Concurrent use of hormonal long-acting reversible contraception by women of reproductive age dispensed teratogenic medications, Australia, 2013-2021: a retrospective cohort study.

OBJECTIVES: To examine patterns in the dispensing of category X medications (Therapeutic Goods Administration categorisation system for prescribing medicines in pregnancy) to women aged 15-49 years in Australia during 2008-2021, and patterns of concurrent use of hormonal long-acting reversible contraception (LARC) and other hormonal contraception. STUDY DESIGN: Retrospective cohort study; analysis of 10% random sample of national Pharmaceutical Benefits Scheme dispensing data. PARTICIPANTS, SETTING: Women aged 15-49 years dispensed category X medications, Australia, 1 January 2013 - 31 December 2021. MAIN OUTCOME MEASURES: Incident and prevalent dispensing of category X medications, by medication class, age group, and year; contraceptive overlap (proportions of women dispensed hormonal LARC or other hormonal contraception that overlapped the first dispensing of category X medications), by medication class. RESULTS: Among 15 627 women aged 15-49 years dispensed category X medications during 2013-2021, the prevalence of dispensing increased from 4.6 in 2013 to 8.7 per 1000 women aged 15-49 years in 2021; the largest increase was for the dispensing of dermatological agents, from 3.9 to 7.9 per 1000 women aged 15-49 years. LARC overlap was inferred for 2059 women at the time of first dispensing of category X medications (13.2%); 3441 had been dispensed any type of hormonal contraception (22.1%). The proportion with LARC overlap was smallest for those dispensed dermatological agents (1806 of 14 331 women, 12.6%); for this drug class, both LARC overlap (adjusted odds ratio [aOR], 0.17; 95% confidence interval [CI], 0.14-0.20) and any hormonal contraception overlap (aOR, 0.28; 95% CI, 0.25-0.32) were less likely for those aged 15-19 years than for women aged 25-29 years. CONCLUSIONS: Concurrent use of highly effective hormonal contraception at the time of first dispensing of category X medications is low in Australia, raising concerns about potential fetal harms during unintended pregnancies. Awareness of the importance of hormonal contraception and its uptake by women prescribed category X medications should be increased.

Breastmilk use in preterm infants <29 weeks' gestational age in Australia, New Zealand and Singapore.

AIMS: To describe the prevalence of use of breastmilk and explore demographic characteristics and clinical outcomes associated with breastmilk provision in infants born <29 weeks' gestational age in Australia, New Zealand and Singapore. METHODS: This is a secondary analysis of data from a randomised controlled trial, which enrolled 1273 infants in 13 neonatal units across Australia, New Zealand and Singapore from 2012 to 2015. Infants were classified as formula-fed, donor milk-fed or mother's milk-fed at their first enteral feed and separately, at hospital discharge. RESULTS: The percentage of infants receiving mother's own milk differed between centres both at first feed (79% to 100%), and at hospital discharge (47.1% to 71.6%). Aboriginal, Torres Strait Islander and Southeast Asian heritage, drug use and smoking were associated with lower rates of fully breastmilk feeding at hospital discharge. There was no significant difference in growth outcomes, length of stay and feeding tolerance between feeding groups. CONCLUSIONS: Achieving high breastmilk feeding rates at hospital discharge for all preterm infants born <29 weeks' gestational age at hospital discharge is possible; however, targeted support for mothers who are Indigenous, Southeast Asian and/or using recreational drugs and/or smoking and/or experiencing social disadvantage may be needed. A better understanding and shared knowledge of practice variations within neonatal units with high breastfeeding rates could improve breastmilk access and equity for preterm infants. AUSTRALIAN NEW ZEALAND CLINICAL TRIALS REGISTRY: ACTRN12612000503820.

Reducing intravenous antibiotics in neonates born ≥35 weeks' gestation: A quality improvement study.

AIM: To assess the impact of the Early Onset Sepsis (EOS) calculator, implemented as a quality improvement study, to reduce the rate of unnecessary antibiotics in neonates born ≥35 weeks' gestation. METHODS: An audit of routinely collected hospital data from January 2008 to March 2014 (retrospective) and from January 2018 to September 2019 (prospective) determined baseline incidence of EOS intravenous antibiotic use in neonates born ≥35 weeks' gestation in a tertiary level perinatal centre. Plan-do-study-act (PDSA) cycles were applied to implement the EOS calculator. Statistical process control methodology and time series analysis assessments were used to assess the potential impact of the PDSA cycles on the rate of intravenous antibiotics, blood culture collection, EOS, length of stay and health care costs (not adjusted for potential confounders). RESULTS: In the study population, from January 2008 to March 2014, the baseline incidence of intravenous antibiotic use was 10.49% (2970/28290), whilst only 0.067% (19/28290) neonates had culture proven EOS. From January 2018 to October 2019, prior to implementation of the EOS calculator, 13.3% (1119/8411) neonates were treated with intravenous antibiotic and the use decreased to 8.3% (61/734) post-implementation. The rate of blood culture collection decreased from 14.4% (1211/8411) to 11.9% (87/734). There were no cases of missed EOS. Length of stay decreased from 2.68 to 2.39 days, with an estimated cost saving of $366 per patient per admission. CONCLUSION: Implementing the EOS calculator in a tertiary hospital setting reduced invasive investigations for EOS and intravenous antibiotic use among neonates ≥35 weeks' gestation. This can result in reduced length of neonatal hospital stays, and associated health care cost savings and may reduce separation of mother and baby.

'Like fumbling around in the dark': Young people's perceptions and realities of healthy relationships.

Learning to negotiate relationships is a key feature of adolescence, yet insight into young people's perspectives on what constitutes healthy relationships is lacking. In this study, therefore, insights were sought on healthy relationship qualities, common issues encountered, and relevant educational experiences. Semi-structured interviews were undertaken with 18 young people (11 self-identified as female, 5 male, and 2 trans/gender-diverse) aged 14-20 years, residing in Adelaide, South Australia. Relationships with parents, siblings, peers and intimate partners were topics for discussion. Reflexive thematic analysis was utilised to generate codes and themes. The Five Cs of Positive Youth Development were used to aid understanding of findings. Young people's accounts suggested a disjuncture between desired relationship qualities, realities and education on relationships and sexual health. Young people articulated tensions navigating peer norms and societal expectations in relation to dating and sex, including unrealistic representations, gender stereotyping and strong 'sexpectations'. Participants in this study relied more heavily on personal experience and observation than formal education to develop an understanding of healthy relationships. Achieving healthy relationships was generally perceived to be complex and requiring skills or understanding informants were unsure about. Positive Youth Development could provide a framework for meeting the needs expressed by young people, notably by building communication skills, confidence and agency.

Online platforms for prescription and supply of hormonal contraception in Australia: a mapping review.

Online platforms have emerged as a convenient way for individuals to access contraception. However, the extent to which such services exist in Australia and how they operate is currently unknown. We aimed to identify Australian online contraception platforms and evaluate the services they provide to determine the degree to which they may facilitate equitable access to contraception. We conducted an internet search to identify online contraception platforms operating in Australia. Data were extracted from each of the platforms relating to operating policies, services provided and associated payment processes, as well as prescribing and screening processes for assessing user suitability. As of July 2022, eight online contraception platforms operating within Australia were identified. All platforms offered oral contraception, with two also offering the vaginal ring, and one emergency oral contraception. None of the platforms provided access to long-acting reversible contraception. Significant variability existed in product and membership costs across platforms, with only one platform providing access to subsidised medicines. Five platforms restricted services to those already using oral contraception. Overall, online questionnaires were deemed to be adequately screening for important contraindications to using oral contraception. While online contraception platforms may be a valuable option for some individuals who face access barriers and are willing to pay out-of-pocket for to have their contraception sent straight to their home, they do not necessarily ensure that individuals can access their contraceptive method of choice or address recognised financial and structural barriers to contraceptive care.

Antenatal magnesium sulphate for preventing cerebral palsy: An economic evaluation of the impact of a quality improvement program.

Previous work demonstrated that implementing a quality improvement (QI) program improves the uptake of guideline-recommended antenatal magnesium sulphate, a critical intervention known to reduce cerebral palsy risk. Here we estimate potential cost savings attributable to the improved uptake. By expanding coverage from 63 to 83% of eligible women, we estimated that five children potentially would not have received a diagnosis of cerebral palsy, a potential cost saving of $AU4.8 million in lifetime healthcare costs. Our findings strengthen the case for embedding QI approaches in perinatal care to reduce the incidence of cerebral palsy.

Diagnosis delayed: health profile differences between women with undiagnosed polycystic ovary syndrome and those with a clinical diagnosis by age 35 years.

STUDY QUESTION: Are reproductive, metabolic or psychological health profiles of women with clinically diagnosed polycystic ovary syndrome (PCOS) different from those with undiagnosed PCOS? SUMMARY ANSWER: Obtaining a clinical diagnosis of PCOS is strongly linked to the experience of fertility problems, but not clinical depression or poor metabolic health, although these were highly prevalent in women with PCOS irrespective of when they were diagnosed. WHAT IS KNOWN ALREADY: PCOS is an endocrine disorder that is relative common, but heterogeneous in presentation. This may impact on the pathways to diagnosis and timely treatment. STUDY DESIGN, SIZE, DURATION: A cross-sectional analysis of a community-based cohort of 974 women, established retrospectively when women were around 30 years of age. PARTICIPANTS/MATERIALS, SETTING, METHODS: In this cohort of women born in Adelaide, South Australia, half of women who met the Rotterdam criteria for PCOS were previously undiagnosed. We compared women with prior clinical diagnosis of PCOS, those diagnosed through participation in this research, and the remainder in the cohort. Sociodemographic characteristics, reproductive, metabolic and psychological health, including medical conditions and medications were considered. Logistic regression was undertaken to identify independent predictors of prior clinical diagnosis. MAIN RESULTS AND THE ROLE OF CHANCE: There were 56 women with a prior clinical diagnosis of PCOS (5.7%) and a further 64 (6.6%) were undiagnosed until study entry. The great majority of women with a prior diagnosis of PCOS reported having had problems with periods (95%) and excess body hair (63%). Corresponding proportions for women undiagnosed until study participation were slightly lower (81% and 45%, respectively). Although the proportion of women attempting or achieving pregnancy was similar across all groups, those with a prior diagnosis of PCOS were four times more likely to have reported difficulties becoming pregnant than those undiagnosed (odds ratio = 4.05, 95% CI 1.74-9.45) and frequently sought medical assistance. Metabolic problems were higher in both PCOS groups compared to women without PCOS. In both PCOS groups, the prevalence of clinical depression was 50% higher than in those with no PCOS (P = 0.021). LIMITATIONS, REASONS FOR CAUTION: The number of women who were diagnosed with PCOS both prior to and during the study limited statistical power available to detect modest differences between the PCOS groups. Some women in the group classified as not having PCOS may have remained undiagnosed, but any bias from this source would contribute to more conservative findings. WIDER IMPLICATIONS OF THE FINDINGS: Findings reinforce the need for early detection of PCOS symptoms from adolescence, ensuring timely diagnosis and appropriate health care. The high prevalence of depression among clinically diagnosed and undiagnosed women with PCOS suggests this is a feature of the condition and supports recent recommendations in the international PCOS guidelines to screen all women with PCOS for depression and anxiety. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by a project grant (2017) from the National Health and Medical Research Council of Australia (NHMRC) Centre for Research Excellence in Polycystic Ovary Syndrome (Grant ID APP1078444). R.C.F. and J.C.A. were supported by Robinson Research Institute Lloyd Cox Career Development Fellowships (2018). Establishment of the cohort was funded by an NHMRC Strategic Award No. 465455, a Career Development Award in Population Health (No. 349548) and the Australian Research Council (Future Fellowship FT100101018) awarded to M.J.D. All authors declared no conflict of interest. TRIAL REGISTRATION NUMBER: N/A.

Adverse pregnancy and neonatal outcomes associated with Neisseria gonorrhoeae: systematic review and meta-analysis.

OBJECTIVE: To examine associations between Neisseria gonorrhoeae (NG) infection during pregnancy and the risk of preterm birth, spontaneous abortion, premature rupture of membranes, perinatal mortality, low birth weight and ophthalmia neonatorum. DATA SOURCES: We searched Medline, EMBASE, the Cochrane Library and Cumulative Index to Nursing and Allied Health Literature for studies published between 1948 and 14 January 2020. METHODS: Studies were included if they reported testing for NG during pregnancy and compared pregnancy, perinatal and/or neonatal outcomes between women with and without NG. Two reviewers independently assessed papers for inclusion and extracted data. Risk of bias was assessed using established checklists for each study design. Summary ORs with 95% CIs were generated using random effects models for both crude and, where available, adjusted associations. RESULTS: We identified 2593 records and included 30 in meta-analyses. Women with NG were more likely to experience preterm birth (OR 1.55, 95% CI 1.21 to 1.99, n=18 studies); premature rupture of membranes (OR 1.41, 95% CI 1.02 to 1.92, n=9); perinatal mortality (OR 2.16, 95% CI 1.35 to 3.46, n=9); low birth weight (OR 1.66, 95% CI 1.12 to 2.48, n=8) and ophthalmia neonatorum (OR 4.21, 95% CI 1.36 to 13.04, n=6). Summary adjusted ORs were, for preterm birth 1.90 (95% CI 1.14 to 3.19, n=5) and for low birth weight 1.48 (95% CI 0.79 to 2.77, n=4). In studies with a multivariable analysis, age was the variable most commonly adjusted for. NG was more strongly associated with preterm birth in low-income and middle-income countries (OR 2.21, 95% CI 1.40 to 3.48, n=7) than in high-income countries (OR 1.38, 95% CI 1.04 to 1.83, n=11). CONCLUSIONS: NG is associated with a number of adverse pregnancy and newborn outcomes. Further research should be done to determine the role of NG in different perinatal mortality outcomes because interventions that reduce mortality will have the greatest impact on reducing the burden of disease in low-income and middle-income countries. PROSPERO REGISTRATION NUMBER: CRD42016050962.

Avoidance of bottles during the establishment of breastfeeds in preterm infants.

BACKGROUND: Preterm infants often start milk feeds by gavage tube. As they mature, sucking feeds are gradually introduced. Women with preterm infants may not always be in hospital to breastfeed their baby and need an alternative approach to feeding. Most commonly, milk (expressed breast milk or formula) is given by bottle. Whether using bottles during establishment of breastfeeds is detrimental to breastfeeding success is a topic of ongoing debate. OBJECTIVES: To identify the effects of avoidance of bottle feeds during establishment of breastfeeding on the likelihood of successful breastfeeding, and to assess the safety of alternatives to bottle feeds. SEARCH METHODS: A new search strategy was developed for this update. Searches were conducted without date or language limits in September 2021 in: MEDLINE, CENTRAL, and CINAHL.  We also searched the ISRCTN trial registry and the reference lists of retrieved articles for randomised controlled trials (RCTs) and quasi-RCTs.  SELECTION CRITERIA: We included RCTs and quasi-RCTs comparing avoidance of bottles with use of bottles for preterm infants where their mothers planned to breastfeed. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trial quality and extracted data. When appropriate, we contacted study authors for additional information. We used the GRADE approach to assess the certainty of evidence. Outcomes included full breastfeeding and any breastfeeding on discharge home and at three and six months after discharge, as well as length of hospital stay and episodes of infant infection. We synthesised data using risk ratios (RR), risk differences (RD) and mean differences (MD), with 95% confidence intervals (CI). We used the GRADE approach to assess the certainty of the evidence. MAIN RESULTS: We included seven trials with 1152 preterm infants in this updated review. There are three studies awaiting classification. Five included studies used a cup feeding strategy, one used a tube feeding strategy and one used a novel teat when supplements to breastfeeds were needed. We included the novel teat study in this review as the teat was designed to closely mimic the sucking action of breastfeeding. The trials were of small to moderate size, and two had high risk of attrition bias. Adherence with cup feeding was poor in one of the studies, indicating dissatisfaction with this method by staff or parents (or both); the remaining four cup feeding studies provided no such reports of dissatisfaction or low adherence. Avoiding bottles may increase the extent of full breastfeeding on discharge home (RR 1.47, 95% CI 1.19 to 1.80; 6 studies, 1074 infants; low-certainty evidence), and probably increases any breastfeeding (full and partial combined) on discharge (RR 1.11, 95% CI 1.06 to 1.16; studies, 1138 infants; moderate-certainty evidence). Avoiding bottles probably increases the occurrence of full breastfeeding three months after discharge (RR 1.56, 95% CI 1.37 to 1.78; 4 studies, 986 infants; moderate-certainty evidence), and may also increase full breastfeeding six months after discharge (RR 1.64, 95% CI 1.14 to 2.36; 3 studies, 887 infants; low-certainty evidence). Avoiding bottles may increase the occurrence of any breastfeeding (full and partial combined) three months after discharge (RR 1.31, 95% CI 1.01 to 1.71; 5 studies, 1063 infants; low-certainty evidence), and six months after discharge (RR 1.25, 95% CI 1.10 to 1.41; 3 studies, 886 infants; low-certainty evidence). The effects on breastfeeding outcomes were evident at all time points for the tube alone strategy and for all except any breastfeeding three months after discharge for cup feeding, but were not present for the novel teat. There were no other benefits or harms including for length of hospital stay (MD 2.25 days, 95% CI -3.36 to 7.86; 4 studies, 1004 infants; low-certainty evidence) or episodes of infection per infant (RR 0.70, 95% CI 0.35 to 1.42; 3 studies, 500 infants; low-certainty evidence). AUTHORS' CONCLUSIONS: Avoiding the use of bottles when preterm infants need supplementary feeds probably increases the extent of any breastfeeding at discharge, and may improve any and full breastfeeding (exclusive) up to six months postdischarge. Most of the evidence demonstrating benefit was for cup feeding. Only one study used a tube feeding strategy. We are uncertain whether a tube alone approach to supplementing breastfeeds improves breastfeeding outcomes; further studies of high certainty are needed to determine this.

A systematic review and meta-analysis of the association between periodontitis and oral high-risk human papillomavirus infection.

BACKGROUND: The incidence of human papillomavirus (HPV)-related oropharyngeal squamous cell carcinomas (OPSCCs) is increasing globally. Common oral conditions such as periodontitis may contribute. We undertook a meta-analysis to quantify the association between periodontitis, oral HPV and OPSCCs. METHODS: Multiple electronic databases were searched until 12 February 2020. Studies conducted in males and/or females aged ≥ 18 years that examined periodontitis, periodontal procedures, oral HPV infection, and where possible, oral cancers, were eligible. Meta-analyses were conducted and the GRADE approach was used to examine the quality of evidence. RESULTS: Of 2709 studies identified, 13 met the eligibility criteria. Five studies could be included in the meta-analyses. There was no significant increase in the odds of high-risk oral HPV infection among individuals with confirmed periodontitis (odds ratio 4.71, 95% confidence interval 0.57-38.97). Individuals with periodontitis had a 3.65 times higher odds of having any type of oral HPV infection compared with those without periodontitis (95% confidence interval 1.67-8.01). The overall body of evidence was rated as low to very-low certainty. CONCLUSION: Meta-analysis confirms there is a positive association between periodontitis and oral HPV infection, although the overall quality of this evidence is low. Evidence for an association between periodontitis and high-risk oral HPV infection is inconclusive.

"We are only looking at the tip of the iceberg in infertility": perspectives of health providers about fertility issues and management among Aboriginal and Torres Strait Islander people.

INTRODUCTION: Aboriginal and Torres Strait Islander women and men are disproportionately affected by a range of risk factors for infertility. However, remarkably little is known about the prevalence of infertility in this group, or how Aboriginal and Torres Strait Islander people access fertility treatments including assisted reproductive technology (ART). This qualitative study aims to explore health care provider (HCP) perspectives on the health burden of infertility among Aboriginal and Torres Strait Islander people, as well as factors that may affect access to infertility treatment for this group. METHOD: Semi-structured interviews were conducted with HCPs (8 doctors; 3 nurses and 1 Aboriginal Health Practitioner) working in fertility care in the Northern Territory, Australia. Transcribed interviews were analysed using an iterative thematic approach using the NVivo-9 software package. RESULTS: Providers perceive infertility as an underestimated health issue in this patient population, reporting a high prevalence of infertility-related risk factors but fewer clinical encounters of diagnosis and treatment. Perceived barriers to accessing fertility care included cultural differences such as the shame and stigma associated with reproductive health and the separation of men's business and women's business; service-related barriers such as limited timely and affordable access to specialist health services and; a lack of culturally responsive and appropriate fertility services. Providers had mixed opinions on their role in ameliorating inequities of access, and hence a range of strategies to address barriers were suggested. These included a greater patient education, ongoing patient support and providing a culturally safe environment. CONCLUSION: The current study adds to the understanding of how Aboriginal and Torres Strait Islander people access fertility treatments. There is a need for further research to quantify infertility in Aboriginal and Torres Strait Islander people, investigate community perceptions towards infertility and identify community-driven priorities to improve access to fertility care for this population.

The impact of interpersonal racism on oral health related quality of life among Indigenous South Australians: a cross-sectional study.

BACKGROUND: Interpersonal racism has had a profound impact on Indigenous populations globally, manifesting as negative experiences and discrimination at an individual, institutional and systemic level. Interpersonal racism has been shown to negatively influence a range of health outcomes but has received limited attention in the context of oral health. The aim of this paper was to examine the effects of experiences of interpersonal racism on oral health-related quality of life (OHRQoL) among Indigenous South Australians. METHODS: Data were sourced from a large convenience sample of Indigenous South Australian adults between February 2018 and January 2019. Questionnaires were used to collect data on sociodemographic characteristics, cultural values, utilization of dental services, and other related factors. OHRQoL was captured using the Oral Health Impact Profile (OHIP-14) questionnaire. We defined the dependent variable 'poor OHRQoL' as the presence of one or more OHIP-14 items rated as 'very often' or 'fairly often'. Experiences of racism were recorded using the Measure of Indigenous Racism Experiences instrument. Interpersonal racism was classified into two categories ('no racism' vs 'any racism in ≥ 1 setting') and three categories ('no racism', 'low racism' (experienced in 1-3 settings), and 'high racism' (experienced in 4-9 settings)). Logistic regression was used to examine associations between interpersonal racism, covariates and OHRQoL, adjusting for potential confounding related to socioeconomic factors and access to dental services. RESULTS: Data were available from 885 participants (88.7% of the total cohort). Overall, 52.1% reported experiencing any interpersonal racism in the previous 12 months, approximately one-third (31.6%) were classified as experiencing low racism, and one-fifth (20.5%) experienced high racism. Poor OHRQoL was reported by half the participants (50.2%). Relative to no experiences of racism in the previous 12 months, those who experienced any racism (≥ 1 setting) were significantly more likely to report poor OHRQoL (Odds Ratio (OR): 1.43; 95% Confidence Interval (CI): 1.08-1.92), after adjusting for age, education level, possession of an income-tested health care card, car ownership, self-reported oral health status, timing of and reason for last dental visit, not going to a dentist because of cost, and having no family support. This was particularly seen among females, where, relative to males, the odds of having poor OHRQoL among females experiencing racism were 1.74 times higher (95% CI: 1.07-2.81). CONCLUSION: Our findings indicate that the experience of interpersonal racism has a negative impact on OHRQoL among Indigenous Australians. The association persisted after adjusting for potential confounding factors. Identifying this link adds weight to the importance of addressing OHRQoL among South Australian's Indigenous population by implementing culturally-sensitive strategies to address interpersonal racism.

External validation of prognostic models predicting pre-eclampsia: individual participant data meta-analysis.

BACKGROUND: Pre-eclampsia is a leading cause of maternal and perinatal mortality and morbidity. Early identification of women at risk during pregnancy is required to plan management. Although there are many published prediction models for pre-eclampsia, few have been validated in external data. Our objective was to externally validate published prediction models for pre-eclampsia using individual participant data (IPD) from UK studies, to evaluate whether any of the models can accurately predict the condition when used within the UK healthcare setting. METHODS: IPD from 11 UK cohort studies (217,415 pregnant women) within the International Prediction of Pregnancy Complications (IPPIC) pre-eclampsia network contributed to external validation of published prediction models, identified by systematic review. Cohorts that measured all predictor variables in at least one of the identified models and reported pre-eclampsia as an outcome were included for validation. We reported the model predictive performance as discrimination (C-statistic), calibration (calibration plots, calibration slope, calibration-in-the-large), and net benefit. Performance measures were estimated separately in each available study and then, where possible, combined across studies in a random-effects meta-analysis. RESULTS: Of 131 published models, 67 provided the full model equation and 24 could be validated in 11 UK cohorts. Most of the models showed modest discrimination with summary C-statistics between 0.6 and 0.7. The calibration of the predicted compared to observed risk was generally poor for most models with observed calibration slopes less than 1, indicating that predictions were generally too extreme, although confidence intervals were wide. There was large between-study heterogeneity in each model's calibration-in-the-large, suggesting poor calibration of the predicted overall risk across populations. In a subset of models, the net benefit of using the models to inform clinical decisions appeared small and limited to probability thresholds between 5 and 7%. CONCLUSIONS: The evaluated models had modest predictive performance, with key limitations such as poor calibration (likely due to overfitting in the original development datasets), substantial heterogeneity, and small net benefit across settings. The evidence to support the use of these prediction models for pre-eclampsia in clinical decision-making is limited. Any models that we could not validate should be examined in terms of their predictive performance, net benefit, and heterogeneity across multiple UK settings before consideration for use in practice. TRIAL REGISTRATION: PROSPERO ID: CRD42015029349 .

Comparison of different protein concentrations of human milk fortifier for promoting growth and neurological development in preterm infants.

BACKGROUND: Human milk alone may provide inadequate amounts of protein to meet the growth requirements of preterm infants because of restrictions in the amount of fluid they can tolerate. It has become common practice to feed preterm infants with breast milk fortified with protein and other nutrients but there is debate about the optimal concentration of protein in commercially available fortifiers. OBJECTIVES: To compare the effects of different protein concentrations in human milk fortifier, fed to preterm infants, on growth and neurodevelopment. SEARCH METHODS: We used the standard search strategy of Cochrane Neonatal to search CENTRAL (2019, Issue 8), Ovid MEDLINE and CINAHL on 15 August 2019. We also searched clinical trials databases and the reference lists of retrieved articles for randomised controlled trials and quasi-randomised trials. SELECTION CRITERIA: We included all published and unpublished randomised, quasi-randomised and cluster-randomised trials comparing two different concentrations of protein in human milk fortifier. We included preterm infants (less than 37 weeks' gestational age). Participants may have been exclusively fed human milk or have been supplemented with formula. The concentration of protein was classified as low (< 1g protein/100 mL expressed breast milk (EBM)), moderate (≥ 1g to < 1.4g protein/100 mL EBM) or high (≥ 1.4g protein/100 mL EBM). We excluded trials that compared two protein concentrations that fell within the same category. DATA COLLECTION AND ANALYSIS: We undertook data collection and analyses using the standard methods of Cochrane Neonatal. Two review authors independently evaluated trials. Primary outcomes included growth, neurodevelopmental outcome and mortality. Data were synthesised using risk ratios (RR), risk differences and mean differences (MD), with 95% confidence intervals (CI). We used the GRADE approach to assess the certainty of the evidence. MAIN RESULTS: We identified nine trials involving 861 infants. There is one trial awaiting classification, and nine ongoing trials. The trials were mostly conducted in infants born < 32 weeks' gestational age or < 1500 g birthweight, or both. All used a fortifier derived from bovine milk. Two trials fed infants exclusively with mother's own milk, three trials gave supplementary feeds with donor human milk and four trials supplemented with preterm infant formula. Overall, trials were small but generally at low or unclear risk of bias. High versus moderate protein concentration of human milk fortifier There was moderate certainty evidence that a high protein concentration likely increased in-hospital weight gain compared to moderate concentration of human milk fortifier (MD 0.66 g/kg/day, 95% CI 0.51 to 0.82; trials = 6, participants = 606). The evidence was very uncertain about the effect of high versus moderate protein concentration on length gain (MD 0.01 cm/week, 95% CI -0.01 to 0.03; trials = 5, participants = 547; very low certainty evidence) and head circumference gain (MD 0.00 cm/week, 95% CI -0.01 to 0.02; trials = 5, participants = 549; very low certainty evidence). Only one trial reported neonatal mortality, with no deaths in either group (participants = 45). Moderate versus low protein concentration of human milk fortifier A moderate versus low protein concentration fortifier may increase weight gain (MD 2.08 g/kg/day, 95% CI 0.38 to 3.77; trials = 2, participants = 176; very low certainty evidence) with little to no effect on head circumference gain (MD 0.13 cm/week, 95% CI 0.00 to 0.26; I² = 85%; trials = 3, participants = 217; very low certainty evidence), but the evidence is very uncertain. There was low certainty evidence that a moderate protein concentration may increase length gain (MD 0.09 cm/week, 95% CI 0.05 to 0.14; trials = 3, participants = 217). Only one trial reported mortality and found no difference between groups (RR 0.48, 95% CI 0.05 to 5.17; participants = 112). No trials reported long term growth or neurodevelopmental outcomes including cerebral palsy and developmental delay. AUTHORS' CONCLUSIONS: Feeding preterm infants with a human milk fortifier containing high amounts of protein (≥ 1.4g/100 mL EBM) compared with a fortifier containing moderate protein concentration (≥ 1 g to < 1.4 g/100 mL EBM) results in small increases in weight gain during the neonatal admission. There may also be small increases in weight and length gain when infants are fed a fortifier containing moderate versus low protein concentration (< 1 g protein/100 mL EBM). The certainty of this evidence is very low to moderate; therefore, results may change when the findings of ongoing studies are available. There is insufficient evidence to assess the impact of protein concentration on adverse effects or long term outcomes such as neurodevelopment. Further trials are needed to determine whether modest increases in weight gain observed with higher protein concentration fortifiers are associated with benefits or harms to long term growth and neurodevelopment.

Provision of assisted reproductive technologies (ART) to Aboriginal and Torres Strait Islander peoples: Limited engagement in an online survey of Medical Directors of ART services.

Current knowledge about infertility and access to infertility treatment among Aboriginal and Torres Strait Islander peoples is extremely limited. We conducted an online survey of Medical Directors of registered ART providers in Australia (n = 59) to obtain preliminary information on this topic. Six (10%) Directors responded; only two reported routinely collecting the Aboriginal and Torres Strait Islander status of clients. While the low response rate prevents generalising the findings, the poor engagement may indicate gaps in awareness of fertility issues for this group. This warrants further investigation, to understand whether Aboriginal and Torres Strait Islander people are appropriately accessing infertility care.

Infertility in Aboriginal and Torres Strait Islander people: A cause for concern?

In many Aboriginal and Torres Strait Islander communities, women and men are disproportionately affected by a range of risk factors for infertility including sexually transmitted infections, polycystic ovary syndrome and obesity. However, very little is known about the occurrence of infertility in this group or how Aboriginal and Torres Strait Islander people access fertility treatments. This opinion piece aims to reflect on current evidence concerning infertility risk factors and infertility per se among Aboriginal and Torres Strait Islander people, highlighting gaps in the literature about access and outcomes in this group.

Recurrence patterns identify aggressive form of human papillomavirus-dependent vulvar cancer.

BACKGROUND: Vulvar cancer is rare and, as a result, is understudied. Treatment is predominantly surgery, irrespective of the type of vulvar cancer, and is associated with physical, emotional and sexual complications. A cluster of human papillomavirus (HPV)-dependent vulvar cancer patients was identified in Arnhem Land Northern Territory (NT), Australia, in which young Indigenous women were diagnosed at 70 times the national incidence rate. AIMS: To assess whether women from the Arnhem Land cluster differ from women with vulvar squamous cell carcinoma (VSCC) and vulvar intraepithelial neoplasia (VIN) resident elsewhere in the NT in recurrence after treatment, disease progression and mortality. MATERIALS AND METHODS: A retrospective cohort study of NT-resident women diagnosed with VIN or invasive vulvar cancer (VSCC) between 1 January 1993 and 30 June 2015 was undertaken. Time to recurrence was assessed using cumulative incidence plots and Fine and Gray competing risk regression models. Mean cumulative count was used to estimate the burden of recurrent events. RESULTS: Indigenous women from Arnhem Land experienced more recurrences after treatment than non-Indigenous women, the cancers recurred faster, and Indigenous women have worse survival at five years. CONCLUSIONS: In characterising the epidemiological features of this cluster, we have identified a particularly aggressive form of vulvar cancer. This provides a unique opportunity for elucidating the aetiopathological pathways driving vulvar cancer development that may ultimately lead to preventive and therapeutic targets for this neglected malignancy. Further, these findings have important implications for clinical practice and HPV vaccination policy in the affected population.

Analysis of diagnostic data for sexually transmissible infections in South Australian Aboriginal Community Controlled Health Services (2008-16).

Australian Aboriginal communities experience a high burden of sexually transmissible infections (STIs). Since 2009, a comprehensive sexual health program has been implemented at nine Aboriginal Community Controlled Health Services in South Australia. This study assessed trends in STI testing and positivity using deidentified diagnostic data from this period (2008-16). METHODS: Testing data for Chlamydia trachomatis (CT), Neisseria gonorrhoeae (NG) and Trichomonas vaginalis (TV) from one urban, three regional and five remote Aboriginal health services were analysed using logistic regression. RESULTS: From 2008 to 2016, testing increased for CT (twofold), NG (threefold) and TV (sixfold). On average, 30% of testing occurred during an annual 6-week screen. Fewer males were tested (range 27-38% annually). Mean annual STI testing coverage was 28% for 16- to 30-year-old clients attending regional or remote services (2013-16). Positivity at first testing episode for all three infections declined during the study period. From 2013 to 2016, when testing was stable and changes in positivity were more likely to indicate changes in prevalence, there were significant reductions in CT positivity (adjusted odds ratio (aOR) 0.4; 95% confidence interval (CI) 0.2-0.5) and TV positivity (aOR 0.6, 95% CI 0.4-0.9), although declines were statistically significant for females only. There was no significant decrease in NG positivity (aOR 0.9; 95% CI 0.5-1.5). CONCLUSIONS: Since the sexual health program began, STI testing increased and STI positivity declined, but significant reductions observed in CT and TV positivity were confined to females. These findings suggest evidence of benefit from sustained, comprehensive sexual health programs in Aboriginal communities with a high STI prevalence, but highlight the need to increase STI testing among men in these communities.

Perspectives of primary health care staff on the implementation of a sexual health quality improvement program: a qualitative study in remote aboriginal communities in Australia.

BACKGROUND: Young people living in remote Australian Aboriginal communities experience high rates of sexually transmissible infections (STIs). STRIVE (STIs in Remote communities, ImproVed and Enhanced primary care) was a cluster randomised control trial of a sexual health continuous quality improvement (CQI) program. As part of the trial, qualitative research was conducted to explore staff perceptions of the CQI components, their normalisation and integration into routine practice, and the factors which influenced these processes. METHODS: In-depth semi-structured interviews were conducted with 41 clinical staff at 22 remote community clinics during 2011-2013. Normalisation process theory was used to frame the analysis of interview data and to provide insights into enablers and barriers to the integration and normalisation of the CQI program and its six specific components. RESULTS: Of the CQI components, participants reported that the clinical data reports had the highest degree of integration and normalisation. Action plan setting, the Systems Assessment Tool, and the STRIVE coordinator role, were perceived as adding value to the program, but were less readily integrated or normalised. The remaining two components (dedicated funding for health promotion and service incentive payments) were seen as least relevant. Our analysis also highlighted factors which enabled greater integration of the CQI components. These included familiarity with CQI tools, increased accountability of health centre staff and the translation of the CQI program into guideline-driven care. The analysis also identified barriers, including high staff turnover, limited time involved in the program and competing clinical demands and programs. CONCLUSIONS: Across all of the CQI components, the clinical data reports had the highest degree of integration and normalisation. The action plans, systems assessment tool and the STRIVE coordinator role all complemented the data reports and allowed these components to be translated directly into clinical activity. To ensure their uptake, CQI programs must acknowledge local clinical guidelines, be compatible with translation into clinical activity and have managerial support. Sexual health CQI needs to align with other CQI activities, engage staff and promote accountability through the provision of clinic specific data and regular face-to-face meetings. TRIAL REGISTRATION: Australian and New Zealand Clinical Trials Registry ACTRN12610000358044 . Registered 6/05/2010. Prospectively Registered.

The impact of specific fertility treatments on cognitive development in childhood and adolescence: a systematic review.

STUDY QUESTION: Does fertility treatment influence cognitive ability in school aged children, and does the impact vary with the type of treatment? SUMMARY ANSWER: The available high-quality evidence indicates that specific treatments may give rise to different effects on cognitive development, with certain treatments, including ICSI, associated with cognitive impairment. WHAT IS KNOWN ALREADY: Previous reviews of the literature concerning cognitive outcomes among children conceived with medical assistance have concluded that study findings are generally 'reassuring', but limited attention has been paid to the quality of this research. In addition, no review has separately assessed the range of treatment modalities available, which vary in invasiveness, and thus, potentially, in their effects on developmental outcomes. STUDY DESIGN, SIZE, DURATION: A systematic review was undertaken. We searched PubMed, PsycINFO and the Educational Resources Information Centre database to identify English-language studies published up until 21 November 2016. PARTICIPANTS/MATERIALS, SETTING, METHODS: Two authors independently reviewed identified articles, extracted data and assessed study quality. Studies were eligible if they assessed cognitive development from age 4 years or more, among children conceived with fertility treatment compared with either children conceived naturally or children born from a different type of fertility treatment. Where available, data were extracted and reported separately according to the various components of treatment (e.g. mode of fertilization, embryo freezing, etc.). Risk of bias was assessed using the Newcastle-Ottawa Scale, with a score ≥7/9 indicative of high quality. MAIN RESULTS AND THE ROLE OF CHANCE: The search identified 861 articles, of which 35 were included. Of these, seven were rated high quality. Most studies (n = 22) were subject to selection bias, due to the exclusion of children at increased risk of cognitive impairment. Among high-quality studies, there was no difference in cognitive outcomes among children conceived with conventional IVF and those conceived naturally. Findings among high-quality studies of children conceived with ICSI were inconsistent: when compared with children conceived naturally, one study reported lower intelligence quotient (IQ; 5-7 points, on average) among ICSI children whereas the remaining two high-quality studies reported no difference between groups. Furthermore, among the three high-quality studies comparing children conceived with ICSI compared with conventional IVF, one reported a significant increase in the risk of mental retardation, one reported a small difference in IQ (3 points lower, on average) and one no difference at all. There were scant studies examining exposure to embryo freezing, or less invasive treatments such as ovulation induction without IVF/ICSI. LIMITATION, REASONS FOR CAUTION: Most existing studies had methodological limitations including selection bias and/or failure to address confounding by family background. In addition, a meta-analysis could not be performed due to heterogeneity in the assessment of cognitive outcomes. These factors impeded our ability to synthesize the evidence and draw reliable conclusions. WIDER IMPLICATIONS OF THE FINDINGS: The conflicting findings among studies of children conceived with ICSI require clarification, in light of the increasing use of this technique for reasons other than male-factor infertility. Further population-based studies are needed that utilize contemporary data to examine specific aspects of treatment and combinations of techniques (e.g. ICSI with frozen embryo cycles). Importantly, studies should include the complete group of children exposed to treatment. STUDY FUNDING/COMPETING INTEREST(S): A.R.R. is supported by a Career Development Fellowship from the National Health and Medical Research Council of Australia. L.J.M. is funded by a fellowship from the Heart Foundation of Australia. The authors declare there are no competing interests. TRIAL REGISTRATION NUMBER: Not applicable.