Obstetrics and Gynaecology - Research Publications
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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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ItemAccuracy of clinical suspicion of growth restriction at term despite a normal growth ultrasound: A retrospective cohort study(WILEY, 2020-08)BACKGROUND: Small for gestational age (SGA) is a major determinant of poor perinatal outcome. Detecting SGA at term using ultrasound is challenging and we often plan birth based on clinical assessment. AIMS: To determine the incidence of SGA infants with birthweight <10th centile among women undergoing planned birth at term for suspected SGA despite a normal estimated fetal weight (EFW) on ultrasound at 35-37 weeks. MATERIALS AND METHODS: We performed a retrospective study including all women with a fetal growth ultrasound at ≥35 weeks reporting an EFW ≥ 10th centile (appropriate for gestational age, AGA) who subsequently had an induction of labour or caesarean birth at ≥37 weeks due to ongoing clinical suspicion of SGA between 2012-2014. The primary outcome was the incidence of SGA newborns using customised centiles. RESULTS: There were 532 women who had a planned birth for clinical suspicion of SGA during the study period. Of these, 205 (38.5%) had an AGA fetus on ultrasound ≥35 weeks but were subsequently delivered because of a persisting clinical suspicion of SGA on abdominal assessment. Sixty-eight percent (n = 139/205) delivered an SGA infant. Furthermore, almost half of these SGA infants (47.5%) had a birthweight <3rd centile. Neonatal outcomes were worse for the SGA infants, with 15.1% (n = 21/205) requiring special care nursery compared to 1.5% (n = 1/205) of those AGA at birth. CONCLUSIONS: A reassuring ultrasound with EFW ≥10th centile in the late third trimester should not override clinical concerns of impaired fetal growth at term.
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ItemDAAM2 is elevated in the circulation and placenta in pregnancies complicated by fetal growth restriction and is regulated by hypoxia(NATURE PORTFOLIO, 2021-03-10)Previously, we identified increased maternal circulating DAAM2 mRNA in pregnancies complicated by preterm fetal growth restriction (FGR). Here, we assessed whether circulating DAAM2 mRNA could detect FGR, and whether the DAAM2 gene, known to play roles in the Wnt signalling pathway is expressed in human placenta and associated with dysfunction and FGR. We performed linear regression analysis to calculate area under the ROC curve (AUC) for DAAM2 mRNA expression in the maternal circulation of pregnancies complicated by preterm FGR. DAAM2 mRNA expression was assessed across gestation by qPCR. DAAM2 protein and mRNA expression was assessed in preterm FGR placenta using western blot and qPCR. DAAM2 expression was assessed in term cytotrophoblasts and placental explant tissue cultured under hypoxic and normoxic conditions by qPCR. Small interfering RNAs were used to silence DAAM2 in term primary cytotrophoblasts. Expression of growth, apoptosis and oxidative stress genes were assessed by qPCR. Circulating DAAM2 mRNA was elevated in pregnancies complicated by preterm FGR [p < 0.0001, AUC = 0.83 (0.78-0.89)]. Placental DAAM2 mRNA was detectable across gestation, with highest expression at term. DAAM2 protein was increased in preterm FGR placentas but demonstrated no change in mRNA expression. DAAM2 mRNA expression was increased in cytotrophoblasts and placental explants under hypoxia. Silencing DAAM2 under hypoxia decreased expression of pro-survival gene, BCL2 and oxidative stress marker, NOX4, whilst increasing expression of antioxidant enzyme, HMOX-1. The increased DAAM2 associated with FGR and hypoxia implicates a potential role in placental dysfunction. Decreasing DAAM2 may have cytoprotective effects, but further research is required to elucidate its role in healthy and dysfunctional placentas.
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ItemReduced growth velocity from the mid-trimester is associated with placental insufficiency in fetuses born at a normal birthweight.(Biomed Central, 2020-12-24)BACKGROUND: Fetal growth restriction (FGR) due to placental insufficiency is a major risk factor for stillbirth. While small-for-gestational-age (SGA; weight < 10th centile) is a commonly used proxy for FGR, detection of FGR among appropriate-for-gestational-age (AGA; weight ≥ 10th centile) fetuses remains an unmet need in clinical care. We aimed to determine whether reduced antenatal growth velocity from the time of routine mid-trimester ultrasound is associated with antenatal, intrapartum and postnatal indicators of placental insufficiency among term AGA infants. METHODS: Three hundred and five women had biometry measurements recorded from their routine mid-trimester (20-week) ultrasound, at 28 and 36 weeks' gestation, and delivered an AGA infant. Mid-trimester, 28- and 36-week estimated fetal weight (EFW) and abdominal circumference (AC) centiles were calculated. The EFW and AC growth velocities between 20 and 28 weeks, and 20-36 weeks, were examined as predictors of four clinical indicators of placental insufficiency: (i) low 36-week cerebroplacental ratio (CPR; CPR < 5th centile reflects cerebral redistribution-a fetal adaptation to hypoxia), (ii) neonatal acidosis (umbilical artery pH < 7.15) after the hypoxic challenge of labour, (iii) low neonatal body fat percentage (BF%) reflecting reduced nutritional reserve and (iv) placental weight < 10th centile. RESULTS: Declining 20-36-week fetal growth velocity was associated with all indicators of placental insufficiency. Each one centile reduction in EFW between 20 and 36 weeks increased the odds of cerebral redistribution by 2.5% (odds ratio (OR) = 1.025, P = 0.001), the odds of neonatal acidosis by 2.7% (OR = 1.027, P = 0.002) and the odds of a < 10th centile placenta by 3.0% (OR = 1.030, P < 0.0001). Each one centile reduction in AC between 20 and 36 weeks increased the odds of neonatal acidosis by 3.1% (OR = 1.031, P = 0.0005), the odds of low neonatal BF% by 2.8% (OR = 1.028, P = 0.04) and the odds of placenta < 10th centile by 2.1% (OR = 1.021, P = 0.0004). Falls in EFW or AC of > 30 centiles between 20 and 36 weeks were associated with two-threefold increased relative risks of these indicators of placental insufficiency, while low 20-28-week growth velocities were not. CONCLUSIONS: Reduced growth velocity between 20 and 36 weeks among AGA fetuses is associated with antenatal, intrapartum and postnatal indicators of placental insufficiency. These fetuses potentially represent an important, under-recognised cohort at increased risk of stillbirth. Encouragingly, this novel fetal assessment would require only one additional ultrasound to current routine care, and adds to the potential benefits of routine 36-week ultrasound.
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ItemAppropriate-for-gestational-age infants who exhibit reduced antenatal growth velocity display postnatal catch-up growth(PUBLIC LIBRARY SCIENCE, 2020-09-08)BACKGROUND: Postnatally, small-for-gestational-age (SGA; birthweight <10th centile) infants who are growth restricted due to uteroplacental insufficiency (UPI) demonstrate 'catch-up growth' to meet their genetically-predetermined size. Infants who demonstrate slowing growth during pregnancy are those that cross estimated fetal weight centiles at serial ultrasound examinations. These infants that slow in growth but are born appropriate-for-gestational-age (AGA; ≥10th centile), exhibit antenatal, intrapartum and postnatal indicators of UPI. Here, we examine if and when these infants (labelled as AGA-FGR) also demonstrate catch-up growth like SGA infants, when compared with AGA infants with normal antenatal growth velocity (AGA-NG). METHODS: We followed-up the infants of women who had previously undergone ultrasound assessment of fetal size at 28- and 36-weeks' gestation, enabling calculation of antenatal growth velocity. To assess postnatal growth, we asked parents to send their infant's growth measurements, up to two years post-birth, which are routinely collected through the state-wide Maternal-Child Health service. Infants with medical conditions affecting postnatal growth were excluded from the analysis. From the measurements obtained we calculated age-adjusted z-scores for postnatal weight, length and body mass index (BMI; weight(kg)/height(m2)) at birth and 4, 8, 12, 18 and 24 months. We used linear spline regression modelling to predict mean weight, length and BMI z-scores at intervals post birth. Predicted mean age-adjusted z-scores were then compared between three groups; SGA, AGA with low antenatal growth (AGA-FGR; loss of >20 customised estimated fetal weight centiles), and AGA-NG to determine if catch-up growth occurred. In addition, we compared the rates of catch-up growth (defined as an increase in weight age-adjusted z-score of ≥0.67 over 1 year) between the groups with Fisher's exact tests. RESULTS: Of 158 (46%) infant growth records received, 146 were AGA, with low antenatal growth velocity occurring in 34/146 (23.2%). Rates of gestational diabetes and SGA birthweight were higher in those lost to follow-up. Compared to AGA-NG infants, AGA-FGR infants had significantly lower predicted mean weight (p<0.001), length (p = 0.04) and BMI (p = 0.001) z-scores at birth. These significant differences were no longer evident at 4 months, suggesting that catch-up growth had occurred. As expected, the catch-up growth that occurred among the AGA-FGR was not as great in magnitude as that demonstrated by the SGA. When assessed categorically, there was no significant difference between the rate of catch-up growth among the AGA-FGR and the SGA. Catch-up growth was significantly more frequent among both the AGA-FGR and the SGA groups compared to the AGA-NG. CONCLUSIONS: AGA infants that have exhibited reduced antenatal fetal growth velocity also exhibit significant catch-up growth in the first 12 months of life. This finding represents further evidence that AGA fetuses that slow in growth during pregnancy do so due to UPI.
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ItemCirculating SPINT1 is a biomarker of pregnancies with poor placental function and fetal growth restriction(NATURE PUBLISHING GROUP, 2020-05-15)Purpose To investigate the relationship between patient-reported outcome (PRO) questionnaire responses and time to late age-related macular degeneration (AMD; neovascular AMD [nAMD] or multimodal imaging [MMI]-defined atrophy) among individuals with bilateral large drusen, and the prognostic value of baseline PROs for 36-month AMD status. Design Exploratory analyses from a multicenter randomized controlled trial of an AMD intervention (Australian New Zealand Clinical Trials Registry identifier, ACTRN12612000704897). Participants Sham treatment group of the Laser Intervention in Early Stages of Age-Related Macular Degeneration (LEAD) Study (n = 141; age, 50–88 years; 77% female). Methods The 28-item Impact of Vision Impairment (IVI-28) and 10-item Night Vision Questionnaire (NVQ-10) were administered at the baseline visit. The PRO scores were derived using rating scale models. Multivariate Cox regression adjusting for demographics and clinical measures of vision (low-luminance visual acuity, low-luminance deficit, and microperimetric sensitivity) from the poorer-performing eye was used to investigate the association between PRO scores and time to late AMD in either eye. Multivariate competing-risk regression was used to estimate cause-specific subhazard ratios for nAMD and atrophy in either eye. Cross-validated logistic lasso models were used to estimate the predicted probability of AMD at 36 months. The area under the receiver operating characteristic curve was assessed to compare prognostic accuracy between models with and without PROs. Main Outcome Measure Time until nAMD or atrophy in either eye. Results The PRO scores were skewed toward higher functional vision. Higher IVI-28 scores were associated with a lower risk of progression to MMI-defined atrophy (20 events: adjusted hazard ratio, 0.65/logit increase; P = 0.002) but not nAMD (10 events; P = 0.562). Insufficient evidence was found of an association between NVQ-10 score and rate of progression to late AMD (P ≥0.149). Baseline IVI-28 scores were found to contribute to the prognosis of atrophy at the 36-month visit (P = 0.010). Conclusions On average, PROs were associated with an increased risk of progression from intermediate AMD to MMI-defined atrophy. Continuing development of instruments to record PROs in the early stages of AMD have the potential to produce inexpensive and efficient tools to assist in the assessment of disease severity and risk of AMD progression.