Obstetrics and Gynaecology - Research Publications
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ItemEnoxaparin for the prevention of preeclampsia and intrauterine growth restriction in women with a prior history - an open-label randomised trial (the EPPI trial): study protocol(BMC, 2016-11-22)BACKGROUND: Preeclampsia and intrauterine fetal growth restriction (IUGR) are two of the most common causes of maternal and perinatal morbidity and mortality. Current methods of predicting those at most risk of these conditions remain relatively poor, and in clinical practice past obstetric history remains the most commonly used tool. Aspirin and, in women at risk of preeclampsia only, calcium have been demonstrated to have a modest effect on risk reduction. Several observational studies and randomised trials suggest that low molecular weight heparin (LMWH) therapy may confer some benefit. METHODS/DESIGN: This is a multicentre open label randomised controlled trial to determine the effect of the LMWH, enoxaparin, on the prevention of recurrence of preeclampsia and/or IUGR in women at high risk due to their past obstetric history in addition to standard high risk care for all participants. INCLUSION CRITERIA: A singleton pregnancy >6+0 and <16+0 weeks gestation with most recent prior pregnancy with duration >12 weeks having; (1) preeclampsia delivered <36+0 weeks, (2) Small for gestational age (SGA) infant <10th customised birthweight centile delivered <36+0 weeks or, (3) SGA infant ≤3rd customised birthweight centile delivered at any gestation. Randomisation is stratified for maternal thrombophilia status and women are randomly assigned to 'standard high risk care' or 'standard high risk care' plus enoxaparin 40 mg from recruitment until 36+0 weeks or delivery, whichever occurs sooner. Standard high risk care includes the use of aspirin 100 mg daily and calcium 1000-1500 mg daily (unless only had previous SGA with no preeclampsia). The primary outcome is preeclampsia and/or SGA <5th customised birthweight centile. Analysis will be by intention to treat. DISCUSSION: The EPPI trial has more focussed and clinically relevant inclusion criteria than other randomised trials with a more restricted composite primary outcome. The inclusion of standard use of aspirin (and calcium) for all participants will help to ensure that any differences observed in outcome are likely to be related to enoxaparin use. These data will make a significant contribution to future meta-analyses and systematic reviews on the use of LMWH for the prevention of placental mediated conditions. TRIAL REGISTRATION: ACTRN12609000699268 Australian New Zealand Clinical Trials Registry. Date registered 13/Aug/2009 (prospective registration).
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ItemSystematic review of areca (betel nut) use and adverse pregnancy outcomes(WILEY, 2019-12)BACKGROUND: Betel nut is the fourth most commonly abused substance worldwide and has been associated with significant adverse health outcomes. Little is known about its effects on the fetus. OBJECTIVE: To perform a systematic review of studies investigating prenatal betel nut use and adverse perinatal outcomes. SEARCH STRATEGY: Pubmed, Embase, and Cochrane databases were searched from inception until July 2018 using the terms areca, betel nut, pregnancy, pregnancy complications, and infection. SELECTION CRITERIA: Eligible studies included case-control, cohort, and randomized control studies involving pregnant women. DATA COLLECTION AND ANALYSIS: Where appropriate, bivariate meta-analysis was performed, and odds ratios (ORs) and 95% confidence intervals (CIs) were calculated. MAIN RESULTS: In total, 28 studies were screened and eight studies (including 15 270 women) were included in the review and meta-analysis. Preterm birth, low birthweight, and anemia were most commonly investigated. Meta-analysis revealed a significant association between betel nut use and low birthweight, with a pooled OR of 1.75 (95% CI, 1.35-2.27). CONCLUSIONS: The review identified only eight eligible studies, all based in the Asia-Pacific region. There was a significant association between low birthweight and betel nut exposure in pregnancy. Further prospective studies are needed to confirm this association.
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ItemBlood-based biomarkers in the maternal circulation associated with fetal growth restriction(WILEY, 2019-10)Fetal growth restriction (FGR) is associated with threefold to fourfold increased risk of stillbirth. Identifying FGR, through its commonly used surrogate-the small-for-gestational-age (SGA, estimated fetal weight and/or abdominal circumference <10th centile) fetus-and instituting fetal surveillance and timely delivery decrease stillbirth risk. Methods available to clinicians for antenatal identification of SGA fetuses have surprisingly poor sensitivity. About 80% of cases remain undetected. Measuring the symphysis-fundal height detects only 20% of SGA fetuses, and even universal third trimester ultrasound detects, at best, 57% of those born SGA. There is an urgent need to find better ways to identify this at-risk cohort. This review summarises efforts to identify molecular biomarkers (proteins, metabolites, or ribonucleic acids) that could be used to better predict FGR. Most studies examining potential biomarkers to date have utilised case-control study designs without proceeding to validation in independent cohorts. To develop a robust test for FGR, large prospective studies are required with a priori validation plans and cohorts. Given that current clinical care detects 20% of SGA fetuses, even a screening test with ≥60% sensitivity at 90% specificity could be clinically useful, if developed. This may be an achievable aspiration. If discovered, such a test may decrease stillbirth.
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ItemPhase II single arm open label multicentre clinical trial to evaluate the efficacy and side effects of a combination of gefitinib and methotrexate to treat tubal ectopic pregnancies (GEM II): study protocol(BMJ PUBLISHING GROUP, 2013)INTRODUCTION: Tubal ectopic pregnancy (tEP) is the most common life-threatening condition in gynaecology. tEPs with pretreatment serum human chorionic gonadotrophin (hCG) levels <1000 IU/L respond well to outpatient medical treatment with intramuscular methotrexate (MTX). TEPs with hCG >1000 IU/L take a significant time to resolve with MTX and require multiple outpatient monitoring visits. Gefitinib is an orally active epidermal growth factor receptor (EGFR) antagonist. In preclinical studies, we found that EP implantation sites express high levels of EGFR and that gefitinib augments MTX-induced regression of pregnancy-like tissue. We performed a phase I toxicity study administering oral gefitinib and intramuscular MTX to 12 women with tEPs. The combination therapy did not cause significant toxicities and was well tolerated. We noted that combination therapy resolved the tEPs faster than MTX alone. We now describe the protocol of a larger single arm trial to estimate the efficacy and side effects of combination gefitinib and MTX to treat stable tEPs with hCG 1000-10 000 IU/L METHODS AND ANALYSIS: We propose to undertake a single-arm multicentre open label trial (in Edinburgh and Melbourne) and recruit 28 women with tEPs (pretreatment serum hCG 1000-10 000 IU/L). We intend to give a single dose of intramuscular MTX (50 mg/m(2)) and oral gefitinib (250 mg) daily for 7 days. Our primary outcome is the resolution of EP to non-pregnant hCG levels <15 IU/L without requirement of surgery. Our secondary outcomes are comparison of time to resolution against historical controls given MTX only, and safety and tolerability as determined by clinical/biochemical assessment. ETHICS AND DISSEMINATION: Ethical approval has been obtained from Scotland A Research Ethics Committee (MREC 11/AL/0350), Southern Health Human Research Ethics Committee B (HREC 11180B) and the Mercy Health Human Research Ethics Committee (R12/25). Data will be presented at international conferences and published in peer-reviewed journals. TRIAL REGISTRATION NUMBER: ACTRN12611001056987.
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ItemUsing a decline in serum hCG between days 0-4 to predict ectopic pregnancy treatment success after single-dose methotrexate: a retrospective cohort study(BMC, 2013-02-01)BACKGROUND: The current measure of treatment efficacy of single-dose methotrexate for ectopic pregnancy, is a fall in serum hCG of ≥15% between days 4-7 of treatment, which has a positive predictive value of 93% for treatment success. Two small studies have proposed a fall in serum hCG between days 0-4 after treatment confers similar, earlier prognostic information, with positive predictive values of 100% and 88% for treatment success. We sought to validate this in a large, independent cohort because of the potentially significant clinical implications. METHODS: We conducted a retrospective study of women (n=206) treated with single-dose methotrexate for ectopic pregnancy (pre-treatment serum hCG levels ≤3000 IU/L) at Scottish hospitals between 2006-2011. Women were divided into two cohorts based on whether their serum hCG levels rose or fell between days 0-4 after methotrexate. Treatment outcomes of women in each cohort were compared, and the test performance characteristics calculated. This methodology was repeated for the current measure (≥15% fall in serum hCG between days 4-7 of treatment) and an alternate early measure (<20% fall in serum hCG between days 0-4 of treatment), and all three measures were compared for their ability to predict medical treatment success. RESULTS: In our cohort, the positive predictive value of the current clinical measure was 89% (95% CI 84-94%) (121/136). A falling serum hCG between days 0-4 predicted treatment success in 85% (95% CI 79-92%) of cases (94/110) and a <20% fall in serum hCG between days 0-4 predicted treatment success in 94% (95% CI 88-100%) of cases (59/63). There was no significant difference in the ability of these tests to predict medical treatment success. CONCLUSIONS: We have verified that a decline in serum hCG between days 0-4 after methotrexate treatment for ectopic pregnancies, with pre-treatment serum hCG levels ≤3000 IU/L, provides an early indication of likelihood of treatment success, and performs just as well as the existing measure, which only provides prognostic information on day 7.
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ItemUltrasound Reference Chart Based on IVF Dates to Estimate Gestational Age at 6-9 weeks' Gestation.(Hindawi Limited, 2012)Accurate determination of gestational age underpins good obstetric care. We assessed the performance of six existing ultrasound reference charts to determine gestational age in 1268 singleton IVF pregnancies, where "true" gestational age could be precisely calculated from date of fertilisation. All charts generated dates significantly different to IVF dates (P < 0.0001 all comparisons). Thus we generated a new reference chart, The Monash Chart, based on a line of best fit describing crown-rump length across 6 + 1 to 9 + 0 weeks of gestation (true gestational age) in the IVF singleton cohort. The Monash Chart, but none of the existing charts, accurately determined gestational age among an independent IVF twin cohort (185 twin pairs). When applied to 3052 naturally-conceived singletons scans, The Monash Chart generated estimated due dates that were different to all existing charts (P ≤ 0.004 all comparisons). We conclude that commonly used ultrasound reference charts have inaccuracies. We have generated a CRL reference chart based on true gestational age in an IVF cohort that can accurately determine gestational age at 6-9 weeks of gestation.
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ItemEffects of Maternal Obstructive Sleep Apnoea on Fetal Growth: A Prospective Cohort Study(PUBLIC LIBRARY SCIENCE, 2013-07-24)OBJECTIVE: The objective of this study is to determine whether obstructive sleep apnea (OSA) is associated with reduced fetal growth, and whether nocturnal oxygen desaturation precipitates acute fetal heart rate changes. STUDY DESIGN: We performed a prospective observational study, screening 371 women in the second trimester for OSA symptoms. 41 subsequently underwent overnight sleep studies to diagnose OSA. Third trimester fetal growth was assessed using ultrasound. Fetal heart rate monitoring accompanied the sleep study. Cord blood was taken at delivery, to measure key regulators of fetal growth. RESULTS: Of 371 women screened, 108 (29%) were high risk for OSA. 26 high risk and 15 low risk women completed the longitudinal study; 14 had confirmed OSA (cases), and 27 were controls. The median (interquartile range) respiratory disturbance index (number of apnoeas, hypopnoeas or respiratory related arousals/hour of sleep) was 7.9 (6.1-13.8) for cases and 2.2 (1.3-3.5) for controls (p<0.001). Impaired fetal growth was observed in 43% (6/14) of cases, vs 11% (3/27) of controls (RR 2.67; 1.25-5.7; p = 0.04). Using logistic regression, only OSA (OR 6; 1.2-29.7, p = 0.03) and body mass index (OR 2.52; 1.09-5.80, p = 0.03) were significantly associated with impaired fetal growth. After adjusting for body mass index on multivariate analysis, the association between OSA and impaired fetal growth was not appreciably altered (OR 5.3; 0.93-30.34, p = 0.06), although just failed to achieve statistical significance. Prolonged fetal heart rate decelerations accompanied nocturnal oxygen desaturation in one fetus, subsequently found to be severely growth restricted. Fetal growth regulators showed changes in the expected direction- with IGF-1 lower, and IGFBP-1 and IGFBP-2 higher- in the cord blood of infants of cases vs controls, although were not significantly different. CONCLUSION: OSA may be associated with reduced fetal growth in late pregnancy. Further evaluation is warranted to establish whether OSA may be an important contributor to adverse perinatal outcome, including stillbirth.
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ItemMaternal Serum Macrophage Inhibitory Cytokine-1 as a Biomarker for Ectopic Pregnancy in Women with a Pregnancy of Unknown Location(PUBLIC LIBRARY SCIENCE, 2013-06-18)BACKGROUND: Ectopic pregnancy (EP) occurs in 1-2% of pregnancies, but is over-represented as a leading cause of maternal death in early pregnancy. It remains a challenge to diagnose early and accurately. Women often present in early pregnancy with a 'pregnancy of unknown location' (PUL) and the diagnosis and exclusion of EP is difficult due to a lack of reliable biomarkers. A serum biomarker able to clearly distinguish between EP and other pregnancy outcomes would greatly assist clinicians in diagnosing and safely managing PULs. This study evaluates the ability of maternal serum macrophage inhibitory cytokine-1 (MIC-1) levels to differentiate between EP and other pregnancy outcomes in women with a PUL. METHODS: Sera were collected from 120 women with a PUL at first clinical presentation and assayed for MIC-1 by ELISA. Results were classified according to ultimate pregnancy outcome and the discriminatory ability of MIC-1 to diagnose EP was assessed. RESULTS: Serum MIC-1 levels were lower in women with histologically confirmed (definite) EP (dEP) (median 552 ng/mL; interquartile range (IQR) 414-693 ng/mL) compared to women with definite viable intra-uterine pregnancies (dVIUPs) (722 ng/mL; IQR 412-1122 ng/mL), and higher when compared to women with definite non-viable intra-uterine pregnancies (dNVIUPs) (465 ng/mL; IQR 341-675 ng/mL). MIC-1 levels were significantly higher in women with dEP compared to women whose PULs resolved without medical intervention (srPUL) (401 ng/mL; IQR 315-475 ng/mL) (p<0.003). There were no women with an ectopic pregnancy where serum MIC-1>1000 ng/mL. CONCLUSION: Serum MIC-1 levels in PUL were not able to categorically diagnose EP, however, MIC-1 could distinguish women with an EP that required medical intervention and those women whose PULs spontaneously resolved. A single serum MIC-1 measurement also excluded EP at levels above 1000 ng/mL. MIC-1 may play a role in the development of a combined assay of biomarkers for the diagnosis of EP.