFM. It has long been recognised that there is a relationship between DFM and stillbirth. Women who report DFM have a 2.4‐fold increased risk of stillbirth.8 However, translating this into an effective intervention has been challenging. Thirty years ago, it was shown that the use of formal fetal movement counting charts failed to reduce stillbirth.9 More recently, a large randomised controlled trial — the AFFIRM trial — assessed a care package for women presenting with DFM. In over 400 000 women attending 33 health services in the UK, increasing the awareness of DFM and standardising the care of those women presenting with DFM did not significantly reduce stillbirth.10 Moreover, there was evidence of harm to both mother and baby. Despite clear guidance for clinicians about what investigations to offer women with DFM and under what circumstances delivery was merited,11 there was an increase in the rates of induction of labour and caesarean delivery,10 with an additional 500 babies born between 32 and 34 weeks’ gestation and 5000 more born between 34 and 37 weeks’ gestation. The number of babies requiring admission to a neonatal unit also increased.10 The fact that most women with DFM will go on to give birth to a healthy baby suggests that the care package assessed by AFFIRM needs to be better targeted to women at risk. So what lessons can be drawn from these experiences for the Australian Safer Baby Bundle? Foremost, it is to be aware of the potential harm of any intervention and to look for this harm. This is possible with the use of balance performance measures12 —essentially, measures of unnecessary early delivery such as the proportion of babies delivered for suspected FGR but who were normally grown, or the number of neonatal unit admissions of term babies. Stillbirth programs elsewhere did not embed balance measures as part of their planned evaluation. Benefiting from the lessons learned by others, the Australian Safer Baby Bundle will include these measures to ensure that strategies designed to reduce stillbirth are targeted towards babies who are at most risk.1 The ultimate goal of balance measures is to reduce the unintended harm of our interventions. At present, no strategy has been shown to increase the sensitivity of FGR detection without causing harm. Neither is there a reliable tool to differentiate patterns of fetal movement that correspond to adverse outcome from those that are just a normal event. It is likely that more discriminatory screening tools reside in improved use of ultrasonography and biomarkers that assess fetoplacental function13 or in a better understanding of circadian patterns of fetal movements.14 Until then, caution is needed so that population‐level reductions in the stillbirth rate are not offset by iatrogenic harm to healthy babies. It is crucial that the potential for unintended harm is made explicit and that measures of unnecessary early delivery are used to monitor progress of the Safer Baby Bundle implementation in Australia.

Roshan Selvaratnam · Mary‐Ann Davey · Euan M Wallace

The negative impact of cannabis use by pregnant women is independent of tobacco use

Luke E Grzeskowiak · Jessica A Grieger · Prabha Andraweera · Emma J Knight · Shalem Leemaqz · Lucilla Poston · Lesley McCowan · Louise Kenny · Jenny Myers · James J Walker · Gustaaf A Dekker · Claire T Roberts

Iron deficiency anaemia, which affects 14–22% of women of reproductive age,1 has adverse effects on pregnant women and their infants. Oral iron supplementation is the first‐line treatment, but intravenous iron therapy is sometimes preferred because of gastrointestinal effects, low patient adherence, and the delayed effect of oral iron therapy. Further, guidelines now recommend intravenous iron therapy in certain situations,2 and more rapidly infusible intravenous iron preparations have recently become available in Australia. We investigated the use of intravenous iron by women of reproductive age, analysing dispensing data for a 10% random sample of Australians eligible to receive subsidised medicines under the Pharmaceutical Benefits Scheme (PBS).3 We included data for all women aged 18–44 years with a dispensing claim for intravenous iron during January 2013 to December 2017. Three preparations were available: iron polymaltose and iron sucrose during 2013–2017, and ferric carboxymaltose from June 2014. We calculated the annual number and rate of intravenous iron dispensing claims and iron preparation types by age group, using Australian Bureau of Statistics 2017 population data,4 and estimated overall dispensing rates by extrapolating these numbers to the national level (Supporting Information). The study was approved by the New South Wales Population and Health Services Research Ethics Committee (reference, 2013/11/494) and the federal Department of Human Services External Request Evaluation Committee. An estimated 259 700 intravenous iron dispensing claims were made for 190 490 women of reproductive age during 2013–2017; the annual number of dispensing claims increased from 17 920 in 2013 to 97 040 in 2017, and the annual rate of intravenous iron dispensing rose from 0.4 per 100 women in 2013 to 2.1 claims per 100 women in 2017 (Box). By iron type, 187 800 dispensing claims were for ferric carboxymaltose (72.3%), 71 110 for iron polymaltose (27.4%), and 790 for iron sucrose (0.3%). Most preparations were prescribed by general practitioners (111 870 claims, 43%), specialists (54 640 claims, 21%), and other medical practitioners (50 868 claims, 20%). The number of dispensing claims increased with age (18–24 years, 1.6 per 100 women; 35–44 years, 2.5 per 100 women). In 2017, intravenous iron was dispensed to one in fifty Australian women of reproductive age, five times the proportion in 2013; in 2017, 90% of these women received ferric carboxymaltose. The optimal rate of intravenous iron treatment is unknown, and there are no comparable overseas data. As possible adverse outcomes include permanent skin staining and the risk (albeit rare) of potentially fatal anaphylaxis,5 intravenous iron should be administered in settings where allergic reactions can be treated promptly, but whether this is generally the case is not known. Intravenous iron therapy for women of reproductive age also has considerable financial implications: based on average PBS prices,6 its total annual cost increased 35‐fold, from $0.75 million in 2013 to $26.9 million in 2017. However, we have probably underestimated the use of intravenous iron therapy, as we included only PBS‐subsidised dispensing, which may not include preparations administered to public hospital inpatients. The reasons for the rise in the use of intravenous iron are unclear, but may include increased awareness of patient blood management guidelines, the ease of treatment, and the perception that its side effect profile is more favourable than for oral iron therapy. The rapid growth raises concerns about whether it is being employed appropriately and cost‐effectively, given the potential harms and the lack of strong evidence for its value for improving quality of life and reproductive health outcomes. Box – Pharmaceutical Benefits Scheme dispensing claims for intravenous iron preparations for women aged 18–44 years, Australia, 2013–2017 *The small numbers of dispensing claims for iron sucrose are not separately depicted, but were included when calculating the rates of dispensing.

Antonia W Shand · Jane Bell · Amanda Henry · Luke E Grzeskowiak · Giselle Kidson‐Gerber · Sallie Pearson · Natasha Nassar

In 2014, we reported in the MJA our findings, based on linked data for cervical screening and human papillomavirus (HPV) vaccination of women in Victoria, that participation of young women in cervical screening during 2010 and 2011 was significantly lower among HPV‐vaccinated than among unvaccinated women.1 In 2018, we had the opportunity to repeat the study at the national level as part of a broader data linkage study of cancer outcomes and screening behaviour across the three national cancer screening programs in Australia.2 In the original study (2014), the Australian Institute of Health and Welfare (AIHW) data linkage unit applied probabilistic name‐based linkage to HPV vaccination and cervical screening data. We acknowledged it was likely that some screened women who were vaccinated would be incorrectly identified as unvaccinated because many young women would have changed their names and addresses between vaccination and cervical screening. In the more recent study (2018), the AIHW again used probabilistic name‐based linkage, but first updated HPV vaccination and cervical screening data by obtaining histories of name and address changes from the Medicare Enrolment File. Medicare registrants’ details are updated when new data are provided to Medicare, the national health care scheme, and are recorded in new records with dates of change. The Australian Department of Human Services agreed to provide these data to the AIHW for data linkage purposes for our 2018 study. Our investigation was approved by the AIHW Ethics Committee (reference, EO 2014‐4‐130) and by state and territory human research ethics committees. After incorporating Medicare data, annual cervical screening rates for Victorian women aged 20–24 years or 25–29 years were higher during 2010 and 2011 for vaccinated than unvaccinated women,2 contrary to our 2014 findings.1 For 20–24‐year‐old Victorian women, the difference in rate changed from 10.1% lower to 14.7% higher for vaccinated women, and for 25–29‐year‐old women from 13.5% lower to 10.0% higher (Box). Our updated findings are consistent with findings from other countries of higher cervical screening participation among women who have been vaccinated against HPV.3,4,5 Incorporating the Medicare Enrolment File into the 2018 linkage was a test of proof of concept. Its successful use in this and similar studies has led to the AIHW data linkage unit granting ethics approval and relevant authorisations for employing the Medicare Enrolment File as a tool for improving the quality of other data linkage studies. The key message of our original study, however, remains unchanged. All women, whether vaccinated against HPV or not, should be encouraged to participate in cervical screening: the HPV vaccine does not protect against all HPV types, and many women in Australia were sexually active before they were vaccinated. While it is as yet unclear whether the association between vaccination and screening will persist for women who were routinely vaccinated at school, it is crucial that we focus on strategies that effectively engage women who do not currently participate in screening. Box – Estimated participation of Victorian women in cervical screening during 2010 and 2011, by HPV vaccination status and age group: 2014 and 2018 data linkage studies HPV = human papillomavirus.

Alison C Budd · Andrew Powierski · Theresa Chau · Marion Saville · Julia ML Brotherton

A 39-year-old woman was referred for colposcopy with a positive human papillomavirus (HPV) type 16 infection result on a self-collected HPV vaginal swab

Monica FG McGauran · Adam Pendlebury

M ost cervical cancers can be prevented with HPV vaccination and screening

Julia ML Brotherton · Alison C Budd · Marion Saville

The change from vaginal births to operative births may entail unforeseen longer term consequences

David A Ellwood

To the Editor: As reported by Rowe and colleagues1 in their retrospective analysis of maternal immunisation, uptake of influenza and acellular pertussis vaccines among pregnant women remains unacceptably low. One contributing factor may be inconsistent messaging. Historically, vaccine manufacturers have included precautions about the lack of data on use in pregnancy in their product information sheets. Such precautions have been shown to lead to vaccination hesitancy and refusal among pregnant women.2,3 In contrast, the current edition of the Australian Immunisation Handbook states: “Pregnant women are routinely recommended to receive influenza vaccine … and pertussis‐containing vaccine”.4 In 2018, the Therapeutic Goods Administration asked its Advisory Committee on Vaccines to provide independent expert advice on the available safety data on influenza vaccination in pregnancy with regards to the pregnancy category of influenza vaccines. The Advisory Committee on Vaccines advised that “adoption of Australian Pregnancy Category A should be considered by sponsors for certain inactivated influenza vaccines”.5 Pregnancy Category A signals to doctors and the public that the vaccine has been used by large numbers of expectant mothers with no evidence of harm to their babies. This is in line with the Australian Immunisation Handbook: “Clinical trial data and observational studies show no increased risk of congenital defects or adverse effects in the fetuses of women who received influenza vaccine during pregnancy”.4 Following the publication of the Advisory Committee on Vaccines statement, two of the four adult influenza vaccines and one of the two acellular pertussis vaccines used to vaccinate pregnant women in Australia have changed their pregnancy category to Category A. These changes show that the Australian regulator is receptive to feedback from the medical community on how to improve immunisation rates. Hopefully, the reclassification of the pregnancy category of these vaccines will translate into increased maternal uptake and better outcomes for Australian mothers and babies.

Heidi Shukralla · Michael Coory

Changes in the modes of twin birth in Victoria, 1983–2015

Yizhen (Amy) Liu · Mary‐Ann Davey · Rilka Lee · Kirsten R Palmer · Euan M Wallace

Australia needs to develop and implement policies to ensure that data are disaggregated, analysed and presented by sex and gender

The Sex and Gender Sensitive Research Call to Action Group

To the Editor: We read with interest the recent publication by Rowe and colleagues.1 The authors reported low influenza vaccine coverage (39%) among pregnant women in Victoria from 2015 to 2017. Individual‐level factors associated with this finding included greater maternal age, primigravidity, early antenatal care and GP‐led antenatal care.1 As the authors accurately concluded, integrating vaccine delivery into antenatal care pathways is important to improve pregnant women's vaccination coverage.1 Our team reported on this previously, with coverage approximating 90% achieved by introducing standing orders for midwives.2 In collaboration with key stakeholders from six Victorian maternity services, a Monash University‐led project funded by Better Care Victoria is currently underway to implement integrated vaccination strategies and measure the cost and magnitude of improvement in maternal immunisation coverage in Victoria,3 the results of which will be available by the end of 2019. One of the key findings in the article by Rowe and colleagues1 is higher odds of influenza vaccination in women who gave birth after 37 weeks' gestation compared with women who gave birth before 28 weeks (adjusted odds ratio [aOR], 4.74; 95% CI, 3.54–6.35). A similar finding was reported for women who gave birth between 28 and 36 weeks gestation (aOR, 4.13; 95% CI, 3.07–5.56).1 This finding has two important implications. Firstly, it may indicate a potential beneficial effect of influenza vaccine received by pregnant women in reducing pre‐term birth (< 37 weeks' gestation). This is consistent with a recent systematic review and meta‐analysis that reported inactivated influenza vaccine to have a protective effect against pre‐term birth and low birth weight.4 Secondly, this finding may serve as an opportunity to emphasise the safety and benefits of influenza vaccines on perinatal outcomes. As the authors alluded to in their discussion, pregnant women tend to view influenza as primarily a health risk for themselves rather than for their infants.1 Given the importance of health care providers' recommendations in encouraging influenza vaccination among pregnant women, timely dissemination of the potential benefit in lowering the chance of pre‐term birth could further empower health care providers to recommend influenza vaccines to pregnant women.5

Khai Lin Kong · Michelle L Giles · Euan M Wallace

To the Editor: I thank Whitfield and colleagues for their article about hyperemesis gravidarum and abnormal liver function in pregnancy.1 In a 15‐month prospective study in South West Wales, abnormalities of liver function were present in 3% of pregnancies.2 In managing pregnant women with hepatic dysfunction, it is important to consider uncommon causes of liver disease that may be associated with serious maternal and fetal morbidity and mortality if untreated. Addison disease is a rare but potentially life‐threatening condition that may imitate hyperemesis gravidarum in presenting with vomiting, weight loss, postural hypotension and hyponatraemia.3,4 Addison disease has also been associated with elevated hepatic transaminases in 16 published cases, reversing with glucocorticoid replacement.5 In excluding Addison disease, the physiological rise in cortisol during pregnancy must be considered using trimester‐specific reference ranges for short synacthen testing.6 In the pregnant woman with unexplained liver disease and fever, acyclovir should be administered empirically, given the absence of cutaneous vesicles in up to 80% of affected patients and the extreme maternal and fetal mortality associated with untreated herpes simplex virus hepatitis.7 Budd–Chiari syndrome should be considered with abnormal liver function in pregnancy with abdominal pain, hepatomegaly and ascites. Additionally, the use of herbal and over‐the‐counter medications should be sought in pregnant women with abnormal liver function, given the high rates of complementary and alternative medicine use in pregnancy and their potential to cause liver injury.8 Investigations need to be interpreted with regard to gestational physiological changes, as copper, ceruloplasmin, α‐1 antitrypsin and alkaline phosphatase levels rise significantly in pregnancy. Serum lipase levels are commonly elevated in hyperemesis gravidarum — levels up to ten times normal have been reported in the absence of pancreatitis.9 Antithrombin III levels may be useful to distinguish acute fatty liver of pregnancy from pre‐eclampsia with haemolysis, elevated liver enzymes and low platelets.10 Bile acid levels are not specific for intrahepatic cholestasis of pregnancy, being elevated in many hepatic disorders including non‐alcoholic fatty liver disease. Twenty per cent of women with pruritus typical of intrahepatic cholestasis of pregnancy have normal bile acids and liver function at presentation, and symptoms may precede abnormal biochemistry by up to 6 weeks.11 In addition to ondansetron and glucocorticoids, mirtazapine has been effective in the management of hyperemesis gravidarum in case reports.12

Adam Morton

To the Editor: In their article, De Costa and colleagues1 clearly demonstrate the importance of making mifepristone freely available for prescription to all registered Australian medical practitioners, and they emphasise that the current need for special registration discourages general practitioners to become involved in medical abortion provision. We conducted a cross‐sectional study of 39 GPs and 30 primary health care nurses from regional or rural Victoria and identified additional uptake barriers.2 Most study participants showed important gaps in medical abortion knowledge, despite their overall positive stance on abortion and extensive experience with women with unplanned pregnancies, and only a few indicated to be current medical abortion providers. Although nearly all health practitioners indicated they would support a colleague in providing abortions, fewer GPs than nurses were interested in medical abortion training. The main reported uptake barriers to medical abortion provision included a lack of training opportunities as well as the absence of local support services required in Australia for the recommended pre‐abortion ultrasound and for surgical back‐up in the case of complications. Participants additionally worried about the legality of providing abortions, and some indicated that their practices would not allow the provision of this service. Abortion access for Australian women in regional and rural regions is still very restricted. By moving early medical abortion provision into the primary health care setting of underserved regions, and particularly in general practice, this situation can be considerably improved. However, the uptake among GPs remains low.3 In addition to addressing uptake barriers, alternative solutions to improve abortion access in underserved areas should be further explored as well, such as the use of telemedicine (until recently provided by the Tabbot Foundation) and the inclusion of primary health care nurses in the abortion provision process — an evidence‐based practice that is already extensively implemented in a range of high income countries.4,5 A nurse‐led model approach not only addresses the shortage of physicians but also the time‐intensive aspect of the medical abortion process, and it provides women with choice and flexibility, which is indispensable to their reproductive autonomy and, thus, to their overall welfare.

Caroline Moel‐Mandel · Melissa Graham