Ascertainment of Aboriginal and Torres Strait Islander status for assessment of perinatal health outcomes: Reported versus derived maternal ethnicity in Western Australian pregnancy data.

BACKGROUND: Under-identification of Aboriginal and Torres Strait Islander (hereafter referred to as Aboriginal) people can result in inaccurate estimation of health outcomes. Data linkage has improved identification of Aboriginal people in administrative datasets. AIM: To compare three methods of ascertainment of Aboriginal status using only pregnancy data from the Western Australian Midwives Notification System (MNS), to the linked Indigenous Status Flag (ISF) derived by the Department of Health. MATERIALS AND METHODS: This retrospective population-based cohort study utilised logistic regression to determine which demographic characteristics were associated with under-identification, and the effect of ascertainment method on perinatal adverse outcomes. RESULTS: All methods identified a core group of 19 017 (83.0%) Aboriginal women and the ISF identified 2298 (10.0%) women who were not identified using any other method. Under-ascertainment was lowest when a woman's Aboriginal status was determined by ever being recorded as Aboriginal in the MNS data, and highest when taken as it had been recorded for the birth in question. Maternal age <20 years, smoking during pregnancy, pre-existing diabetes, a history of singleton preterm birth and being in the lowest 20% of Socio-Economic Indexes for Areas score were all associated with a higher chance of being identified by the methods using only the MNS. These methods were less likely to identify nulliparous women, and those with maternal age ≥35 years. The method of ascertainment of Aboriginality did not make a significant difference to the adjusted predicted marginal probabilities of adverse perinatal outcomes. CONCLUSION: Unlinked pregnancy data can be used for epidemiological research in Aboriginal obstetric populations.

Longitudinal effects of prenatal exposure to plastic-derived chemicals and their metabolites on asthma and lung function from childhood into adulthood.

BACKGROUND AND OBJECTIVE: Environmental exposure to phthalates and bisphenol A (BPA), chemicals used in the production of plastics, may increase risk for asthma and allergies. However, little is known about the long-term effects of early life exposure to these compounds. We investigated if prenatal exposure to these compounds was associated with asthma, allergy and lung function outcomes from early childhood into adulthood in a cohort study. METHODS: Maternal serum samples collected from 846 pregnant women in the Raine Study were assayed for BPA and phthalate metabolites. The children of these women were followed up at 5, 13 and 22 years where spirometry and respiratory questionnaires were conducted to determine asthma and allergy status. Lung function trajectories were derived from longitudinal spirometry measurements. Multinomial logistic regression and weighted quantile sum regression was used to test associations of individual and chemical mixtures with asthma phenotypes and lung function trajectories. RESULTS: Effects of prenatal BPA and phthalates on asthma phenotypes were seen in male offspring, where BPA was associated with increased risk for persistent asthma, while mono-iso-butyl phthalate and mono-iso-decyl phthalate was associated with increased risk for adult asthma. Prenatal BPA had no effect on lung function trajectories, but prenatal phthalate exposure was associated with improved lung function. CONCLUSION: Prenatal BPA exposure was associated with increased likelihood of persistent asthma in males, while prenatal phthalate exposure was associated with increased likelihood of adult asthma in males. Results suggest that prenatal exposure to prenatal BPA and phthalates affect asthma risk, particularly in males, however lung function was not adversely affected.

The Western Australian preterm birth prevention initiative: a whole of state singleton pregnancy cohort study showing the need to embrace alternative models of care for Aboriginal women.

BACKGROUND: Preterm birth (PTB) is the greatest cause of mortality and morbidity in children up to five years of age globally. The Western Australian (WA) PTB Prevention Initiative, the world's first whole-of-population whole-of-state program aimed at PTB prevention, was implemented across WA in 2014. METHODS: We conducted a prospective population-based cohort study using pregnancy data for singleton births in WA from 2009 to 2019. Logistic regression using the last full year before the Initiative (2013) as the reference, and run charts were used to examine changes in PTB rates compared to pre-Initiative levels, by gestational age group, hospital type, low and high risk of PTB in mid-pregnancy, and onset of labour (spontaneous/medically initiated). Analyses were stratified by Aboriginal and non-Aboriginal maternal ethnicity. RESULTS: Amongst non-Aboriginal women, there was initially a reduction in the PTB rate across the state, and in recent years it returned to pre-Initiative levels. Amongst Aboriginal women there was a small, non- significant reduction in the state-wide PTB rate in the first three years of the Initiative, followed by a rise in recent years. For non-Aboriginal women, the reduction in the rate of PTB at the tertiary centre was sustained and improved further for women of all risk levels and onsets of labour. This reduction was not observed for Aboriginal women giving birth at the tertiary centre, amongst whom there was an increase in the PTB rate overall and in all subgroups, with the exception of medically initiated PTB. Amongst Aboriginal women the PTB rate has also increased across the state. At non-tertiary hospitals there was a large increase in PTB amongst both Aboriginal and non-Aboriginal women, largely driven by medically initiated late PTB. Maternal risk factors cannot account for this increase. CONCLUSIONS: The reduction in PTB rates amongst non-Aboriginal women at the state's tertiary hospital demonstrates that with the right strategies, PTB can be reduced. A sustained collaborative model is required to realise this success in non-tertiary hospitals. The series of interventions was of limited use in Aboriginal women, and future efforts will need to be directed at strategies more likely to be successful, such as midwifery continuity of care models, with Aboriginal representation in the healthcare workforce.

Mifepristone priming and subsequent misoprostol for second trimester medical abortion in women with previous caesarean delivery.

AIMS: To assess clinical outcomes and complications in women with ≥1 prior caesarean delivery (CS) during mid-pregnancy medical abortion with misoprostol following mifepristone priming. MATERIALS AND METHODS: Retrospective analysis of abortions at 13-28 weeks gestation using sequential mifepristone and misoprostol at a single centre from 1/2008-12/2018. Procedural outcomes were compared between cases with no prior CS, one prior and ≥2 prior CS. RESULTS: There were 1399 consecutive women who underwent a medical abortion, with 304 (21.7%) having ≥1 prior lower segment CS (241 one, 49 two, 12 three, one four) and one a prior classical CS. Median gestation was 19 weeks (interquartile range (IQR) 17-21) among nulliparas, multiparas with no prior CS and multiparas with prior CS, P = 0.505. Compared with nulliparas (median procedural duration 10.8 h, IQR 7.5-16.5; adjusted hazards ratio (aHR) = 1.20 95%CI 1.04-1.40, P = 0.015), multiparas with prior CS had a shorter procedural duration (9.5 h, IQR 6.5-13.5) while multiparas with no CS had the shortest duration (7.0 h, IQR 5.0-9.8; aHR = 2.28 95%CI 2.01-2.58, P < 0.001). Complications were more frequent with prior CS: estimated blood loss (medians: 100 cc no CS vs 150 cc ≥1 CS, P = 0.002), blood loss >1000 cc (3.6% no CS vs 7.2% ≥1 CS; odds ratio (OR) = 2.11 95%CI 1.23-3.62, P = 0.007) and placental retention (17.3% no CS vs 25.3% ≥1 CS; adjusted OR = 1.44 95%CI 1.05-1.99, P = 0.024). Uterine rupture occurred in 4/304 women with ≥1 prior CS (1.3%). CONCLUSIONS: Mifepristone-misoprostol abortion in women with prior CS is generally safe but associated with an increased risk of procedural complications. Lowering of the misoprostol dosage with prior CS may reduce uterine rupture, although this hypothesis requires ongoing research.

Asthma and allergies in a cohort of adolescents conceived with ART.

RESEARCH QUESTION: Are asthma and allergies more common in adolescents conceived with assisted reproductive technologies (ART) compared with adolescents conceived without? DESIGN: The Growing Up Healthy Study (GUHS) is a prospective cohort study including ART-conceived offspring born between 1991 and 2001 in Perth, Australia. Their long-term health outcomes, including asthma and allergy parameters, were compared with those of their counterparts conceived without ART from the Raine Study Generation 2 (Gen2), born in 1989-1991. At age 14, 152 GUHS and 1845 Gen2 participants completed the following assessments: the International Studies of Asthma and Allergies in Childhood (ISAAC) questionnaire, spirometry, methacholine challenge testing and skin prick testing (SPT). RESULTS: No differences were detected in the prevalence of current asthma (7.7% versus 10.8%, adjusted odds ratio [aOR] 0.82 (95% CI 0.44-1.52), P = 0.530). Spirometry-measured lung volumes were larger in the ART adolescents. Bronchial hyperresponsiveness was less prevalent in the ART cohort (8.8 versus 18.6%, P = 0.006). Current allergic rhinoconjunctivitis (ARC) rates were significantly higher in the ART cohort (32.4% versus 25.2%, aOR 1.52 [95% CI 1.03-2.26], P = 0.036), with no cohort differences in atopic dermatitis. Food allergies were more prevalent in the ART cohort (20.7 versus 10.9%, aOR 1.89 [95% CI 1.17-3.06], P = 0.010) with more adolescents having a positive SPT (68.0% versus 45.4%, aOR 3.03 [95% 1.99-4.63], P < 0.001). CONCLUSIONS: This study reports no differences in asthma prevalence, slightly altered lung function, an increase in ARC, food allergies and positive SPT in the ART-conceived adolescents. These findings are important to families and healthcare providers and may open up possibilities for targeted screening and treatment. Further studies are required to confirm these findings.

The perceptions of obstetric care providers about cervical length screening for preterm birth prevention.

BACKGROUND: Routine cervical length (CL) measurement at the mid-pregnancy ultrasound is a central recommendation of the Western Australian Preterm Birth Prevention Initiative (Initiative). AIM: To evaluate the perceptions and changes in practice of Western Australian obstetric care providers regarding routine CL screening for preterm birth (PTB) prevention following the Initiative introduction. METHODS: Two self-administered questionnaires were completed by providers from a range of practices. The first was during site visits with the Initiative Outreach team in 2015-2016. The questionnaire was re-issued in 2021 via online dissemination. Participant demographic data and opinions on CL screening for PTB prevention were collected. RESULTS: Two hundred and fourteen providers participated in 2015-2016 and 109 in 2021. In both surveys, providers were more likely to discuss transvaginal CL screening with high-risk women (48.1%, 76.1%; P < 0.001) compared with low-risk (7.5%, 18.3%; P = 0.002) and the importance of CL screening (13.5%, 40.4%; P < 0.001), in 2015-2016 and 2021, respectively. Responses relating to CL screening, including what constitutes a short cervix on ultrasound were varied. A transabdominal CL <35 mm was classified as short by 46.2% and 37.6% and <25 mm on transvaginal ultrasound by 49.1% and 64.2%, in the respective surveys. Most providers ceased progesterone (68.6%, 75.2%) at >28 weeks gestation. CONCLUSIONS: Providers focused on women with overt PTB risk factors, rather than a universal CL screening approach. Although there was improvement between the surveys, the definition of what constitutes a short cervix on ultrasound and how to treat and monitor women with a short CL remained varied.

The health and educational costs of preterm birth to 18 years of age in Australia.

BACKGROUND: Preterm birth is the greatest cause of death up to five years of age and an important contributor to lifelong disability. There is increasing evidence that a meaningful proportion of early births may be prevented, but widespread introduction of effective preventive strategies will require financial support. AIMS: This study estimated the economic cost to the Australian government of preterm birth, up to 18 years of age. MATERIALS AND METHODS: A decision-analytic model was developed to estimate the costs of preterm birth in Australia for a hypothetical cohort of 314 814 children, the number of live births in 2016. Costs to Australia's eight jurisdictions included medical expenditures and additional costs to educational services. RESULTS: The total cost of preterm birth to the Australian government associated with the annual cohort was estimated at $1.413 billion (95% CI 1047-1781). Two-thirds of the costs were borne by healthcare services during the newborn period and one-quarter of the costs by educational services providing special assistance. For each child, the costs were highest for those born at the earliest survivable gestational age, but the larger numbers of children born at later gestational ages contributed heavily to the overall economic burden. CONCLUSION: Preterm birth leaves many people with lifelong disabilities and generates a significant economic burden to society. The costs extend beyond those to the healthcare system and include additional educational needs. Assessments of economic costs should inform economic evaluations of interventions aimed at the prevention or treatment of preterm birth.

A specific bacterial DNA signature in the vagina of Australian women in midpregnancy predicts high risk of spontaneous preterm birth (the Predict1000 study).

BACKGROUND: Intrauterine infection accounts for a quarter of the cases of spontaneous preterm birth; however, at present, it is not possible to efficiently identify pregnant women at risk to deliver preventative treatments. OBJECTIVE: This study aimed to establish a vaginal microbial DNA test for Australian women in midpregnancy that will identify those at increased risk of spontaneous preterm birth. STUDY DESIGN: A total of 1000 women with singleton pregnancies were recruited in Perth, Australia. Midvaginal swabs were collected between 12 and 23 weeks' gestation. DNA was extracted for the detection of 23 risk-related microbial DNA targets by quantitative polymerase chain reaction. Obstetrical history, pregnancy outcome, and demographics were recorded. RESULTS: After excluding 64 women owing to losses to follow-up and insufficient sample for microbial analyses, the final cohort consisted of 936 women of predominantly white race (74.3%). The overall preterm birth rate was 12.6% (118 births); the spontaneous preterm birth rate at <37 weeks' gestation was 6.2% (2.9% at ≤34 weeks' gestation), whereas the preterm premature rupture of the membranes rate was 4.2%. No single individual microbial target predicted increased spontaneous preterm birth risk. Conversely, women who subsequently delivered at term had higher amounts of Lactobacillus crispatus, Lactobacillus gasseri, or Lactobacillus jensenii DNA in their vaginal swabs (13.8% spontaneous preterm birth vs 31.2% term; P=.005). In the remaining women, a specific microbial DNA signature was identified that was strongly predictive of spontaneous preterm birth risk, consisting of DNA from Gardnerella vaginalis (clade 4), Lactobacillus iners, and Ureaplasma parvum (serovars 3 and 6). Risk prediction was improved if Fusobacterium nucleatum detection was included in the test algorithm. The final algorithm, which we called the Gardnerella Lactobacillus Ureaplasma (GLU) test, was able to detect women at risk of spontaneous preterm birth at <37 and ≤34 weeks' gestation, with sensitivities of 37.9% and 44.4%, respectively, and likelihood ratios (plus or minus) of 2.22 per 0.75 and 2.52 per 0.67, respectively. Preterm premature rupture of the membranes was more than twice as common in GLU-positive women. Adjusting for maternal demographics, ethnicity, and clinical history did not improve prediction. Only a history of spontaneous preterm birth was more effective at predicting spontaneous preterm birth than a GLU-positive result (odds ratio, 3.6). CONCLUSION: We have identified a vaginal bacterial DNA signature that identifies women with a singleton pregnancy who are at increased risk of spontaneous preterm birth and may benefit from targeted antimicrobial therapy.

The influence of prenatal exposure to phthalates on subsequent male growth and body composition in adolescence.

Phthalates are ubiquitous environmental chemicals with predominantly anti-androgenic, and potentially obesogenic effects. We hypothesised that antenatal phthalate exposure may influence subsequent boy's growth and body composition through childhood and adolescence. Among 1399 singleton males from the Raine Study, 410 had maternal serum and at least one height, BMI or DEXA outcome available after birth and up to 20 years of age. Maternal serum collected at 18 and 34 weeks' gestation was pooled, and analyzed for concentrations of 32 metabolites of 15 phthalate diesters. Their serum concentrations were categorized into undetectable/detectable levels or tertiles. Linear mixed models were used to determine associations between maternal serum phthalate levels and longitudinal height and body mass index (BMI) z-scores in boys from birth to 20 years of age (n = 250 and n = 295 respectively). Linear regression was used to determine associations between maternal phthalate levels and deviation from mid-parental height (n = 177) and DEXA scan outcomes (n = 191) at the 20 year follow-up. Weak positive associations of participants height z-score increase were detected with exposure to some phthalate metabolites in particular to the lower molecular weight phthalate metabolites. Less consistent findings, by mixed model analyses, were detected for BMI and body composition, by dual energy X-ray absorptiometry (DEXA), with some positive associations of phthalate metabolites with BMI and some negative associations with DEXA fat tissue measures, although no consistent findings were evident. In conclusion, we derived some associations of childhood growth with prenatal phthalate exposure, particularly with respect to the lower molecular weight phthalate metabolites.

The perceptions of pregnant women about cervical length screening for preterm birth prevention.

BACKGROUND: The Western Australian Preterm Birth Prevention Initiative was officially launched in November 2014. It demonstrated an initial decrease in the preterm birth rate in Western Australia. One of the key points of this initiative is the routine ultrasound measurement of the cervical length in mid-pregnancy. AIM: The aim of this study was to evaluate the perceptions and attitudes of Western Australian women regarding transvaginal cervical length (TVCL) screening for preterm birth prevention. MATERIALS AND METHODS: Self-administered questionnaires were completed by pregnant women before and after their mid-trimester obstetric ultrasound. Maternal demographical and medical data were collected in addition to opinions of TVCL screening. RESULTS: A total of 598 women participated with the maternal age range representative of the Western Australian obstetric population. There was a high rate of acceptance of TVCL imaging, with 2% of the 149 women declining a transvaginal ultrasound (TVU) offered in this study, 1.5% refusing a TVU in the past and 5.7% reporting that they would have a concern in having a TVU in the future. Women stated that they either had declined TVCL in the past (11%) or would decline in the future (30.7%) as they wanted to discuss the procedure with their clinician first, had been advised not to have a TVU by their clinician (11% in the past and 47.7% in the future) or felt uncomfortable with the operator (22% at a previous TVU and 34.4% in the future). CONCLUSION: Pregnant women participating in this study had a high acceptance of TVCL screening for preterm birth prevention.

Preventing early births in a regional tertiary maternity unit: Evaluating preterm and early term birth rates before and after implementation of the Preterm Birth Prevention Initiative in the Australian Capital Territory.

BACKGROUND: A multifaceted preterm birth (PTB) prevention initiative was launched in the Australian Capital Territory (ACT) in 2019. The aim of this initiative was to safely lower the rate of early births across the ACT and the surrounding areas in New South Wales. Modelled on the Western Australian PTB Prevention Initiative, the program included new clinical guidelines and a new PTB prevention clinic at the main tertiary hospital. AIM: To evaluate the initiative and its effects on preterm and early term birth rates at the main tertiary hospital after 16 months of implementation. MATERIALS AND METHODS: A before and after intervention study was conducted. Rates of preterm and early term birth before (previous five years) and after 16 months of implementation of the ACT PTB Prevention Initiative were evaluated. RESULTS: At the main tertiary hospital in The Canberra Hospital, the rate of PTB was significantly reduced by 10% after 16 months of implementation of the initiative. Rates of PTB were lower than any of the preceding five years and resulted in 45 averted or delayed PTBs. The number of planned early term births with no medical indication was significantly reduced by 34.5% and resulted in 77 averted or delayed early term births. CONCLUSIONS: The multifaceted PTB Prevention Initiative safely lowered the rates of early birth in the ACT context. These results highlight the importance of prioritising early birth prevention, education, research and expanding the initiative nationwide.

Updated adolescent diagnostic criteria for polycystic ovary syndrome: impact on prevalence and longitudinal body mass index trajectories from birth to adulthood.

BACKGROUND: Polycystic ovary syndrome (PCOS) is challenging to diagnose. While the 2003 Rotterdam criteria are widely used for adults, the 2018 international PCOS guideline recommended updated Rotterdam criteria with both hyperandrogenism and oligo-anovulation for adolescents based on evidence-informed expert consensus. This study compared the prevalence of PCOS using updated and original Rotterdam criteria in community-based adolescents and explored long-term body mass index (BMI) trajectories across different diagnostic phenotypes. METHODS: Overall, 227 postmenarchal adolescent females from the prospective cohort Raine Study undertook comprehensive PCOS assessment at age 14-16 years. Detailed anthropometric measurements were collected from birth until age 22 years. Cross-sectional and longitudinal BMI were analyzed using t tests and generalized estimating equations. RESULTS: PCOS was diagnosed in 66 (29.1%) participants using original criteria versus 37 (16.3%) participants using updated Rotterdam criteria. Using updated criteria, participants with PCOS had higher BMI than participants without PCOS from prepubertal. Only the phenotype meeting the updated criteria was significantly associated with higher long-term BMI gain whereas other PCOS phenotypes had similar BMI trajectories to participants without PCOS (p < 0.001). CONCLUSIONS: The use of the 2018 updated Rotterdam criteria reduces over-diagnosis of PCOS in adolescents and identifies those at the greatest risk of long-term weight gain, a key contributor to disease severity and long-term health implications. The BMI trajectories of females with PCOS on updated criteria diverge prepubertally compared to those without PCOS. This work supports targeting adolescents diagnosed with PCOS on the 2018 updated criteria for early lifestyle interventions to prevent long-term health complications.

Physiology and Predictors of Impaired Gas Exchange in Infants with Bronchopulmonary Dysplasia.

Rationale: A sensitive outcome measure for infants with bronchopulmonary dysplasia would facilitate clinical benchmarking and enhance epidemiologic understanding, evaluation of clinical interventions, and outcome prediction.Objectives: Noninvasive assessment of pulmonary gas exchange in preterm infants with and without bronchopulmonary dysplasia to grade disease severity and to identify determinants of impaired gas exchange.Methods: This is a prospective observational study in very preterm infants. Inspired oxygen partial pressure (PiO2) was decreased stepwise to achieve oxygen saturation as measured by pulse oximetry (SpO2) that decreased from 95% to 86%. Right shift, V⋅a/Q⋅, and right-left shunt were derived from the resulting SpO2 versus PiO2 curve and compared with current disease severity classification. Potential determinants of shift, V⋅a/Q⋅, and shunt were identified using principal components analysis and multiple linear regression.Measurements and Main Results: A total of 219 infants with median (interquartile range) gestation of 28 weeks and 0 days (26 weeks and 0 days to 29 weeks and 0 days) had a valid study at 35 weeks and 4 days (34 weeks and 1 day to 39 weeks and 3 days) of postmenstrual age. Shift increased and V⋅a/Q⋅ decreased as severity of bronchopulmonary dysplasia increased. Infants with moderate-severe disease also had increased shunt. Extent of impaired gas exchange overlapped between severity groups. Infants requiring mechanical support but no supplemental oxygen at 36 weeks' postmenstrual age had similar values of shift, V⋅a/Q⋅, and shunt to preterm infants without bronchopulmonary dysplasia. Lower gestation and increased duration of invasive ventilation independently predicted increased shift, decreased V⋅a/Q⋅, and increased shunt. Shift was the most sensitive and specific index of the severity of bronchopulmonary dysplasia.Conclusions: Most infants with bronchopulmonary dysplasia have impaired oxygenation quantified by a simple, sensitive bedside test. Shift of the SpO2/PiO2 curve may be useful for prediction and measurement of preterm infant respiratory outcomes.

Attitudes towards abortion in male and female adolescents with diverse sexual and pregnancy experiences: a cross-sectional study.

Background Research focused on adolescents' attitudes towards abortion is limited, and validated scales are not routinely used. A greater understanding of adolescents' attitudes towards abortion could better inform the sexuality education strategies targeted at this age group. METHODS: A cross-sectional survey was completed by 1470 adolescents (437 males, 1033 females) aged 12-19 years and living in Perth, Australia. Participants were recruited from secondary schools, antenatal clinics and termination clinics to capture varying experiences of sexual activity and pregnancy. Survey items investigated abortion attitudes, sexual behaviour and pregnancy history alongside other demographic and psychosocial factors. Analyses included comparative means and adjusted linear regressions. RESULTS: Sexually active participants (n = 554) and females reporting a previous abortion (n = 196) held more supportive attitudes towards abortion (P < 0.001 for both). Among sexually active females, more supportive attitudes were held by those reporting a previous abortion (ß = 2.60, 95% confidence interval 0.93-4.27, P = 0.002), later age (≥16 years) at first vaginal intercourse (P < 0.001), use of oral contraception at last sex (P = 0.029), previous condom use (P < 0.001) and/or three or more oral sex partners in the previous 12 months (P = 0.005). For sexually active males, more supportive attitudes were reported by those whose female partners had used oral contraception at last sex (P = 0.013) or ever (P = 0.017). Multivariable analyses indicated that other correlates, including risky sexual behaviour, had minimal or no effect on attitudes. CONCLUSIONS: Adolescents' attitudes towards abortion appear to be influenced by their ability to personalise and contextualise the effect of a pregnancy. Associations between less-effective contraceptive use and reduced support for abortion may be explained by a diminished perceived risk of parenthood. Educational strategies should acknowledge and respond to differences in abortion attitudes as adolescents commence and navigate sexual relationships.

Effects of maturation and size on population pharmacokinetics of pentoxifylline and its metabolites in very preterm infants with suspected late-onset sepsis or necrotizing enterocolitis: a pilot study incorporating clinical outcomes.

AIMS: Infection-induced inflammation is associated with adverse long-term outcomes in preterm infants. Pentoxifylline (PTX) is a candidate for adjunct immunomodulatory therapy in preterm infants with late-onset sepsis (LOS) and necrotizing enterocolitis (NEC), but pharmacokinetic data in this population are extremely limited. This study aims to characterize the pharmacokinetic properties of intravenous PTX and its metabolites in preterm infants. METHOD: An open label pilot clinical study of intravenous PTX as an adjunct therapy in preterm infants (gestation <32 weeks) with suspected LOS or NEC was undertaken. PTX was infused for 12 h for two days (60 mg kg-1 per 12 h), and in infants with confirmed diagnosis of LOS or NEC, for 6 h for another 4 days (30 mg kg-1 per 6 h). Plasma concentrations of PTX and its principal metabolites from collected blood samples were measured using a validated LCMS assay. NONMEM was used to analyse the data using population pharmacokinetic modelling. RESULTS: The preterm infants (n = 26) had a median (range) gestation of 24.8 weeks (23.3-30.4) and birthweight of 689 g (370-1285). PTX was well tolerated and without treatment-limiting adverse effects. Changes in size (weight) and maturation were successfully modelled for PTX and metabolites. After allometric scaling, clearance increased with postmenstrual age, increasing by approximately 30% per week for PTX and M1 (lisofylline) and simulations of current dosing demonstrated a six-fold difference in exposure between 24 and 35 weeks postmenstrual age. CONCLUSIONS: The developed model can be used to explore dosing strategies based on size and maturation for preterm infants.

The impact of antenatal Bisphenol A exposure on male reproductive function at 20-22 years of age.

Bisphenol A (BPA) is a ubiquitous chemical suspected to possess oestrogenic hormonal activities. Male population studies suggest a negative impact on testicular function. As Sertoli cell proliferation occurs during fetal or early postnatal life, it is speculated that oestrogenic environmental exposures may influence mature testicular function. Among 705 Western Australian Pregnancy Cohort (Raine) Study men aged 20-22 years, 404 underwent testicular ultrasound examination (149 had maternal serum available), and/or 365 provided semen (136 had maternal serum) and/or 609 serum samples for sex steroids, gonadotrophins and inhibin B analysis (244 had maternal serum). Maternal serum collected at 18 and 34 weeks' gestation was pooled and assayed for concentrations of total BPA (free plus conjugated) as an estimate of antenatal exposure. Testicular volume was calculated by ultrasonography, and semen analysis performed. Serum LH, FSH and inhibin B were measured by immunoassay; testosterone, oestradiol, oestrone andBPA were measured by liquid chromatography-mass spectrometry. BPA levels were detectable in most (89%) maternal serum samples. After adjustment for maternal smoking, abstinence and varicocele, sperm concentration and motility were significantly correlated to maternal serum BPA (r = 0.18; P = 0.04 for both). No other associations of maternal serum BPA with testicular function were observed.

Long-term survival of patients with mismatch repair protein-deficient, high-stage ovarian clear cell carcinoma.

AIMS: Gynaecological cancer patients with germline mutations appear to have a better prognosis than those with sporadic malignancies. Following the observation of long-term survival in a patient with stage III ovarian clear cell carcinoma (CCC) and possible Lynch syndrome (LS), DNA mismatch repair (MMR) protein immunohistochemistry was performed in a series of high-stage CCC and correlated with patient outcomes. METHODS AND RESULTS: Thirty-two consecutive cases of stage III/IV ovarian CCCs accessioned between 1992 and 2015 were examined. The tumours from two patients (6%), including the index case, showed loss of MSH2/MSH6 expression while MLH1/PMS2 staining was retained. The index patient subsequently developed colonic and rectal carcinomas that were also MSH2/MSH6-deficient, while the second patient had a genetically confirmed germline MSH2 mutation. All other tumours showed retained expression of the four MMR proteins. The two patients with MMR protein-deficient tumours were alive 160 months and 124 months following surgery, whereas the median survival of patients with MMR protein-intact CCCs was 11.8 months (75th and 25th percentiles of 8.1 months and 39.3 months, respectively), with 21 patients deceased due to tumour. CONCLUSIONS: Larger studies are required but high-stage, MMR protein-deficient CCCs may have a relatively favourable prognosis.

Reducing preterm birth by a statewide multifaceted program: an implementation study.

BACKGROUND: A comprehensive preterm birth prevention program was introduced in the state of Western Australia encompassing new clinical guidelines, an outreach program for health care practitioners, a public health program for women and their families based on print and social media, and a new clinic at the state's sole tertiary level perinatal center for referral of those pregnant women at highest risk. The initiative had the single aim of safely lowering the rate of preterm birth. OBJECTIVE: The objective of the study was to evaluate the outcomes of the initiative on the rates of preterm birth both statewide and in the single tertiary level perinatal referral center. STUDY DESIGN: This was a prospective population-based cohort study of perinatal outcomes before and after 1 full year of implementation of the preterm birth prevention program. RESULTS: In the state overall, the rate of singleton preterm birth was reduced by 7.6% and was lower than in any of the preceding 6 years. This reduction amounted to 196 cases relative to the year before the introduction of the initiative and the effect extended from the 28-31 week gestational age group onward. Within the tertiary level center, the rate of preterm birth in 2015 was also significantly lower than in the preceding years. CONCLUSION: A comprehensive and multifaceted preterm birth prevention program aimed at both health care practitioners and the general public, operating within the environment of a government-funded universal health care system can significantly lower the rate of early birth. Further research is now required to increase the effect and to determine the relative contributions of each of the interventions.

Levels of innate immune factors in preterm and term mothers' breast milk during the 1st month postpartum.

There is a paucity of data on the effect of preterm birth on the immunological composition of breast milk throughout the different stages of lactation. We aimed to characterise the effects of preterm birth on the levels of immune factors in milk during the 1st month postpartum, to determine whether preterm milk is deficient in antimicrobial factors. Colostrum (days 2-5 postpartum), transitional milk (days 8-12) and mature milk (days 26-30) were collected from mothers of extremely preterm (<28 weeks of gestation, n 15), very preterm (28-<32 weeks of gestation, n 15), moderately preterm (32-<37 weeks of gestation, n 15) and term infants (37-41 weeks of gestation, n 15). Total protein, lactoferrin, secretory IgA, soluble CD14 receptor (sCD14), transforming growth factor-ß2 (TGF-ß2), α defensin 5 (HD5), ß defensins 1 (HBD1) and 2, IL-6, IL-10, IL-13, interferon-γ, TNF-α and lysozyme (LZ) were quantified in milk. We examined the effects of lactation stage, gestational age, volume of milk expressed, mode of delivery, parity and maternal infection on milk immune factor concentrations using repeated-measures regression analysis. The concentrations of all factors except LZ and HD5 decreased over the 1st month postpartum. Extremely preterm mothers had significantly higher concentrations of HBD1 and TGF-ß2 in colostrum than term mothers did. After controlling for other variables in regression analyses, preterm birth was associated with higher concentrations of HBD1, LZ and sCD14 in milk samples. In conclusion, preterm breast milk contains significantly higher concentrations of some immune proteins than term breast milk.