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.

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.

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.

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.

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.

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.

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.

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.

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.

NR4A2 expression is not altered in placentas from cases of growth restriction or preeclampsia, but is reduced in hypoxic cytotrophoblast.

Nuclear Receptor Subfamily 4 Group A Member 2 (NR4A2) transcripts are elevated in the circulation of individuals whose pregnancies are complicated by preterm fetal growth restriction (FGR). In this paper, we show that the cases with preeclampsia (PE) have increased circulating NR4A2 transcripts compared to those with normotensive FGR. We aimed to establish whether the dysfunctional placenta mirrors the increase in NR4A2 transcripts and further, to uncover the function of placental NR4A2. NR4A2 expression was detected in preterm and term placental tissue; expressed higher at term. NR4A2 mRNA expression and protein were not altered in placentas from preterm FGR or PE pregnancies. Hypoxia (1% O2 compared to 8% O2) significantly reduced cytotrophoblast NR4A2 mRNA expression, but not placental explant NR4A2 expression. Silencing cytotrophoblast NR4A2 expression under hypoxia (via short interfering (si)RNAs) did not alter angiogenic Placental Growth Factor, nor anti-angiogenic sFlt-1 mRNA expression or protein secretion, but increased expression of cellular antioxidant, oxidative stress, inflammatory, and growth genes. NR4A2 expression was also not altered in a model of tumour necrosis factor-α-induced endothelial dysfunction, or with pravastatin treatment. Further studies are required to identify the origin of the circulating transcripts in pathological pregnancies, and investigate the function of placental NR4A2.

How can obstetricians improve outcomes for infants born extremely preterm?

Prematurity remains a leading cause of perinatal morbidity and mortality, and also has significant implications for long-term health. Obstetricians have a key role to play in improving outcomes for infants born at extremely preterm gestations. This review explores the evidence for interventions available to obstetricians caring for women at risk of birthing at extremely preterm gestations, including antenatal corticosteroids, magnesium sulfate, tocolysis and antibiotics. It also addresses the importance of strategies to facilitate safe in-utero transfer, to maximise the chance of extremely preterm births occurring in tertiary centers, and the clinical value of strategies by which preterm birth can be predicted. The paper concludes with an appraisal of evidence for different modes of birth at extremely preterm gestations, and for delayed cord clamping.

LOX-1 expression is reduced in placenta from pregnancies complicated by preeclampsia and in hypoxic cytotrophoblast.

OBJECTIVES: The lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) is upregulated in the maternal vasculature in preeclampsia, and contributes to oxidative stress and endothelial dysfunction. However, its function in the placenta is unclear. This paper investigated LOX-1 expression in models of placental dysfunction and preeclampsia, and whether candidate therapeutics for preeclampsia could alter its expression. STUDY DESIGN: Placentas were collected from preterm pregnancies and cases of preterm preeclampsia and fetal growth restriction. Blood was collected from participants whose pregnancies were complicated by preterm fetal growth restriction and/or preeclampsia. Primary cytotrophoblast and placental explant tissue were cultured under hypoxic (1% O2) or normoxic (8% O2) conditions. Cytotrophoblast were exposed to 10% preeclamptic or control serum. Cytotrophoblast and preeclamptic explant tissue were treated with 100 µM esomeprazole, lansoprazole or rabeprazole. MAIN OUTCOME MEASURES: LOX-1 expression was assessed in all samples via qPCR. RESULTS: LOX-1 expression was reduced in placentas from cases of preterm preeclampsia, but not fetal growth restriction, compared to controls. LOX-1 expression was reduced in cytotrophoblast under hypoxia, but not in explant tissue. Treatment with preeclamptic serum in vitro did not alter cytotrophoblast LOX-1 expression. Circulating LOX-1 mRNA was unaltered in patients with fetal growth restriction, preeclampsia, and fetal hypoxia, compared to controls. Treatment with esomeprazole or lansoprazole in vitro increased placental LOX-1 expression. CONCLUSIONS: LOX-1 expression is reduced in preeclamptic placentas and hypoxic cytotrophoblast. Esomeprazole and lansoprazole increase placental LOX-1 expression. These findings demonstrate a role for LOX-1 in the placenta, and improve our understanding of maternal adaptations in pregnancy complications.

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 effect of symptom-tracking apps on symptom reporting.

OBJECTIVE: The use of health apps is increasing worldwide, with a common feature being daily symptom tracking. However, symptom tracking has been shown to increase symptom reporting. This study investigated whether using a menstrual-monitoring app with a symptom-tracking feature increases symptom reporting compared to an app without this feature or no app at all. DESIGN: Experimental study. METHODS: Ninety-one participants were randomly allocated to use either a menstrual-monitoring app with a symptom tracker or a simple calendar app, or to a no app control group. The number of period-related symptoms as well as general symptom reporting was assessed at baseline prior to group allocation and then 1 and 4 months later. The change in the proportion of people classified as high symptom reporters was also examined. RESULTS: We found that the symptom-tracking app group reported significantly more period-related symptoms at 4 months than the calendar app group (mean difference = 1.16 symptoms, p = .010). At the 4-month time point, significantly more participants in the symptom-tracking group were now classified as high period symptom reporters (baseline 50%, 4 months 70%, p = .031), while the other two groups did not change from baseline. There were no differences in general symptom reporting across the three groups. CONCLUSION: A period-monitoring app with a symptom tracker may increase the reporting of period symptoms. This effect does not appear to generalize to broader symptom reporting. Further research is needed to support these findings and to examine the impact of symptom-tracking apps on daily functioning and health anxiety. Statement of contribution What is already known on this subject? The experience of transient symptoms is common in day-to-day life. These symptoms often do not have an underlying cause or are a sign of illness. Actively tracking symptoms has been shown to result in greater symptom reporting, symptom severity, and slower recovery from injury. The use of health apps is increasing, with a common feature being symptom tracking. Menstrual-monitoring apps, in particular, frequently require users to track symptoms. What does this study add? Using a menstrual-monitoring app with a symptom tracker for 4 months increases the number of period-specific symptoms reported compared a basic calendar app. A greater proportion of people were now classified as high period symptom reporters after using the symptom-tracking app. These effects do not seem to generalize to broader non-specific symptom reporting.

The placenta in fetal growth restriction: What is going wrong?

The placenta is essential for the efficient delivery of nutrients and oxygen from mother to fetus to maintain normal fetal growth. Dysfunctional placental development underpins many pregnancy complications, including fetal growth restriction (FGR) a condition in which the fetus does not reach its growth potential. The FGR placenta is smaller than normal placentae throughout gestation and displays maldevelopment of both the placental villi and the fetal vasculature within these villi. Specialized epithelial cells called trophoblasts exhibit abnormal function and development in FGR placentae. This includes an altered balance between proliferation and apoptotic death, premature cellular senescence, and reduced colonisation of the maternal decidual tissue. Thus, the placenta undergoes aberrant changes at the macroscopic to cellular level in FGR, which can limit exchange capacity and downstream fetal growth. This review aims to compile stereological, in vitro, and imaging data to create a holistic overview of the FGR placenta and its pathophysiology, with a focus on the contribution of trophoblasts.

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.

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.

Protect-me: a parallel-group, triple blinded, placebo-controlled randomised clinical trial protocol assessing antenatal maternal melatonin supplementation for fetal neuroprotection in early-onset fetal growth restriction.

INTRODUCTION: Fetal growth restriction (FGR) is a serious pregnancy complication, associated with increased rates of perinatal death and morbidity among survivors. Most commonly FGR results from placental insufficiency, where the placenta fails to deliver the oxygen and nutrients required for normal fetal growth. This leads to fetal oxidative stress, resulting in organ damage through lipid peroxidation. The early developing brain is particularly susceptible, such that FGR is associated with poorer neurodevelopment, witnessed as cognitive and behavioural dysfunction, and cerebral palsy. Promisingly, melatonin, a lipid soluble antioxidant is neuroprotective in animal models of FGR. We present a protocol outlining a randomised, placebo-controlled trial to explore whether antenatal maternal melatonin supplementation in pregnancies with severe, early-onset FGR can improve neurodevelopment among survivors at 2 years of age. METHODS AND ANALYSES: We will recruit 336 women with a singleton pregnancy complicated by FGR between 23+0 and 31+6 weeks gestation. Participants will be randomised, stratified by gestational age, to either 30 mg melatonin per day or a visually identical placebo, continued until birth. Measures of maternal and fetal health will be collected until birth. Timing of birth will be determined by the treating clinical team in discussion with the woman. Neonatal and infant neurodevelopmental assessments will be undertaken, consisting of brain MRI at term corrected age, general movements assessment at term and 3 months' corrected age, and Bayley Scales of Infant & Toddler Development-III and Infant Toddler Social Emotional Assessment at 2.5 years corrected age. Analyses will be on intention to treat. The primary outcome is a difference of 5 points in the cognitive domain of the Bayley-III. Secondary outcomes address maternal and fetal safety. ETHICS AND DISSEMINATION: This trial has Monash Health Human Research and Ethics committee approval (17-0000-583A). Findings will be disseminated through peer-reviewed publications, conference presentations and to participants. TRIAL REGISTRATION NUMBER: ACTRN12617001515381; Pre-results.

Antenatal corticosteroids after 34 weeks' gestation: Do we have the evidence?

There is evidence to support the use of antenatal corticosteroids prior to late preterm birth at 35+0 to 36+6 weeks' gestation and for specific 'at-risk' populations, such as planned cesarean section birth and infants of women with diabetes in pregnancy, to reduce short-term neonatal respiratory morbidity. However, the overall size of effect at late preterm and term gestational ages is less than for early and moderate preterm birth and should be countered against the potential harms. Evidence from randomized trials suggest an increase in the incidence of neonatal hypoglycemia after corticosteroid use prior to late preterm birth; any effect of antenatal corticosteroids on neonatal glycemic control after planned cesarean section birth or for infants born to mothers with diabetes in pregnancy is unknown. Accumulating evidence suggests neonatal hypoglycemia may adversely affect childhood development. To date, no trials of antenatal corticosteroids after 34 weeks' gestation have reliably assessed outcomes beyond the neonatal period.