An evaluation of the quality, suitability and impact on equity of clinical practice guidelines relevant to preterm birth for use in Aotearoa New Zealand.

BACKGROUND: Preterm birth is a leading cause of perinatal morbidity and mortality and a defining event for pregnant people, infants, and whanau (extended families). Recommendations have been made for a national preterm birth prevention initiative focusing on equity in Aotearoa New Zealand, including the development of a national best practice guide. An understanding of the number and quality of guidelines, and consideration of their suitability and impact on equity is required. METHODS: Guidelines were identified through a systematic literature search, search of professional bodies websites, and invitation to regional health services in Aotearoa New Zealand. Obstetric and midwifery clinical directors were invited to report on guideline use. Identified guidelines were appraised by a 23-member trans-disciplinary Review Panel; quantitatively using the AGREE-II instrument and qualitatively using modified ADAPTE questions. The quality of guidelines available but not in use was compared against those in current use, and by health services by level of maternity and neonatal care. Major themes affecting implementation and impact on equity were identified using Braun and Clarke methodology. RESULTS: A total of 235 guidelines were included for appraisal. Guidelines available but not in use by regional health services scored higher in quality than guidelines in current use (median domain score Rigour and Development 47.5 versus 18.8, p < 0.001, median domain score Overall Assessment 62.5 versus 44.4, p < 0.001). Guidelines in use by regional health services with tertiary maternity and neonatal services had higher median AGREE II scores in several domains, than those with secondary level services (median domain score Overall Assessment 50.0 versus 37.5, p < 0.001). Groups identified by the Review Panel as experiencing the greatest constraints and limitations to guideline implementation were rural, provincial, low socioeconomic, Maori, and Pacific populations. Identified themes to improve equity included a targeted approach to groups experiencing the least advantage; a culturally considered approach; nationally consistent guidance; and improved funding to support implementation of guideline recommendations. CONCLUSIONS: We have systematically identified and assessed guidelines on preterm birth. High-quality guidelines will inform a national best practice guide for use in Taonga Tuku Iho, a knowledge translation project for equity in preterm birth care and outcomes in Aotearoa.

Interventions affecting the nitric oxide pathway versus placebo or no therapy for fetal growth restriction in pregnancy.

BACKGROUND: Fetal growth restriction (FGR) is a condition of poor growth of the fetus in utero. One of the causes of FGR is placental insufficiency. Severe early-onset FGR at < 32 weeks of gestation occurs in an estimated 0.4% of pregnancies. This extreme phenotype is associated with a high risk of fetal death, neonatal mortality, and neonatal morbidity. Currently, there is no causal treatment, and management is focused on indicated preterm birth to prevent fetal death. Interest has risen in interventions that aim to improve placental function by administration of pharmacological agents affecting the nitric oxide pathway causing vasodilatation. OBJECTIVES: The objective of this systematic review and aggregate data meta-analysis is to assess the beneficial and harmful effects of interventions affecting the nitric oxide pathway compared with placebo, no therapy, or different drugs affecting this pathway against each other, in pregnant women with severe early-onset FGR. SEARCH METHODS: We searched Cochrane Pregnancy and Childbirth's Trials Register, ClinicalTrials.gov, the WHO International Clinical Trials Registry Platform (ICTRP) (16 July 2022), and reference lists of retrieved studies. SELECTION CRITERIA: We considered all randomised controlled comparisons of interventions affecting the nitric oxide pathway compared with placebo, no therapy, or another drug affecting this pathway in pregnant women with severe early-onset FGR of placental origin, for inclusion in this review. DATA COLLECTION AND ANALYSIS: We used standard Cochrane Pregnancy and Childbirth methods for data collection and analysis. MAIN RESULTS: We included a total of eight studies (679 women) in this review, all of which contributed to the data and analysis. The identified studies report on five different comparisons: sildenafil compared with placebo or no therapy, tadalafil compared with placebo or no therapy, L-arginine compared with placebo or no therapy, nitroglycerin compared with placebo or no therapy and sildenafil compared with nitroglycerin. The risk of bias of included studies was judged as low or unclear. In two studies the intervention was not blinded. The certainty of evidence for our primary outcomes was judged as moderate for the intervention sildenafil and low for tadalafil and nitroglycerine (due to low number of participants and low number of events). For the intervention L-arginine, our primary outcomes were not reported. Sildenafil citrate compared to placebo or no therapy (5 studies, 516 women) Five studies (Canada, Australia and New Zealand, the Netherlands, the UK and Brazil) involving 516 pregnant women with FGR were included. We assessed the certainty of the evidence as moderate. Compared with placebo or no therapy, sildenafil probably has little or no effect on all-cause mortality (risk ratio (RR) 1.01, 95% confidence interval (CI) 0.80 to 1.27, 5 studies, 516 women); may reduce fetal mortality (RR 0.82, 95% CI 0.60 to 1.12, 5 studies, 516 women), and increase neonatal mortality (RR 1.45, 95% CI 0.90 to 2.33, 5 studies, 397 women), although the results are uncertain for fetal and neonatal mortality as 95% confidence intervals are wide crossing the line of no effect. Tadalafil compared with placebo or no therapy (1 study, 87 women) One study (Japan) involving 87 pregnant women with FGR was included. We assessed the certainty of the evidence as low. Compared with placebo or no therapy, tadalafil may have little or no effect on all-cause mortality (risk ratio 0.20, 95% CI 0.02 to 1.60, one study, 87 women); fetal mortality (RR 0.11, 95% CI 0.01 to 1.96, one study, 87 women); and neonatal mortality (RR 0.89, 95% CI 0.06 to 13.70, one study, 83 women). L-Arginine compared with placebo or no therapy (1 study, 43 women) One study (France) involving 43 pregnant women with FGR was included. This study did not assess our primary outcomes. Nitroglycerin compared to placebo or no therapy (1 studies, 23 women) One study (Brazil) involving 23 pregnant women with FGR was included. We assessed the certainty of the evidence as low. The effect on the primary outcomes is not estimable due to no events in women participating in both groups. Sildenafil citrate compared to nitroglycerin (1 study, 23 women) One study (Brazil) involving 23 pregnant women with FGR was included. We assessed the certainty of the evidence as low. The effect on the primary outcomes is not estimable due to no events in women participating in both groups. AUTHORS' CONCLUSIONS: Interventions affecting the nitric oxide pathway probably do not seem to influence all-cause (fetal and neonatal) mortality in pregnant women carrying a baby with FGR, although more evidence is needed. The certainty of this evidence is moderate for sildenafil and low for tadalafil and nitroglycerin. For sildenafil a fair amount of data are available from randomised clinical trials, but with low numbers of participants. Therefore, the certainty of evidence is moderate. For the other interventions investigated in this review there are insufficient data, meaning we do not know whether these interventions improve perinatal and maternal outcomes in pregnant women with FGR.

Is Three a Crowd? The Influence of Companions on a Patient's Decision to Transition to a Biosimilar.

BACKGROUND: Involving patients in treatment decisions is commonplace in healthcare, and patients are frequently accompanied by a companion (support person). Companions are often actively involved in medical consultations, yet their impact on decisions to change medications is unknown. PURPOSE: This study examines the influence of companions on a patient's decision to transition from their bio-originator therapy to a biosimilar. METHODS: A parallel, two-arm randomized controlled trial was conducted with 79 patients taking a bio-originator for rheumatic diseases who regularly attend clinic with a companion. Patients were randomized to receive an explanation about a hypothetical transition to a biosimilar alone or with their companion. Patients reported willingness to transition, risk perceptions, difficulty understanding, social support, and completed the Decisional Conflict Scale and Satisfaction with Decision Scale. RESULTS: Companions did not influence decisions to transition to biosimilars or cognitive and affective risk perceptions. Accompanied patients reported more difficulty understanding the explanation (p = .006, Cohen's d = .64) but thought it was more important to receive information with companions (p = .023, Cohen's d = -.52). Companions did not impact decision satisfaction or decisional conflict. Receiving emotional, but not practical support, was associated with less decisional conflict in accompanied patients (p = .038, r2 = 0.20). CONCLUSIONS: The presence of companions does not seem to influence risk perceptions or decisions about transitioning to biosimilars. Companions, however, impact the patient's reporting of their ability to understand treatment explanations. Providers should check understanding in all patients but may need to provide additional time or educational resources to accompanied patients and companions. TRIAL REGISTRATION: Australian New Zealand Clinical Trial Registry: ACTRN12619001435178.

Antiphospholipid antibodies can specifically target placental mitochondria and induce ROS production.

Women with antiphospholipid antibodies (aPL) have increased risks of pregnancy complications, including a ten-fold increased risk of preeclampsia, which is potentially triggered by the release of placental toxins. Previously, aPL were shown to enter the outer layer of the placenta, the syncytiotrophoblast, associate with mitochondria, and alter mitochondrial function. We hypothesised that aPL may also increase mitochondrial reactive oxygen species (ROS) production, leading to cellular dysfunction and release of toxins. First trimester placental explants were incubated with monoclonal aPL, ID2 and IIC5 (25, 50, and 100 µg/mL), for 3 h at 37 °C and ROS production followed using CellROX Deep Red. In addition, the candidate treatment compounds chloroquine, melatonin, and Mito-Q were tested at therapeutic concentrations for their ability to prevent ROS production. Mitochondria isolated from term placentae were incubated with fluorescently-labelled ID2, IIC5, or control IgG antibodies (2.5, 5, 10, or 20 µg/mL) for 30 min, and mitochondria with bound antibodies were quantified using flow cytometry. In addition, respirometry coupled with fluorimetry was used to interrogate explant mitochondrial respiration and ROS production following incubation with 25, 50, or 100 µg/mL ID2, IIC5, or control IgG for 3 h at 37 °C. ID2 increased explant ROS production in a manner that was completely prevented by the endocytosis inhibitor chloroquine, and partially prevented by the antioxidants melatonin and Mito-Q. Both ID2 and IIC5 displayed a greater ability to bind isolated mitochondria than control antibodies, and increased ROS production attributable to the mitochondrial enzyme glycerol 3-phosphate dehydrogenase (mGPDH). Our evidence supports the hypothesis that aPL interact with syncytiotrophoblast mitochondria, likely via the binding of cardiolipin and ß2 glycoprotein I in mitochondrial membranes, and induce ROS production which contributes to overall oxidative stress and placental dysfunction.

Growing human trophoblasts in vitro: a review of the media commonly used in trophoblast cell culture.

Trophoblasts are unique epithelial cells found only in the placenta. It has been possible to isolate and maintain human trophoblasts in in vitro culture for many decades. During this period there have been a vast array of media and supplements reported for trophoblast culture and often the reasons for using the media and specific supplements employed in any given laboratory have been lost in the 'mists of time'. After a gradual development over many years this field has recently changed, with the publication of several reports of the isolation, growth and differentiation of human trophoblast stem or stem-like cells. This advance was made largely because of a greater understanding of the molecular pathways that control human trophoblasts and availability of media supplements that can be used to manipulate those pathways. We have searched the literature and here summarise many of the different media and supplements and describe how and why they were developed and are used to culture human trophoblasts.

The Biomarkers for Preterm Birth Study-A prospective observational study comparing the impact of vaginal biomarkers on clinical practice when used in women with symptoms of preterm labor.

INTRODUCTION: This study aims to compare the use of qualitative fetal fibronectin, quantitative fetal fibronectin, and placental α-microglobulin-1 in women with symptoms of preterm labor, to evaluate which vaginal biomarker performs the best in clinical practice. MATERIAL AND METHODS: This prospective observational study included women who presented with symptoms of preterm labor at 24+0 to 34+0  weeks of gestation at a large tertiary maternity hospital in Auckland, New Zealand. Women were managed according to hospital guidelines using qualitative fetal fibronectin. Quantitative fetal fibronectin and placental α-microglobulin-1 tests were also taken, with clinicians blinded to the results. Management and delivery outcomes were collected from clinical records. The primary outcome was the rate of antenatal hospital admission. Analysis was performed according to predefined management protocols for each of the tests. RESULTS: A total of 128 women had all three biomarkers tests taken. Spontaneous preterm birth rates were 7/128 (5.5%) ≤34+0  weeks and 20/128 (15.6%) <37+0  weeks of gestation; 5/128 (3.9%) delivered within 7 days of testing. Positive results were recorded in 28 qualitative fetal fibronectin tests, 25 quantitative fetal fibronectin tests with 11 ≥200 ng/mL, and 16 placental α-microglobulin-1 tests. The use of quantitative fetal fibronectin or placental α-microglobulin-1 would have lowered antenatal admission rates: 27/128 (21.1%) for qualitative fetal fibronectin, 11/128 (8.6%) for quantitative fetal fibronectin (admission threshold ≥200 ng/mL), and 15/128 (11.7%) for placental α-microglobulin-1. No additional women with quantitative fetal fibronectin <200 ng/mL delivered within 7 days or missed corticosteroids compared with standard care (qualitative fetal fibronectin); however, an additional 3 cases had a false-negative placental α-microglobulin-1 and clinical care may have been compromised (no antenatal corticosteroids or admission). CONCLUSIONS: The use of quantitative fetal fibronectin (admission threshold ≥200 ng/mL) has the potential to reduce the rate of antenatal admissions for women with symptoms of preterm labor without compromising use of antenatal interventions that improve outcomes for babies born preterm.

The role of aspirin, heparin, and other interventions in the prevention and treatment of fetal growth restriction.

Fetal growth restriction and related placental pathologies such as preeclampsia, stillbirth, and placental abruption are believed to arise in early pregnancy when inadequate remodeling of the maternal spiral arteries leads to persistent high-resistance and low-flow uteroplacental circulation. The consequent placental ischaemia, reperfusion injury, and oxidative stress are associated with an imbalance in angiogenic/antiangiogenic factors. Many interventions have centered on the prevention and/or treatment of preeclampsia with results pertaining to fetal growth restriction and small-for-gestational-age pregnancy often included as secondary outcomes because of the common pathophysiology. This renders the study findings less reliable for determining clinical significance. For the prevention of fetal growth restriction, a recent large-study level meta-analysis and individual patient data meta-analysis confirm that aspirin modestly reduces small-for-gestational-age pregnancy in women at high risk (relative risk, 0.90, 95% confidence interval, 0.81-1.00) and that a dose of ≥100 mg should be recommended and to start at or before 16 weeks of gestation. These findings support national clinical practice guidelines. In vitro and in vivo studies suggest that low-molecular-weight heparin may prevent fetal growth restriction; however, evidence from randomized control trials is inconsistent. A meta-analysis of multicenter trial data does not demonstrate any positive preventative effect of low-molecular-weight heparin on a primary composite outcome of placenta-mediated complications including fetal growth restriction (18% vs 18%; absolute risk difference, 0.6%; 95% confidence interval, 10.4-9.2); use of low-molecular-weight heparin for the prevention of fetal growth restriction should remain in the research setting. There are even fewer treatment options once fetal growth restriction is diagnosed. At present the only management option if the risk of hypoxia, acidosis, and intrauterine death is high is iatrogenic preterm birth, with the use of peripartum maternal administration of magnesium sulphate for neuroprotection and corticosteroids for fetal lung maturity, to prevent adverse neonatal outcomes. The pipeline of potential therapies use different strategies, many aiming to increase fetal growth by improving poor placentation and uterine blood flow. Phosphodiesterase type 5 inhibitors that potentiate nitric oxide availability such as sildenafil citrate have been extensively researched both in preclinical and clinical studies; results from the Sildenafil Therapy In Dismal Prognosis Early-Onset Intrauterine Growth Restriction consortium of randomized control clinical trials are keenly awaited. Targeting the uteroplacental circulation with novel therapeutics is another approach, the most advanced being maternal vascular endothelial growth factor gene therapy, which is being translated into the clinic via the doEs Vascular endothelial growth factor gene therapy safEly impRove outcome in seveRe Early-onset fetal growth reSTriction consortium. Other targeting approaches include nanoparticles and microRNAs to deliver drugs locally to the uterine arterial endothelium or trophoblast. In vitro and in vivo studies and animal models have demonstrated effects of nitric oxide donors, dietary nitrate, hydrogen sulphide donors, statins, and proton pump inhibitors on maternal blood pressure, uteroplacental resistance indices, and angiogenic/antiangiogenic factors. Data from human pregnancies and, in particular, pregnancies with fetal growth restriction remain very limited. Early research into melatonin, creatine, and N-acetyl cysteine supplementation in pregnancy suggests they may have potential as neuro- and cardioprotective agents in fetal growth restriction.

Enoxaparin for the prevention of preeclampsia and intrauterine growth restriction in women with a history: a randomized trial.

BACKGROUND: Preeclampsia and small-for-gestational-age pregnancy are major causes of maternal and perinatal morbidity and mortality. Women with a previous pregnancy affected by these conditions are at an increased risk of recurrence in a future pregnancy. Past trials evaluating the effect of low-molecular-weight heparin for the prevention of recurrence of preeclampsia and small-for-gestational-age pregnancy have shown conflicting results with high levels of heterogeneity displayed when trials were compared. OBJECTIVE: We sought to assess the effectiveness of enoxaparin in addition to high-risk care for the prevention of preeclampsia and small-for-gestational-age pregnancy in women with a history of these conditions. STUDY DESIGN: This was an open-label randomized controlled trial in 5 tertiary care centers in 3 countries. Women with a viable singleton pregnancy were invited to participate between >6+0 and <16+0 weeks if deemed to be at high risk of preeclampsia and/or small for gestational age based on their obstetric history. Eligible participants were randomly assigned in a 1-to-1 ratio to standard high-risk care or standard high-risk care plus enoxaparin 40 mg (4000 IU) by subcutaneous injection daily from recruitment until 36+0 weeks or delivery, whichever occurred sooner. Standard high-risk care was defined as care coordinated by a high-risk antenatal clinic service, aspirin 100 mg daily until 36+0 weeks, and-for women with prior preeclampsia-calcium 1000-1500 mg daily until 36+0 weeks. In a subgroup of participants serum samples were taken at recruitment and at 20 and 30 weeks' gestation and later analyzed for soluble fms-like tyrosine kinase-1, soluble endoglin, endothelin-1, placental growth factor, and soluble vascular cell adhesion molecule 1. The primary outcome was a composite of preeclampsia and/or small-for-gestational-age <5th customized birthweight percentile. All data were analyzed on an intention-to-treat basis. The trial is registered with the Australian New Zealand Clinical Trials Registry (ACTRN12609000699268). RESULTS: Between July 26, 2010, and Oct. 28, 2015, a total of 156 participants were enrolled and included in the analysis. In all, 149 participants were included in the outcome analysis (72 receiving standard high-risk care plus enoxaparin and 77 receiving standard high-risk care only). Seven women who miscarried <16 weeks' gestation were excluded. The majority of participants (151/156, 97%) received aspirin. The addition of enoxaparin had no effect on the rate of preeclampsia and/or small-for-gestational-age <5th customized birthweight percentile: enoxaparin 18/72 (25%) vs no enoxaparin 17/77 (22.1%) (odds ratio, 1.19; 95% confidence interval, 0.53-2.64). There was also no difference in any of the secondary outcome measures. Levels of soluble fms-like tyrosine kinase-1 and soluble endoglin increased among those who developed preeclampsia, but there was no difference in levels of these antiangiogenic factors (nor any of the other serum analytes measured) among those treated with enoxaparin compared to those receiving standard high-risk care only. CONCLUSION: The use of enoxaparin in addition to standard high-risk care does not reduce the risk of recurrence of preeclampsia and small-for-gestational-age infants in a subsequent pregnancy.

Randomised clinical trials in perinatal health care: a cost-effective investment.

OBJECTIVE: To compare the health and economic impacts of implementing efficacious treatment interventions with maintaining standard practice in maternal and perinatal health care. DESIGN AND SETTING: We identified randomised clinical trials (RCTs) in the Perinatal Society of Australia and New Zealand trials database that commenced recruitment during 2008 and had completed recruitment by 2015. Data from clinical trial registries and publications were collated to calculate the potential cost savings achievable by implementing efficacious treatment interventions. MAIN OUTCOME MEASURE: Projected net cost savings over 5 years. RESULTS: Twenty-three eligible RCTs covering a range of behavioural and clinical interventions were identified, of which six reported interventions superior to standard practice (four trials) or placebo (two). The outcomes (but not the costs) of 17 trials were excluded from analysis (no difference between intervention and comparator groups in seven trials, recruitment problems in six, findings not yet published in four). The total funding amount for the 23 trials was $20.3 million; the potential cost savings over 5 years if the findings of the six trials reporting superior interventions were implemented was estimated to be $26.3 million if 10% of the eligible populations received the effective interventions, and $262.8 million with 100% implementation. CONCLUSIONS: Our retrospective analysis highlights the value of research in perinatal care and the importance of implementing positive findings for realising its value. Future trials in maternal and perinatal health care may provide significant returns on investment by informing clinical practice, improving patient outcomes and reducing health care costs.

Investigating antenatal corticosteroid clinical guideline practice at an organisational level.

BACKGROUND: High-quality, evidence-based guidelines can improve the quality of health care and facilitate standardisation of practice within and across healthcare organisations. Limited information is known regarding existing antenatal corticosteroid (ACS) guideline practices within organisations across Australia and New Zealand. AIMS: To assess existing ACS clinical practice guidelines (CPG). To describe current organisational practice related to the production, implementation and renewal of CPG. DESIGN: A cross-sectional survey of hospital practice using an online questionnaire. METHODS: Clinical Managers at 27 secondary and 25 tertiary maternity hospitals, that contribute data to the Australia and New Zealand Neonatal Network, were approached from May to September 2015 and completed the questionnaire on behalf of their organisation. RESULTS: Of the hospitals surveyed, 93% reported having a CPG or protocol. Of these, 89% of CPG included recommendations on a single course of ACS, 37% on the use of repeat course/s and 41% on use prior to elective caesarean section at term. Variation in the recommendations provided existed between countries and depending on the level of neonatal care provided. A guideline development group existed in 85% of hospitals. The preferred tools to facilitate implementation of a CPG include: email with a link to the hospital intranet, education sessions and an opinion leader. Only 28% of respondents reported auditing the use of ACS administration. CONCLUSIONS: There is significant variation in the recommendations provided by current ACS CPGs. Utilisation of a single ACS CPG reflective of the current available evidence base may limit this variation.

A prospective audit of the adherence to a new magnesium sulphate guideline for the neuroprotection of infants born less than 30 weeks' gestation.

Antenatal magnesium sulphate reduces the risk of cerebral palsy in babies born <30 weeks' gestation. A guideline for its use in women at imminent risk of preterm birth was implemented at National Women's Health, Auckland City Hospital in 2012. This prospective audit assessed adherence to the guideline in women delivering at <30 weeks in the first year after its implementation. Magnesium sulphate was safely administered to 58 of 71 (82%) eligible women and 58 of 61 (95%) of women where it was clinically appropriate and practically achievable.

The accuracy of ultrasound-estimated fetal weight in extremely preterm infants: a comparison of small for gestational age and appropriate for gestational age.

OBJECTIVES: To compare the accuracy of estimated fetal weight (EFW) in extremely preterm small for gestational age (SGA) and appropriate for gestational age (AGA) infants and report other significant factors influencing the accuracy of EFW. METHODS: A retrospective cohort study of singleton pregnancies 22(+0) -27(+6)  weeks. Women were included in the study if an ultrasound scan had been performed within seven days of delivery, with no major fetal anomaly and data available to calculate customised birthweight (BW) centiles. Mean error of EFW and actual BW and mean % error of EFW and actual birthweight were compared for SGA and AGA infants. A stepwise backward elimination linear regression model was used to determine the significant factors influencing the accuracy of EFW. RESULTS: A total of 134 cases (51 SGA and 83 AGA) were analysed. The mean gestational age at delivery was 25(+2)  weeks (SD 11.5 days) and mean BW 711 g (SD 227 g). Overall mean percentage error of EFW and actual BW was 8.8% (range 0-34.6%). There was a significant difference in mean error of EFW and actual BW for SGA and AGA deliveries (mean +16 g versus -23 g, respectively, P = 0.01) and in mean % error of EFW (11.2%, 95%CI 9.1-13.3 versus 7.4%, 95% CI 6.2-8.6 P = 0.009). Factors that significantly influenced the accuracy of EFW included SGA (P = 0.001, coeff. = -3.73, 95% CI -5.94/-1.52), scan to delivery interval (P = 0.02, coeff. = 0.66, 95% CI 0.12/1.21) and reduced amniotic fluid (P = 0.008, coeff = 3.61, 95% CI -5.47/-0.85). CONCLUSIONS: Ultrasonographic EFW for extreme preterm SGA fetuses is less accurate than AGA fetuses and is more likely to overestimate EFW. This should be considered when counselling women with growth restricted fetuses at the limits of viability.

Childhood outcomes after maternal antenatal sildenafil treatment for severe early-onset fetal growth restriction: a randomized trial (STRIDER NZAus).

In this follow-up at 2.5 years of children from the STRIDER NZAus Trial (N = 112), in which women with singleton pregnancies affected by severe early fetal growth restriction were randomized to sildenafil citrate 75 mg daily or placebo until 32 weeks, there was no difference between groups in survival without neurosensory impairment, defined as any of cerebral palsy, deafness, blindness, cognitive delay (Bayley III cognition or language score >1 SD below mean) or motor delay: 30/56[54%] vs. 34/56[61%]; aOR = 0.74, 95%CI: 0.31, 1.77. However, children exposed to sildenafil appeared to be more likely to have cognitive delay (13/45[29%] vs. 4/40[10%]; aOR = 3.71, 95% CI: 1.01, 13.63) but less likely to have emotional-behavioural difficulties (2/43[5%] vs. 8/38[21%]; aOR = 0.19, 95%CI: 0.03, 1.00). Conclusion: maternal sildenafil treatment for severe early-onset FGR was not associated with altered survival free of neurosensory impairment at 2.5 years' corrected age.

Elevated maternal lipids in early pregnancy are not associated with risk of intrapartum caesarean in overweight and obese nulliparous women.

BACKGROUND: Maternal overweight and obesity are associated with slower labour progress and increased caesarean delivery for failure to progress. Obesity is also associated with hyperlipidaemia and cholesterol inhibits myometrial contractility in vitro. Our aim was, among overweight and obese nulliparous women, to investigate 1. the role of early pregnancy serum cholesterol and 2. clinical risk factors associated with first stage caesarean for failure to progress at term. METHODS: Secondary data analysis from a prospective cohort of overweight/obese New Zealand and Australian nullipara recruited to the SCOPE study. Women who laboured at term and delivered vaginally (n=840) or required first stage caesarean for failure to progress (n=196) were included. Maternal characteristics and serum cholesterol at 14-16 weeks' of gestation were compared according to delivery mode in univariable and multivariable analyses (adjusted for BMI, maternal age and height, obstetric care type, induction of labour and gestation at delivery ≥41 weeks). RESULTS: Total cholesterol at 14-16 weeks was not higher among women requiring first stage caesarean for failure to progress compared to those with vaginal delivery (5.55 ± 0.92 versus 5.67 ± 0.85 mmol/L, p= 0.10 respectively). Antenatal risk factors for first stage caesarean for failure to progress in overweight and obese women were BMI (adjusted odds ratio [aOR (95% CI)] 1.15 (1.07-1.22) per 5 unit increase, maternal age 1.37 (1.17-1.61) per 5 year increase, height 1.09 (1.06-1.12) per 1cm reduction), induction of labour 1.94 (1.38-2.73) and prolonged pregnancy ≥41 weeks 1.64 (1.14-2.35). CONCLUSIONS: Elevated maternal cholesterol in early pregnancy is not a risk factor for first stage caesarean for failure to progress in overweight/obese women. Other clinically relevant risk factors identified are: increasing maternal BMI, increasing maternal age, induction of labour and prolonged pregnancy ≥41 weeks' of gestation.

Activities critical to success and growth of clinical trials networks. What is needed and how are we doing? An Australian and New Zealand perspective.

BACKGROUND: Clinical trial evidence underpins evidence-based medicine and the improvement of healthcare worldwide. In Australasia, a significant proportion of clinical trials are conducted by geographically dispersed and multidisciplinary clinical researchers under the auspices of Clinical Trials Networks (CTNs). These groups play an important role in contributing to evidence-based medicine, primarily by conducting investigator-initiated clinical trials. Despite their clear benefits in terms of return on investment, CTNs suffer significant challenges. METHODS: We conducted surveys and focus groups with Australian and New Zealand CTNs to identifying the activities and attributes that enable CTNs to operate successfully. Based on our findings, we then conducted further surveys of Australian and New Zealand CTNs to identify the prevalence of these success factors in existing CTNs. RESULTS: Our focus groups identified three key themes associated with success and growth of a CTN: engaged membership, established infrastructure, and sustainability; and thirteen critical success factors: shared vision and motivation; strong leaders, governance and succession planning; an executive officer; sustainable funding for operations; effective communication; diverse representation and consumer input; transparent processes; a strong pipeline of trials; a reputable and recognised CTN brand; innovation and adaption; an effective group of network sites with a skilled workforce; embedded trials and prioritisation of research. These key themes and the relevant key areas were presented to 30 CTNs. Two factors were almost universally present in CTNs, reflecting the importance of these attributes: the presence of an executive officer, and a strong pipeline of trials. Three factors had a particularly low prevalence: sustainable funding for operations, effective communication, and embedded trials. CONCLUSIONS: By supporting both emerging and established CTNs to achieve critical success factors, we can improve the efficiency of CTNs to continue to contribute and expand their clinical trial activities. Particular focus needs to be on finding sustainable funding for CTNs, and raising awareness of the critical role undertaken by CTNs to improve healthcare and health outcomes.

Research priorities for maternal and perinatal health clinical trials and methods used to identify them: A systematic review.

OBJECTIVE: Research prioritisation helps to target research resources to the most pressing health and healthcare needs of a population. This systematic review aimed to report research priorities in maternal and perinatal health and to assess the methods that were used to identify them. METHODS: A systematic review was undertaken. Projects that aimed to identify research priorities that were considered to be amenable to clinical trials research were eligible for inclusion. The search, limited to the last decade and publications in English, included MEDLINE, EMBASE, CINHAL, relevant Cochrane priority lists, Cochrane Priority Setting Methods Group homepage, James Lind Alliance homepage, Joanna Brigg's register, PROSPERO register, reference lists of all included articles, grey literature, and the websites of relevant professional bodies, until 13 October 2020. The methods used for prioritisation were appraised using the Reporting Guideline for Priority Setting of Health Research (REPRISE). FINDINGS: From the 62 included projects, 757 research priorities of relevance to maternal and perinatal health were identified. The most common priorities related to healthcare systems and services, pregnancy care and complications, and newborn care and complications. The least common priorities related to preconception and postpartum health, maternal mental health, contraception and pregnancy termination, and fetal medicine and surveillance. The most commonly used prioritisation methods were Delphi (20, 32%), Child Health Nutrition Research Initiative (17, 27%) and the James Lind Alliance (10, 16%). The fourteen projects (23%) that reported on at least 80% of the items included in the REPRISE guideline all used an established research prioritisation method. CONCLUSIONS: There are a large number of diverse research priorities in maternal and perinatal health that are amenable to future clinical trials research. These have been identified by a variety of research prioritisation methods.

Real-world experience of adding placental histopathology studies into perinatal clinical trials.

Addition of placental histopathology studies to obstetric trials is likely to be cost-effective and may reveal structural changes suggestive of functional dysfunction to explain the success or failure of a clinical intervention. We share our recent experience in adding placental pathological examination to two clinical trials, retrospectively in one and at the outset in the other, so that other clinical trial investigators may benefit from it. The practical issues can be summarised as being regulatory and ethical, operational and reporting. Prospective inclusion of placental pathological examination as part of a clinical trial protocol is easier than retrospective, and is facilitated by fully-costed funding.

Maternal obesity and postpartum haemorrhage after vaginal and caesarean delivery among nulliparous women at term: a retrospective cohort study.

BACKGROUND: Increasing rates of postpartum haemorrhage in developed countries over the past two decades are not explained by corresponding changes in risk factors and conjecture has been raised that maternal obesity may be responsible. Few studies investigating risk factors for PPH have included BMI or investigated PPH risk among nulliparous women. The aim of this study was to determine in a cohort of nulliparous women delivering at term whether overweight and obesity are independent risk factors for major postpartum haemorrhage (PPH ≥1000ml) after vaginal and caesarean section delivery. METHODS: The study population was nulliparous singleton pregnancies delivered at term at National Women's Hospital, Auckland, New Zealand from 2006 to 2009 (N=11,363). Multivariable logistic regression was adjusted for risk factors for major PPH. RESULTS: There were 7238 (63.7%) women of normal BMI, 2631 (23.2%) overweight and 1494 (13.1%) obese. Overall, PPH rates were increased in overweight and obese compared with normal-weight women (n=255 [9.7%], n=233 [15.6%]), n=524 [7.2%], p <.001) respectively. There was an approximate twofold increase in risk in obese nulliparous women that was independent of confounders, adjusted odds ratio [aOR (95% CI)] for all deliveries 1.86 (1.51-2.28). Being obese was a risk factor for major PPH following both caesarean 1.73 (1.32-2.28) and vaginal delivery 2.11 (1.54-2.89) and the latter risk was similar after exclusion of women with major perineal trauma and retained placentae. Three additional factors were consistently associated with risk for major PPH regardless of mode of delivery: increasing infant birthweight, antepartum haemorrhage and Asian ethnicity. CONCLUSION: Nulliparous obese women have a twofold increase in risk of major PPH compared to women with normal BMI regardless of mode of delivery. Higher rates of PPH among obese women are not attributable to their higher rates of caesarean delivery. Obesity is an important high risk factor for PPH, and the risk following vaginal delivery is emphasised. We recommend in addition to standard practice of active management of third stage of labour, there should be increased vigilance and preparation for PPH management in obese women.

Psychological well-being of women at high risk of spontaneous preterm birth cared for in a specialised preterm birth clinic: a prospective longitudinal cohort study.

OBJECTIVES: To assess the psychological well-being of pregnant women at increased risk of spontaneous preterm birth, and the impact of care from a preterm birth clinic. DESIGN: Single-centre longitudinal cohort study over 1 year, 2018-2019. SETTING: Tertiary maternity hospital in Auckland, New Zealand. PARTICIPANTS: Pregnant women at increased risk of spontaneous preterm birth receiving care in a preterm birth clinic. INTERVENTION: Participants completed three sets of questionnaires (State-Trait Anxiety Inventory, Edinburgh Postnatal Depression Scale, and 36-Item Short Form Survey)-prior to their first, after their second, and after their last clinic appointments. Study-specific questionnaires explored pregnancy-related anxiety and perceptions of care. PRIMARY AND SECONDARY OUTCOME MEASURES: The primary outcome was the mean State-Anxiety score. Secondary outcomes included depression and quality of life measures. RESULTS: 73/97 (75.3%) eligible women participated; 41.1% had a previous preterm birth, 31.5% a second trimester loss and 28.8% cervical surgery; 20.6% had a prior mental health condition. 63/73 (86.3%) women completed all questionnaires. The adjusted mean state-anxiety score was 39.0 at baseline, which decreased to 36.5 after the second visit (difference -2.5, 95% CI -5.5 to 0.5, p=0.1) and to 32.6 after the last visit (difference -3.9 from second visit, 95% CI -6.4 to -1.5, p=0.002). Rates of anxiety (state-anxiety score >40) and depression (Edinburgh Postnatal Depression Scale score >12) were 38.4%, 34.8%, 19.0% and 13.7%, 8.7%, 9.5% respectively, at the same time periods. Perceptions of care were favourable; 88.9% stated the preterm birth clinic made them significantly or somewhat less anxious and 87.3% wanted to be seen again in a future pregnancy. CONCLUSIONS: Women at increased risk of spontaneous preterm birth have high levels of anxiety. Psychological well-being improved during the second trimester; women perceived that preterm birth clinic care reduced pregnancy-related anxiety. These findings support the ongoing use and development of preterm birth clinics.

The priorities for future clinical trials and large cohort studies addressing health and healthcare for mothers and babies in Aotearoa New Zealand.

AIMS: To identify priorities for clinical trials and large cohort studies addressing maternal and perinatal health and healthcare in Aotearoa New Zealand. METHODS: An Aotearoa New Zealand specific Research Prioritisation Framework was developed. Knowledge gaps were collected from an Audience Group via online questionnaires, video call interviews, and by systematic review. These were formulated into research questions. An Advisory Group reviewed questions suited to a clinical trial or large cohort study. A Ranking Group weighted the ranking criteria and ranked the research questions. RESULTS: A total of 305 online questionnaires, 62 interviews and 62 published prioritisation projects generated 3,347 knowledge gaps. After content analysis, 358 unanswered research questions were ranked. Rating criteria weightings were: effect on equity 26.1%; potential to reduce disease burden 20.5%; effectiveness 20.0%; deliverability 17.9%; and answerability 16.0%. All of the top 20 prioritised research questions directly related to Maori and/or Pacific health and predominantly involved research into healthcare systems and workforce rather than disease conditions. CONCLUSIONS: This project has identified the most important questions for future clinical trials and large cohort studies addressing maternal and perinatal health and healthcare in Aotearoa New Zealand. The Framework and methodology can be adapted for use across all areas of health.