The fatigue after infusion or transfusion pilot trial and feasibility study: A three-armed randomized pilot trial of intravenous iron and blood transfusion for the treatment of postpartum anemia.

BACKGROUND: Evidence for the management of moderate-to-severe postpartum anemia is limited. A randomized trial is needed; recruitment may be challenging. STUDY DESIGN AND METHODS: Randomized pilot trial with feasibility surveys. INCLUSION: hemoglobin 65-79 g/L, ≤7 days of birth, hemodynamically stable. EXCLUSION: ongoing heavy bleeding; already received, or contraindication to intravenous (IV)-iron or red blood cell transfusion (RBC-T). Intervention/control: IV-iron; RBC-T; or IV-iron and RBC-T. PRIMARY OUTCOME: number of recruits; proportion of those approached; proportion considered potentially eligible. SECONDARY OUTCOMES: fatigue, depression, baby-feeding, and hemoglobin at 1, 6 and 12 weeks; ferritin at 6 and 12 weeks. Surveys explored attitudes to trial participation. RESULTS: Over 16 weeks and three sites, 26/34 (76%) women approached consented to trial participation, including eight (31%) Maori women. Of those potentially eligible, 26/167 (15.6%) consented to participate. Key participation enablers were altruism and study relevance. For clinicians and stakeholders the availability of research assistance was the key barrier/enabler. Between-group rates of fatigue and depression were similar. Although underpowered to address secondary outcomes, IV-iron and RBC-T compared with RBC-T were associated with higher hemoglobin concentrations at 6 (mean difference [MD] 11.7 g/L, 95% confidence interval [CI] 2.7-20.7) and 12 (MD 12.8 g/L, 95% CI 1.5-24.2) weeks, and higher ferritin concentrations at 6 weeks (MD 136.8 mcg/L, 95% CI 76.6-196.9). DISCUSSION: Willingness to participate supports feasibility for a future trial assessing the effectiveness of IV-iron and RBC-T for postpartum anemia. Dedicated research assistance will be critical to the success of an appropriately powered trial including women-centered outcomes.

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.

Normotensive placental extracellular vesicles provide long-term protection against hypertension and cardiovascular disease.

BACKGROUND: Women with normotensive pregnancy are at a reduced risk of developing cardiovascular disease postpartum compared with those who experience hypertensive conditions during pregnancy. However, the underlying mechanisms remain poorly understood. During normotensive pregnancy, vast numbers of placental extracellular vesicles are released into the maternal circulation, which protect endothelial cells from activation and alter maternal vascular tone. We hypothesized that placental extracellular vesicles play a mechanistic role in lowering the risk of cardiovascular disease following normotensive pregnancy. OBJECTIVE: This study aimed to investigate the long-term effects of placental extracellular vesicles derived from normotensive term placentae on the cardiovascular system and explore the mechanisms underlying their biological effects. STUDY DESIGN: Spontaneously hypertensive rats were injected with placental extracellular vesicles from normotensive term pregnancies (2 mg/kg each time, n=8) or vehicle control (n=9) at 3 months of age. Blood pressure and cardiac function were regularly monitored from 3 months to 15 months of age. The response of mesenteric resistance arteries to vasoactive substances was investigated to evaluate vascular function. Cardiac remodeling, small artery remodeling, and renal function were investigated to comprehensively assess the impact of placental extracellular vesicles on cardiovascular and renal health. RESULTS: Compared with vehicle-treated control animals, rats treated with normotensive placental extracellular vesicles exhibited a significantly lower increase in blood pressure and improved cardiac function. Furthermore, the vasodilator response to the endothelium-dependent agonist acetylcholine was significantly enhanced in the normotensive placental extracellular vesicle-treated spontaneously hypertensive rats compared with the control. Moreover, treatment with placental extracellular vesicles reduced wall thickening of small renal vessels and attenuated renal fibrosis. CONCLUSION: Placental extracellular vesicles from normotensive term pregnancies have long-lasting protective effects reducing hypertension and mitigating cardiovascular damage in vivo.

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.

Postpartum anaemia in three New Zealand district health board regions: An observational study of incidence and management.

BACKGROUND: The incidence of postpartum anaemia (PPA) in New Zealand, and the extent of intravenous iron (IV-iron) use in its treatment, are unknown. AIMS: To report the incidence of PPA in three district health board (DHB) regions and describe current management of moderate to severe PPA, including by ethnicity. MATERIALS AND METHODS: Retrospective observational study of PPA (haemoglobin (Hb) <100 g/L) in three DHBs from July-December 2019. Cases with moderate to severe PPA (Hb <90 g/L) were reviewed and management compared to local and national guidance. Logistic regression examined demographic associations of PPA. RESULTS: There were 8849 women who gave birth during the study period: 4076 (46%) had postpartum Hb testing and 1544 (38%) had PPA. Of those tested, and after adjusting for deprivation and region, European women had lower adjusted odds ratios compared to Maori for being identified as having PPA (0.46, 95% CI 0.37-0.57, P < 0.01). Of 681 women with Hb <90 g/L, 278 (41%) received IV-iron only, 66 (10%) red blood cell transfusion (RBC-T) only and 155 (23%) both. Of those receiving RBC-T, 40/221 (18%) were actively bleeding. Maori (92/138, 67%) and Pacific (127/188, 68%) women with Hb <90 g/L had the highest incidence of IV-iron use. No guidelines provided recommendations for haemodynamically stable women without active bleeding. CONCLUSION: The incidence and management of PPA differs by ethnicity but fewer than half of the women had Hb testing, making precise determination of incidence impossible. The majority of women with Hb <90 g/L received IV-iron, with or without RBC-T.

The Blocking of Integrin-Mediated Interactions with Maternal Endothelial Cells Reversed the Endothelial Cell Dysfunction Induced by EVs, Derived from Preeclamptic Placentae.

Placental extracellular vesicles (EVs) have increasingly been recognized as a major mediator of feto-maternal communication. However, the cellular and molecular mechanisms of the uptake of placental EVs by recipient cells are still not well-understood. We previously reported that placental EVs target a limited number of organs in vivo. In the current study, we investigated the mechanisms underlying the uptake of placental EVs into target cells. Placental EVs were derived from explant cultures of normal or preeclamptic placentae. The mechanisms underlying the uptake of placental EVs were elucidated, using the phagocytosis or endocytosis inhibitor, trypsin-treatment or integrin-blocking peptides. The endothelial cell activation was studied using the monocyte adhesion assay after the preeclamptic EVs exposure, with and/or without treatment with the integrin blocking peptide, YIGSR. The cellular mechanism of the uptake of the placental EVs was time, concentration and energy-dependent and both the phagocytosis and endocytosis were involved in this process. Additionally, proteins on the surface of the placental EVs, including integrins, were involved in the EV uptake process. Furthermore, inhibiting the uptake of preeclamptic EVs with YIGSR, reduced the endothelial cell activation. The interaction between the placental EVs and the recipient cells is mediated by integrins, and the cellular uptake is mediated by a combination of both phagocytosis and endocytosis.

Delayed versus Immediate Cord Clamping in Preterm Infants.

BACKGROUND: The preferred timing of umbilical-cord clamping in preterm infants is unclear. METHODS: We randomly assigned fetuses from women who were expected to deliver before 30 weeks of gestation to either immediate clamping of the umbilical cord (≤10 seconds after delivery) or delayed clamping (≥60 seconds after delivery). The primary composite outcome was death or major morbidity (defined as severe brain injury on postnatal ultrasonography, severe retinopathy of prematurity, necrotizing enterocolitis, or late-onset sepsis) by 36 weeks of postmenstrual age. Analyses were performed on an intention-to-treat basis, accounting for multiple births. RESULTS: Of 1634 fetuses that underwent randomization, 1566 were born alive before 30 weeks of gestation; of these, 782 were assigned to immediate cord clamping and 784 to delayed cord clamping. The median time between delivery and cord clamping was 5 seconds and 60 seconds in the respective groups. Complete data on the primary outcome were available for 1497 infants (95.6%). There was no significant difference in the incidence of the primary outcome between infants assigned to delayed clamping (37.0%) and those assigned to immediate clamping (37.2%) (relative risk, 1.00; 95% confidence interval, 0.88 to 1.13; P=0.96). The mortality was 6.4% in the delayed-clamping group and 9.0% in the immediate-clamping group (P=0.03 in unadjusted analyses; P=0.39 after post hoc adjustment for multiple secondary outcomes). There were no significant differences between the two groups in the incidences of chronic lung disease or other major morbidities. CONCLUSIONS: Among preterm infants, delayed cord clamping did not result in a lower incidence of the combined outcome of death or major morbidity at 36 weeks of gestation than immediate cord clamping. (Funded by the Australian National Health and Medical Research Council [NHMRC] and the NHMRC Clinical Trials Centre; APTS Australian and New Zealand Clinical Trials Registry number, ACTRN12610000633088 .).

Circulating mRNAs are differentially expressed in pregnancies with severe placental insufficiency and at high risk of stillbirth.

BACKGROUND: Fetuses affected by placental insufficiency do not receive adequate nutrients and oxygenation, become growth restricted and acidemic, and can demise. Preterm fetal growth restriction is a severe form of placental insufficiency with a high risk of stillbirth. We set out to identify maternal circulating mRNA transcripts that are differentially expressed in preterm pregnancies complicated by very severe placental insufficiency, in utero fetal acidemia, and are at very high risk of stillbirth. METHODS: We performed a cohort study across six hospitals in Australia and New Zealand, prospectively collecting blood from 128 pregnancies complicated by preterm fetal growth restriction (delivery < 34 weeks' gestation) and 42 controls. RNA-sequencing was done on all samples to discover circulating mRNAs associated with preterm fetal growth restriction and fetal acidemia in utero. We used RT-PCR to validate the associations between five lead candidate biomarkers of placental insufficiency in an independent cohort from Europe (46 with preterm fetal growth restriction) and in a third cohort of pregnancies ending in stillbirth. RESULTS: In the Australia and New Zealand cohort, we identified five mRNAs that were highly differentially expressed among pregnancies with preterm fetal growth restriction: NR4A2, EMP1, PGM5, SKIL, and UGT2B1. Combining three yielded an area under the receiver operative curve (AUC) of 0.95. Circulating NR4A2 and RCBTB2 in the maternal blood were dysregulated in the presence of fetal acidemia in utero. We validated the association between preterm fetal growth restriction and circulating EMP1, NR4A2, and PGM5 mRNA in a cohort from Europe. Combining EMP1 and PGM5 identified fetal growth restriction with an AUC of 0.92. Several of these genes were differentially expressed in the presence of ultrasound parameters that reflect placental insufficiency. Circulating NR4A2, EMP1, and RCBTB2 mRNA were differentially regulated in another cohort destined for stillbirth, compared to ongoing pregnancies. EMP1 mRNA appeared to have the most consistent association with placental insufficiency in all cohorts. CONCLUSIONS: Measuring circulating mRNA offers potential as a test to identify pregnancies with severe placental insufficiency and at very high risk of stillbirth. Circulating mRNA EMP1 may be promising as a biomarker of severe placental insufficiency.

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.

Endoplasmic reticulum stress occurs in association with the extrusion of toxic extracellular vesicles from human placentae treated with antiphospholipid antibodies.

Antiphospholipid autoantibodies (aPLs), a major maternal risk factor for preeclampsia, are taken into the syncytiotrophoblast where they bind intracellular vesicles and mitochondria. Subsequently, large quantities of extracellular vesicles (EVs) extruded from syncytiotrophoblast into the maternal circulation are altered such that they cause maternal endothelial cell activation. However, the mechanism driving this change is unknown. First trimester placental explants were treated with aPL for 18 h. The EVs were then collected by different centrifugation. The levels of HSP 70, misfolded proteins, caspase 8 activity, and Mixed Lineage Kinase domain-Like (MLKL) were measured in placental explants and EVs. In addition, the levels of TNF-α and CD95 in conditioned medium were also measured. Treating placental explants with aPL caused an increase in levels of HSP 70, misfolded proteins and MLKL in placental explants and EVs. Increased activity of caspase 8 was also seen in placental explants. Higher levels of TNF-α were seen conditioned medium from aPL-treated placental explant cultures. aPLs appear to induce endoplasmic reticulum stress in the syncytiotrophoblast in a manner that involved caspase 8 and TNF-α. To avoid accumulation of the associated misfolded proteins and MLKL, the syncytiotrophoblast exports these potentially dangerous proteins in EVs. It is likely that the dangerous proteins that are loaded into placental EVs in preeclampsia contribute to dysfunction of the maternal cells.

The use of specialised preterm birth clinics for women at high risk of spontaneous preterm birth: a systematic review.

BACKGROUND: Specialised preterm birth clinics care for women at high risk of spontaneous preterm birth. This systematic review assesses current practice within preterm birth clinics globally. METHODS: A comprehensive search strategy was used to identify all studies on preterm birth clinics on the MEDLINE, Embase, PsycINFO, CENTRAL and CINAHL databases. There were no restrictions to study design. Studies were limited to the English language and publications from 1998 onwards. Two reviewers assessed studies for inclusion, performed data extraction and reviewed methodological quality. Primary outcomes were referral criteria, investigations and interventions offered in preterm birth clinics. Secondary outcomes were the timing of planned first and last appointments and frequency of review. RESULTS: Thirty-two records fulfilled eligibility criteria and 20 studies were included in the main analysis following grouping of records describing the same study or clinic. Studies were of mixed study design and methodological quality. A total of 39 clinics were described; outcome data was not available for all clinics. Referral criteria included previous spontaneous preterm birth (38/38, 100%), previous mid-trimester loss (34/38, 89%) and previous cervical surgery (33/38, 87%). All clinics offered transvaginal cervical length scans. Additional investigations varied, including urogenital swabs (16/28, 57%) and fetal fibronectin (8/28, 29%). The primary treatment of choice for a sonographic short cervix was cervical cerclage in 10/33 (30%) clinics and vaginal progesterone in 6/33 (18%), with 10/33 (30%) using multiple first-line options and 6/33 (18%) using a combination of treatments. The majority of clinics planned timing of first review for 12-16 weeks (30/35, 86%) and the frequency of review was usually determined by clinical findings (18/24, 75%). There was a wide variation in gestational age at clinic discharge between 24 and 37 weeks. CONCLUSIONS: There is variation in the referral criteria, investigations and interventions offered in preterm birth clinics and in the timing and frequency of review. Consistency in practice may improve with the introduction of consensus guidelines and national preterm birth prevention programmes. TRIAL REGISTRATION: Systematic review registration number: CRD42019131470.

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.

Perinatal care provided for babies born at 23 and 24 weeks of gestation.

In recent years, significant improvements in survival and survival-free of major morbidity in babies born at 23+0 to 24+6  weeks of gestation have led to a more pro-active approach to resuscitation at these peri-viable gestations. Antenatal counselling and interventions, intrapartum care and postnatal advice should be part of the package of care provided to optimise outcomes for these babies and their families. This observational study assesses the perinatal care provided to mothers and their babies who were born at 23 and 24 weeks of gestations over a two-year period at a tertiary maternity hospital in New Zealand.

The experience and outcomes of a specialised preterm birth clinic in New Zealand.

BACKGROUND: A greater understanding of the risk factors for spontaneous preterm birth and the importance of risk stratification to guide interventions has led to the introduction of preterm birth prevention clinics. AIM: To evaluate the experience and outcomes of the first specialised preterm birth clinic in New Zealand. MATERIALS AND METHODS: This observational study reviewed pregnancies cared for in a preterm birth clinic from 2013 to 2018. Cases were identified and data collected from a maternity database and electronic medical records. Analysis was by referral type. RESULTS: A total of 423 cases were included; 309 elective and 22 acute referrals in pregnancy, and 92 consultations outside pregnancy. For those referred electively in pregnancy, 138/309 (44.7%) fulfilled multiple referral criteria, and 57/309 (18.4%) had ≥2 previous spontaneous preterm births or second trimester losses. Excluding five pregnancies with first trimester miscarriage, 77/304 (25.3%) were managed with a history-indicated cerclage (11 placed pre-conception) and 217/304 (71.4%) had cervical surveillance as primary management, of which 133 (61.3%) did not require treatment. The remaining had treatment for a short cervix; 37 (17.0%) received an ultrasound-indicated cerclage only, 21 (9.7%) vaginal progesterone only and 26 (12.0%) both. Five women (1.6%) had a second trimester loss at 13+0 -19+6 and 58/297 (19.5%) had a spontaneous preterm birth at 20+0 -36+6  weeks. The 'take home baby' rate was 95.4%. CONCLUSIONS: Pregnancy outcomes were similar to those reported by other preterm birth prevention clinics. The majority of women who received cervical surveillance as primary management were able to avoid additional treatment.

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.