Creatine and pregnancy outcomes: a prospective cohort study of creatine metabolism in low-risk pregnant females.

BACKGROUND: Physiological adaptations during pregnancy alter nutrient and energy metabolism. Creatine may be important for maintaining cellular energy homeostasis throughout pregnancy. However, the impact of pregnancy on endogenous and exogenous creatine availability has never been comprehensively explored. OBJECTIVES: To undertake a prospective cohort study and determine the physiological ranges of creatine and associated metabolites throughout human pregnancy. METHODS: Females with a singleton low-risk pregnancy were recruited at an Australian health service. Maternal blood and urine were collected at 5-time points from 10-36 weeks of gestation, and cord blood and placental samples were collected at birth. Creatine and associated amino acids and metabolites of creatine synthesis were analyzed. Dietary data were captured to determine effects of exogenous creatine intake. Associations between creatine metabolism and neonatal growth parameters were examined. RESULTS: Two hundred and eighty-two females were included. Maternal plasma creatine remained stable throughout pregnancy [ß: -0.003 µM; 95% confidence interval (CI): -0.07, 0.07; P = 0.94], though urinary creatine declined in late gestation (ß: 0.38 µM/mmol/L creatinine (CRN); 95% CI: -0.47, -0.29; P < 0.0001). Plasma guanidinoacetate (GAA; the precursor to creatine during endogenous synthesis) fell from 10-29 weeks of gestation before rising until birth (ß: -0.38 µM/mmol/L CRN; 95% CI: -0.47, -0.29; P < 0.0001). Urinary GAA followed an opposing pattern (ß: 2.52 µM/mmol/L CRN; 95% CI: 1.47, 3.58, P < 0.001). Animal protein intake was positively correlated with maternal plasma creatine until ∼32 weeks of gestation (ß: 0.07-0.18 µM; 95% CI: 0.006, 0.25; P ≤ 0.001). There were no links between creatine and neonatal growth, but increased urinary GAA in early pregnancy was associated with a slight reduction in head circumference at birth (ß: -0.01 cm; 95% CI: -0.02, -0.004; P = 0.003). CONCLUSIONS: Although maternal plasma creatine concentrations were highly conserved, creatine metabolism appears to adjust throughout pregnancy. An ability to maintain creatine concentrations through diet and shifts in endogenous synthesis may impact fetal growth. This trial was registered at [registry name] as ACTRN12618001558213.

Thiopurine metabolite shunting in late pregnancy increases the risk of intrahepatic cholestasis of pregnancy in women with inflammatory bowel disease, and can be managed with split-dosing.

BACKGROUND AND AIMS: The risk of intrahepatic cholestasis of pregnancy (ICP) is increased in thiopurine exposed pregnancies. Thiopurine 'shunting', with a 6-methylmecrcaptopurine (MMP) to 6-thioguanine (TGN) ratio of >11, progresses over pregnancy, and may promote ICP development. We aimed to explore the association between thiopurine exposure and ICP, including the hypothesized impact of thiopurine shunting, and identify risk minimization strategies. METHODS: This prospective multi-centre cohort study compared thiopurine and biologic monotherapy exposed pregnant participants. Disease activity and obstetric outcome data, thiopurine metabolites, bile acids and transaminases were obtained preconception, in each trimester, at delivery, and post-partum. Thiopurine dose management was at the discretion of the treating physician. RESULTS: 131 thiopurine and 147 biologic monotherapy exposed pregnancies were included. MMP/TGN ratio increased from preconception to third trimester (p<0.01), with approximately 25% of participants shunting in pregnancy. Second trimester split-dosing led to a decrease in the median MMP/TGN ratio from 18 (IQR 6-57) to 3 (IQR 2-3.5) at delivery (p=0.04). The risk of ICP was increased in thiopurine exposed pregnancies (6.7% (7/105) vs 0% (0/112), p<0.001), with all ICP cases occurring in the setting of antenatal thiopurine shunting. Thiopurine dose increases (RR 8.10 [95% CI 1.88-34.85] p=0.005) and shunting in third trimester (6.20 [1.21-30.73] p=0.028) and at delivery (14.18 [1.62-123.9] p=0.016) were associated with an increased risk of ICP. CONCLUSIONS: Thiopurine exposure is associated with an increased risk of ICP, particularly following dose increases antenatally and with shunting in late pregnancy. The latter may be effectively managed with split dosing, although further studies are warranted.

Reduction in spontaneous and iatrogenic preterm births in twin pregnancies during COVID-19 lockdown in Melbourne, Australia: a multicenter cohort study.

BACKGROUND: Melbourne, Australia, recorded one of the longest and most stringent pandemic lockdowns in 2020, which was associated with an increase in preterm stillbirths among singleton pregnancies. Twin pregnancies may be particularly susceptible to the impacts of pandemic disruptions to maternity care due to their higher background risk of adverse perinatal outcomes. METHODS: Multicenter retrospective cohort study of all twin pregnancies birthing in public maternity hospitals in Melbourne. Multivariable log-binomial regression models were used to compare perinatal outcomes between a pre-pandemic group to women in whom weeks 20+0 to 40+0 of gestation occurred entirely during one of two lockdown-exposure periods: exposure 1 from 22 March 2020 to 21 March 2021 and exposure 2 from 22 March 2021 to 27 March 2022. RESULTS: Total preterm births < 37 weeks were significantly lower in exposure 1 compared with the pre-pandemic period (63.1% vs 68.3%; adjusted risk ratio 0.92 95% CI 0.87-0.98, p = 0.01). This was mainly driven by fewer spontaneous preterm births (18.9% vs 20.3%; adjusted risk ratio 0.95 95% CI 0.90-0.99, p = 0.04). There were also lower rates of preterm birth < 34 weeks (19.9% vs 23.0%, adjusted risk ratio 0.93 95% CI 0.89-0.98 p = 0.01) and total iatrogenic births for fetal compromise (13.4% vs 20.4%; adjusted risk ratio 0.94 95% CI 0.89-0.98, p = 0.01). There were fewer special care nursery admissions (38.5% vs 43.4%; adjusted risk ratio 0.91 95% CI 0.87-0.95, p < 0.001) but no significant changes in stillbirth (1.5% vs 1.6%; adjusted risk ratio 1.00 95% CI 0.99-1.01, p = 0.82). Compared with the pre-pandemic period, there were more preterm births < 28 weeks and neonatal intensive care unit admissions in exposure 2. CONCLUSIONS: Melbourne's first lockdown-exposure period was associated with lower preterm births in twins without significant differences in adverse newborn outcomes. Our findings provide insights into the influences on preterm birth and the optimal timing of delivery for twins.

Feasibility of a pregnancy intervention mimicking viral transmission mitigation measures on the incidence of preterm birth in high-risk pregnant women enrolled in antenatal clinics in Melbourne, Australia: protocol for a pilot, randomised trial.

INTRODUCTION: Preterm birth is a leading cause of perinatal morbidity and mortality. During the COVID-19 pandemic, reduction in rates of preterm birth in women exposed to viral mitigation measures was reported by multiple studies. In addition, others and we observed a more pronounced reduction of preterm birth in women who had previously experienced a preterm birth. The aim of this pilot study is to establish the feasibility of a lifestyle intervention based on viral mitigation measures in high-risk pregnancies, with the ultimate aim to reduce the incidence of preterm birth. METHODS AND ANALYSIS: One hundred pregnant women, enrolled in antenatal clinics at two tertiary maternity centres in Melbourne, Australia, who have had a previous preterm birth between 22 and 34 weeks gestation will be recruited. This is a two-arm, parallel group, open-label randomised controlled feasibility trial: 50 women will be randomised to the intervention group, where they will be requested to comply with a set of lifestyle changes (similar to the viral mitigation measures observed during the pandemic). Another 50 women will be randomised to the control group, where they will undergo standard pregnancy care. The primary outcome of this trial is feasibility, which will be assessed by measuring patient eligibility rate, recruitment rate, compliance rate and data completion rate. Secondary outcomes include incidence of preterm birth, maternal satisfaction, maternal quality of life and other pregnancy outcomes. Standard methods in statistical analysis for randomised controlled trials on an intention to treat basis will be followed. ETHICS AND DISSEMINATION: This trial has been approved by the Monash Human Research Ethics Committee; approval reference number RES-22-0000-122A. Study findings will be reported and submitted to peer-reviewed journals for publication, and presentation at conferences. TRIAL REGISTRATION NUMBER: ACTRN12622000753752; Pre-results.

Effect of telehealth-integrated antenatal care on pregnancy outcomes in Australia: an interrupted time-series analysis.

BACKGROUND: During the COVID-19 pandemic, rapid integration of telehealth into antenatal care occurred to support ongoing maternity care. A programme of this scale had not been previously implemented. We evaluated whether telehealth-integrated antenatal care in an Australian public health system could achieve pregnancy outcomes comparable to those of conventional care to assess its safety and efficacy. METHODS: Routinely collected data for individuals who gave birth at Monash Health (Melbourne, VIC, Australia) during a conventional care period (Jan 1, 2018, to March 22, 2020) and telehealth-integrated period (April 20, 2020, to April 25, 2021) were analysed. We included all births that occurred at 20 weeks' gestation or later or with a birthweight of at least 400 g (if duration of gestation was unknown). We excluded multiple births, births for which private antenatal care was received, and births to individuals transferred from other hospitals or who had no antenatal care. Baseline demographics, telehealth uptake, and pregnancy complications (related to pre-eclampsia, fetal growth restriction [FGR], gestational diabetes, stillbirth, neonatal intensive care [NICU] admission, and preterm birth [<37 weeks' gestation]) were compared using comparative statistics and an interrupted time-series analysis. Results were stratified by care stream, with high-risk models consisting of obstetric specialist-led care, and all other streams categorised as low-risk models. The impact of the integrated period on outcomes was also assessed with stratification by parity. FINDINGS: 17 873 births occurred in the conventional period and 8131 in the integrated period. Compared with the conventional period, women giving birth during the integrated period were slightly older (30·63 years vs 30·88 years) and had slightly higher BMI (25·52 kg/m2vs 26·14 kg/m2), and more Australian-born women gave birth during the integrated period (37·37% vs 39·79%). There were no significant differences in smoking status or parity between the two groups. 107 (0·08%) of 129 514 antenatal consultations in the conventional period and 34 444 (45·94%) of 74 982 in the integrated period were delivered by telehealth. No significant differences between the conventional and integrated periods were seen in median gestational age at pre-eclampsia diagnosis (low-risk models 37·4 weeks in the conventional period vs 37·1 weeks in the integrated period, difference -0·3 weeks [-0·7 to 0·1]; high-risk models 35·5 weeks vs 36·3 weeks, difference 0·3 weeks [-0·3 to 1·1]), incidence of FGR below the 3rd birthweight percentile (low-risk models 1·62% vs 1·74%, difference 0·12 percentage points [-0·26 to 0·50]; high-risk 4·04% vs 4·13%, difference 0·089 percentage points [-1·08 to 1·26]), and incidence of preterm birth (low-risk models 4·99% vs 5·01%, difference 0·02% [-0·62 to 0·66]; high-risk models 15·76% vs 14·43%, difference -1·33% [-3·42 to 0·77]). Parity did not affect these findings. Interrupted time-series analysis showed a significant reduction in induction of labour for singletons with suspected FGR among women in low-risk models during the integrated period (-0·04% change per week [95% CI -0·07 to -0·01], p=0·0040), and NICU admission declined after telehealth integration (low-risk models -0·02% change per week [-0·03 to -0·003], p=0·018; high-risk models -0·10% change per week, -0·19 to -0·001; p=0·047). No significant differences in stillbirth rates were observed. The proportion of women diagnosed with gestational diabetes was significantly higher in the integrated period compared with the conventional period for both low-risk care models (22·28% vs 25·13%, difference 2·85 percentage points [1·60 to 4·11]) and high-risk care models (28·70% vs 34·02%, difference 5·32 percentage points [2·57 to 8·07]). However overall, when compared with the conventional period, there was no significant difference in proportion of women with gestational diabetes requiring insulin therapy (low-risk models 8·08% vs 7·73%, difference -0·35 percentage points [-1·13 vs 0·44]; high-risk models 14·81% vs 15·71%, difference 0·89 percentage points [-1·23 to 3·02]), or proportion of women with gestational diabetes who gave birth to a baby with macrosomia in the integrated period (low-risk models 3·16% vs 2·33%, difference -0·83 percentage points [-1·77 to 0·12]; high-risk models 5·58% vs 4·81%, difference -0·77 percentage points [-3·06 to 1·52]). INTERPRETATION: Telehealth-integrated antenatal care replaced around 46% of in-person consultations without compromising pregnancy outcomes. It might be associated with a reduction in labour induction for suspected FGR, particularly for women in low-risk models, without compromising FGR detection or perinatal morbidity. These findings support the ongoing use of telehealth in providing flexible antenatal care. FUNDING: None.

CO-Sprout-A Pilot Double-Blinded Placebo-Controlled Randomised Trial of Broccoli Sprout Powder Supplementation for Pregnant Women with COVID-19 on the Duration of COVID-19-Associated Symptoms: Study Protocol.

Since its discovery in late 2019, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been estimated to be responsible for at least 769.3 million infections and over 6.95 million deaths. Despite significant global vaccination efforts, there are limited therapies that are considered safe and effective for use in the management of COVID-19 during pregnancy despite the common knowledge that pregnant patients have a much higher risk of adverse outcomes. A bioactive compound found in broccoli sprout-sulforaphane-is a potent inducer of phase-II detoxification enzymes promoting a series of potentially beneficial effects notably as an antioxidant, anti-inflammatory, and anti-viral. A pilot, double-blinded, placebo-controlled randomised trial is to be conducted in Melbourne, Australia, across both public and private hospital sectors. We will assess a commercially available broccoli sprout extract in pregnant women between 20+0 and 36+0 weeks gestation with SARS-CoV-2 infection to investigate (i) the duration of COVID-19 associated symptoms, (ii) maternal and neonatal outcomes, and (iii) biomarkers of infection and inflammation. We plan to enrol 60 outpatient women with COVID-19 irrespective of vaccination status diagnosed by PCR swab or RAT (rapid antigen test) within five days and randomised to 14 days of oral broccoli sprout extract (42 mg of sulforaphane daily) or identical microcrystalline cellulose placebo. The primary outcome of this pilot trial will be to assess the feasibility of conducting a larger trial investigating the duration (days) of COVID-19-associated symptoms using a broccoli sprout supplement for COVID-19-affected pregnancies. Pregnant patients remain an at-risk group for severe disease following infection with SARS-CoV-2 and currently unclear consequences for the offspring. Therefore, this study will assess feasibility of using a broccoli sprout supplement, whilst providing important safety data for the use of sulforaphane in pregnancy.

Aspects of human uterine creatine metabolism during the menstrual cycle and at term pregnancy†.

Creatine metabolism likely contributes to energy homeostasis in the human uterus, but whether this organ synthesizes creatine and whether creatine metabolism is adjusted throughout the menstrual cycle and with pregnancy are largely unknown. This study determined endometrial protein expression of creatine-synthesizing enzymes arginine:glycine amidinotransferase (AGAT) and guanidinoacetate methyltransferase (GAMT), creatine kinase (CKBB), and the creatine transporter (SLC6A8) throughout the menstrual cycle in fertile and primary infertile women. It also characterized creatine metabolism at term pregnancy, measuring aspects of creatine metabolism in myometrial and decidual tissue. In endometrial samples, AGAT, GAMT, SLC6A8, and CKBB were expressed in glandular and luminal epithelial cells. Except for SLC6A8, the other proteins were also located in stromal cells. Irrespective of fertility, AGAT, GAMT, and SLC6A8 high-intensity immunohistochemical staining was greatest in the early secretory phase of the menstrual cycle. During the proliferative phase, staining for SLC6A8 protein was greater (P = 0.01) in the primary infertile compared with the fertile group. Both layers of the term pregnant uterus contained creatine, phosphocreatine, guanidinoacetic acid, arginine, glycine, and methionine; detectable gene and protein expression of AGAT, GAMT, CKBB, and ubiquitous mitochondrial CK (uMt-CK); and gene expression of SLC6A8. The proteins AGAT, GAMT, CKBB, and SLC6A8 were uniformly distributed in the myometrium and localized to the decidual glands. In conclusion, endometrial tissue has the capacity to produce creatine and its capacity is highest around the time of fertilization and implantation. Both layers of the term pregnant uterus also contained all the enzymatic machinery and substrates of creatine metabolism.

Preeclampsia to COVID-19: A journey towards improved placental and vascular function using sulforaphane.

Excess inflammation and oxidative stress are common themes in many pathologies of pregnancy including preeclampsia and more recently severe COVID-19. The risk of preeclampsia increases following maternal infection with COVID-19, potentially relating to significant overlap in pathophysiology with endothelial, vascular and immunological dysfunction common to both. Identifying a therapy which addresses these injurious processes and stabilises the endothelial and vascular maternal system would help address the significant global burden of maternal and neonatal morbidity and mortality they cause. Sulforaphane is a naturally occurring phytonutrient found most densely within cruciferous vegetables. It has anti-inflammatory, antioxidant and immune modulating properties via upregulation of phase-II detoxification enzymes. This review will cover the common pathways shared by COVID-19 and preeclampsia and offer a potential therapeutic target via nuclear factor erythroid 2-related factor upregulation in the form of sulforaphane.

Pharmacokinetics and safety of inhaled oxytocin compared with intramuscular oxytocin in women in the third stage of labour: A randomized open-label study.

AIMS: To compare pharmacokinetics (PK) and safety of heat-stable inhaled (IH) oxytocin with intramuscular (IM) oxytocin in women in third stage of labour (TSL), the primary endpoint being PK profiles of oxytocin IH and secondary endpoint of safety. METHODS: A phase 1, randomized, cross-over study was undertaken in 2 UK and 1 Australian centres. Subjects were recruited into 2 groups: Group 1, women in TSL; Group 2, nonpregnant women of childbearing potential (Cohort A, combined oral contraception; Cohort B, nonhormonal contraception). Participants were randomized 1:1 to: Group 1, oxytocin 10 IU (17 µg) IM or oxytocin 240 IU (400 µg) IH immediately after delivery; Group 2, oxytocin 5 IU (8.5 µg) intravenously and oxytocin 240 IU (400 µg) IH at 2 separate dosing sessions. RESULTS: Participants were recruited between 23 November 2016 to 4 March 2019. In Group 1, 17 participants were randomized; received either IH (n = 9) or IM (n = 8) oxytocin. After IH and IM administration, most plasma oxytocin concentrations were below quantification limits (2 pg/mL). In Group 2 (n = 14), oxytocin IH concentrations remained quantifiable ≤3 h postdose. Adverse events were reported in both groups, with no deaths reported: Group 1, IH n = 3 (33%) and IM n = 2 (25%); Group 2, n = 14 (100%). CONCLUSION: Safety profiles of oxytocin IH and IM were similar. However, PK profiles could not be established for oxytocin IH or IM in women in TSL, despite using a highly sensitive and specific assay.

Endometrial Origins of Stillbirth (EOS), a case-control study of menstrual fluid to understand and prevent preterm stillbirth and associated adverse pregnancy outcomes: study protocol.

INTRODUCTION: Current research aimed at understanding and preventing stillbirth focuses almost exclusively on the role of the placenta. The underlying origins of poor placental function leading to stillbirth, however, remain poorly understood. There is evidence demonstrating that the endometrial environment in which the embryo implants impacts not only the establishment of pregnancy but also the development of some pregnancy outcomes. Menstrual fluid has recently been applied to the study of menstrual disorders such as heavy menstrual bleeding or endometriosis, however, it has great potential in the study of adverse pregnancy outcomes. This study aims to identify differences in menstrual fluid and menstrual cycle characteristics of women who have experienced preterm stillbirth and other associated adverse pregnancy outcomes, compared with those who have not. The association between menstrual fluid composition and menstrual cycle characteristics will also be determined. METHODS AND ANALYSIS: This is a case-control study of women who have experienced a late miscarriage, spontaneous preterm birth or preterm stillbirth or a pregnancy complicated by placental insufficiency (fetal growth restriction or pre-eclampsia), compared with those who have had a healthy term birth. Cases will be matched for maternal age, body mass index and gravidity. Participants will not currently be on hormonal therapy. Women will be provided with a menstrual cup and will collect their sample on day 2 of menstruation. Primary exposure measures include morphological and functional differences in decidualisation of the endometrium (cell types, immune cell subpopulations and protein composition secreted from the decidualised endometrium). Women will complete a menstrual history survey to capture menstrual cycle length, regularity, level of pain and heaviness of flow. ETHICS AND DISSEMINATION: Ethics approval was obtained from Monash University Human Research Ethics Committee (27900) on 14/07/2021 and will be conducted in accordance with these conditions. Findings from this study will be disseminated through peer-reviewed publications and conference presentations.

Double-vs single-balloon catheter for induction of labor: Systematic review and individual participant data meta-analysis.

INTRODUCTION: Evidence comparing double-balloon vs single-balloon catheter for induction of labor is divided. We aim to compare the efficacy and safety of double-vs single-balloon catheters using individual participant data. MATERIAL AND METHODS: A search of Ovid MEDLINE, Embase, Ovid Emcare, CINAHL Plus, Scopus, and clinicaltrials.gov was conducted for randomized controlled trials published from March 2019 until April 13, 2021. Earlier trials were identified from the Cochrane Review on Mechanical Methods for Induction of Labour. Randomized controlled trials that compared double-balloon with single-balloon catheters for induction of labor in singleton gestations were eligible. Participant-level data were sought from trial investigators and an individual participant data meta-analysis was performed. The primary outcomes were rates of vaginal birth achieved, a composite measure of adverse maternal outcomes and a composite measure of adverse perinatal outcomes. We used a two-stage random-effects model. Data were analyzed from the intention-to-treat perspective. RESULTS: Of the eight eligible randomized controlled trials, three shared individual-level data with a total of 689 participants, 344 women in the double-balloon catheter group and 345 women in the single-balloon catheter group. The difference in the rate of vaginal birth between double-balloon catheter and single-balloon catheter was not statistically significant (relative risk [RR] 0.93, 95% confidence interval [CI] 0.86-1.00, p = 0.050; I2 0%; moderate-certainty evidence). Both perinatal outcomes (RR 0.81, 95% CI 0.54-1.21, p = 0.691; I2 0%; moderate-certainty evidence) and maternal composite outcomes (RR 0.65, 95% CI 0.15-2.87, p = 0.571; I2 55.46%; low-certainty evidence) were not significantly different between the two groups. CONCLUSIONS: Single-balloon catheter is at least comparable to double-balloon catheter in terms of vaginal birth rate and maternal and perinatal safety outcomes.

Activin A and pathologies of pregnancy: a review.

Activin A is a two-subunit protein belonging to the transforming growth factor ß superfamily. First discovered almost three decades ago, it has since been implicated in diverse physiological roles, ranging from wound repair to reproduction. After 30 years of research, altered activin A levels are now understood to be associated with the development of various diseases, making activin A a potential therapeutic target. In pregnancy, the placenta and fetal membranes are major producers of activin A, with significantly enhanced serum concentrations now recognised as a contributor to numerous gestational disorders. Evidence now suggests that circulating levels of activin A may be clinically relevant in the early detection of pregnancy complications, including miscarriage and preeclampsia. This review aims to summarise our current understanding of activin A as a potential diagnostic marker in common pregnancy pathologies.

The impact of assisted reproductive technology and ovulation induction on breech presentation: A whole of population-based cohort study.

AIMS: Multiple studies have suggested a likely association between breech presentation and assisted reproductive technology (ART) for conception. The aims were to determine whether conception via in vitro fertilisation (IVF) and ovulation induction (OI) is associated with fetal malpresentation at birth and to ascertain what mediating factors most significantly contribute to fetal malpresentation. METHODS: This whole-population-based cohort study included 355 990 singleton pregnancies born in Queensland, Australia, between July 2012 and July 2018. Multinomial logistic regression models estimated the adjusted odds of breech, transverse/shoulder and face/brow malpresentations in pregnancies conceived via spontaneous conception, OI (OI group) and IVF with or without intracytoplasmic sperm injection (ART group). RESULTS: After adjustment for potential confounding factors, breech presentation occurred approximately 20% more often in singleton pregnancies conceived via both ART (adjusted odds ratio: 1.20, 95% confidence interval: 1.10-1.30, P < 0.001) and OI (1.21, 95% confidence interval: 1.04-1.39, P < 0.05). No significant associations were observed between the three modes of conception and transverse/shoulder or face/brow presentations. Low birthweight was found to be the most significant mediating factor for breech presentation in pregnancies conceived via ART and OI. CONCLUSIONS: Similar levels of increased odds of breech presentation are present in pregnancies conceived via OI and ART, suggesting a shared underlying mechanism for the aetiology of breech presentation. For women who are considering or have conceived via these methods, counselling with respect to this increased risk is recommended.

Mechanical methods for induction of labour.

BACKGROUND: Mechanical methods were the first methods developed to ripen the cervix and induce labour. During recent decades they have been substituted by pharmacological methods. Potential advantages of mechanical methods, compared with pharmacological methods may include reduction in side effects that could improve neonatal outcomes. This is an update of a review first published in 2001, last updated in 2012. OBJECTIVES: To determine the effectiveness and safety of mechanical methods for third trimester (> 24 weeks' gestation) induction of labour in comparison with prostaglandin E2 (PGE2) (vaginal and intracervical), low-dose misoprostol (oral and vaginal), amniotomy or oxytocin. SEARCH METHODS: For this update, we searched Cochrane Pregnancy and Childbirth's Trials Register, ClinicalTrials.gov, the WHO International Clinical Trials Registry Platform (ICTRP), and reference lists of retrieved studies (9 January 2018). We updated the search in March 2019 and added the search results to the awaiting classification section of the review. SELECTION CRITERIA: Clinical trials comparing mechanical methods used for third trimester cervical ripening or labour induction with pharmacological methods. Mechanical methods include: (1) the introduction of a catheter through the cervix into the extra-amniotic space with balloon insufflation; (2) introduction of laminaria tents, or their synthetic equivalent (Dilapan), into the cervical canal; (3) use of a catheter to inject fluid into the extra-amniotic space (EASI). This review includes the following comparisons: (1) specific mechanical methods (balloon catheter, laminaria tents or EASI) compared with prostaglandins (different types, different routes) or with oxytocin; (2) single balloon compared to a double balloon; (3) addition of prostaglandins or oxytocin to mechanical methods compared with prostaglandins or oxytocin alone. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trials for inclusion and assessed risk of bias. Two review authors independently extracted data and assessed the quality of the evidence using the GRADE approach. MAIN RESULTS: This review includes a total of 112 trials, with 104 studies contributing data (22,055 women; 21 comparisons). Risk of bias of trials varied. Overall, the evidence was graded from very-low to moderate quality. All evidence was downgraded for lack of blinding and, for many comparisons, the effect estimates were too imprecise to make a valid judgement.   Balloon versus vaginal PGE2: there may be little or no difference in vaginal deliveries not achieved within 24 hours (risk ratio (RR) 1.01, 95% confidence interval (CI) 0.82 to 1.26; 7 studies; 1685 women; low-quality evidence) and there probably is little or no difference in caesarean sections (RR 1.00, 95% CI 0.92 to 1.09; 28 studies; 6619 women; moderate-quality evidence) between induction of labour with a balloon catheter and vaginal PGE2. A balloon catheter probably reduces the risk of uterine hyperstimulation with fetal heart rate (FHR) changes (RR 0.35, 95% CI 0.18 to 0.67; 6 studies; 1966 women; moderate-quality evidence), serious neonatal morbidity or perinatal death (RR 0.48, 95% CI 0.25 to 0.93; 8 studies; 2757 women; moderate-quality evidence) and may slightly reduce the risk of aneonatal intensive care unit (NICU) admission (RR 0.82, 95% CI 0.65 to 1.04; 3647 women; 12 studies; low-quality evidence). It is uncertain whether there is a difference in serious maternal morbidity or death (RR 0.20, 95% CI 0.01 to 4.12; 4 studies; 1481 women) or five-minute Apgar score < 7 (RR 0.74, 95% CI 0.49 to 1.14; 4271 women; 14 studies) because the quality of the evidence was found to be very low and low, respectively. Balloon versus low-dose vaginal misoprostol: it is uncertain whether there is a difference in vaginal deliveries not achieved within 24 hours between induction of labour with a balloon catheter and vaginal misoprostol (RR 1.09, 95% CI 0.85 to 1.39; 340 women; 2 studies; low-quality evidence). A balloon catheter probably reduces the risk of uterine hyperstimulation with FHR changes (RR 0.39, 95% CI 0.18 to 0.85; 1322 women; 8 studies; moderate-quality evidence) but may increase the risk of a caesarean section (RR 1.28, 95% CI 1.02 to 1.60; 1756 women; 12 studies; low-quality evidence). It is uncertain whether there is a difference in serious neonatal morbidity or perinatal death (RR 0.58, 95% CI 0.12 to 2.66; 381 women; 3 studies), serious maternal morbidity or death (no events; 4 studies, 464 women), both very low-quality evidence, and five-minute Apgar score < 7 (RR 1.00, 95% CI 0.50 to 1.97; 941 women; 7 studies) and NICU admissions (RR 1.00, 95% CI 0.61 to 1.63; 1302 women; 9 studies) both low-quality evidence. Balloon versus low-dose oral misoprostol: a balloon catheter probably increases the risk of a vaginal delivery not achieved within 24 hours (RR 1.28, 95% CI 1.13 to 1.46; 782 women, 2 studies, and probably slightly increases the risk of a caesarean section (RR 1.17, 95% CI 1.04 to 1.32; 3178 women; 7 studies; both moderate-quality evidence) when compared to oral misoprostol. It is uncertain whether there is a difference in uterine hyperstimulation with FHR changes (RR 0.81, 95% CI 0.48 to 1.38; 2033 women; 2 studies), serious neonatal morbidity or perinatal death (RR 1.11, 95% CI 0.60 to 2.06; 2627 women; 3 studies), both low-quality evidence, serious maternal morbidity or death (RR 0.50, 95% CI 0.05 to 5.52; 2627 women; 3 studies), very low-quality evidence, five-minute Apgar scores < 7 (RR 0.71, 95% CI 0.38 to 1.32; 2693 women; 4 studies) and NICU admissions (RR 0.82, 95% CI 0.58 to 1.17; 2873 women; 5 studies) both low-quality evidence. AUTHORS' CONCLUSIONS: Low- to moderate-quality evidence shows mechanical induction with a balloon is probably as effective as induction of labour with vaginal PGE2. However, a balloon seems to have a more favourable safety profile. More research on this comparison does not seem warranted. Moderate-quality evidence shows a balloon catheter may be slightly less effective as oral misoprostol, but it remains unclear if there is a difference in safety outcomes for the neonate. When compared to low-dose vaginal misoprostol, low-quality evidence shows a balloon may be less effective, but probably has a better safety profile. Future research could be focused more on safety aspects for the neonate and maternal satisfaction.

Perspectives on the Use of Placental Growth Factor (PlGF) in the Prediction and Diagnosis of Pre-Eclampsia: Recent Insights and Future Steps.

Pre-eclampsia (PE) is a complex multisystem disease of pregnancy that is becoming increasingly recognized as a state of angiogenic imbalance characterized by low concentrations of placental growth factor (PlGF) and elevated soluble fms-like tyrosine kinase (sFlt-1). PlGF is a protein highly expressed by the placenta with vasculogenic and angiogenic properties, which has a central role in spiral artery remodeling and the development of a low-resistance placental capillary network. PlGF concentrations are significantly lower in women with preterm PE, and these reduced levels have been shown to precede the clinical onset of disease. Subsequently, the clinical utility of maternal serum PlGF has been extensively studied in singleton gestations from as early as 11 to 13 weeks' gestation, utilizing a validated multimarker prediction model, which performs superiorly to the National Institute for Health and Care Excellence (NICE) and American College of Obstetricians and Gynecologists (ACOG) guidelines in the detection of preterm PE. There is extensive research highlighting the role of PlGF-based testing utilizing commercially available assays in accelerating the diagnosis of PE in symptomatic women over 20 weeks' gestation and predicting time-to-delivery, allowing individualized risk stratification and appropriate antenatal surveillance to be determined. "Real-world" data has shown that interpretation of PlGF-based test results can aid clinicians in improving maternal outcomes and a growing body of evidence has implied a role for sFlt-1/PlGF in the prognostication of adverse pregnancy and perinatal events. Subsequently, PlGF-based testing is increasingly being implemented into obstetric practice and is advocated by NICE. This literature review aims to provide healthcare professionals with an understanding of the role of angiogenic biomarkers in PE and discuss the evidence for PlGF-based screening and triage. Prospective studies are warranted to explore if its implementation significantly improves perinatal outcomes, explore the value of repeat PlGF testing, and its use in multiple pregnancies.

School readiness of children at high risk of cerebral palsy randomised to early neuroprotection and neurorehabilitation: protocol for a follow-up study of participants from four randomised clinical trials.

INTRODUCTION: School readiness includes cognitive, socio-emotional, language and physical growth and development domains which share strong associations with life-course opportunities. Children with cerebral palsy (CP) are at increased risk of poor school readiness compared with their typically developing peers. Recently, earlier diagnosis of CP has allowed interventions to commence sooner, harnessing neuroplasticity. First, we hypothesise that early referral to intervention for children at-risk of CP will lead to improved school readiness at 4-6 years relative to placebo or care as usual. Second, we hypothesise that receipt of early diagnosis and early intervention will lead to cost-savings in the form of reduced healthcare utilisation. METHODS AND ANALYSIS: Infants identified as at-risk of CP ≤6 months corrected age (n=425) recruited to four randomised trials of neuroprotectants (n=1), early neurorehabilitation (n=2) or early parenting support (n=1) will be re-recruited to one overarching follow-up study at age 4-6 years 3 months. A comprehensive battery of standardised assessments and questionnaires will be administered to assess all domains of school readiness and associated risk factors. Participants will be compared with a historical control group of children (n=245) who were diagnosed with CP in their second year of life. Mixed-effects regression models will be used to compare school readiness outcomes between those referred for early intervention versus placebo/care-as-usual. We will also compare health-resource use associated with early diagnosis and intervention versus later diagnosis and intervention. ETHICS AND DISSEMINATION: The Children's Health Queensland Hospital and Health Service, The University of Queensland, University of Sydney, Monash University and Curtin University Human Research Ethics Committees have approved this study. Informed consent will be sought from the parent or legal guardian of every child invited to participate. Results will be disseminated in peer-reviewed journals, scientific conferences and professional organisations, and to people with lived experience of CP and their families. TRIAL REGISTRATION NUMBER: ACTRN12621001253897.

Prevalence of pre-eclampsia and adverse pregnancy outcomes in women with pre-existing cardiomyopathy: a multi-centre retrospective cohort study.

Pre-eclampsia is associated with postnatal cardiac dysfunction; however, the nature of this relationship remains uncertain. This multicentre retrospective cohort study aimed to determine the prevalence of pre-eclampsia in women with pre-existing cardiac dysfunction (left ventricular ejection fraction < 55%) and explore the relationship between pregnancy outcome and pre-pregnancy cardiac phenotype. In this cohort of 282 pregnancies, pre-eclampsia prevalence was not significantly increased (4.6% [95% C.I 2.2-7.0%] vs. population prevalence of 4.6% [95% C.I. 2.7-8.2], p = 0.99); 12/13 women had concurrent obstetric/medical risk factors for pre-eclampsia. The prevalence of preterm pre-eclampsia (< 37 weeks) and fetal growth restriction (FGR) was increased (1.8% vs. 0.7%, p = 0.03; 15.2% vs. 5.5%, p < 0.001, respectively). Neither systolic nor diastolic function correlated with pregnancy outcome. Antenatal ß blockers (n = 116) were associated with lower birthweight Z score (adjusted difference - 0.31 [95% C.I. - 0.61 to - 0.01], p = 0.04). To conclude, this study demonstrated a modest increase in preterm pre-eclampsia and significant increase in FGR in women with pre-existing cardiac dysfunction. Our results do not necessarily support a causal relationship between cardiac dysfunction and pre-eclampsia, especially given the population's background risk status. The mechanism underpinning the relationship between cardiac dysfunction and FGR merits further research but could be influenced by concomitant ß blocker use.

A prospective, longitudinal, case-control study to evaluate the neurodevelopment of children from birth to adolescence exposed to COVID-19 in utero.

BACKGROUND: The Coronavirus disease (COVID-19) pandemic has created unprecedented acute global health challenges. However, it also presents a set of unquantified and poorly understood risks in the medium to long term, specifically, risks to children whose mothers were infected with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) during pregnancy. Infections during pregnancy can increase the risk of atypical neurodevelopment in the offspring, but the long-term neurodevelopmental impact of in utero COVID-19 exposure is unknown. Prospective, longitudinal studies are needed to evaluate children exposed in utero to SARS-CoV2 to define this risk. METHODS: We have designed a prospective, case-controlled study to investigate the long-term impacts of SARS-CoV2 exposure on children exposed in utero. Women infected with SARS-CoV-2 during pregnancy will be recruited from Monash Health, the Royal Women's Hospital and Western Health (Melbourne, Australia) and Londrina Municipal Maternity Hospital Lucilla Ballalai and PUCPR Medical Clinical (Londrina, Brazil). A control group in a 2:1 ratio (2 non-exposed: 1 exposed mother infant dyad) comprising women who gave birth in the same month of delivery, are of similar age but did not contract SARS-CoV-2 during their pregnancy will also be recruited. We aim to recruit 170 exposed and 340 non-exposed mother-infant dyads. Clinical and socio-demographic data will be collected directly from the mother and medical records. Biospecimens and clinical and epidemiological data will be collected from the mothers and offspring at multiple time points from birth through to 15 years of age using standardised sample collection, and neurological and behavioural measures. DISCUSSION: The mapped neurodevelopmental trajectories and comparisons between SARS-CoV-2 exposed and control children will indicate the potential for an increase in atypical neurodevelopment. This has significant implications for strategic planning in the mental health and paediatrics sectors and long-term monitoring of children globally.

Maternal SARS-CoV-2 exposure alters infant DNA methylation.

Background: Infection during pregnancy can increase the risk of neurodevelopmental disorders in offspring. The impact of maternal SARS-CoV-2 infection on infant neurodevelopment is poorly understood. The maternal immune response to infection may be mimicked in rodent models of maternal immune activation which recapitulate altered neurodevelopment and behavioural disturbances in the offspring. In these models, epigenetic mechanisms, in particular DNA methylation, are one pathway through which this risk is conferred in utero to offspring. We hypothesised that in utero exposure to SARS-CoV-2 in humans may alter infant DNA methylation, particularly in genes associated with neurodevelopment. We aimed to test this hypothesis in a pilot sample of children in Victoria, Australia, who were exposed in utero to SARS-CoV-2. Methods: DNA was extracted from buccal swab specimens from (n = 4) SARS-CoV-2 in utero exposed and (n = 4) non-exposed infants and methylation status assessed across 850,000 methylation sites using an Illumina EPIC BeadChip. We also conducted an exploratory enrichment analysis using Gene Ontology annotations. Results: 1962 hypermethylated CpG sites were identified with an unadjusted p-value of 0.05, where 1133 CpGs mapped to 959 unique protein coding genes, and 716 hypomethylated CpG sites mapped to 559 unique protein coding genes in SARS-CoV-2 exposed infants compared to non-exposed. One differentially methylated position (cg06758191), located in the gene body of AFAP1 that was hypomethylated in the SARS-CoV-2 exposed cohort was significant after correction for multiple testing (FDR-adjusted p-value <0.00083). Two significant differentially methylated regions were identified; a hypomethylated intergenic region located in chromosome 6p proximal to the genes ZP57 and HLA-F (fwer <0.004), and a hypomethylated region in the promoter and body of the gene GAREM2 (fwer <0.036). Gene network enrichment analysis revealed differential methylation in genes corresponding to pathways relevant to neurodevelopment, including the ERBB pathway. Conclusion: These pilot data suggest that exposure to SARS-CoV-2 in utero differentially alters methylation of genes in pathways that play a role in human neurodevelopment.