Pregnancy and COVID-19.

There are many unknowns for pregnant women during the coronavirus disease 2019 (COVID-19) pandemic. Clinical experience of pregnancies complicated with infection by other coronaviruses e.g., Severe Acute Respiratory Syndrome (SARS) and Middle Eastern Respiratory Syndrome, has led to pregnant woman being considered potentially vulnerable to severe SARS-CoV-2 infection. Physiological changes during pregnancy have a significant impact on the immune system, respiratory system, cardiovascular function, and coagulation. These may have positive or negative effects on COVID-19 disease progression. The impact of SARS-CoV-2 in pregnancy remains to be determined, and a concerted, global effort is required to determine the effects on implantation, fetal growth and development, labor, and neonatal health. Asymptomatic infection presents a further challenge regarding service provision, prevention, and management. Besides the direct impacts of the disease, a plethora of indirect consequences of the pandemic adversely affect maternal health, including reduced access to reproductive health services, increased mental health strain, and increased socioeconomic deprivation. In this review, we explore the current knowledge of COVID-19 in pregnancy and highlight areas for further research to minimize its impact for women and their children.

Nitroglycerin for treatment of retained placenta: A randomised, placebo-controlled, multicentre, double-blind trial in the UK.

BACKGROUND: Retained placenta following vaginal delivery is a major cause of postpartum haemorrhage. Currently, the only effective treatments for a retained placenta are the surgical procedures of manual removal of placenta (MROP) and uterine curettage, which are not universally available, particularly in low- and middle-income countries. The objective of the trial was to determine whether sublingual nitroglycerin spray was clinically effective and cost-effective for medical treatment of retained placenta following vaginal delivery. METHODS AND FINDINGS: A randomised, placebo-controlled, double-blind trial was undertaken between October 2014 and July 2017 at 29 delivery units in the UK (Edinburgh, Glasgow, Manchester, Newcastle, Preston, Warrington, Chesterfield, Crewe, Durham, West Middlesex, Aylesbury, Furness, Southampton, Bolton, Sunderland, Oxford, Nottingham [2 units], Burnley, Chertsey, Stockton-on-Tees, Middlesborough, Chester, Darlington, York, Reading, Milton Keynes, Telford, Frimley). In total, 1,107 women with retained placenta following vaginal delivery were recruited. The intervention was self-administered 2 puffs of sublingual nitroglycerin (800 µg; intervention, N = 543) or placebo spray (control, N = 564). The primary clinical outcome was the need for MROP, assessed at 15 minutes following administration of the intervention. Analysis was based on the intention-to-treat principle. The primary safety outcome was measured blood loss between study drug administration and transfer to the postnatal ward or other clinical area. The primary patient-sided outcomes were satisfaction with treatment and side-effect profile, assessed by questionnaires pre-discharge and 6 weeks post-delivery. Secondary clinical outcomes were measured at 5 and 15 minutes after study drug administration and prior to hospital discharge. There was no statistically significant or clinically meaningful difference in need for MROP by 15 minutes (primary clinical outcome, 505 [93.3%] for nitroglycerin versus 518 [92.0%] for placebo, odds ratio [OR] 1.01 [95% CI 0.98-1.04], p = 0.393) or blood loss (<500 ml: nitroglycerin, 238 [44.3%], versus placebo, 249 [44.5%]; 500 ml-1,000 ml: nitroglycerin, 180 [33.5%], versus placebo, 224 [40.0%]; >1,000 ml: nitroglycerin, 119 [22.2%], versus placebo, 87 [15.5%]; ordinal OR 1.14 [95% CI 0.88-1.48], p = 0.314) or satisfaction with treatment (nitroglycerin, 288 [75.4%], versus placebo, 303 [78.1%]; OR 0.87 [95% CI 0.62-1.22], p = 0.411) or health service costs (mean difference [£] 55.3 [95% CI -199.20 to 309.79]). Palpitations following drug administration were reported more often in the nitroglycerin group (36 [9.8%] versus 15 [4.0%], OR 2.60 [95% CI 1.40-4.84], p = 0.003). There were 52 serious adverse events during the trial, with no statistically significant difference in likelihood between groups (nitroglycerin, 27 [5.0%], versus placebo, 26 [4.6%]; OR 1.13 [95% CI 0.54-2.38], p = 0.747). The main limitation of our study was the low return rate for the 6-week postnatal questionnaire. There were, however, no differences in questionnaire return rates between study groups or between women who did and did not have MROP, with the patient-reported use of outpatient and primary care services at 6 weeks accounting for only a small proportion (approximately 5%) of overall health service costs. CONCLUSIONS: In this study, we found that nitroglycerin is neither clinically effective nor cost-effective as a medical treatment for retained placenta, and has increased side effects, suggesting it should not be used. Further research is required to identify an effective medical treatment for retained placenta to reduce the morbidity caused by this condition, particularly in low- and middle-income countries where surgical management is not available. TRIAL REGISTRATION: ISRCTN.com ISRCTN88609453 ClinicalTrials.gov NCT02085213.

Sensors for Fetal Hypoxia and Metabolic Acidosis: A Review.

This article reviews existing clinical practices and sensor research undertaken to monitor fetal well-being during labour. Current clinical practices that include fetal heart rate monitoring and fetal scalp blood sampling are shown to be either inadequate or time-consuming. Monitoring of lactate in blood is identified as a potential alternative for intrapartum fetal monitoring due to its ability to distinguish between different types of acidosis. A literature review from a medical and technical perspective is presented to identify the current advancements in the field of lactate sensors for this application. It is concluded that a less invasive and a more continuous monitoring device is required to fulfill the clinical needs of intrapartum fetal monitoring. Potential specifications for such a system are also presented in this paper.

Prenatal exposure to maternal very severe obesity is associated with impaired neurodevelopment and executive functioning in children.

BackgroundPrenatal maternal obesity has been associated with an increased risk of neurocognitive problems in childhood, but there are fewer studies on executive functioning.MethodsTests and questionnaires to assess neurodevelopment, executive functioning, and the ability to delay gratification were conducted in 113 children (mean (SD)=4.24 (0.63) years of age) born to mothers with very severe obesity (SO, body mass index (BMI)⩾40 kg/m2, n=51) or to lean mothers (BMI⩽25 kg/m2, n=62).ResultsPrenatal maternal SO predicted poorer neurodevelopment (unstandardized regression coefficient (B)=-0.42, 95% confidence interval (CI) (-0.82; -0.02)), worse problem-solving (odd ratio (OR)=0.60, 95% CI (1.13; 0.07)), and fine motor skills (OR=4.91, 95% CI (1.27; 19.04)), poorer executive functioning in areas of attention, inhibitory control, and working memory (standardized B=3.75, 95% CI (1.01; 13.93)) but not in self-gratification delay. The effects were independent of maternal concurrent psychological well-being and child's BMI, but not independent of maternal education.ConclusionFuture studies should investigate whether perinatal management of maternal obesity could prevent adverse outcomes in child neurodevelopment.

Is the first urinary albumin/creatinine ratio (ACR) in women with suspected preeclampsia a prognostic factor for maternal and neonatal adverse outcome? A retrospective cohort study.

INTRODUCTION: The aim of this study was to determine the prognostic value of the first urinary albumin/creatinine ratio (ACR) for adverse maternal and neonatal outcomes and how it relates to other prognostic factors. MATERIAL AND METHODS: We performed a retrospective cohort study from December 2009 to February 2012 with analysis of demographic, clinical and biochemical data from two obstetric day assessment units in hospitals in Southeast Scotland. We included 717 pregnant women, with singleton pregnancies after 20 weeks' gestation, referred for evaluation of suspected preeclampsia and having their first ACR performed. The ability of ACR to predict future outcomes was assessed in both univariable and multivariable logistic regression models. The latter assessed its prognostic value independent of (adjusting for) existing prognostic factors. Primary outcome measures were maternal and neonatal composite adverse outcomes, and a secondary outcome was gestation at delivery. RESULTS: In all, 204 women (28.5%) experienced a composite adverse maternal outcome and 146 women (20.4%) experienced a composite adverse neonatal outcome. Multivariate analysis of log-transformed ACR demonstrated that a 1-unit increase in log ACR is associated with an increased odds of adverse maternal [odds ratio 1.60, 95% confidence interval (CI) 1.45-1.80] and adverse neonatal (odds ratio 1.15, 95% CI 1.02-1.29) composite outcomes, and with reduced gestational age at delivery (coefficient: -0.46, 95% CI -0.54 to -0.38). CONCLUSIONS: ACR is an independent prognostic factor for maternal and neonatal adverse outcomes in suspected preeclampsia. ACR may be useful to inform risk predictions within a prognostic model.

Glibenclamide and metfoRmin versus stAndard care in gEstational diabeteS (GRACES): a feasibility open label randomised trial.

BACKGROUND: Metformin is widely used to treat gestational diabetes (GDM), but many women remain hyperglycaemic and require additional therapy. We aimed to determine recruitment rate and participant throughput in a randomised trial of glibenclamide compared with standard therapy insulin (added to maximum tolerated metformin) for treatment of GDM. METHODS: We conducted an open label feasibility study in 5 UK antenatal clinics among pregnant women 16 to 36 weeks' gestation with metformin-treated GDM. Women failing to achieve adequate glycaemic control on metformin monotherapy were randomised to additional glibenclamide or insulin. The primary outcome was recruitment rate. We explored feasibility with uptake, retention, adherence, safety, glycaemic control, participant satisfaction and clinical outcomes. RESULTS: Records of 197 women were screened and 23 women randomised to metformin and glibenclamide (n = 13) or metformin and insulin (n = 10). Mean (SD) recruitment rate was 0.39 (0.62) women/centre/month. 9/13 (69.2%, 95%CI 38.6-90.9%) women adhered to glibenclamide and all provided outcome data (100% retention). There were no episodes of severe hypoglycaemia, but metformin and insulin gave superior glycaemic control to metformin and glibenclamide, with fewer blood glucose readings <3.5 mmol/l (median [IQR] difference/woman/week of treatment 0.58 [0.03-1.87]). CONCLUSIONS: A large randomised controlled trial comparing glibenclamide or insulin in combination with metformin for women with GDM would be feasible but is unlikely to be worthwhile, given the poorer glycaemic control with glibenclamide and metformin in this pilot study. The combination of metformin and glibenclamide should be reserved for women with GDM with true needle phobia or inability to use insulin therapy. TRIAL REGISTRATION: www.clinicaltrials.gov registration number:NCT02080377 February 11th 2014.

Web-based interventions for prevention and treatment of perinatal mood disorders: a systematic review.

BACKGROUND: Perinatal depression is strikingly common with a prevalence of 10-15%. The adverse effects of perinatal depression on maternal and child health are profound with considerable costs. Despite this, few women seek medical attention. E-health, providing healthcare via the Internet is an accessible and effective solution for the treatment of depression in the general population. We aimed to conduct a systematic review of web-based interventions for the prevention and treatment of mood disorders in the perinatal period, defined as the start of pregnancy to 1 year post-partum. METHODS: Six databases were searched until 26(th) March 2015. Two researchers independently screened articles for eligibility. Of the 547 screened articles, four met the inclusion criteria. These included three randomised-controlled trials and one feasibility trial, with total data from 1274 participants. MOOSE and PRISMA guidelines were adhered to for the conduct and reporting of the systematic review. RESULTS: All studies were conducted in the post-partum period. All reported an improvement in maternal mood following intervention. A significant improvement in depressive symptoms was measured using validated rating scales, such as the Edinburgh Postnatal Depression Scale (EPDS), either at post-treatment or follow-up which ranged from 3 to 12 months post study completion. For the two RCTs utilising the EPDS, the EPDS score reductions were (mean ± SEM) 8.52 ± 0.22 (Range 19.46 to10.94) and 9.19 ± 0.63 (Range, 20.24 to 11.05) for treatment groups and 5.16 ± 0.25 (Range 19.44 to 14.28) and 6.81 ± 0.71 (Range 21.07 to 14.26) for comparator groups. However attrition within studies ranged from 13 to 61%. One study was rated as 'good' quality. CONCLUSIONS: Preliminary data suggests web-based therapies for perinatal depression delivered in the post-partum period may play a role in improving maternalmood but more studies are needed, particularly with interventions delivered antenatally. Further research is needed to address the limitations of the existing evidence base.

Convergence in insulin resistance between very severely obese and lean women at the end of pregnancy.

AIMS: Disrupted intermediary metabolism may contribute to the adverse pregnancy outcomes in women with very severe obesity. Our aim was to study metabolism in such pregnancies. METHODS: We recruited a longitudinal cohort of very severely obese (n = 190) and lean (n = 118) glucose-tolerant women for anthropometric and metabolic measurements at early, mid and late gestation and postpartum. In case-control studies of very severely obese and lean women we measured glucose and glycerol turnover during low- and high-dose hyperinsulinaemic-euglycaemic clamps (HEC) at early and late pregnancy and in non-pregnant women (each n = 6-9) and body fat distribution by MRI in late pregnancy (n = 10/group). RESULTS: Although greater glucose, insulin, NEFA and insulin resistance (HOMA-IR), and greater weight and % fat mass (FM) was observed in very severely obese vs lean participants, the degree of worsening was attenuated in the very severely obese individuals with advancing gestation, with no difference in triacylglycerol (TG) concentrations between very severely obese and lean women at term. Enhanced glycerol production was observed in early pregnancy only in very severely obese individuals, with similar intrahepatic FM in very severely obese vs lean women by late gestation. Offspring from obese mothers were heavier (p = 0.04). CONCLUSIONS/INTERPRETATION: Pregnancies complicated by obesity demonstrate attenuation in weight gain and insulin resistance compared with pregnancies in lean women. Increased glycerol production is confined to obese women in early pregnancy and obese and lean individuals have similar intrahepatic FM by term. When targeting maternal metabolism to treat adverse pregnancy outcomes, therapeutic intervention may be most effective applied early in pregnancy.

Screening and management of gestational diabetes mellitus in Scottish obstetric units: a national survey.

BACKGROUND AND AIMS: The last study of screening practices for gestational diabetes (GDM) in the UK concluded that a lack of consensus about screening was due to a lack of clinical guidelines. We aimed to determine current practices in Scotland since new guidelines recommended that diagnosis should be made at a lower level of hyperglycaemia. METHOD AND RESULTS: An online questionnaire designed to investigate the screening and management of GDM was distributed to all maternity units in Scotland managing women with GDM (n = 15) for completion by relevant clinical team members. The response rate was 100%. Considerable variation in clinical practice existed between units. Thirteen units (86.7%) had adopted the lower glucose tolerance values for diagnosis of GDM (fasting ≥5.1 mmol/L; 2-h ≥8.5 mmol/L) recommended by the Scottish Intercollegiate Guidelines Network in 2010. Available data from units using this guideline (n = 3) revealed a significant increase in the percentage of women diagnosed with GDM between 2010 and 2012 (2010: 1.28%, 2012: 2.54%; p < 0.0001). CONCLUSION: Despite provision of clinical guidelines, there are still inconsistencies in screening and management of GDM in Scotland. If a similar increase in the prevalence of GDM is experienced across Scotland, there will be major implications for health care provision and resource allocation.

Phosphorylation-related modification at the dimer interface of 14-3-3ω dramatically alters monomer interaction dynamics.

14-3-3 proteins are generally believed to function as dimers in a broad range of eukaryotic signaling pathways. The consequences of altering dimer stability are not fully understood. Phosphorylation at Ser58 in the dimer interface of mammalian 14-3-3 isoforms has been reported to destabilise dimers. An equivalent residue, Ser62, is present across most Arabidopsis isoforms but the effects of phosphorylation have not been studied in plants. Here, we assessed the effects of phosphorylation at the dimer interface of Arabidopsis 14-3-3ω. Protein kinase A phosphorylated 14-3-3ω at Ser62 and also at a previously unreported residue, Ser67, resulting in a monomer-sized band on native-PAGE. Phosphorylation at Ser62 alone, or with additional Ser67 phosphorylation, was investigated using phosphomimetic versions of 14-3-3ω. In electrophoretic and chromatographic analyses, these mutants showed mobilities intermediate between dimers and monomers. Mobility was increased by detergents, by reducing protein concentration, or by increasing pH or temperature. Urea gradient gels showed complex structural transitions associated with alterations of dimer stability, including a previously unreported 14-3-3 aggregation phenomenon. Overall, our analyses showed that dimer interface modifications such as phosphorylation reduce dimer stability, dramatically affecting the monomer-dimer equilibrium and denaturation trajectory. These findings may have dramatic implications for 14-3-3 structure and function in vivo.

14-3-3 proteins in plant physiology.

Plant 14-3-3 isoforms, like their highly conserved homologues in mammals, function by binding to phosphorylated client proteins to modulate their function. Through the regulation of a diverse range of proteins including kinases, transcription factors, structural proteins, ion channels and pathogen defense-related proteins, they are being implicated in an expanding catalogue of physiological functions in plants. 14-3-3s themselves are affected, both transcriptionally and functionally, by the extracellular and intracellular environment of the plant. They can modulate signaling pathways that transduce inputs from the environment and also the downstream proteins that elicit the physiological response. This review covers some of the key emerging roles for plant 14-3-3s including their role in the response to the plant extracellular environment, particularly environmental stress, pathogens and light conditions. We also address potential key roles in primary metabolism, hormone signaling, growth and cell division.

Spaceflight engages heat shock protein and other molecular chaperone genes in tissue culture cells of Arabidopsis thaliana.

PREMISE OF THE STUDY: Gravity has been a major force throughout the evolution of terrestrial organisms, and plants have developed exquisitely sensitive, regulated tropisms and growth patterns that are based on the gravity vector. The nullified gravity during spaceflight allows direct assessment of gravity roles. The microgravity environments provided by the Space Shuttle and International Space Station have made it possible to seek novel insights into gravity perception at the organismal, tissue, and cellular levels. Cell cultures of Arabidopsis thaliana perceive and respond to spaceflight, even though they lack the specialized cell structures normally associated with gravity perception in intact plants; in particular, genes for a specific subset of heat shock proteins (HSPs) and factors (HSFs) are induced. Here we ask if similar changes in HSP gene expression occur during nonspaceflight changes in gravity stimulation. METHODS: Quantitative RT-qPCR was used to evaluate mRNA levels for Hsp17.6A and Hsp101 in cell cultures exposed to four conditions: spaceflight (mission STS-131), hypergravity (centrifugation at 3 g or 16 g), sustained two-dimensional clinorotation, and transient milligravity achieved on parabolic flights. KEY RESULTS: We showed that HSP genes were induced in cells only in response to sustained clinorotation. Transient microgravity intervals in parabolic flight and various hypergravity conditions failed to induce HSP genes. CONCLUSIONS: We conclude that nondifferentiated cells do indeed sense their gravity environment and HSP genes are induced only in response to prolonged microgravity or simulated microgravity conditions. We hypothesize that HSP induction upon microgravity indicates a role for HSP-related proteins in maintaining cytoskeletal architecture and cell shape signaling.

Qualitative evaluation of rapid implementation of remote blood pressure self-monitoring in pregnancy during Covid-19.

In March 2020, the World Health Organisation named the severe acute respiratory syndrome coronavirus 2 (Sars-CoV-2), which causes corona virus disease 2019 (COVID -19), as a pandemic. Pregnant women were considered at increased risk of developing severe COVID-19 after viral infection. In response maternity services reduced face-to-face consultations with high-risk pregnant women by supplying blood pressure monitors for supported self-monitoring. This paper explores the experiences of patients and clinicians of the rapid roll-out of supported self-monitoring programme in Scotland during the first and second wave of the COVID-19 pandemic. We conducted semi-structured telephone interviews with high-risk women and healthcare professionals who were using supported self-monitoring of blood pressure (BP) In four case studies during the COVID-19 pandemic. 20 women, 15 midwives and 4 obstetricians took part in the interviews. Interviews with healthcare professionals showed that while implementation occurred at pace and at scale across the National Health Service (NHS) in Scotland, implementation differed locally, resulting in mixed experiences. Study Participants observed several barriers and facilitators to implementation. Women value the simplicity of use and convenience of the digital communications platforms while health professionals were more interested in their impact on reducing workload for both women and health professionals largely found self-monitoring acceptable, with only a few exceptions. These results show that rapid change can occur in the NHS at a national level when there is a shared motivation. While self-monitoring is acceptable to most women, decisions regarding self-monitoring should be made jointly and on an individual basis.

Prokineticin 1 induces inflammatory response in human myometrium: a potential role in initiating term and preterm parturition.

The infiltration of human myometrium and cervix with leukocytes and the formation of a pro-inflammatory environment within the uterus have been associated with the initiation of both term and preterm parturition. The mechanism regulating the onset of this pro-inflammatory cascade is not fully elucidated. We demonstrate that prokineticin 1 (PROK1) is up-regulated in human myometrium and placenta during labor. The expression of PROK1 receptor remains unchanged during labor and is abundantly expressed in the myometrium. Gene array analysis identified 65 genes up-regulated by PROK1 in human myometrium, mainly cytokines and chemokines, including IL-1ß, chemokine C-C motif ligand 3, and colony-stimulating factor 3. In addition, we demonstrate that PROK1 increases the expression of chemokine C-C motif ligand 20, IL-6, IL-8, prostaglandin synthase 2, and prostaglandin E(2) and F(2α) secretion. The treatment of myometrial explants with 100 ng/mL of lipopolysaccharide up-regulates the expression of PROK1, PROK1 receptor, and inflammatory mediators. The infection of myometrial explants with lentiviral microRNA targeting PROK1, preceding treatment with lipopolysaccharide, reduces the expression of inflammatory genes. We propose that PROK1 is a novel inflammatory mediator that can contribute to the onset of human parturition at term and partially mediate premature onset of inflammatory pathways during bacterial infection.

Evaluation of kisspeptin levels in obese pregnancy as a biomarker for pre-eclampsia.

OBJECTIVES: Circulating concentrations of the peptide kisspeptin have been proposed as a novel biomarker for early detection of pre-eclampsia. Our aims were to assess analytical and clinical performance characteristics of a commercial kisspeptin assay and to determine sensitivity and specificity of the test for pre-eclampsia. DESIGN: Prospective, longitudinal study in a United Kingdom tertiary referral Antenatal Metabolic Clinic. PATIENTS: Severely obese (body mass index, BMI > 40 kg/m(2), n = 194) and lean (BMI < 25 kg/m(2), n = 78) pregnant women. MEASUREMENTS: A commercial kisspeptin ELISA (Phoenix Pharmaceuticals) was assessed for analytical sensitivity, specificity, precision, linearity, recovery and stability in maternal plasma samples at 16, 28 and 36 weeks gestation. Pre-eclampsia, defined using International Society for the Study of Hypertension in Pregnancy guidelines; blood pressure; delivery gestation; birthweight. RESULTS: Kisspeptin concentrations were lower in early pregnancy in obese women (P < 0.001), and in women who later developed pre-eclampsia (P < 0.05), compared with women with uncomplicated pregnancies. For 16-week plasma kisspeptin in prediction of pre-eclampsia, area under the receiver-operator characteristic curve was 0.80 (P < 0.01), positive and negative likelihood ratios were 3.0 and 0.2, and test sensitivity and specificity were 85.7 and 71.4%, respectively. In regression analyses, kisspeptin (16 weeks) associated positively with delivery gestation (P < 0.05) and birthweight (P < 0.0001), and negatively with 28- and 36-week blood pressure (P < 0.0001). CONCLUSIONS: Kisspeptin concentration in early pregnancy is a promising biomarker for pre-eclampsia and low birthweight but cannot be recommended, in isolation, for universal screening because of inadequate test sensitivity and specificity. Large-scale studies are required to assess its potential in a panel of biomarkers.

A role for lipoxin A4 as anti-inflammatory and proresolution mediator in human parturition.

The purpose of this study was to investigate the role of lipoxin A(4), an anti-inflammatory and proresolution modulator, during human parturition. We measured serum levels of lipoxin A(4) and myometrial protein release using ELISA, quantified lipoxin receptor (FPR2/ALX) mRNA expression using qRT-PCR, and localized protein expression using immunohistochemstry in myometrial biopsies from pregnant women. In addition, we compared the effects of lipoxin A(4) (100 nM) with vehicle on basal and LPS-stimulated expression of proinflammatory cytokines from samples of myometrium from pregnant women. Mean ± SE circulating level of lipoxin A(4) was 5.89 ± 0.63 nM at 24-wk gestation, with a further modest increase during pregnancy (P<0.05), but no differences in gestation matched women before and after labor (P>0.05). Levels of lipoxin A(4) in nonpregnant women were 0.48 ± 0.04 nM, significantly lower than in pregnant women (P<0.001). FPR2/ALX localized to myocytes and neutrophils, with a 9-fold increase in mRNA expression in labor (P<0.001). Lipoxin A(4) significantly reduced LPS-induced but not basal expression of the proinflammatory cytokines IL-6 and IL-8 in cultured myometrium (P<0.05), compared to vehicle-treated controls. We demonstrate for the first time a potential role for lipoxin A(4) and its receptor in the resolution of the inflammatory events of both physiological and pathological labor.

Metformin in obese pregnancy has no adverse effects on cardiovascular risk in early childhood.

Metformin is widely used in pregnancy, despite lack of long-term safety for children. We hypothesised that metformin exposure in utero is associated with increased cardiovascular risk. We tested this hypothesis in a follow-up study of children born to obese mothers who had participated in a randomised controlled trial of metformin versus placebo in pregnancy (EMPOWaR). We measured body composition, peripheral blood pressure (BP), arterial pulse wave velocity and central haemodynamics (central BP and augmentation index) using an oscillometric device in 40 children of mean (SD) age 5.78 (0.93) years, exposed to metformin (n = 19) or placebo (n = 21) in utero. There were no differences in any of the anthropometric or vascular measures between metformin and placebo-exposed groups in univariate analyses, or after adjustment for potential confounders including the child's behaviour, diet and activity levels. Post-hoc sample size calculation indicated we would have detected large clinically significant differences between the groups but would need an unfeasible large number to detect possible subtle differences in key cardiovascular risk parameters in children at this age of follow-up. Our findings suggest no evidence of increased cardiovascular risk in children born to obese mothers who took metformin in pregnancy and increase available knowledge of the long-term safety of metformin on childhood outcomes.

Gene expression profiling of placentae from women with obesity and obstructive sleep apnoea.

INTRODUCTION: Obstructive sleep apnoea (OSA), a condition characterised by intermittent hypoxia and reoxygenation during sleep, is associated with an increased risk of adverse pregnancy outcomes including gestational diabetes and hypertensive disorders of pregnancy. The biological mechanisms of these associations are poorly understood. The impact of OSA on placental function has not been well characterised. METHODS: We performed 3' mRNA sequencing on placenta from women with obesity and OSA (n = 11) and women with obesity and no OSA (n = 9). RESULTS: After correcting for multiple testing, there were no statistically significant differences in gene expression between OSA and no OSA groups (adjusted p < 0.05). In unadjusted analyses, 101 genes were differentially expressed in OSA compared to no OSA placentae (p < 0.01). In Reactome pathway and GO term analysis, this included downregulation of genes involved in O-linked glycosylation (B3GNT5 and B3GNT8) and Wnt signalling (TRABD2B and FRZB) pathways. In gene set enrichment analysis, genes within 24 pathways had a non-random distribution in OSA compared to no OSA placentae (adjusted p < 0.05). This included an increase in genes relating to the reversible hydration of carbon dioxide in OSA placentae, a potential novel mechanism contributing to the development of adverse pregnancy outcomes in women with OSA. DISCUSSION: There is overall similarity in the placental transcriptome of women with obesity who do and do not have OSA during pregnancy. Alterations in the reversible hydration of carbon dioxide are a potential mechanism contributing to the development of adverse pregnancy outcomes in maternal OSA, however this finding requires validation in larger cohorts.

High prevalence of obstructive sleep apnea in pregnant women with class III obesity: a prospective cohort study.

STUDY OBJECTIVES: To determine the prevalence of obstructive sleep apnea (OSA) in a cohort of women with class III obesity, and a comparator lean group, in the second and third trimesters of pregnancy. Secondary objectives were to compare characteristics of women with obesity with and without OSA and to assess factors that were predictive of OSA. METHODS: We performed a prospective cohort study involving 33 women with class III obesity (mean body mass index 43.5 ± 3.9 kg/m2) and 39 lean women (body mass index 22.0 ± 1.7 kg/m2) with singleton pregnancies. Participants completed 2 level 3 sleep studies between 12-22 weeks and 32-38 weeks gestation. OSA was defined as a respiratory event index ≥ 5 events/h (≥ 3% desaturation criteria). Levels of interleukin-6, glucose, and C-peptide were quantified in maternal blood. Logistic regression analysis was performed to determine predictors of OSA. RESULTS: OSA was identified in 12 (37.5%) and 14 (50.0%) women with obesity and in 1 (2.6%) and 3 (9.1%) lean women in the second and third trimesters, respectively. Women with obesity with OSA were older than those with no OSA but otherwise had similar characteristics. In unadjusted analysis of women with obesity, increased age, body mass index, homeostatic model assessment of insulin resistance, and history of nonsmoking were associated with increased odds of OSA. In multivariable analysis, only increased age remained significantly associated with OSA. CONCLUSIONS: OSA is highly prevalent in pregnant women with class III obesity. Further research is required to establish effective management strategies for the growing number of women in this high-risk group. CITATION: Johns EC, Hill EA, Williams S, et al. High prevalence of obstructive sleep apnea in pregnant women with class III obesity: a prospective cohort study. J Clin Sleep Med. 2022;18(2):423-432.