Obstetrics and Gynaecology - Research Publications
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ItemRisk of obstetric anal sphincter injury among women who birth vaginally after a prior caesarean section: A state-wide cohort study(WILEY, 2022-07)OBJECTIVE: Vaginal birth after caesarean (VBAC) has been suggested to be associated with an increased risk of obstetric anal sphincter injury (compared with primiparous women who birth vaginally). However, prior studies have been small or have used outdated methodology. We set out to validate whether the risk of obstetric anal sphincter injury among women having their first VBAC is greater than that among primiparous women having a vaginal birth. DESIGN: State-wide retrospective cohort study. SETTING: Victoria, Australia. POPULATION: All births (455 000) between 2009 and 2014. METHODS: The risk of severe perineal injury between the first vaginal birth and the first VBAC was compared, after adjustment for potential confounding variables. Covariates were examined using logistic regression for categorical data and the Wilcoxon rank-sum test for continuous data. Missing data were handled using multiple imputation; the analysis was performed using regression adjustment and stata 16 multiple imputation and suite of effects commands. RESULTS: Women having a VBAC (n = 5429) were significantly more likely than primiparous women (n = 123 353) to sustain a third- or fourth-degree tear during vaginal birth (7.1 versus 5.7%, p < 0.001). After adjustment for mode of birth, body mass index, maternal age, infant birthweight, episiotomy and epidural, there was a 21% increased risk of severe perineal injury (RR 1.21, 95% CI 1.07-1.38). CONCLUSIONS: Women having their first VBAC have a significantly increased risk of sustaining a third- or fourth-degree tear, compared with primiparous women having a vaginal birth. Patient counselling and professional guidelines should reflect this increased risk.
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ItemAdjusting growth standards for fetal sex improves correlation of small babies with stillbirth and adverse perinatal outcomes: A state-wide population study(PUBLIC LIBRARY SCIENCE, 2022-10-10)OBJECTIVES: Sex impacts birthweight, with male babies heavier on average. Birthweight charts are thus sex specific, but ultrasound fetal weights are often reported by sex neutral standards. We aimed to identify what proportion of infants would be re-classified as SGA if sex-specific charts were used, and if this had a measurable impact on perinatal outcomes. METHODS: Retrospective cohort study including all infants born in Victoria, Australia, from 2005-2015 (529,261 cases). We applied GROW centiles, either adjusted or not adjusted for fetal sex. We compared overall SGA populations, and the populations of males considered small by sex-specific charts only (SGAsex-only), and females considered small by sex-neutral charts only (SGAunadjust-only). RESULTS: Of those <10th centile by sex-neutral charts, 39.6% were male and 60.5% female, but using sex-specific charts, 50.3% were male and 49.7% female. 19.2% of SGA females were reclassified as average for gestational age (AGA) using sex-specific charts. These female newborns were not at increased risk of stillbirth, combined perinatal mortality, NICU admissions, low Apgars or emergency CS compared with an AGA infant, but were at greater risk of being iatrogenically delivered on suspicion of growth restriction. 25.0% male infants were reclassified as SGA by sex-specific charts. These male newborns, compared to the AGAall infant, were at greater risk of stillbirth (RR 1.94, 95%CI 1.30-2.90), combined perinatal mortality (RR 1.80, 95%CI 1.26-2.57), NICU admissions (RR 1.38, 95%CI 1.12-1.71), Apgars <7 at 5 minutes (RR 1.40, 95%CI 1.25-1.56) and emergency CS (RR 1.12, 95%CI 1.06-1.18). CONCLUSIONS: Use of growth centiles not adjusted for fetal sex disproportionately classifies female infants as SGA, increasing their risk of unnecessary intervention, and fails to identify a cohort of male infants at increased risk of adverse outcomes, including stillbirth. Sex-specific charts may help inform decisions and improve outcomes.
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ItemNo Preview AvailableEndothelial protein C receptor is increased in preterm preeclampsia and fetal growth restriction(WILEY, 2022-12)Placental dysfunction is the leading cause of both preeclampsia and fetal growth restriction. This study aimed to characterize endothelial protein C receptor (EPCR) in preterm preeclampsia, term preeclampsia, and fetal growth restriction (defined by delivery of a small for gestational age [SGA] infant [<10% birthweight centile]) and examine its regulation in primary syncytiotrophoblast. Placental EPCR mRNA and protein were significantly increased in patients with preterm preeclampsia (<34 weeks gestation) compared to gestation-matched controls (p < .0001). In the plasma, EPCR was also significantly elevated (p = .01) in established preterm preeclampsia while its substrate, protein C (PC) was significantly reduced (p = .0083). Placentas from preterm small for gestational age (SGA) cases, had elevated EPCR mRNA expression (p < .0001) relative to controls. At 36 weeks, no significant changes in plasma EPCR were detected in samples from patients destined to develop preeclampsia or deliver an SGA infant at term. In terms of syncytiotrophoblast, hypoxia significantly increased EPCR mRNA expression (p = .008), but Tumor Necrosis Factor Alpha (TNF-α) decreased EPCR mRNA. Interleukin-6 (IL-6) had no significant effect on EPCR mRNA expression. When isolated syncytiotrophoblast was treated with metformin under hypoxia (1% O2 ) or normoxia (8% O2 ), EPCR mRNA expression was significantly reduced (p = .008) relative to control. In conclusion, EPCR is markedly elevated in the placenta and the circulation of patients with established preterm preeclampsia and placental increases may be associated with hypoxia. Additionally, fetal growth-restricted pregnancies (as defined by the delivery of an SGA infant) also demonstrated elevated placental EPCR.
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ItemNo Preview AvailableEstimation of neonatal body fat percentage predicts neonatal hypothermia better than birthweight centile(TAYLOR & FRANCIS LTD, 2022)INTRODUCTION: PEA POD™ air displacement plethysmography quickly and noninvasively estimates neonatal body fat percentage (BF%). Low PEA POD™ BF% predicts morbidity better than classification as small-for-gestational-age (SGA; <10th centile), but PEA PODs are not widely available. We examined whether skinfold measurements could effectively identify neonates at risk; comparing skinfold BF%, PEA POD™ BF% and birthweight centiles' prediction of hypothermia - a marker of reduced in utero nutrition. METHODS: Neonates had customized birthweight centiles calculated, and BF% prospectively estimated by: (i) triceps and subscapular skinfolds using sex-specific equations; and (ii) PEA POD™. Medical record review identified hypothermic (<36.5 °C) episodes. RESULTS: 42/149 (28%) neonates had hypothermia. Skinfold BF%, with an area under the curve (AUC) of 0.66, predicted hypothermia as well as PEA POD™ BF% (AUC = 0.62) and birthweight centile (AUC = 0.61). Birthweight <10th centile demonstrated 11.9% sensitivity, 38.5% positive predictive value (PPV) and 92.5% specificity for hypothermia. At equal specificity, skinfold and PEA POD™ BF% more than doubled sensitivity (26.2%) and PPV increased to 57.9%. CONCLUSION: Neonatal BF% performs better to predict neonatal hypothermia than birthweight centile, and may be a better measure of true fetal growth restriction. Estimation of neonatal BF% by skinfold measurements is an inexpensive alternative to PEA POD™.
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ItemNo Preview AvailableDevelopmental Outcomes for Children After Elective Birth at 39 Weeks' Gestation(AMER MEDICAL ASSOC, 2022-07)IMPORTANCE: Elective births at 39 weeks' gestation are increasing. While this option may improve maternal and perinatal outcomes compared with expectant management, longer-term childhood developmental outcomes are uncertain. OBJECTIVE: To investigate the association between elective birth at 39 weeks' gestation and the risk of childhood developmental vulnerability. DESIGN, SETTING, AND PARTICIPANTS: For this cohort study, 2 causal inference analyses were conducted using Australian statewide, population-based data. Perinatal data from births between January 1, 2005, and December 31, 2013, were linked to childhood developmental outcomes at age 4 to 6 years (assessed using multiple imputation via inverse probability-weighted regression adjustment). Data analyses were conducted between September 7 and November 9, 2021. EXPOSURES: Two exposure groups were considered: (1) elective birth between 39 weeks and 0 days' and 39 weeks and 6 days' gestation vs expectant management and (2) birth via induction of labor vs planned cesarean delivery among those born electively at 39 weeks' gestation. MAIN OUTCOMES AND MEASURES: Childhood developmental vulnerability at school entry, defined as scoring below the 10th percentile in at least 2 of 5 developmental domains (physical health and well-being, social competence, emotional maturity, school-based language and cognitive skills, and communication skills and general knowledge). RESULTS: Of 176 236 births with linked outcome data, 88 165 met the inclusion criteria. Among these, 15 927 (18.1%) were elective births at 39 weeks' gestation (induction of labor or planned cesarean delivery), and 72 238 (81.9%) were expectantly managed with subsequent birth between 40 and 43 weeks' gestation. Compared with expectant management, elective birth at 39 weeks' gestation was not associated with an altered risk of childhood global developmental vulnerability (adjusted relative risk [aRR], 1.03; 95% CI, 0.96-1.12) or with developmental vulnerability in any of the individual domains. In an analysis restricted to elective births at 39 weeks' gestation, induction of labor (n = 7928) compared with planned cesarean delivery (n = 7999) was not associated with childhood developmental vulnerability (aRR, 0.96; 95% CI, 0.82-1.12) or with vulnerability in any individual domains. CONCLUSIONS AND RELEVANCE: In this cohort study, elective birth at 39 weeks' gestation was not associated with childhood developmental vulnerability. For those born electively at 39 weeks' gestation, birth after induction of labor or by elective cesarean delivery had similar developmental outcomes.
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ItemIncidence and causes of stillbirth in the only tertiary referral hospital in the Solomon Islands: a hospital-based retrospective cohort study(BMJ PUBLISHING GROUP, 2022-12)OBJECTIVES: Stillbirth is a major global health issue, which disproportionately affects families living in low-income and middle-income countries. The Solomon Islands is a Pacific nation with poor perinatal outcomes, however research investigating stillbirth is lacking. Thus, we aimed to investigate the incidence and cause of stillbirth occurring at the National Referral Hospital, Solomon Islands. DESIGN: We conducted a retrospective cohort study from January 2017 to December 2018. SETTING: At the only tertiary referral hospital in the Solomon Islands, on the main island of Guadalcanal. PARTICIPANTS: All births occurring in the hospital during the study period. OUTCOME MEASURES: Number of, causes and risk factors for stillbirths (fetal deaths before birth at ≥20 estimated gestational weeks, or ≥500 g in birth weight). RESULTS: Over 2 years 341 stillbirths and 11 056 total births were recorded, giving an institutional incidence of 31 stillbirths per 1000 births. Of the cases with a recorded cause of death, 72% were deemed preventable. Most stillbirths occurred antenatally and 62% at preterm gestations (<37 weeks). 59% had a birth weight below 2500 g and preventable maternal conditions were present in 42% of the cases. 46% of the cases were caused by an acute intrapartum event, and among these 92% did not receive intrapartum monitoring. CONCLUSIONS: Stillbirth affects 31 in every 1000 births at the National Referral Hospital in the Solomon Islands and many cases are preventable. Our findings highlight the urgent need for increased focus on perinatal deaths in the Solomon Islands with universal classification and targeted training, improved quality of obstetrical care and community awareness.
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ItemPlacental galectin-3 is reduced in early-onset preeclampsia(FRONTIERS MEDIA SA, 2022-10-14)Preeclampsia is a disease of pregnancy responsible for significant maternal and neonatal mortality. Galectin-3 is a β-Galactoside binding protein. This study aimed to characterise galectin-3 in women with preeclampsia and human trophoblast stem cells (hTSCs). Galectin-3 was measured in placental lysates and plasma collected from patients with early-onset preeclampsia (delivered <34 weeks' gestation) and gestation matched controls. Placental galectin-3 protein was significantly reduced in 43 women with early-onset preeclampsia compared to 21 controls. mRNA expression of LGALS3 (galectin-3 encoding gene) was reduced in 29 women with early-onset preeclampsia, compared to 18 controls (p = 0.009). There was no significant difference in plasma galectin-3 protein in 46 women with early-onset preeclampsia compared to 20 controls. In a separate cohort of samples collected at 36 weeks' gestation, circulating galectin-3 was not altered in 23 women who later developed preeclampsia, versus 182 who did not. In syncytialised hTSCs, hypoxia increased mRNA expression of LGALS3 (p = 0.01). Treatment with inflammatory cytokines (TNF-α and IL-6) had no effect on LGALS3 mRNA expression. However, TNF-α treatment caused an increase in mRNA expression of LGALS3BP (galectin-3 binding protein encoding gene) in hTSCs (p = 0.03). This study showed a reduction of galectin-3 in placenta from pregnancies complicated by early-onset preeclampsia. LGALS3 mRNA expression was dysregulated by hypoxia exposure in placental stem cells.
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ItemPlacental OLAH Levels Are Altered in Fetal Growth Restriction, Preeclampsia and Models of Placental Dysfunction(MDPI, 2022-09)Previously, we identified elevated transcripts for the gene Oleoyl-ACP Hydrolase (OLAH) in the maternal circulation of pregnancies complicated by preterm fetal growth restriction. As placental dysfunction is central to the pathogenesis of both fetal growth restriction and preeclampsia, we aimed to investigate OLAH levels and function in the human placenta. We assessed OLAH mRNA expression (qPCR) throughout pregnancy, finding placental expression increased as gestation progressed. OLAH mRNA and protein levels (Western blot) were elevated in placental tissue from cases of preterm preeclampsia, while OLAH protein levels in placenta from growth-restricted pregnancies were comparatively reduced in the preeclamptic cohort. OLAH expression was also elevated in placental explant tissue, but not isolated primary cytotrophoblast cultured under hypoxic conditions (as models of placental dysfunction). Further, we discovered that silencing cytotrophoblast OLAH reduced the expression of pro- and anti-apoptosis genes, BAX and BCL2, placental growth gene, IGF2, and oxidative stress gene, NOX4. Collectively, these findings suggest OLAH could play a role in placental dysfunction and may be a therapeutic target for mitigating diseases associated with this vital organ. Further research is required to establish the role of OLAH in the placenta, and whether these changes may be a maternal adaptation or consequence of disease.
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ItemAssociations Between Soluble fms-Like Tyrosine Kinase-1 and Placental Growth Factor and Disease Severity Among Women With Preterm Eclampsia and Preeclampsia(WILEY, 2022-08-16)Background The angiogenic factors soluble fms-like tyrosine kinase-1 (sFlt-1) and placental growth factor (PlGF) are postulated to be pathogenic disease drivers of preeclampsia. If true, then circulating levels should become more deranged with increasing disease severity. Methods and Results We investigated the association between circulating sFlt-1 and PlGF levels and severe adverse maternal outcomes among 348 women with preeclampsia. Compared with 125 women with preeclampsia without severe features, 25 women with preeclampsia and any of hemolysis, elevated liver enzymes, low platelet count syndrome, disseminated intravascular coagulation, or severe renal involvement had sFlt-1 levels that were 2.63-fold higher (95% CI, 1.81-3.82), sFlt-1/PlGF levels that were 10.07-fold higher (95% CI, 5.36-18.91) and PlGF levels that were 74% lower (adjusted fold change, 0.26 [95% CI, 0.18-0.39]). Compared with 125 women with preeclampsia without severe features, 37 with eclampsia had sFlt-1 levels that were 2-fold higher (2.02 [95% CI, 1.32-3.09]), sFlt-1/PIGF levels that were 4.71-fold higher (95% CI, 2.30-9.66) and PIGF levels that were 63% lower (0.43-fold change [95% CI, 0.27-0.68]). Compared with those without severe features, preeclampsia with severe hypertension (n=146) was also associated with altered angiogenic levels (sFlt-1, 1.71-fold change [95% CI, 1.39-2.11]; sFlt/PlGF, 2.91 [95% CI, 2.04-4.15]; PlGF, 0.59 [95%CI 0.47-0.74]). We also found that sFlt-1 and PlGF levels were altered by the number of maternal complications experienced. Conclusions Further angiogenic imbalance among women with preeclampsia is likely a pathogenic disease driver responsible for the life-threatening maternal complications.