Obstetrics and Gynaecology - Research Publications

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    The New Generation Antiplatelet Agent Prasugrel Represents an Exciting Novel Candidate Therapy for Preeclampsia.
    De Alwis, N ; Binder, N ; Beard, S ; Vi, N ; Tu'uhevaha, K-L ; Tong, S ; Hannan, N (SPRINGER HEIDELBERG, 2020-03)
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    Combination methotrexate and gefitinib: A potential medical treatment for inoperable nontubal ectopic pregnancy
    Italiano, S ; Tong, S ; Readman, E ; Tassone, M ; Hastie, R ; Pritchard, N (WILEY, 2020-03)
    Nontubal ectopic pregnancies present as a therapeutic challenge. A 35-year-old primigravida at 7 weeks gestation had a live interstitial ectopic pregnancy and contraindications to surgery. The patient was treated with a multidose methotrexate regimen combined with oral gefitinib (250 mg daily for 7 days). The peak human chorionic gonadotropin (hCG) of the patient was recorded at 19 510 IU/L and began declining from day 4 of combination therapy (day 6 of initial treatment). Successful resolution of the ectopic was demonstrated by cessation of the fetal heart by day 15 and hCG falling to 23 IU/L by day 42. A 10-year review of all nontubal ectopic pregnancies treated with methotrexate identified 46 cases, which had a comparable time to resolution to combination therapy. However, for cases where cardiac activity was present, the median time to resolution following methotrexate treatment was 64 days (47-87 days), 22 days longer than combination therapy. Combination therapy may provide a safe medical treatment for inoperable nontubal ectopic pregnancy.
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    Acupuncture in pregnancy; primum non nocere
    Hastie, R ; Mol, BW ; Tong, S (WILEY, 2020-01)
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    Maternal mortality at the National Referral Hospital in Honiara, Solomon Islands over a five-year period
    De Silva, M ; Panisi, L ; Maepioh, A ; Mitchell, R ; Lindquist, A ; Tong, S ; Hastie, R (WILEY, 2020-04)
    BACKGROUND: The Solomon Islands is a developing country facing significant barriers to the provision of quality antenatal and obstetric care. The maternal mortality rate is 114/100 000 live births, ranking the Solomon Islands 113th globally. Investigating maternal mortality may yield valuable insight into improving these numbers. AIM: The objective of this study was to review all cases of maternal mortality at the National Referral Hospital, Solomon Islands over a five-year period. MATERIALS AND METHODS: This was a retrospective review of maternal deaths occurring at the National Referral Hospital, Solomon Islands from 2013 to 2017. Data on maternal demographics, characteristics and cause of death were collected. RESULTS: There were 39 maternal deaths at the National Referral Hospital from 2013 to 2017. The maternal mortality rate of the National Referral Hospital (139/100 000) is higher than the national rate (114/100 000). Most deaths were direct, with 28% attributed to haemorrhage. Overall, 79% of the total maternal deaths had elements that may be considered preventable, with laboratory delays present in 54% and medication shortages present in 29% of cases. CONCLUSION: Maternal mortality is high in the Solomon Islands, with many potentially preventable deaths occurring at the National Referral Hospital. Continued focus on improving data collection, access to resources, and training is vital to reduce maternal mortality in the Solomon Islands.
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    Accuracy of clinical suspicion of growth restriction at term despite a normal growth ultrasound: A retrospective cohort study
    Green, B ; Hui, L ; Hastie, R ; Tong, S ; Brownfoot, FC (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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    Preventable stillbirths in the Solomon Islands - A hidden tragedy
    De Silva, M ; Panisi, L ; Manubuasa, L ; Honimae, C ; Taragwanu, S ; Burggraaf, S ; Ogaoga, D ; Lindquist, A ; Walker, S ; Tong, S ; Hastie, R (ELSEVIER, 2020-12)
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    Reduced growth velocity from the mid-trimester is associated with placental insufficiency in fetuses born at a normal birthweight.
    Kennedy, LM ; Tong, S ; Robinson, AJ ; Hiscock, RJ ; Hui, L ; Dane, KM ; Middleton, AL ; Walker, SP ; MacDonald, TM (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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    MicroRNAs 363 and 149 are differentially expressed in the maternal circulation preceding a diagnosis of preeclampsia
    Whigham, C-A ; MacDonald, TM ; Walker, SP ; Hiscock, R ; Hannan, NJ ; Pritchard, N ; Cannon, P ; Tuong, VN ; Miranda, M ; Tong, S ; Kaitu'u-Lino, TJ (NATURE PORTFOLIO, 2020-10-22)
    Preeclampsia is a pregnancy complication associated with angiogenic dysbalance, maternal endothelial dysfunction and end-organ injury. A predictive test to identify those who will develop preeclampsia could substantially decrease morbidity and mortality. MicroRNAs (miRs) are small RNA molecules involved in post-transcriptional gene regulation. We screened for circulating miRs differentially expressed at 36 weeks' gestation in pregnancies before the development of preeclampsia. We used a case-control group (198 controls, 34 pre-preeclampsia diagnosis) selected from a prospective cohort (n = 2015) and performed a PCR-based microarray to measure the expression of 41 miRs. We found six circulating miRs (miRs 363, 149, 18a, 1283, 16, 424) at 36 weeks' had significantly reduced expression (p < 0.0001-0.04). miR363 was significantly downregulated at 28 weeks' gestation, 10-12 weeks before the onset of clinical disease. In the circulation of another cohort of 34 participants with established preterm preeclampsia (vs 23 controls), we found miRs363, 18a, 149 and 16 were significantly down regulated (p < 0.0001-0.04). Combined expression of miRs149 and 363 in the circulation at 36 weeks' gestation provides a test with 45% sensitivity (at a specificity of 90%) which suggests measuring both miRs may have promise as part of a multi-marker test to predict preeclampsia.
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    Appropriate-for-gestational-age infants who exhibit reduced antenatal growth velocity display postnatal catch-up growth
    McLaughlin, EJ ; Hiscock, RJ ; Robinson, AJ ; Hui, L ; Tong, S ; Dane, KM ; Middleton, AL ; Walker, SP ; MacDonald, TM ; Simeoni, U (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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    Circulating mRNAs are differentially expressed in pregnancies with severe placental insufficiency and at high risk of stillbirth
    Hannan, NJ ; Stock, O ; Spencer, R ; Whitehead, C ; David, AL ; Groom, K ; Petersen, S ; Henry, A ; Said, JM ; Seeho, S ; Kane, SC ; Gordon, L ; Beard, S ; Chindera, K ; Karegodar, S ; Hiscock, R ; Pritchard, N ; Kaitu'u-Lino, TJ ; Walker, SP ; Tong, S (BMC, 2020-05-22)
    Background Fetuses affected by placental insufficiency do not receive adequate nutrients and oxygenation, become growth restricted and acidemic, and can demise. Preterm fetal growth restriction is a severe form of placental insufficiency with a high risk of stillbirth. We set out to identify maternal circulating mRNA transcripts that are differentially expressed in preterm pregnancies complicated by very severe placental insufficiency, in utero fetal acidemia, and are at very high risk of stillbirth. Methods We performed a cohort study across six hospitals in Australia and New Zealand, prospectively collecting blood from 128 pregnancies complicated by preterm fetal growth restriction (delivery < 34 weeks’ gestation) and 42 controls. RNA-sequencing was done on all samples to discover circulating mRNAs associated with preterm fetal growth restriction and fetal acidemia in utero. We used RT-PCR to validate the associations between five lead candidate biomarkers of placental insufficiency in an independent cohort from Europe (46 with preterm fetal growth restriction) and in a third cohort of pregnancies ending in stillbirth. Results In the Australia and New Zealand cohort, we identified five mRNAs that were highly differentially expressed among pregnancies with preterm fetal growth restriction: NR4A2, EMP1, PGM5, SKIL, and UGT2B1. Combining three yielded an area under the receiver operative curve (AUC) of 0.95. Circulating NR4A2 and RCBTB2 in the maternal blood were dysregulated in the presence of fetal acidemia in utero. We validated the association between preterm fetal growth restriction and circulating EMP1, NR4A2, and PGM5 mRNA in a cohort from Europe. Combining EMP1 and PGM5 identified fetal growth restriction with an AUC of 0.92. Several of these genes were differentially expressed in the presence of ultrasound parameters that reflect placental insufficiency. Circulating NR4A2, EMP1, and RCBTB2 mRNA were differentially regulated in another cohort destined for stillbirth, compared to ongoing pregnancies. EMP1 mRNA appeared to have the most consistent association with placental insufficiency in all cohorts. Conclusions Measuring circulating mRNA offers potential as a test to identify pregnancies with severe placental insufficiency and at very high risk of stillbirth. Circulating mRNA EMP1 may be promising as a biomarker of severe placental insufficiency.