Obstetrics and Gynaecology - Research Publications

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    Use of Metformin to Prolong Gestation in Preterm Pre-eclampsia: Randomised, Double Blind, Placebo Controlled Trial
    Cluver, CA ; Hiscock, R ; Decloedt, EH ; Hall, DR ; Schell, S ; Mol, BW ; Brownfoot, F ; Kaitu'U-Lino, TJ ; Walker, SP ; Tong, S (Ovid Technologies (Wolters Kluwer Health), 2022-03-01)
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    Cerebral biomarkers in neurologic complications of preeclampsia.
    Bergman, L ; Hastie, R ; Bokström-Rees, E ; Zetterberg, H ; Blennow, K ; Schell, S ; Imberg, H ; Langenegger, E ; Moodley, A ; Walker, S ; Tong, S ; Cluver, C (Elsevier BV, 2022-08)
    BACKGROUND: There is no tool to accurately predict who is at risk of developing neurologic complications of preeclampsia, and there is no objective method to determine disease severity. OBJECTIVE: We assessed whether plasma concentrations of the cerebral biomarkers neurofilament light, tau, and glial fibrillary acidic protein could reflect disease severity in several phenotypes of preeclampsia. Furthermore, we compared the cerebral biomarkers with the angiogenic biomarkers soluble fms-like tyrosine kinase 1, placental growth factor, and soluble endoglin. STUDY DESIGN: In this observational study, we included women from the South African Preeclampsia Obstetric Adverse Events biobank. Plasma samples taken at diagnosis (preeclampsia cases) or admission for delivery (normotensive controls) were analyzed for concentrations of neurofilament light, tau, glial fibrillary acidic protein, placental growth factor, soluble fms-like tyrosine kinase 1, and soluble endoglin. The cerebrospinal fluid concentrations of inflammatory markers and albumin were analyzed in a subgroup of 15 women. Analyses were adjusted for gestational age, time from seizures and delivery to sampling, maternal age, and parity. RESULTS: Compared with 28 women with normotensive pregnancies, 146 women with preeclampsia demonstrated 2.18-fold higher plasma concentrations of neurofilament light (95% confidence interval, 1.64-2.88), 2.17-fold higher tau (95% confidence interval, 1.49-3.16), and 2.77-fold higher glial fibrillary acidic protein (95% confidence interval, 2.06-3.72). Overall, 72 women with neurologic complications (eclampsia, cortical blindness, and stroke) demonstrated increased plasma concentrations of tau (2.99-fold higher; 95% confidence interval, 1.92-4.65) and glial fibrillary acidic protein (3.22-fold higher; 95% confidence interval, 2.06-5.02) compared with women with preeclampsia without pulmonary edema; hemolysis, elevated liver enzymes, and low platelet count; or neurologic complications (n=31). Moreover, angiogenic markers were higher, but to a lesser extent. Women with hemolysis, elevated liver enzymes, and low platelet count (n=20) demonstrated increased plasma concentrations of neurofilament light (1.64-fold higher; 95% confidence interval, 1.06-2.55), tau (4.44-fold higher; 95% confidence interval, 1.85-10.66), and glial fibrillary acidic protein (1.82-fold higher; 95% confidence interval, 1.32-2.50) compared with women with preeclampsia without pulmonary edema; hemolysis, elevated liver enzymes, and low platelet count; or neurologic complications. There was no difference shown in the angiogenic biomarkers. There was no difference between 23 women with preeclampsia complicated by pulmonary edema and women with preeclampsia without pulmonary edema; hemolysis, elevated liver enzymes, and low platelet count; or neurologic complications for any of the biomarkers. Plasma concentrations of tau and glial fibrillary acidic protein were increased in women with several neurologic complications compared with women with eclampsia only. CONCLUSION: Plasma neurofilament light, glial fibrillary acidic, and tau were candidate biomarkers for the diagnosis and possibly prediction of cerebral complications of preeclampsia.
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    PSG7 and 9 (Pregnancy-Specific beta-1 Glycoproteins 7 and 9): Novel Biomarkers for Preeclampsia
    Kandel, M ; MacDonald, TM ; Walker, SP ; Cluver, C ; Bergman, L ; Myers, J ; Hastie, R ; Keenan, E ; Hannan, NJ ; Cannon, P ; Nguyen, T-V ; Pritchard, N ; Tong, S ; Kaitu'u-Lino, TJ (WILEY, 2022-04-05)
    Background Preeclampsia is pregnancy specific, involving significant maternal endothelial dysfunction. Predictive biomarkers are lacking. We evaluated the biomarker potential, expression, and function of PSG7 (pregnancy-specific β-1 glycoprotein 7) and PSG9 (pregnancy-specific β-1 glycoprotein 9) in preeclampsia. Methods and Results At 36 weeks gestation preceding term preeclampsia diagnosis, PSG7 and PSG9 (in Australian cohorts of n=918 and n=979, respectively) were significantly increased before the onset of term preeclampsia (PSG7, P=0.013; PSG9, P=0.0011). In samples collected at 28 to 32 weeks from those with preexisting cardiovascular disease and at high risk of preeclampsia (Manchester Antenatal Vascular Service, UK cohort, n=235), both PSG7 and PSG9 were also significantly increased preceding preeclampsia onset (PSG7, P<0.0001; PSG9, P=0.0003) relative to controls. These changes were validated in the plasma and placentas of patients with established preeclampsia who delivered at <34 weeks gestation (PSG7, P=0.0008; PSG9, P<0.0001). To examine whether PSG7 and PSG9 are associated with increasing disease severity, we measured them in a cohort from South Africa stratified for this outcome, the PROVE (Preeclampsia Obstetric Adverse Events) cohort (n=72). PSG7 (P=0.0027) and PSG9 (P=0.0028) were elevated among patients who were preeclamptic with severe features (PROVE cohort), but not significantly changed in those without severe features or with eclampsia. In syncytialized first trimester cytotrophoblast stem cells, exposure to TNFα (tumor necrosis factor α) or IL-6 (interleukin 6) significantly increased the expression and secretion of PSG7 and PSG9. In contrast, when we treated primary endothelial cells with recombinant PSG7 and PSG9, we only observed modest changes in Flt-1 (FMS-like tyrosine kinase-1) expression and Plgf (placental growth factor) expression, and no other effects on proangiogenic/antiangiogenic or endothelial dysfunction markers were observed. Conclusions Circulating PSG7 and PSG9 are increased before preeclampsia onset and among those with established disease with their production and release potentially driven by placental inflammation.
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    Maternal factors during pregnancy influencing maternal, fetal and childhood outcomes: Meet the Guest Editors.
    Muglia, L ; Tong, S ; Ozanne, S ; Benhalima, K (Springer Science and Business Media LLC, 2022-03-10)
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    Low-Dose Aspirin for Preventing Birth of a Small-For-Gestational Age Neonate in a Subsequent Pregnancy.
    Hastie, R ; Tong, S ; Wikström, A-K ; Walker, SP ; Lindquist, A ; Cluver, CA ; Kupka, E ; Bergman, L ; Hesselman, S (Ovid Technologies (Wolters Kluwer Health), 2022-04-01)
    OBJECTIVE: To estimate whether low-dose aspirin use is associated with an altered risk of delivering a small-for-gestational age (SGA) neonate among women with a history of having an SGA neonate in a prior pregnancy. METHODS: We performed a Swedish register-based cohort study including women in their second pregnancy who had a history of having an SGA neonate (birth weight less than the 10th percentile). The association between use of low-dose aspirin in subsequent pregnancy and birth of an SGA neonate or a severely SGA neonate (birth weight less than the third percentile) were estimated using inverse propensity-weighted estimation, accounting for potential confounders. RESULTS: Among 8,416 women who gave birth to an SGA neonate in their first pregnancy, 801 (9.5%) used low-dose aspirin during their second pregnancy. The incidence of SGA neonates was similar among women using low-dose aspirin (21.7%) and those who did not use aspirin (20.7%). Low-dose aspirin use in pregnancy was not associated with an altered risk of having an SGA neonate (adjusted relative risk [aRR] 0.86, 95% CI 0.67-1.10) or a severely SGA neonate (aRR 0.98, 95% CI 0.71-1.34). Given the strong association between preeclampsia and SGA, we performed subgroup analyses based on preeclampsia status. Among women who had an SGA neonate and co-existing preeclampsia in their first pregnancy, low-dose aspirin was not associated with an altered risk of having an SGA (aRR 0.83, 95% CI 0.63-1.10) or severely SGA (aRR 1.02, 95% CI 0.73-1.44) neonate. Additionally, no association was seen among women who developed preeclampsia in their second pregnancy. CONCLUSION: Among women with a history of having an SGA neonate, low-dose aspirin was not associated with a decreased risk of having an SGA or severely SGA neonate in subsequent pregnancy. These findings suggest that low-dose aspirin should not be used to prevent recurrent SGA.
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    Clinical tools and biomarkers to predict preeclampsia
    MacDonald, TM ; Walker, SP ; Hannan, NJ ; Tong, S ; Kaitu'u-Lino, TJ (ELSEVIER, 2022-01-01)
    Preeclampsia is pregnancy-specific, and significantly contributes to maternal, and perinatal morbidity and mortality worldwide. An effective predictive test for preeclampsia would facilitate early diagnosis, targeted surveillance and timely delivery; however limited options currently exist. A first-trimester screening algorithm has been developed and validated to predict preterm preeclampsia, with poor utility for term disease, where the greatest burden lies. Biomarkers such as sFlt-1 and placental growth factor are also now being used clinically in cases of suspected preterm preeclampsia; their high negative predictive value enables confident exclusion of disease in women with normal results, but sensitivity is modest. There has been a concerted effort to identify potential novel biomarkers that might improve prediction. These largely originate from organs involved in preeclampsia's pathogenesis, including placental, cardiovascular and urinary biomarkers. This review outlines the clinical imperative for an effective test and those already in use and summarises current preeclampsia biomarker research.
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    Transcriptomic analysis of patient plasma reveals circulating miR200c as a potential biomarker for high-grade serous ovarian cancer
    Hannan, NJ ; Cohen, PA ; Beard, S ; Bilic, S ; Zhang, B ; Tong, S ; Whitehead, C ; Hui, L (ELSEVIER SCIENCE INC, 2021-12-20)
    BACKGROUND: High-grade serous tubo-ovarian cancer (HGSC) is the most common histological subtype of epithelial ovarian cancer, and highly lethal. Currently there is no effective screening test and prognosis is poor as the majority of cases are diagnosed at the advanced stage. Cell free RNAs including microRNAs (miRNAs) are dysregulated in ovarian cancer tissue and are detectable in the circulation. This study aimed to determine whether circulating cell free miRNAs may be potential biomarkers for the detection of HGSC. METHODS: Plasma was collected from women with HGSC (Grade 3, n = 24), and benign ovarian masses (n = 24). RNA was extracted from patient plasma and subjected to miRNA targeted next generation sequencing (NGS). A subsequent validation cohort was assessed using plasma collected from women with HGSC (n = 14) and controls (with a benign ovarian mass; n = 15). RNA was extracted and assessed using quantitative RT-PCR. RESULTS: Differential gene expression (DGE) of the NGS data revealed a significant increase in the miRNA, miR200c, in the circulation of women with HGSC (p less than 0.05) compared to controls. In the validation cohort miR200c expression by qPCR was found to also be increased in the circulation of women with HGSC compared to controls (p = 0.0023). CONCLUSIONS: Circulating miR200c may be a promising candidate biomarker for the detection of HGSC. Further larger cohort studies exploring earlier stages are needed to determine whether circulating miR200c may be a sensitive and specific biomarker of tubo-ovarian cancer.
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    Obituary: Professor Roger Valentine Short, 31 July 1930-6 August 2021
    Craig, JM ; Hopper, JL ; Martin, NG ; Tong, S ; Umstad, MP (CAMBRIDGE UNIV PRESS, 2021-08-01)
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    Use of metformin to prolong gestation in preterm pre-eclampsia: randomised, double blind, placebo controlled trial
    Cluver, CA ; Hiscock, R ; Decloedt, EH ; Hall, DR ; Schell, S ; Mol, BW ; Brownfoot, F ; Kaitu'u-Lino, TJ ; Walker, SP ; Tong, S (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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    Circulating SPINT1 Is Reduced in a Preeclamptic Cohort with Co-Existing Fetal Growth Restriction.
    Murphy, CN ; Cluver, CA ; Walker, SP ; Keenan, E ; Hastie, R ; MacDonald, TM ; Hannan, NJ ; Brownfoot, FC ; Cannon, P ; Tong, S ; Kaitu'u-Lino, TJ (MDPI AG, 2022-02-09)
    Fetal growth restriction (FGR), when undetected antenatally, is the biggest risk factor for preventable stillbirth. Maternal circulating SPINT1 is reduced in pregnancies, which ultimately deliver small for gestational age (SGA) infants at term (birthweight < 10th centile), compared to appropriate for gestational age (AGA) infants (birthweight ≥ 10th centile). SPINT1 is also reduced in FGR diagnosed before 34 weeks' gestation. We hypothesised that circulating SPINT1 would be decreased in co-existing preterm preeclampsia and FGR. Plasma SPINT1 was measured in samples obtained from two double-blind, randomised therapeutic trials. In the Preeclampsia Intervention with Esomeprazole trial, circulating SPINT1 was decreased in women with preeclampsia who delivered SGA infants (n = 75, median = 18,857 pg/mL, IQR 10,782-29,890 pg/mL, p < 0.0001), relative to those delivering AGA (n = 22, median = 40,168 pg/mL, IQR 22,342-75,172 pg/mL). This was confirmed in the Preeclampsia Intervention 2 with metformin trial where levels of SPINT1 in maternal circulation were reduced in SGA pregnancies (n = 95, median = 57,764 pg/mL, IQR 42,212-91,356 pg/mL, p < 0.0001) compared to AGA controls (n = 40, median = 107,062 pg/mL, IQR 70,183-176,532 pg/mL). Placental Growth Factor (PlGF) and sFlt-1 were also measured. PlGF was significantly reduced in the SGA pregnancies, while ratios of sFlt-1/SPINT1 and sFlt1/PlGF were significantly increased. This is the first study to demonstrate significantly reduced SPINT1 in co-existing FGR and preeclamptic pregnancies.