Metformin in pregnancy and childhood neurodevelopmental outcomes: a systematic review and meta-analysis.

OBJECTIVE: This study aimed to examine the impact of maternal metformin use during pregnancy on offspring neurodevelopmental outcomes. DATA SOURCES: MEDLINE, Embase, and Web of Science (Core Collection) were searched from inception until July 1, 2023. STUDY ELIGIBILITY CRITERIA: Studies of women who received treatment with metformin at any stage of pregnancy for any indication with neurodevelopmental data available for their offspring were included. Studies without a control group were excluded. Randomized controlled trials, case-control, cohort, and cross-sectional studies were included in the review. METHODS: Studies were screened for inclusion and data were extracted independently by 2 reviewers. Risk of bias was assessed using a modified version of the Newcastle-Ottawa Scale for nonrandomized studies, and the Risk of Bias 2 tool for randomized trials. RESULTS: A total of 7 studies met the inclusion criteria, including a combined cohort of 14,042 children with 7641 children who were exposed and followed for up to 14 years of age. Metformin use during pregnancy was not associated with neurodevelopmental delay in infancy (relative risk, 1.09; 95% confidence interval, 0.54-2.17; 3 studies; 9668 children) or at ages 3 to 5 years (relative risk, 0.90; 95% confidence interval, 0.56-1.45; 2 studies; 6118 children). When compared with unexposed peers, metformin use during pregnancy was not associated with altered motor scores (mean difference, 0.30; 95% confidence interval, -1.15 to 1.74; 3 studies; 714 children) or cognitive scores (mean difference, -0.45; 95% confidence interval, -1.45 to 0.55; 4 studies; 734 children). Studies that were included were of high quality and deemed to be at low risk of bias. CONCLUSION: In utero exposure to metformin does not seem to be associated with adverse neurodevelopmental outcomes in children up to the age of 14 years. These findings provide reassurance to clinicians and pregnant women considering metformin use during pregnancy.

School-age outcomes among IVF-conceived children: A population-wide cohort study.

BACKGROUND: In vitro fertilisation (IVF) is a common mode of conception. Understanding the long-term implications for these children is important. The aim of this study was to determine the causal effect of IVF conception on primary school-age childhood developmental and educational outcomes, compared with outcomes following spontaneous conception. METHODS AND FINDINGS: Causal inference methods were used to analyse observational data in a way that emulates a target randomised clinical trial. The study cohort comprised statewide linked maternal and childhood administrative data. Participants included singleton infants conceived spontaneously or via IVF, born in Victoria, Australia between 2005 and 2014 and who had school-age developmental and educational outcomes assessed. The exposure examined was conception via IVF, with spontaneous conception the control condition. Two outcome measures were assessed. The first, childhood developmental vulnerability at school entry (age 4 to 6), was assessed using the Australian Early Developmental Census (AEDC) (n = 173,200) and defined as scoring <10th percentile in ≥2/5 developmental domains (physical health and wellbeing, social competence, emotional maturity, language and cognitive skills, communication skills, and general knowledge). The second, educational outcome at age 7 to 9, was assessed using National Assessment Program-Literacy and Numeracy (NAPLAN) data (n = 342,311) and defined by overall z-score across 5 domains (grammar and punctuation, reading, writing, spelling, and numeracy). Inverse probability weighting with regression adjustment was used to estimate population average causal effects. The study included 412,713 children across the 2 outcome cohorts. Linked records were available for 4,697 IVF-conceived cases and 168,503 controls for AEDC, and 8,976 cases and 333,335 controls for NAPLAN. There was no causal effect of IVF-conception on the risk of developmental vulnerability at school-entry compared with spontaneously conceived children (AEDC metrics), with an adjusted risk difference of -0.3% (95% CI -3.7% to 3.1%) and an adjusted risk ratio of 0.97 (95% CI 0.77 to 1.25). At age 7 to 9 years, there was no causal effect of IVF-conception on the NAPLAN overall z-score, with an adjusted mean difference of 0.030 (95% CI -0.018 to 0.077) between IVF- and spontaneously conceived children. The models were adjusted for sex at birth, age at assessment, language background other than English, socioeconomic status, maternal age, parity, and education. Study limitations included the use of observational data, the potential for unmeasured confounding, the presence of missing data, and the necessary restriction of the cohort to children attending school. CONCLUSIONS: In this analysis, under the given causal assumptions, the school-age developmental and educational outcomes for children conceived by IVF are equivalent to those of spontaneously conceived children. These findings provide important reassurance for current and prospective parents and for clinicians.

Telehealth in antenatal care: recent insights and advances.

BACKGROUND: For decades, antenatal care in high-resource settings has involved 12-14 face-to-face visits across pregnancy. The COVID-19 pandemic forced many care providers to rapidly embrace telehealth to reduce face-to-face visits. Here we review recent advances in telehealth used to provide antenatal care. MAIN BODY: We conducted a narrative review examining the impact of telehealth on obstetric care. Two broad types of telehealth are used in antenatal care. The first is real-time telehealth, where consultations are done virtually instead of face-to-face. The second is remote monitoring, where in-clinic physical examinations are replaced with at-home alternatives. These can include blood pressure monitoring, fetal heart rate monitoring, and emerging technologies such as tele-ultrasound. Large cohort studies conducted during the pandemic era have shown that telehealth appears not to have increased adverse clinical outcomes for mothers or babies. However, further studies may be required to confidently conclude rare outcomes are unchanged, such as maternal mortality, serious morbidity, or stillbirth. Health economic studies suggest telehealth has the potential to reduce the financial cost of care provision. Telehealth in antenatal care seems to be acceptable to both pregnant women and healthcare providers. CONCLUSION: Adoption of telehealth technologies may improve the antenatal care experience for women and reduce healthcare expenditure without adversely impacting health outcomes for the mother or baby. More studies are warranted to confirm telehealth does not alter the risk of rare outcomes such as maternal or neonatal mortality.

Low-dose aspirin use in pregnancy and the risk of preterm birth: a Swedish register-based cohort study.

BACKGROUND: Preterm birth is the leading cause of neonatal mortality and morbidity. Women who have had a previous preterm birth are at increased risk for preterm birth in their subsequent pregnancies. Low-dose aspirin use reduces the risk for preterm birth among women at risk of developing preeclampsia, however, it is unclear whether low-dose aspirin may reduce the risk of recurrent preterm birth. OBJECTIVE: This study aimed to investigate the association between low-dose aspirin use and preterm birth among women with a previous preterm birth. STUDY DESIGN: We conducted a Swedish register-based cohort study and included women who had a first and second pregnancy between 2006 and 2019, with the first pregnancy ending in preterm birth (medically indicated or with spontaneous onset <37 weeks of gestation). The association between low-dose aspirin use and preterm birth in the second pregnancy was estimated via logistic regression via standardization and expressed as marginal relative risks with the 95% confidence interval. RESULTS: Among the study cohort (N=22,127), 3057 women (14%) were prescribed low-dose aspirin during their second pregnancy and 3703 women (17%) gave birth prematurely. Low-dose aspirin use was associated with a reduced risk for preterm birth, (marginal relative risk, 0.87; 95% confidence interval, 0.77-0.99). There were no statistically significant associations between low-dose aspirin use and an altered risk for moderate preterm birth, defined as birth between 32 and 36 weeks' gestation (marginal relative risk, 0.90; 95% confidence interval, 0.78-1.03), or very preterm birth, defined as birth <32 weeks' gestation (marginal relative risk, 0.75; 95% confidence interval, 0.54-1.04). Regarding the onset of preterm birth, low-dose aspirin use was associated with a reduced risk for spontaneous preterm birth (marginal relative risk, 0.70; 95% confidence interval, 0.57-0.86) but no reduction in the risk for medically indicated preterm birth (marginal relative risk, 1.09; 95% confidence interval, 0.91-1.30) was observed. CONCLUSION: Among women with a previous preterm birth, low-dose aspirin use was associated with a reduced risk for preterm birth. When investigating preterm birth by onset in the second pregnancy, low-dose aspirin use was associated with a reduced risk for spontaneous preterm birth. Our results suggest that low-dose aspirin may be an effective prophylaxis for recurrent preterm birth.

Analysis of a maternal health medicines pipeline database 2000-2021: New candidates for the prevention and treatment of fetal growth restriction.

OBJECTIVE: The Accelerating Innovation for Mothers project established a new database of candidate medicines under development between 2000 and 2021 for five pregnancy-related conditions, including fetal growth restriction. The objective was to assess medicines for fetal growth restriction and their potential for clinical use globally. DESIGN: Landscape analysis. SETTING: Global (focus on low- and middle-income countries, LMICs). SAMPLE: Drugs, dietary supplements and biologics under investigation for prevention or treatment of fetal growth restriction. METHODS: A research pipeline database of medicines was created through searching AdisInsight, PubMed and various grant and clinical trial databases. Analysis of clinical and preclinical candidates were descriptive. MAIN OUTCOMES MEASURES: Fetal growth restriction candidates in clinical development were identified and ranked as high, medium or low potential based on prespecified criteria, including efficacy, safety and accessibility. RESULTS: Of the 444 unique candidates in the database across all five pregnancy-related conditions, 63 were for fetal growth restriction. Of these, 31 were in clinical development (phases I, II or III) and 32 were in preclinical development. Three candidates, aspirin, l-arginine and vitamin D, were ranked as having high potential as preventive agents. There were no high-potential candidates for treating fetal growth restriction, although five candidates were ranked as having medium potential: allylestrenol, dalteparin, omega-3 fatty acids, tadalafil, and United Nations International Multiple Micronutrient Antenatal Preparation (UNIMMAP). CONCLUSIONS: l-Arginine, aspirin and vitamin D are promising, high-potential preventative agents for fetal growth restriction. Based on the medicines pipeline, new pharmacological agents for fetal growth restriction are unlikely to emerge in the near future.

The long-term risk of cardiovascular disease among women with a history of hypertensive disorders of pregnancy: a systematic review of clinical practice guidelines.

BACKGROUND: The lifelong risks of cardiovascular disease following preeclampsia and gestational hypertension are well-established. However, it is unclear whether this evidence has been translated into clinical practice guidelines. Thus, this review aimed to assess the quality and content of Australian clinical practice guidelines regarding the risk of cardiovascular disease following gestational hypertension and preeclampsia. METHODS: We conducted a systematic search of MEDLINE (Ovid), EMBASE (Ovid), and CINAHL databases, as well as hospital, obstetric society, and medical college websites. Publications were included if: they were a clinical practice guideline; were published in the previous ten years; and included recommendations for the management of future cardiovascular disease risk following hypertensive disorders of pregnancy. Quality assessment was performed using Appraisal of Guidelines for Research and Evaluation Instrument Version Two (AGREE-II) and AGREE Recommendations Excellence Instrument (AGREE-REX). RESULTS: Eighteen guidelines were identified, and of these, less than half (n = 8) included recommendations for managing future cardiovascular risk following hypertensive disorders of pregnancy. Across these eight, four main counselling recommendations were found regarding (1) risk of future cardiovascular disease; (2) risk factor screening; (3) lifestyle interventions; and (4) prenatal counselling for future pregnancies. The quality and content of these recommendations varied significantly, and the majority of guidelines (87.5%) were assessed as low to moderate quality. CONCLUSIONS: There are limited Australian clinical practice guidelines providing appropriate advice regarding future risk of cardiovascular disease following hypertensive disorders of pregnancy. The quality and content of these guidelines varied significantly. These findings highlight the need for improved translation from evidence-based research to enhance clinical care and guidance.

New medicines for spontaneous preterm birth prevention and preterm labour management: landscape analysis of the medicine development pipeline.

BACKGROUND: There are few medicines in clinical use for managing preterm labor or preventing spontaneous preterm birth from occurring. We previously developed two target product profiles (TPPs) for medicines to prevent spontaneous preterm birth and manage preterm labor. The objectives of this study were to 1) analyse the research and development pipeline of medicines for preterm birth and 2) compare these medicines to target product profiles for spontaneous preterm birth to identify the most promising candidates. METHODS: Adis Insight, Pharmaprojects, WHO international clinical trials registry platform (ICTRP), PubMed and grant databases were searched to identify candidate medicines (including drugs, dietary supplements and biologics) and populate the Accelerating Innovations for Mothers (AIM) database. This database was screened for all candidates that have been investigated for preterm birth. Candidates in clinical development were ranked against criteria from TPPs, and classified as high, medium or low potential. Preclinical candidates were categorised by product type, archetype and medicine subclass. RESULTS: The AIM database identified 178 candidates. Of the 71 candidates in clinical development, ten were deemed high potential (Prevention: Omega-3 fatty acid, aspirin, vaginal progesterone, oral progesterone, L-arginine, and selenium; Treatment: nicorandil, isosorbide dinitrate, nicardipine and celecoxib) and seven were medium potential (Prevention: pravastatin and lactoferrin; Treatment: glyceryl trinitrate, retosiban, relcovaptan, human chorionic gonadotropin and Bryophyllum pinnatum extract). 107 candidates were in preclinical development. CONCLUSIONS: This analysis provides a drug-agnostic approach to assessing the potential of candidate medicines for spontaneous preterm birth. Research should be prioritised for high-potential candidates that are most likely to meet the real world needs of women, babies, and health care professionals.

Systematic evaluation of the pre-eclampsia drugs, dietary supplements and biologicals pipeline using target product profiles.

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.

Pravastatin, proton-pump inhibitors, metformin, micronutrients, and biologics: new horizons for the prevention or treatment of preeclampsia.

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.

Cerebral biomarkers in neurologic complications of preeclampsia.

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.

Risk of obstetric anal sphincter injury among women who birth vaginally after a prior caesarean section: A state-wide cohort study.

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.

Maternal lithium use and the risk of adverse pregnancy and neonatal outcomes: a Swedish population-based cohort study.

BACKGROUND: Lithium is prescribed during pregnancy, but there is limited information about pregnancy and neonatal outcomes following in utero exposure. Thus, this study aimed to investigate the associations between lithium use and adverse pregnancy and neonatal outcomes. METHODS: This population-based cohort study examined associations between maternal lithium use and major adverse pregnancy and neonatal outcomes via inverse probability weighted propensity score regression models. RESULTS: Of 854,017 women included in this study, 434 (0.05%) used lithium during pregnancy. Among pre-specified primary outcomes, lithium use during pregnancy was associated with an increased risk of spontaneous preterm birth (8.7% vs 3.0%; adjusted relative risk [aRR] 2.64 95% CI 1.82, 3.82) and birth of a large for gestational age infant (9.0% vs 3.5%; aRR 2.64 95% CI 1.91, 3.66), but not preeclampsia nor birth of a small for gestational age infant. Among secondary outcomes, lithium use was associated with an increased risk of cardiac malformations (2.1% vs 0.8%; aRR 3.17 95% CI 1.64, 6.13). In an analysis restricted to pregnant women with a diagnosed psychiatric illness (n=9552), associations remained between lithium and spontaneous preterm birth, birth of a large for gestational age infant, and cardiovascular malformations; and a positive association with neonatal hypoglycaemia was also found. These associations were also apparent in a further analysis comparing women who continued lithium treatment during pregnancy to those who discontinued prior to pregnancy. CONCLUSIONS: Lithium use during pregnancy is associated with an increased risk of spontaneous preterm birth and other adverse neonatal outcomes. These potential risks must be balanced against the important benefit of treatment and should be used to guide shared decision-making.

Risk of major labour-related complications for pregnancies progressing to 42 weeks or beyond.

BACKGROUND: Post-term gestation beyond 41+6 completed weeks of gestation is known to be associated with a sharp increase in the risk of stillbirth and perinatal mortality. However, the risk of common adverse outcomes related to labour, such as shoulder dystocia and post-partum haemorrhage for those delivering at this advanced gestation, remains poorly characterised. The objective of this study was to examine the risk of adverse, labour-related outcomes for women progressing to 42 weeks gestation or beyond, compared with those giving birth at 39 completed weeks. METHODS: We performed a state-wide cohort study using routinely collected perinatal data in Australia. Comparing the two gestation cohorts, we examined the adjusted relative risk of clinically significant labour-related adverse outcomes, including macrosomia (≥ 4500 at birth), post-partum haemorrhage (≥1000 ml), shoulder dystocia, 3rd or 4th degree perineal tear and unplanned caesarean section. Parity, maternal age and mode of birth were adjusted for using logistic regression. RESULTS: The study cohort included 91,314 women who birthed at 39 completed weeks and 4317 at ≥42 completed weeks. Compared to 39 weeks gestation, those giving birth ≥42 weeks gestation had an adjusted relative risk (aRR) of 1.85 (95% CI 1.55-2.20) for post-partum haemorrhage following vaginal birth, 2.29 (95% CI 1.89-2.78) following instrumental birth and 1.44 (95% CI 1.17-1.78) following emergency caesarean section; 1.43 (95% CI 1.16-1.77) for shoulder dystocia (for non-macrosomic babies); and 1.22 (95% CI 1.03-1.45) for 3rd or 4th degree perineal tear (all women). The adjusted relative risk of giving birth to a macrosomic baby was 10.19 (95% CI 8.26-12.57) among nulliparous women and 4.71 (95% CI 3.90-5.68) among multiparous women. The risk of unplanned caesarean section was 1.96 (95% CI 1.86-2.06) following any labour and 1.47 (95% CI 1.38-1.56) following induction of labour. CONCLUSIONS: Giving birth at ≥42 weeks gestation may be an under-recognised risk factor for several important, labour-related adverse outcomes. Clinicians should be aware that labour at this advanced gestation incurs a higher risk of adverse outcomes. In addition to known perinatal risks, the risk of obstetric complications should be considered in the counselling of women labouring at post-term gestation.

Aspirin use during pregnancy and the risk of bleeding complications: a Swedish population-based cohort study.

BACKGROUND: Aspirin is offered to pregnant women to prevent preeclampsia, a severe obstetrical complication. Large studies of nonpregnant populations have consistently shown that aspirin prophylaxis increases the risk of hemorrhagic complications. However, there have not been any population-based studies investigating this in a pregnant population. OBJECTIVE: This study aimed to investigate whether aspirin use during pregnancy is associated with an increased risk of bleeding complications. STUDY DESIGN: We performed a register-based cohort study using the Swedish Pregnancy Register wherein we examined 313,624 women giving birth between January 2013 and July 2017. Logistic regression was used to assess the risk of antepartum, intrapartum, and postpartum hemorrhage. A propensity score and inverse probability treatment weighting was used to generate an odds ratio that corrects for differences in baseline characteristics. RESULTS: Aspirin use was registered in 4088 (1.3%) women during pregnancy. Compared with women who did not take aspirin, aspirin use was not associated with bleeding complications during the antepartum period (adjusted odds ratio, 1.22; 95% confidence interval, 0.97-1.54). However, aspirin users had a higher incidence of intrapartum bleeding (2.9% aspirin users vs 1.5% nonusers; adjusted odds ratio, 1.63; 95% confidence interval, 1.30-2.05), postpartum hemorrhage (10.2% vs 7.8%; adjusted odds ratio, 1.23; 95% confidence interval, 1.08-1.39), and postpartum hematoma (0.4% vs 0.1%; adjusted odds ratio, 2.21; 95% confidence interval, 1.13-4.34). The risk of a neonatal intracranial hemorrhage was also increased (0.07% vs 0.01%; adjusted odds ratio, 9.66; 95% confidence interval, 1.88-49.48). After stratifying by mode of birth, a higher incidence of bleeding among aspirin users was present for those who had a vaginal birth but not those who had a cesarean delivery. CONCLUSION: Using aspirin during pregnancy is associated with increased postpartum bleeding and postpartum hematoma. It may also be associated with neonatal intracranial hemorrhage. When offering aspirin during pregnancy, these risks need to be weighed against the potential benefits.

Combination methotrexate and gefitinib: A potential medical treatment for inoperable nontubal ectopic pregnancy.

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.

Accuracy of clinical suspicion of growth restriction at term despite a normal growth ultrasound: A retrospective cohort study.

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.

Maternal mortality at the National Referral Hospital in Honiara, Solomon Islands over a five-year period.

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.

The incidence of hypertensive disorders of pregnancy following sperm donation in IVF: an Australian state-wide retrospective cohort study.

STUDY QUESTION: Does IVF using donor sperm increase the risk of hypertensive disorders of pregnancy and fetal growth restriction (FGR)? SUMMARY ANSWER: IVF conceptions arising from sperm donation are not associated with an increased risk of hypertensive disorders of pregnancy or FGR. WHAT IS KNOWN ALREADY: It has been hypothesized that the absence of prior exposure to factors within the paternal ejaculate increases the risk of preeclampsia and FGR among nulliparous women or women with a new partner-the concept of 'primipaternity'. It remains unclear which element of the ejaculate is responsible: the sperm cell or the constituents of seminal fluid. IVF pregnancies arising from donor sperm where the seminal fluid is absent provide a unique opportunity to test the theory of primipaternity and the relative contribution of the sperm cell. Pregnancies conceived via artificial reproductive technology are at increased risk of preeclampsia and FGR. STUDY DESIGN, SIZE, DURATION: Theories about the development of preeclampsia and the relative contribution of spermatic factors were explored by comparing the risk of hypertensive disorders of pregnancy and FGR among IVF pregnancies conceived with autologous gametes (own eggs and partner sperm) and those conceived with donor sperm, donor egg (and partner sperm) and donor embryo. To do this, we performed a retrospective cohort analysis of pregnancy outcomes among singleton pregnancies (n = 15 443) conceived through fertility clinics within Australia between 2009 and 2017. PARTICIPANTS/MATERIALS, SETTING, METHODS: All pregnancies resulting in a singleton pregnancy delivering after 20 weeks' gestation were included. The cohort was divided into donor sperm, donor egg and donor embryo (where both gametes came from a donor to create an embryo, or in a surrogate pregnancy) groups. We also compared the data with a control group, defined as IVF-conceived pregnancies from autologous cycles. A multivariable regression model was used to calculate an adjusted odds ratio (aOR). MAIN RESULTS AND THE ROLE OF CHANCE: The final cohort contained 1435, 578 and 239 pregnancies conceived by donor sperm, donor egg and donor embryo, respectively, and 13 191 controls. There were a very small number of women lost to follow-up (31 women; 0.2% of total cohort). Compared to control pregnancies, there was no increase in the risk of hypertensive disorders among pregnancies conceived via donor sperm (aOR 0.94; 95% CI 0.73-1.21). Subgroup analysis was performed for a cohort where parity was known (n = 4551), and of these, 305 multigravida pregnancies were conceived via donor sperm. Among this cohort, no increased risk of preeclampsia or pregnancy-induced hypertension was found (aOR 1.18; 95% CI: 0.69-2.04) as a result of primipaternity (new sperm donor).A significantly increased risk for hypertensive disorders of pregnancy was associated with the use of donor eggs (but partner sperm; aOR 2.34; 95% CI 1.69-3.21). However, the association was no greater among pregnancies conceived with donor embryos (i.e. donated egg and sperm; aOR 2.0; 95% CI 1.25-3.17) than among the donor oocyte group. The overall incidence of FGR (defined as birthweight <10th centile) was 18%. There were no significant differences observed between donor sperm, or donor embryo pregnancies; however, egg donation was associated with a 1.5-fold increase in FGR. LIMITATIONS, REASONS FOR CAUTION: This study was limited by a lower than expected rate of hypertensive disorders of pregnancy (n = 862, 5.6%), which is contrary to the well-established increased risk among women using IVF. However, this is likely to be evenly distributed across the study groups and, therefore, unlikely to have introduced significant bias. WIDER IMPLICATIONS OF THE FINDINGS: These findings suggest that exposure to new sperm may not be implicated in the pathogenesis of preeclampsia. The mechanism of increased risk seen in conceptions arising from egg or embryo donation remains unclear. Further investigation is required to elucidate these mechanisms and, ultimately, improve pregnancy outcomes following IVF. STUDY FUNDING/COMPETING INTEREST(S): This study was supported by the Australian Commonwealth Government-Graduate Research Scheme (A.K.). Salary support was provided by the National Health and Medical Research Council of Australia (S.T.), Mercy Foundation (A.L.), and the Department of Obstetrics and Gynaecology at the University of Melbourne (R.H.). There are no competing interests.

Identifying late-onset fetal growth restriction by measuring circulating placental RNA in the maternal blood at 28 weeks' gestation.

BACKGROUND: Late-onset fetal growth restriction (FGR) is often undetected prior to birth, which puts the fetus at increased risk of adverse perinatal outcomes including stillbirth. OBJECTIVE: Measuring RNA circulating in the maternal blood may provide a noninvasive insight into placental function. We examined whether measuring RNA in the maternal blood at 26-30 weeks' gestation can identify pregnancies at risk of late-onset FGR. We focused on RNA highly expressed in placenta, which we termed "placental-specific genes." STUDY DESIGN: This was a case-control study nested within a prospective cohort of 600 women recruited at 26-30 weeks' gestation. The circulating placental transcriptome in maternal blood was compared between women with late-onset FGR (<5th centile at >36+6 weeks) and gestation-matched well-grown controls (20-95th centile) using microarray (n = 12). TaqMan low-density arrays, reverse transcription-polymerase chain reaction (PCR), and digital PCR were used to validate the microarray findings (FGR n = 40, controls n = 80). RESULTS: Forty women developed late-onset FGR (birthweight 2574 ± 338 g, 2nd centile) and were matched to 80 well-grown controls (birthweight 3415 ± 339 g, 53rd centile, P < .05). Operative delivery and neonatal admission were higher in the FGR cohort (45% vs 23%, P < .05). Messenger RNA coding 137 placental-specific genes was detected in the maternal blood and 37 were differentially expressed in late-onset FGR. Seven were significantly dysregulated with PCR validation (P < .05). Activating transcription factor-3 messenger RNA transcripts were the most promising single biomarker at 26-30 weeks: they were increased in fetuses destined to be born FGR at term (2.1-fold vs well grown at term, P < .001) and correlated with the severity of FGR. Combining biomarkers improved prediction of severe late-onset FGR (area under the curve, 0.88; 95% CI 0.80-0.97). A multimarker gene expression score had a sensitivity of 79%, a specificity of 88%, and a positive likelihood ratio of 6.2 for subsequent delivery of a baby <3rd centile at term. CONCLUSION: A unique placental transcriptome is detectable in maternal blood at 26-30 weeks' gestation in pregnancies destined to develop late-onset FGR. Circulating placental RNA may therefore be a promising noninvasive test to identify pregnancies at risk of developing FGR at term.