Obstetrics and Gynaecology - Research Publications
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ItemHow can safe working hours produce a safe specialist obstetrician & gynaecologist?Permezel, M (WILEY, 2017-10-01)
ItemPreconception management of women with obesity: A systematic reviewPrice, SA ; Sumithran, P ; Nankervis, A ; Permezel, M ; Proietto, J (WILEY, 2019-04-01)The prevalence of women of child-bearing age with obesity continues to rise at an alarming rate. This has significant implications for both the short-term and long-term health of mother and offspring. Given the paucity of evidence-based literature in this field, the preconception management of women with obesity is highly variable both between institutions and around the world. This systematic review aims to evaluate studies that inform us about the role of preconception weight loss in the fertility and pregnancy outcomes of women with obesity. Current therapeutic interventions are discussed, with a specific focus on the suitability of weight loss interventions for women with obesity planning pregnancy. There are significant knowledge gaps in the current literature; these are discussed and areas for future research are explored.
ItemReply to: Severe growth restriction undelivered at term and ultrasound examination. Some clarificationsPritchard, N ; Diksha, P ; Permezel, M (WILEY, 2018-10-01)
ItemCustomised growth charts in large-for-gestational-age infants and the association with emergency caesarean section ratePritchard, N ; Lindquist, A ; Hiscock, R ; Diksha, P ; Walker, SP ; Permezel, M (WILEY, 2019-06-01)BACKGROUND AND AIM: Large-for-gestational-age (LGA) infants are at increased risk of intrapartum complications. However, some infants classified as LGA may be appropriate-for-gestational-age (AGA) if adjusted for maternal stature. We determined whether customisation of birthweight centiles by maternal height, or height and weight, improves the detection of LGA infants at risk of complications. METHODS: We conducted a retrospective analysis of 38 246 term, singleton nulliparous women. We compared population birthweight centiles to those customised by height, or height and weight for complications including intrapartum caesarean section, instrumental delivery, postpartum haemorrhage, anal sphincter injury and neonatal outcomes. RESULTS: Those considered LGA when customised for height but AGA by population centiles (LGA-ht-only) were at increased risk of intrapartum emergency caesarean section compared with infants AGA on all charts (AGA-all); odds ratio (OR) 4.64, 95% CI 3.22-6.76. In contrast, infants considered LGA on population charts, but AGA when customised by height (LGA-pop-only) were not at increased risk compared to the AGA-all group (OR 1.43, 95% CI 0.70-1.88). Infants classified as LGA-ht-only compared to LGA-pop-only remained at significantly higher risk after adjustment for potential confounders (aOR 3.27; 95% CI 2.02-5.31). No difference was seen for any other outcomes. No benefit was seen with customisation by both maternal height and weight. CONCLUSION: Women with an infant classified as AGA on population centiles but LGA when customised for height are at increased risk of intrapartum caesarean section. This is a population unrecognised in current practice. Fetal growth should be customised for maternal height when making assessments regarding the LGA infant.
ItemWhy we miss fetal growth restriction: Identification of risk factors for severely growth-restricted fetuses remaining undelivered by 40 weeks gestationDiksha, P ; Permezel, M ; Pritchard, N (WILEY, 2018-12-01)BACKGROUND: Severe fetal growth restriction (FGR) is a leading cause of adverse perinatal morbidity and mortality; however, in Victoria, 35% of severely growth-restricted infants are undelivered by 40 weeks gestation. AIMS: We aimed to identify factors associated with failure to deliver severely growth-restricted fetuses by 40 weeks gestation. METHODS: We conducted a retrospective case-control study of term singletons born <3rd centile for gestation at a single tertiary centre (2010-2017). Infants with a planned delivery for FGR between 37.0-39.6 weeks gestation ('planned birth' group; n = 187) were compared with those undelivered by 40.0 weeks ('undelivered' group; n = 233). Variables assessed included the presence of risk factors for FGR, model of care, symphyseal-fundal height measurements and third trimester ultrasounds. RESULTS: An equivalent proportion of women were 'high-risk' for FGR on history (31.3% vs 38.0%, P = 0.187) in the planned and undelivered groups. Women booked under low-risk models (shared care and midwifery-led care) were significantly more likely to be in the undelivered group compared to those booked under traditional collaborative models (79.8% vs 37.4%, P < 0.001). Women in the undelivered group were less likely to have received a third trimester ultrasound (93.0% vs 40.3%, P < 0.001); however, they were more likely to have had a reassuring ultrasound with an estimation of fetal weight or abdominal circumference >10th centile (78.7% vs 16.1%, P < 0.001). CONCLUSIONS: Failure to deliver the severely growth-restricted fetus before 40.0 weeks is more likely to occur in the following situations: (i) failure to receive an indicated third trimester ultrasound; (ii) the presence of falsely reassuring third trimester ultrasound scan; and (iii) booking under a low-risk rather than traditional collaborative models of care.
ItemPregnancy associated plasma protein-A links pregnancy and melanoma progression by promoting cellular migration and invasionPrithviraj, P ; Anaka, M ; McKeown, SJ ; Permezel, M ; Walkiewicz, M ; Cebon, J ; Behren, A ; Jayachandran, A (IMPACT JOURNALS LLC, 2015-06-30)Melanoma is the most common cancer diagnosed in pregnant women and an aggressive course with poorer outcomes is commonly described during pregnancy or shortly after childbirth. The underlying mechanisms for this are not understood. Here, we report that melanoma migration, invasiveness and progression are promoted by Pregnancy-Associated Plasma Protein-A (PAPPA), a pregnancy-associated metalloproteinase produced by the placenta that increases the bioavailability of IGF1 by cleaving it from a circulating complex formed with IGFBP4. We show that PAPPA is widely expressed by metastatic melanoma tumors and is elevated in melanoma cells exhibiting mesenchymal, invasive and label-retaining phenotypes. Notably, inhibition of PAPPA significantly reduced invasion and migration of melanoma cells in vitro and in vivo within the embryonic chicken neural tube. PAPPA-enriched pregnancy serum treatment enhanced melanoma motility in vitro. Furthermore, we report that IGF1 can induce the phenotypic and functional effects of epithelial-to-mesenchymal transition (EMT) in melanoma cells. In this study, we establish a clear relationship between a pregnancy-associated protein PAPPA, melanoma and functional effects mediated through IGF1 that provides a plausible mechanism for accelerated melanoma progression during pregnancy. This opens the possibility of targeting the PAPPA/IGF1 axis therapeutically.
ItemIdentification of the optimal growth charts for use in a preterm population: An Australian state-wide retrospective cohort studyPritchard, NL ; Hiscock, RJ ; Lockie, E ; Permezel, M ; McGauren, MFG ; Kennedy, AL ; Green, B ; Walker, SP ; Lindquist, AC ; Myers, JE (PUBLIC LIBRARY SCIENCE, 2019-10-01)BACKGROUND: Preterm infants are a group at high risk of having experienced placental insufficiency. It is unclear which growth charts perform best in identifying infants at increased risk of stillbirth and other adverse perinatal outcomes. We compared 2 birthweight charts (population centiles and INTERGROWTH-21st birthweight centiles) and 3 fetal growth charts (INTERGROWTH-21st fetal growth charts, World Health Organization fetal growth charts, and Gestation Related Optimal Weight [GROW] customised growth charts) to identify which chart performed best in identifying infants at increased risk of adverse perinatal outcome in a preterm population. METHODS AND FINDINGS: We conducted a retrospective cohort study of all preterm infants born at 24.0 to 36.9 weeks gestation in Victoria, Australia, from 2005 to 2015 (28,968 records available for analysis). All above growth charts were applied to the population. Proportions classified as <5th centile and <10th centile by each chart were compared, as were proportions of stillborn infants considered small for gestational age (SGA, <10th centile) by each chart. We then compared the relative performance of non-overlapping SGA cohorts by each chart to our low-risk reference population (infants born appropriate size for gestational age [>10th and <90th centile] by all intrauterine charts [AGAall]) for the following perinatal outcomes: stillbirth, perinatal mortality (stillbirth or neonatal death), Apgar <4 or <7 at 5 minutes, neonatal intensive care unit admissions, suspicion of poor fetal growth leading to expedited delivery, and cesarean section. All intrauterine charts classified a greater proportion of infants as <5th or <10th centile than birthweight charts. The magnitude of the difference between birthweight and fetal charts was greater at more preterm gestations. Of the fetal charts, GROW customised charts classified the greatest number of infants as SGA (22.3%) and the greatest number of stillborn infants as SGA (57%). INTERGROWTH classified almost no additional infants as SGA that were not already considered SGA on GROW or WHO charts; however, those infants classified as SGA by INTERGROWTH had the greatest risk of both stillbirth and total perinatal mortality. GROW customised charts classified a larger proportion of infants as SGA, and these infants were still at increased risk of mortality and adverse perinatal outcomes compared to the AGAall population. Consistent with similar studies in this field, our study was limited in comparing growth charts by the degree of overlap, with many infants classified as SGA by multiple charts. We attempted to overcome this by examining and comparing sub-populations classified as SGA by only 1 growth chart. CONCLUSIONS: In this study, fetal charts classified greater proportions of preterm and stillborn infants as SGA, which more accurately reflected true fetal growth restriction. Of the intrauterine charts, INTERGROWTH classified the smallest number of preterm infants as SGA, although it identified a particularly high-risk cohort, and GROW customised charts classified the greatest number at increased risk of perinatal mortality.
ItemImpact of preconception weight loss on fasting glucose and pregnancy outcomes in women with obesity: A randomized trialPrice, SAL ; Sumithran, P ; Nankervis, AJ ; Permezel, M ; Prendergast, LA ; Proietto, J (WILEY, 2021-09-01)OBJECTIVE: This study examined the effectiveness of a nonsurgical, preconception weight loss intervention on pregnancy outcomes in women with obesity. METHODS: This was a two-arm, parallel-group randomized controlled trial. A total of 164 women with BMI 30 to 55 kg/m2 who were aged 18 to 38 years and planning pregnancy were randomized to a 12-week standard dietary intervention (SDI; n = 79) or a modified very low-energy diet (VLED; n = 85). Participants were observed for ≤48 weeks while trying for pregnancy and then during pregnancy. The primary outcome was maternal fasting plasma glucose at 26 to 28 weeks' gestation. Exploratory outcomes were individual and composite obesity-related adverse pregnancy outcomes. RESULTS: Weight loss was greater in the VLED group (SDI 3.2 [0.6] kg vs. VLED 13.0 [0.5] kg, p < 0.01). In completers who had a singleton live birth (SDI 22/79 vs. VLED 35/85, p = 0.10), there was no difference in fasting glucose at 26 to 28 weeks' gestation (SDI 4.8[0.2] mmol/L vs. VLED 4.6 [0.1] mmol/L, p = 0.42). However, the composite of adverse pregnancy outcomes was significantly lower in the VLED group (p < 0.001). CONCLUSIONS: Substantial prepregnancy weight loss in women with obesity does not alter fasting glucose at 26 to 28 weeks' gestation but does reduce a composite of adverse pregnancy outcomes. A better understanding of metabolic changes in pregnancy after preconception weight loss may assist in improving maternal and neonatal health outcomes.
ItemHealth consequences for mother and baby of substantial pre-conception weight loss in obese women: study protocol for a randomized controlled trialPrice, S ; Nankervis, A ; Permezel, M ; Prendergast, L ; Sumithran, P ; Proietto, J (BMC, 2018-04-24)BACKGROUND: Current guidelines for the management of obesity in women planning pregnancy suggest lifestyle modification before conception. However, there is little evidence that lifestyle modification alters pregnancy outcomes. Bariatric surgery results in significant weight loss. This appears to reduce the risk of adverse pregnancy outcomes for the mother but may increase the risk of adverse outcomes for the infant. In order to reduce the risks of obesity-related adverse pregnancy outcomes for both mother and offspring, alternative approaches to the management of obesity in women planning pregnancy are needed. METHODS/DESIGN: This study, a two-arm, parallel group, randomized control trial, will be conducted at the Metabolic Disorders Centre, University of Melbourne. This trial will recruit 164 women aged 18-38 years with a body mass index of 30-55 kg/m2 who plan to conceive in the next 6-12 months. Women will be randomized to one of two 12-week interventions (Group A and Group B). Group A will aim for modest weight loss (MWL; ≤ 3% body weight) using a hypocaloric diet. Group B will aim for substantial weight loss (SWL; 10-15% body weight) using a modified very low energy diet (VLED) program. All participants will be asked to comply with National Health and Medical Research Council (NHMRC) guidelines for exercise and will be provided with standard pre-pregnancy advice according to Royal Australian and New Zealand College of Obstetrics and Gynaecology guidelines. All participants will then be observed for the subsequent 12 months. If pregnancy occurs within the 12-month follow-up period, data on weight and metabolic status of the mother, and pregnancy outcomes of mother and offspring will be recorded. The primary outcome is maternal fasting plasma glucose at 26-28 weeks' gestation, given that this is known to correlate with pregnancy outcomes. Time to conception, live birth rate, gestational weight gain, and a composite of adverse pregnancy outcomes for mother and baby will comprise the secondary outcomes. DISCUSSION: There is increasing emphasis on obese women losing weight before conception. To date, no randomized controlled trial has demonstrated an effective means of weight loss that results in improved pregnancy outcomes for both mother and baby. This study intends to determine if substantial pre-conception weight loss, achieved using a VLED, improves pregnancy outcomes for mother and baby when compared with standard care. This research will potentially change clinical care of an obese woman planning pregnancy. TRIAL REGISTRATION: ANZCTR, 12,614,001,160,628 . Registered on 5 November 2014.
ItemPostpartum circulating cell-free insulin DNA levels are higher in women with previous gestational diabetes mellitus who develop type 2 diabetes in later lifeLappas, M ; Georgiou, H ; Wilcox, J ; Permezel, M ; Shub, A ; Maynard, C-L ; Joglekar, M ; HARDIKAR, A (Hindawi Publishing Corporation, 2019)Background. Women with previous gestational diabetes mellitus (GDM) have evidence of postpartum β-cell dysfunction, which increases their risk of developing type 2 diabetes (T2DM) later in life. Elevated levels of circulating cell-free preproinsulin (INS) DNA correlate with dying β-cells in both mice and humans. The aim of this study was to determine if cell-free circulating INS DNA levels are higher in women with previous GDM who develop T2DM. Methods. We used droplet digital (dd) PCR to measure the levels of cell-free circulating methylated and unmethylated INS DNA in plasma from 97 women with normal glucose tolerance (NGT), 12 weeks following an index GDM pregnancy. Women were assessed for up to 10 years for the development of T2DM. Results. In the follow-up period, 22% of women developed T2DM. Compared with NGT women, total cell-free INS DNA levels were significantly higher in women who developed T2DM (P = 0.02). There was no difference in cell-free circulating unmethylated and methylated INS DNA levels between NGT women and women who developed T2DM (P = 0.09 and P = 0.07, respectively). Conclusions. In women with a previous index GDM pregnancy, postpartum levels of cell-free circulating INS DNA are significantly higher in those women who later developed T2DM.
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