Obstetrics and Gynaecology - Research Publications

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    Risk of obstetric anal sphincter injury among women who birth vaginally after a prior caesarean section: A state-wide cohort study
    Uebergang, J ; Hiscock, R ; Hastie, R ; Middleton, A ; Pritchard, N ; Walker, S ; Tong, S ; Lindquist, A (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 However, prior studies have been small or have used outdated methodology.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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    Systematic evaluation of the pre-eclampsia drugs, dietary supplements and biologicals pipeline using target product profiles
    McDougall, ARA ; Hastie, R ; Goldstein, M ; Tuttle, A ; Tong, S ; Ammerdorffer, A ; Guelmezoglu, AM ; Vogel, JP (BMC, 2022-11-04)
    BACKGROUND: The Accelerating Innovation for Mothers (AIM) project established a database of candidate medicines in research and development (R&D) between 2000 and 2021 for five pregnancy-related conditions, including pre-eclampsia. In parallel, we published target product profiles (TPPs) that describe optimal characteristics of medicines for use in preventing/treating pre-eclampsia. The study objective was to use systematic double screening and extraction to identify all candidate medicines being investigated for pre-eclampsia prevention/treatment and rank their potential based on the TPPs. METHODS: Adis Insight, Pharmaprojects, WHO international clinical trials registry platform (ICTRP), PubMed and grant databases were searched (Jan-May 2021). The AIM database was screened for all candidates being investigated for pre-eclampsia. Candidates in clinical development were evaluated against nine prespecified criteria from TPPs identified as key for wide-scale implementation, and classified as high, medium or low potential based on matching to the TPPs. Preclinical candidates were categorised by product type, archetype and medicine subclass. RESULTS: The AIM database identified 153 candidates for pre-eclampsia. Of the 87 candidates in clinical development, seven were classified as high potential (prevention: esomeprazole, L-arginine, chloroquine, vitamin D and metformin; treatment: sulfasalazine and metformin) and eight as medium potential (prevention: probiotic lactobacilli, dalteparin, selenium and omega-3 fatty acid; treatment: sulforaphane, pravastatin, rosuvastatin and vitamin B3). Sixty-six candidates were in preclinical development, the most common being amino acid/peptides, siRNA-based medicines and polyphenols. CONCLUSIONS: This is a novel, evidence-informed approach to identifying promising candidates for pre-eclampsia prevention and treatment - a vital step in stimulating R&D of new medicines for pre-eclampsia suitable for real-world implementation.
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    Pravastatin, proton-pump inhibitors, metformin, micronutrients, and biologics: new horizons for the prevention or treatment of preeclampsia
    Tong, S ; Kaitu'u-Lino, TJ ; Hastie, R ; Brownfoot, F ; Cluver, C ; Hannan, N (MOSBY-ELSEVIER, 2022-02)
    There has been increasing research momentum to identify new therapeutic agents for the prevention or treatment of preeclampsia, drugs that can affect the underlying disease pathophysiology. Molecular targets of candidate treatments include oxidative stress, antiangiogenic factors, and the angiotensin, nitric oxide, and proinflammatory pathways. The proposed treatments undergoing preclinical and clinical trial evaluation are thought to act on placental or endothelial disease or both. Most have adopted the pragmatic strategy of repurposing drugs. Of all the therapeutic agents proposed, pravastatin has received the most interest. There are preclinical studies showing that it has pleiotropic actions that favorably impact on multiple molecular targets and can resolve a preeclampsia phenotype in many animal models. An early phase clinical trial suggests that it may have therapeutic activity. Several large prevention trials are planned or ongoing and, when completed, could definitively address whether pravastatin can prevent preeclampsia. Proton-pump inhibitors, metformin, and sulfasalazine are other drugs with preclinical evidence of multiple molecular actions that could resolve the pathophysiology of preeclampsia. These agents are also currently being evaluated in clinical trials. There have been many recent preclinical studies identifying the potential of numerous natural compounds to treat preeclampsia, such as plant extracts and micronutrients that have potent anti-inflammatory or antioxidant activity. Recent preclinical studies have also proposed novel molecular-targeted strategies, such as monoclonal antibodies targeting tumor necrosis factor alpha, placental growth factor, and short interfering RNA technology, to silence the gene expression of soluble fms-like tyrosine kinase-1 or angiotensinogen. Other treatment approaches that have transitioned to human trials (ranging from single-arm to phase III trials that have been completed or are ongoing) include folic acid, nitric oxide donors (such as L-arginine), recombinant antithrombin III, digoxin immune antigen-binding fragment, and melatonin. There have been case series showing the removal of circulating soluble fms-like tyrosine kinase-1 may help stabilize the disease and prolong pregnancy. Interestingly, there are case reports suggesting that monoclonal antibody eculizumab (complement inhibitor) may have therapeutic potential. If new agents are discovered that are proven to be effective in preventing or treating preeclampsia, the potential to improve global maternal and perinatal health will be significant.
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    Developmental Outcomes for Children After Elective Birth at 39 Weeks' Gestation
    Lindquist, A ; Hastie, R ; Kennedy, A ; Gurrin, L ; Middleton, A ; Quach, J ; Cheong, J ; Walker, SP ; Hiscock, R ; Tong, S (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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    Incidence and causes of stillbirth in the only tertiary referral hospital in the Solomon Islands: a hospital-based retrospective cohort study
    De Silva, MS ; Panisi, L ; Manubuasa, L ; Honimae, C ; Taragwanu, S ; Burggraaf, S ; Ogaoga, D ; Lindquist, AC ; Walker, SP ; Tong, S ; Hastie, R (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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    Associations Between Soluble fms-Like Tyrosine Kinase-1 and Placental Growth Factor and Disease Severity Among Women With Preterm Eclampsia and Preeclampsia
    Hastie, R ; Bergman, L ; Walker, SP ; Kaitu'u-Lino, T ; Hannan, NJ ; Brownfoot, F ; Schell, S ; Harper, A ; Cannon, P ; Cluver, CA ; Tong, S (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.
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    Time to resolution of tubal ectopic pregnancy following methotrexate treatment: A retrospective cohort study
    Davenport, MJ ; Lindquist, A ; Brownfoot, F ; Pritchard, N ; Tong, S ; Hastie, R ; Garzon, S (PUBLIC LIBRARY SCIENCE, 2022-05-24)
    OBJECTIVE: To determine the time to resolution of tubal ectopic pregnancy after methotrexate treatment. METHODS: A 14-year retrospective cohort study was performed from 2004-2018 and assessed 216 women treated with single-dose methotrexate for tubal ectopic pregnancy. Women were treated using a single-dose protocol of intramuscular methotrexate (50mg/m2) for confirmed tubal ectopic pregnancy on ultrasound. Ectopic pregnancies were included if the ectopic pregnancy mass was <35mm, no evidence of rupture and no embryonic cardiac activity. Serum hCG was measured on day 1, 4 and 7 of treatment and then at standard weekly intervals until resolution. Where there was not a ≥15% decline in hCG from day 4 and day 7, a second dose of methotrexate was administered. The primary outcome was time to resolution (days), with serum hCG <5 IU/L considered resolved. The secondary outcome was need for rescue surgery. RESULTS: Among women who did not proceed to surgery, the median time to resolution was 22 days (IQR 14,34). Time to resolution and need for rescue surgery increased with baseline hCG. When hCG was <1000 IU/L, the median was 20 days (IQR 13,29) but 34.5 days (IQR 22,48) with hCG >2000 IU/L. Early hCG trends were predictive of time to resolution and likelihood of rescue surgery; a hCG rise of >1000 IU/L between Days 1-4 increased time to resolution to 61 days (IQR 35,80) and an odds ratio of rescue surgery of 28.6 (95% C.I. 5.3,155.4). CONCLUSION: The median time to resolution for ectopic pregnancies treated with methotrexate is 22 days and associated with baseline hCG levels. The predictive value of baseline hCG may be useful in clinical decision making and counselling women considering methotrexate for ectopic pregnancy.
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    Cerebral biomarkers in neurologic complications of preeclampsia
    Bergman, L ; Hastie, R ; Bokstrom-Rees, E ; Zetterberg, H ; Blennow, K ; Schell, S ; Imberg, H ; Langenegger, E ; Moodley, A ; Walker, S ; Tong, S ; Cluver, C (MOSBY-ELSEVIER, 2022-08)
    BACKGROUND: There is no tool to accurately predict who is at risk of developing neurologic complications of preeclampsia, and there is no objective method to determine disease severity. OBJECTIVE: We assessed whether plasma concentrations of the cerebral biomarkers neurofilament light, tau, and glial fibrillary acidic protein could reflect disease severity in several phenotypes of preeclampsia. Furthermore, we compared the cerebral biomarkers with the angiogenic biomarkers soluble fms-like tyrosine kinase 1, placental growth factor, and soluble endoglin. STUDY DESIGN: In this observational study, we included women from the South African Preeclampsia Obstetric Adverse Events biobank. Plasma samples taken at diagnosis (preeclampsia cases) or admission for delivery (normotensive controls) were analyzed for concentrations of neurofilament light, tau, glial fibrillary acidic protein, placental growth factor, soluble fms-like tyrosine kinase 1, and soluble endoglin. The cerebrospinal fluid concentrations of inflammatory markers and albumin were analyzed in a subgroup of 15 women. Analyses were adjusted for gestational age, time from seizures and delivery to sampling, maternal age, and parity. RESULTS: Compared with 28 women with normotensive pregnancies, 146 women with preeclampsia demonstrated 2.18-fold higher plasma concentrations of neurofilament light (95% confidence interval, 1.64-2.88), 2.17-fold higher tau (95% confidence interval, 1.49-3.16), and 2.77-fold higher glial fibrillary acidic protein (95% confidence interval, 2.06-3.72). Overall, 72 women with neurologic complications (eclampsia, cortical blindness, and stroke) demonstrated increased plasma concentrations of tau (2.99-fold higher; 95% confidence interval, 1.92-4.65) and glial fibrillary acidic protein (3.22-fold higher; 95% confidence interval, 2.06-5.02) compared with women with preeclampsia without pulmonary edema; hemolysis, elevated liver enzymes, and low platelet count; or neurologic complications (n=31). Moreover, angiogenic markers were higher, but to a lesser extent. Women with hemolysis, elevated liver enzymes, and low platelet count (n=20) demonstrated increased plasma concentrations of neurofilament light (1.64-fold higher; 95% confidence interval, 1.06-2.55), tau (4.44-fold higher; 95% confidence interval, 1.85-10.66), and glial fibrillary acidic protein (1.82-fold higher; 95% confidence interval, 1.32-2.50) compared with women with preeclampsia without pulmonary edema; hemolysis, elevated liver enzymes, and low platelet count; or neurologic complications. There was no difference shown in the angiogenic biomarkers. There was no difference between 23 women with preeclampsia complicated by pulmonary edema and women with preeclampsia without pulmonary edema; hemolysis, elevated liver enzymes, and low platelet count; or neurologic complications for any of the biomarkers. Plasma concentrations of tau and glial fibrillary acidic protein were increased in women with several neurologic complications compared with women with eclampsia only. CONCLUSION: Plasma neurofilament light, glial fibrillary acidic, and tau were candidate biomarkers for the diagnosis and possibly prediction of cerebral complications of preeclampsia.
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    PSG7 and 9 (Pregnancy-Specific β-1 Glycoproteins 7 and 9): Novel Biomarkers for Preeclampsia
    Kandel, M ; MacDonald, TM ; Walker, SP ; Cluver, C ; Bergman, L ; Myers, J ; Hastie, R ; Keenan, E ; Hannan, NJ ; Cannon, P ; Nguyen, T-V ; Pritchard, N ; Tong, S ; Kaitu'u-Lino, TJ (WILEY, 2022-04-05)
    Background Preeclampsia is pregnancy specific, involving significant maternal endothelial dysfunction. Predictive biomarkers are lacking. We evaluated the biomarker potential, expression, and function of PSG7 (pregnancy-specific β-1 glycoprotein 7) and PSG9 (pregnancy-specific β-1 glycoprotein 9) in preeclampsia. Methods and Results At 36 weeks gestation preceding term preeclampsia diagnosis, PSG7 and PSG9 (in Australian cohorts of n=918 and n=979, respectively) were significantly increased before the onset of term preeclampsia (PSG7, P=0.013; PSG9, P=0.0011). In samples collected at 28 to 32 weeks from those with preexisting cardiovascular disease and at high risk of preeclampsia (Manchester Antenatal Vascular Service, UK cohort, n=235), both PSG7 and PSG9 were also significantly increased preceding preeclampsia onset (PSG7, P<0.0001; PSG9, P=0.0003) relative to controls. These changes were validated in the plasma and placentas of patients with established preeclampsia who delivered at <34 weeks gestation (PSG7, P=0.0008; PSG9, P<0.0001). To examine whether PSG7 and PSG9 are associated with increasing disease severity, we measured them in a cohort from South Africa stratified for this outcome, the PROVE (Preeclampsia Obstetric Adverse Events) cohort (n=72). PSG7 (P=0.0027) and PSG9 (P=0.0028) were elevated among patients who were preeclamptic with severe features (PROVE cohort), but not significantly changed in those without severe features or with eclampsia. In syncytialized first trimester cytotrophoblast stem cells, exposure to TNFα (tumor necrosis factor α) or IL-6 (interleukin 6) significantly increased the expression and secretion of PSG7 and PSG9. In contrast, when we treated primary endothelial cells with recombinant PSG7 and PSG9, we only observed modest changes in Flt-1 (FMS-like tyrosine kinase-1) expression and Plgf (placental growth factor) expression, and no other effects on proangiogenic/antiangiogenic or endothelial dysfunction markers were observed. Conclusions Circulating PSG7 and PSG9 are increased before preeclampsia onset and among those with established disease with their production and release potentially driven by placental inflammation.
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    Low-Dose Aspirin for Preventing Birth of a Small-For-Gestational Age Neonate in a Subsequent Pregnancy
    Hastie, R ; Tong, S ; Wikstrom, A-K ; Walker, SP ; Lindquist, A ; Cluver, CA ; Kupka, E ; Bergman, L ; Hesselman, S (LIPPINCOTT WILLIAMS & WILKINS, 2022-04)
    OBJECTIVE: To estimate whether low-dose aspirin use is associated with an altered risk of delivering a small-for-gestational age (SGA) neonate among women with a history of having an SGA neonate in a prior pregnancy. METHODS: We performed a Swedish register-based cohort study including women in their second pregnancy who had a history of having an SGA neonate (birth weight less than the 10th percentile). The association between use of low-dose aspirin in subsequent pregnancy and birth of an SGA neonate or a severely SGA neonate (birth weight less than the third percentile) were estimated using inverse propensity-weighted estimation, accounting for potential confounders. RESULTS: Among 8,416 women who gave birth to an SGA neonate in their first pregnancy, 801 (9.5%) used low-dose aspirin during their second pregnancy. The incidence of SGA neonates was similar among women using low-dose aspirin (21.7%) and those who did not use aspirin (20.7%). Low-dose aspirin use in pregnancy was not associated with an altered risk of having an SGA neonate (adjusted relative risk [aRR] 0.86, 95% CI 0.67-1.10) or a severely SGA neonate (aRR 0.98, 95% CI 0.71-1.34). Given the strong association between preeclampsia and SGA, we performed subgroup analyses based on preeclampsia status. Among women who had an SGA neonate and co-existing preeclampsia in their first pregnancy, low-dose aspirin was not associated with an altered risk of having an SGA (aRR 0.83, 95% CI 0.63-1.10) or severely SGA (aRR 1.02, 95% CI 0.73-1.44) neonate. Additionally, no association was seen among women who developed preeclampsia in their second pregnancy. CONCLUSION: Among women with a history of having an SGA neonate, low-dose aspirin was not associated with a decreased risk of having an SGA or severely SGA neonate in subsequent pregnancy. These findings suggest that low-dose aspirin should not be used to prevent recurrent SGA.