Obstetrics and Gynaecology - Research Publications
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ItemP160 A trial of a position modification device for the prevention of supine sleep during pregnancy(Oxford University Press (OUP), 2021-10-07)Abstract Self-reported supine position at sleep onset during late pregnancy is related to a 2.6x increase in stillbirth risk, possibly due to the enlarged uterus compressing major blood vessels supplying the placenta. This study aimed to test the effectiveness of a pillow designed to decrease supine sleep in pregnant women. Twelve women in the third trimester of pregnancy used their own pillows for a control week and the intervention pillow for 1 week, in randomised order. Sleep position for each night of both weeks was monitored with the Night Shift Sleep Positioner, with a sleep study (WatchPat300) on the last night of each week to measure the impact of the intervention on SDB. During the control week, the women slept supine for a median of 19.9% (IQR = 11.6, 27.4) of total sleep time (TST), compared to a median of 20.4% (10.2, 31.0) TST using the intervention pillow (p = .64). Use of the intervention pillow did not impact sleep efficiency (control = 85.3% (80.7, 88.0) v. intervention = 85.2% (78.3, 89.0), p = .48). On the sleep study night, supine sleep was reduced in the intervention compared to control condition (12.9% vs. 17.7%, p = .04), but AHI did not differ (intervention = 2.6/hr (0.8, 6.7) vs. control = 1.5/hr (0.6, 3.6), p = .11). We found that the adoption of a pillow designed to discourage supine sleep was not effective in late pregnancy. Considering the reasonably high amount of supine sleep in our participants, alternative devices should be investigated.
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ItemUse of metformin to prolong gestation in preterm pre-eclampsia: randomised, double blind, placebo controlled trial(BMJ PUBLISHING GROUP, 2021-09-23)OBJECTIVE: To evaluate whether extended release metformin could be used to prolong gestation in women being expectantly managed for preterm pre-eclampsia. DESIGN: Randomised, double blind, placebo controlled trial. SETTING: Referral hospital in Cape Town, South Africa. PARTICIPANTS: 180 women with preterm pre-eclampsia between 26+0 to 31+6 weeks' gestation undergoing expectant management: 90 were randomised to extended release metformin and 90 to placebo. INTERVENTION: 3 g of oral extended release metformin or placebo daily, in divided doses, until delivery. MAIN OUTCOME MEASURE: The primary outcome was prolongation of gestation. RESULTS: Of 180 participants, one woman delivered before taking any trial drug. The median time from randomisation to delivery was 17.7 days (interquartile range 5.4-29.4 days; n=89) in the metformin arm and 10.1 (3.7-24.1; n=90) days in the placebo arm, a median difference of 7.6 days (geometric mean ratio 1.39, 95% confidence interval 0.99 to 1.95; P=0.057). Among those who continued to take the trial drug at any dose, the median prolongation of gestation in the metformin arm was 17.5 (interquartile range 5.4-28.7; n=76) days compared with 7.9 (3.0-22.2; n=74) days in the placebo arm, a median difference of 9.6 days (geometric mean ratio 1.67, 95% confidence interval 1.16 to 2.42). Among those who took the full dosage, the median prolongation of gestation in the metformin arm was 16.3 (interquartile range 4.8-28.8; n=40) days compared with 4.8 (2.5-15.4; n=61) days in the placebo arm, a median difference of 11.5 days (geometric mean ratio 1.85, 95% confidence interval 1.14 to 2.88). Composite maternal, fetal, and neonatal outcomes and circulating concentrations of soluble fms-like tyrosine kinase-1, placental growth factor, and soluble endoglin did not differ. In the metformin arm, birth weight increased non-significantly and length of stay decreased in the neonatal nursery. No serious adverse events related to trial drugs were observed, although diarrhoea was more common in the metformin arm. CONCLUSIONS: This trial suggests that extended release metformin can prolong gestation in women with preterm pre-eclampsia, although further trials are needed. It provides proof of concept that treatment of preterm pre-eclampsia is possible. TRIAL REGISTRATION: Pan African Clinical Trial Registry PACTR201608001752102 https://pactr.samrc.ac.za/.
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ItemNo Preview AvailablePSG9-A NOVEL BIOMARKER DERANGED IN PREECLAMPSIA(W B SAUNDERS CO LTD, 2021-09-01)
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ItemIncrease in preterm stillbirths and reduction in iatrogenic preterm births for fetal compromise: a multi-centre cohort study of COVID-19 lockdown effects in Melbourne, Australia( 2021)
ABSTRACT
Objectives
The COVID-19 pandemic has been associated with a worsening of perinatal outcomes in many settings due to the combined impacts of maternal COVID-19 disease, disruptions to maternity care, and overloaded health systems. In 2020, Melbourne endured a unique natural experiment where strict lockdown conditions were accompanied by very low COVID-19 case numbers and the maintenance of health service capacity. The aim of this study was to compare stillbirth and preterm birth rates in women who were exposed or unexposed to lockdown restrictions during pregnancy.Design
Retrospective multi-centre cohort study of perinatal outcomes before and during COVID-19 lockdownSetting
Birth outcomes from all 12 public maternity hospitals in metropolitan MelbourneInclusion criteria
Singleton births without congenital anomalies from 24 weeks’ gestation. The lockdown-exposed cohort were those women for whom weeks 20- 40 of gestation would have occurred during the lockdown period of 23 March 2020 to 14 March 2021. The control cohort comprised all pregnancies in the corresponding periods one and two years prior to the exposed cohort.Main outcome measures
Odds of stillbirth, preterm birth (PTB), birth weight < 3 rd centile, and iatrogenic PTB for fetal compromise, adjusting for multiple covariates.Results
There were 24,017 births in the exposed and 50,017 births in the control group. There was a significantly higher risk of preterm, but not term, stillbirth in the exposed group compared with the control group (0.26% vs 0.18%, aOR 1.49, 95%CI 1.08 to 2.05, P = 0.015). There was also a significant reduction in preterm birth < 37 weeks (5.93% vs 6.23%, aOR 0.93, 95%CI 0.87 to 0.99, P=0.03), largely mediated by a reduction in iatrogenic PTB for live births (3.01% vs 3.27%, aOR 0.89, 95%CI 0.81 to 0.98, P = 0.015), including iatrogenic PTB for suspected fetal compromise (1.25% vs 1.51%, aOR 0.79, 95%CI 0.69 to 0.91, P= 0.001). There was no significant difference in the spontaneous PTB rate between the exposed and control groups (2.69% vs 2.82%, aOR 0.94, 95%CI 0.86 to 0.1.03, P=0.25).Conclusions
Lockdown restrictions in a high-income setting, in the absence of high rates of COVID-19 disease, were associated with a significant increase in preterm stillbirths, and a significant reduction in iatrogenic PTB for suspected fetal compromise.Trial registration
This study was registered as an observational study with the Australian and New Zealand Clinical Trials Registry (ACTRN12620000878976). -
ItemStudy protocol: childhood outcomes of fetal genomic variants: the PrenatAL Microarray (PALM) cohort study(BMC, 2021-10-11)BACKGROUND: The implementation of genomic testing in pregnancy means that couples have access to more information about their child's genetic make-up before birth than ever before. One of the resulting challenges is the management of genetic variations with unclear clinical significance. This population-based study will help to close this critical knowledge gap through a multidisciplinary cohort study of children with and without genomic copy number variants (CNVs) diagnosed before birth. By comparing children with prenatally-ascertained CNVs to children without a CNV, we aim to (1) examine their developmental, social-emotional and health status; (2) measure the impact of prenatal diagnosis of a CNV on maternal perceptions of child health, behavior and development; and (3) determine the proportion of prenatally-ascertained CNVs of unknown or uncertain significance that are reclassified as benign or pathogenic after 2 or more years. METHODS: This study will establish and follow up a cohort of mother-child pairs who have had a prenatal diagnosis with a chromosomal microarray from 2013-2019 in the Australian state of Victoria. Children aged 12 months to 7 years will be assessed using validated, age-appropriate measures. The primary outcome measures will be the Wechsler Preschool and Primary Scale of Intelligence IV (WPSSI-IV) IQ score (2.5 to 7 year old's), the Ages and Stages Questionnaire (12-30 months old), and the Brief Infant- Toddler Social and Emotional Assessment (BITSEA) score. Clinical assessment by a pediatrician will also be performed. Secondary outcomes will be scores obtained from the: Vineland Adaptive Behavior Scale, Maternal Postnatal Attachment Questionnaire, the Vulnerable Child Scale, Profile of Mood States, Parent Sense of Competence Scale. A descriptive analysis of the reclassification rates of CNVs after ≥2 years will be performed. DISCUSSION: This study protocol describes the first Australian cohort study following children after prenatal diagnostic testing with chromosomal microarray. It will provide long-term outcomes of fetal genomic variants to guide evidence-based pre-and postnatal care. This, in turn, will inform future efforts to mitigate the negative consequences of conveying genomic uncertainty during pregnancy. TRIAL REGISTRATION: ACTRN12620000446965p ; Registered on April 6, 2020.
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ItemAccelerated fetal growth velocity across the third trimester is associated with increased shoulder dystocia risk among fetuses who are not large-for-gestational-age: A prospective observational cohort study(PUBLIC LIBRARY SCIENCE, 2021-10-20)OBJECTIVE: To investigate whether fetuses with accelerated third trimester growth velocity are at increased risk of shoulder dystocia, even when they are not large-for-gestational-age (LGA; estimated fetal weight (EFW) >95th centile). METHODS: Fetal growth velocity and birth outcome data were prospectively collected from 347 nulliparous women. Each had blinded ultrasound biometry performed at 28 and 36 weeks' gestation. Change in EFW and abdominal circumference (AC) centiles between 28-36 weeks were calculated, standardised over exactly eight weeks. We examined the odds of shoulder dystocia with increasing EFW and AC growth velocities among women with 36-week EFW ≤95th centile (non-LGA), who went on to have a vaginal birth. We then examined the relative risk (RR) of shoulder dystocia in cases of accelerated EFW and AC growth velocities (>30 centiles gained). Finally, we compared the predictive performances of accelerated fetal growth velocities to 36-week EFW >95th centile for shoulder dystocia among the cohort planned for vaginal birth. RESULTS: Of the 226 participants who had EFW ≤95th centile at 36-week ultrasound and birthed vaginally, six (2.7%) had shoulder dystocia. For each one centile increase in EFW between 28-36 weeks, the odds of shoulder dystocia increased by 8% (odds ratio (OR [95% Confidence Interval (CI)]) = 1.08 [1.04-1.12], p<0.001). For each one centile increase in AC between 28-36 weeks, the odds of shoulder dystocia increased by 9% (OR[95%CI] = 1.09 [1.05-1.12], p<0.001). When compared to the rest of the cohort with normal growth velocity, accelerated EFW and AC velocities were associated with increased relative risks of shoulder dystocia (RR[95%CI] = 7.3 [1.9-20.6], p = 0.03 and 4.8 [1.7-9.4], p = 0.02 respectively). Accelerated EFW or AC velocities predicted shoulder dystocia with higher sensitivity and positive predictive value than 36-week EFW >95th centile. CONCLUSIONS: Accelerated fetal growth velocities between 28-36 weeks' gestation are associated with increased risk of shoulder dystocia, and may predict shoulder dystocia risk better than the commonly used threshold of 36-week EFW >95th centile.
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ItemEvidence of Neuroinflammation and Blood-Brain Barrier Disruption in Women with Preeclampsia and Eclampsia(MDPI, 2021-11)Cerebral complications in preeclampsia are leading causes of maternal mortality. Animal models suggest that an injured blood-brain barrier and neuroinflammation may be important but there is paucity of data from human studies. Therefore, we aimed to evaluate this in women with preeclampsia and eclampsia. We included women recruited to the South African Preeclampsia Obstetric Adverse Events (PROVE) biobank. Blood and cerebrospinal fluid (CSF) were collected around delivery. CSF was analyzed for neuroinflammatory markers interleukin 1β, interleukin 6, interleukin-8 and tumor necrosis factor alpha (TNF-alpha). The CSF to plasma albumin ratio was measured to assess blood-brain barrier function. Women with eclampsia (n = 4) showed increased CSF concentrations of all pro-inflammatory cytokines and TNF-alpha compared to women with normotensive pregnancies (n = 7) and also for interleukin-6 and TNF-alpha compared to women with preeclampsia (n = 4). Women with preeclampsia also showed increases in pro-inflammatory cytokines IL-6 and IL-8 but not TNF-alpha in the CSF compared to women with normotensive pregnancies. In particular, women with eclampsia but also women with preeclampsia showed an increase in the CSF to plasma albumin ratio compared to normotensive women. In conclusion, women with preeclampsia and eclampsia show evidence of neuroinflammation and an injured blood-brain barrier. These findings are seen in particular among women with eclampsia.
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ItemCollaborative maternity and newborn dashboard (CoMaND) for the COVID-19 pandemic: a protocol for timely, adaptive monitoring of perinatal outcomes in Melbourne, Australia(BMJ PUBLISHING GROUP, 2021-11)BACKGROUND: The COVID-19 pandemic has resulted in a range of unprecedented disruptions to maternity care with documented impacts on perinatal outcomes such as stillbirth and preterm birth. Metropolitan Melbourne has endured one of the longest and most stringent lockdowns in globally. This paper presents the protocol for a multicentre study to monitor perinatal outcomes in Melbourne, Australia, during the COVID-19 pandemic. METHODS: Multicentre observational study analysing monthly deidentified maternal and newborn outcomes from births >20 weeks at all 12 public maternity services in Melbourne. Data will be merged centrally to analyse outcomes and create run charts according to established methods for detecting non-random 'signals' in healthcare. Perinatal outcomes will include weekly rates of total births, stillbirths, preterm births, neonatal intensive care admissions, low Apgar scores and fetal growth restriction. Maternal outcomes will include weekly rates of: induced labour, caesarean section, births before arrival to hospital, postpartum haemorrhage, length of stay, general anaesthesia for caesarean birth, influenza and COVID-19 vaccination status, and gestation at first antenatal visit. A prepandemic median for all outcomes will be calculated for the period of January 2018 to March 2020. A significant shift is defined as ≥6 consecutive weeks, all above or below the prepandemic median. Additional statistical analyses such as regression, time series and survival analyses will be performed for an in-depth examination of maternal and perinatal outcomes of interests. ETHICS AND DISSEMINATION: Ethics approval for the collaborative maternity and newborn dashboard project has been obtained from the Austin Health (HREC/64722/Austin-2020) and Mercy Health (ref. 2020-031). TRIAL REGISTRATION NUMBER: ACTRN12620000878976; Pre-results.
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ItemNR4A2 expression is not altered in placentas from cases of growth restriction or preeclampsia, but is reduced in hypoxic cytotrophoblast(NATURE PORTFOLIO, 2021-10-19)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.
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ItemCirculating Growth Differentiation Factor 15 Is Increased Preceding Preeclampsia Diagnosis: Implications as a Disease Biomarker(WILEY, 2021-08-17)Background We investigated the biomarker potential of growth differentiation factor 15 (GDF-15), a stress response protein highly expressed in placenta, to predict preeclampsia. Methods and Results In 2 prospective cohorts (cohort 1: 960 controls, 39 women who developed preeclampsia; cohort 2: 950 controls, 41 developed preeclampsia), plasma concentrations of GDF-15 at 36 weeks' gestation were significantly increased among those who developed preeclampsia (P<0.001), area under the receiver operating characteristic curves (AUC) of 0.66 and 0.71, respectively. In cohort 2 a ratio of sFlt-1/PlGF (a clinical biomarker for preeclampsia) had a sensitivity of 61.0% at 83.2% specificity to predict those who will develop preeclampsia (AUC of 0.79). A ratio of GDF-15×sFlt-1/PlGF yielded a sensitivity of 68.3% at 83.2% specificity (AUC of 0.82). GDF-15 was consistently elevated across a number of international cohorts: levels were higher in placenta and blood from women delivering <34 weeks' gestation due to preterm preeclampsia in Melbourne, Australia; and in the blood at 26 to 32 weeks' gestation among 57 women attending the Manchester Antenatal Vascular Service (MAViS, UK) who developed preeclampsia (P=0.0002), compared with 176 controls. In the Preeclampsia Obstetric adVerse Events biobank (PROVE, South Africa), plasma GDF-15 was significantly increased in women with preeclampsia with severe features (P=0.02; n=14) compared to controls (n=14). Conclusions We conclude circulating GDF-15 is elevated among women more likely to develop preeclampsia or diagnosed with the condition. It may have value as a clinical biomarker, including the potential to improve the sensitivity of sFlt-1/PlGF ratio.