A follow up on the feasibility after national implementation of magnesium sulfate for neuroprotection prior to preterm birth.

INTRODUCTION: The risk for brain injury manifested as cerebral palsy is higher in very preterm born children than in term. Prenatal administration of magnesium sulfate (MgSO4 ) has been shown to be neuroprotective and reduces the proportion of very preterm born children later diagnosed with cerebral palsy. A Swedish national clinical practice guideline was implemented in March 2020, stipulating the administration of a single intravenous dose of 6 g MgSO4 1-24 h prior to delivery before gestational age 32+0, aiming for 90% treatment coverage. The aim of this study was to evaluate the feasibility of this new clinical practice guideline in the first year of its implementation. MATERIAL AND METHODS: Data on MgSO4 treatment were collected by reviewing the medical charts of women who gave birth to live born children in gestational age 22+0-31+6 during the period of March 1, 2020 to February 28, 2021, at five Swedish university hospitals. Women with pre-eclampsia, eclampsia, or high elevated liver enzymes low platelets (HELLP) were excluded. RESULTS: A total of 388 women were eligible and 79% received treatment with MgSO4 . Of the 21% not receiving treatment, 9% did not receive treatment due to lack of knowledge about the clinical practice guideline, 9% were not possible to treat and 3% had missing data. The proportion treated increased from 72% to 87% from the first to the last 3 months. Of those treated, 81% received the drug within the stipulated timeframe (mean 8.7 h, median 3.4 h). CONCLUSIONS: There was a positive trend over time in the proportion of women receiving MgSO4 treatment, but the a priori target of 90% was not reached during the first year of implementation. Our findings indicate that this target could be reached with additional information to clinicians.

Comparing the results from a Swedish pregnancy cohort using data from three automated placental growth factor immunoassay platforms intended for first-trimester preeclampsia prediction.

INTRODUCTION: Risk evaluation for preeclampsia in early pregnancy allows identification of women at high risk. Prediction models for preeclampsia often include circulating concentrations of placental growth factor (PlGF); however, the models are usually limited to a specific PlGF method of analysis. The aim of this study was to compare three different PlGF methods of analysis in a Swedish cohort to assess their convergent validity and appropriateness for use in preeclampsia risk prediction models in the first trimester of pregnancy. MATERIAL AND METHODS: First-trimester blood samples were collected in gestational week 11+0 to 13+6 from 150 pregnant women at Uppsala University Hospital during November 2018 until November 2020. These samples were analyzed using the different PlGF methods from Perkin Elmer, Roche Diagnostics, and Thermo Fisher Scientific. RESULTS: There were strong correlations between the PlGF results obtained with the three methods, but the slopes of the correlations clearly differed from 1.0: PlGFPerkinElmer = 0.553 (95% confidence interval [CI] 0.518-0.588) * PlGFRoche -1.112 (95% CI -2.773 to 0.550); r = 0.966, mean difference -24.6 (95% CI -26.4 to -22.8). PlGFPerkinElmer = 0.673 (95% CI 0.618-0.729) * PlGFThermoFisher -0.199 (95% CI -2.292 to 1.894); r = 0.945, mean difference -13.8 (95% CI -15.1 to -12.6). PlGFRoche = 1.809 (95% CI 1.694-1.923) * PlGFPerkinElmer +2.010 (95% CI -0.877 to 4.897); r = 0.966, mean difference 24.6 (95% CI 22.8-26.4). PlGFRoche = 1.237 (95% CI 1.113-1.361) * PlGFThermoFisher +0.840 (95% CI -3.684 to 5.363); r = 0.937, mean difference 10.8 (95% CI 9.4-12.1). PlGFThermoFisher = 1.485 (95% CI 1.363-1.607) * PlGFPerkinElmer +0.296 (95% CI -2.784 to 3.375); r = 0.945, mean difference 13.8 (95% CI 12.6-15.1). PlGFThermoFisher = 0.808 (95% CI 0.726-0.891) * PlGFRoche -0.679 (95% CI -4.456 to 3.099); r = 0.937, mean difference -10.8 (95% CI -12.1 to -9.4). CONCLUSION: The three PlGF methods have different calibrations. This is most likely due to the lack of an internationally accepted reference material for PlGF. Despite different calibrations, the Deming regression analysis indicated good agreement between the three methods, which suggests that results from one method may be converted to the others and hence used in first-trimester prediction models for preeclampsia.

Cell-free DNA screening for prenatal detection of 22q11.2 deletion syndrome.

BACKGROUND: Historically, prenatal screening has focused primarily on the detection of fetal aneuploidies. Cell-free DNA now enables noninvasive screening for subchromosomal copy number variants, including 22q11.2 deletion syndrome (or DiGeorge syndrome), which is the most common microdeletion and a leading cause of congenital heart defects and neurodevelopmental delay. Although smaller studies have demonstrated the feasibility of screening for 22q11.2 deletion syndrome, large cohort studies with confirmatory postnatal testing to assess test performance have not been reported. OBJECTIVE: This study aimed to assess the performance of single-nucleotide polymorphism-based, prenatal cell-free DNA screening for detection of 22q11.2 deletion syndrome. STUDY DESIGN: Patients who underwent single-nucleotide polymorphism-based prenatal cell-free DNA screening for 22q11.2 deletion syndrome were prospectively enrolled at 21 centers in 6 countries. Prenatal or newborn DNA samples were requested in all cases for genetic confirmation using chromosomal microarrays. The primary outcome was sensitivity, specificity, positive predictive value, and negative predictive value of cell-free DNA screening for the detection of all deletions, including the classical deletion and nested deletions that are ≥500 kb, in the 22q11.2 low-copy repeat A-D region. Secondary outcomes included the prevalence of 22q11.2 deletion syndrome and performance of an updated cell-free DNA algorithm that was evaluated with blinding to the pregnancy outcome. RESULTS: Of the 20,887 women enrolled, a genetic outcome was available for 18,289 (87.6%). A total of 12 22q11.2 deletion syndrome cases were confirmed in the cohort, including 5 (41.7%) nested deletions, yielding a prevalence of 1 in 1524. In the total cohort, cell-free DNA screening identified 17,976 (98.3%) cases as low risk for 22q11.2 deletion syndrome and 38 (0.2%) cases as high risk; 275 (1.5%) cases were nonreportable. Overall, 9 of 12 cases of 22q11.2 were detected, yielding a sensitivity of 75.0% (95% confidence interval, 42.8-94.5); specificity of 99.84% (95% confidence interval, 99.77-99.89); positive predictive value of 23.7% (95% confidence interval, 11.44-40.24), and negative predictive value of 99.98% (95% confidence interval, 99.95-100). None of the cases with a nonreportable result was diagnosed with 22q11.2 deletion syndrome. The updated algorithm detected 10 of 12 cases (83.3%; 95% confidence interval, 51.6-97.9) with a lower false positive rate (0.05% vs 0.16%; P<.001) and a positive predictive value of 52.6% (10/19; 95% confidence interval, 28.9-75.6). CONCLUSION: Noninvasive cell-free DNA prenatal screening for 22q11.2 deletion syndrome can detect most affected cases, including smaller nested deletions, with a low false positive rate.

Cell-free DNA screening for trisomies 21, 18, and 13 in pregnancies at low and high risk for aneuploidy with genetic confirmation.

BACKGROUND: Cell-free DNA noninvasive prenatal screening for trisomies 21, 18, and 13 has been rapidly adopted into clinical practice. However, previous studies are limited by a lack of follow-up genetic testing to confirm the outcomes and accurately assess test performance, particularly in women at a low risk for aneuploidy. OBJECTIVE: To measure and compare the performance of cell-free DNA screening for trisomies 21, 18, and 13 between women at a low and high risk for aneuploidy in a large, prospective cohort with genetic confirmation of results STUDY DESIGN: This was a multicenter prospective observational study at 21 centers in 6 countries. Women who had single-nucleotide-polymorphism-based cell-free DNA screening for trisomies 21, 18, and 13 were enrolled. Genetic confirmation was obtained from prenatal or newborn DNA samples. The test performance and test failure (no-call) rates were assessed for the cohort, and women with low and high previous risks for aneuploidy were compared. An updated cell-free DNA algorithm blinded to the pregnancy outcome was also assessed. RESULTS: A total of 20,194 women were enrolled at a median gestational age of 12.6 weeks (interquartile range, 11.6-13.9). The genetic outcomes were confirmed in 17,851 cases (88.4%): 13,043 (73.1%) low-risk and 4808 (26.9%) high-risk cases for aneuploidy. Overall, 133 trisomies were diagnosed (100 trisomy 21; 18 trisomy 18; 15 trisomy 13). The cell-free DNA screen positive rate was lower in the low-risk vs the high-risk group (0.27% vs 2.2%; P<.0001). The sensitivity and specificity were similar between the groups. The positive predictive value for the low- and high-risk groups was 85.7% vs 97.5%; P=.058 for trisomy 21; 50.0% vs 81.3%; P=.283 for trisomy 18; and 62.5% vs 83.3; P=.58 for trisomy 13, respectively. Overall, 602 (3.4%) patients had no-call result after the first draw and 287 (1.61%) after including cases with a second draw. The trisomy rate was higher in the 287 cases with no-call results than patients with a result on a first draw (2.8% vs 0.7%; P=.001). The updated algorithm showed similar sensitivity and specificity to the study algorithm with a lower no-call rate. CONCLUSION: In women at a low risk for aneuploidy, single-nucleotide-polymorphism-based cell-free DNA has high sensitivity and specificity, positive predictive value of 85.7% for trisomy 21 and 74.3% for the 3 common trisomies. Patients who receive a no-call result are at an increased risk of aneuploidy and require additional investigation.

Induction of labour at 41 weeks of gestation versus expectant management and induction of labour at 42 weeks of gestation: A cost-effectiveness analysis.

OBJECTIVE: To assess the cost-effectiveness of induction of labour (IOL) at 41 weeks of gestation compared with expectant management until 42 weeks of gestation. DESIGN: A cost-effectiveness analysis alongside the Swedish Post-term Induction Study (SWEPIS), a multicentre, randomised controlled superiority trial. SETTING: Fourteen Swedish hospitals during 2016-2018. POPULATION: Women with an uncomplicated singleton pregnancy with a fetus in cephalic position were randomised at 41 weeks of gestation to IOL or to expectant management and induction at 42 weeks of gestation. METHODS: Health benefits were measured in life years and quality-adjusted life years (QALYs) for mother and child. Total cost per birth was calculated, including healthcare costs from randomisation to discharge after delivery, for mother and child. Incremental cost-effectiveness ratios (ICERs) were calculated by dividing the difference in mean cost between the trial arms by the difference in life years and QALYs, respectively. Sampling uncertainty was evaluated using non-parametric bootstrapping. MAIN OUTCOME MEASURES: The cost per gained life year and per gained QALY. RESULTS: The differences in life years and QALYs gained were driven by the difference in perinatal mortality alone. The absolute risk reduction in mortality was 0.004 (from 6/1373 to 0/1373). Based on Swedish life tables, this gives a mean gain in discounted life years and QALYs of 0.14 and 0.12 per birth, respectively. The mean cost per birth was €4108 in the IOL group (n = 1373) and €4037 in the expectant management group (n = 1373), with a mean difference of €71 (95% CI -€232 to €379). The ICER for IOL compared with expectant management was €545 per life year gained and €623 per QALY gained. Confidence intervals were relatively wide and included the possibility that IOL had both lower costs and better health outcomes. CONCLUSIONS: Induction of labour at 41 weeks of gestation results in a better health outcome and no significant difference in costs. IOL is cost-effective compared with expectant management until 42 weeks of gestation using standard threshold values for acceptable cost per life year/QALY. TWEETABLE ABSTRACT: Induction of labour at 41 weeks of gestation is cost-effective compared with expectant management until 42 weeks of gestation.

Maternal and fetal serum concentrations of magnesium after administration of a 6-g bolus dose of magnesium sulfate (MgSO4 ) to women with imminent preterm delivery.

INTRODUCTION: Magnesium sulfate is used world-wide to treat pregnant women at imminent risk of preterm delivery in order to protect the brain of the premature infant. Previous research has shown that magnesium sulfate decreases the risk of cerebral palsy by ~30% in infants born preterm. Despite this, the dosage required for optimal neuroprotection remains unknown. We aimed to investigate whether 6 g magnesium sulfate given as a single bolus dose was tolerable for the women and infants and whether the desired target concentration in the mother's blood was reached and non-toxic level in the infant could be ensured. MATERIAL AND METHODS: In total, 49 women who were at risk of delivery prior to 32 weeks of gestation were recruited. They received a bolus dose of 6 g magnesium sulfate intravenously between 1 and 24 h prior to giving birth and were closely monitored during and after infusion. Blood samples from the patients were analyzed at different time-points (20-30 min after start of infusion, 1, 2, 6 and 24 h) post-administration. Blood samples from the umbilical cord were also taken directly after birth to assess the concentration of magnesium in the infant. RESULTS: None of the women who received magnesium sulfate reached serum magnesium concentrations >3.3 mmol/L. In all, 72% of the women showed serum magnesium levels within the therapeutic interval (2.0-3.5 mmol/L) and no adverse events were observed during the infusion. The serum magnesium levels in the mothers declined to pre-bolus-levels within 24 h after delivery. Serum magnesium levels in the umbilical cord samples ranged from 0.87 to 1.4 mmol/L, which means that all but two were within the normal expected range for a newborn premature infant. CONCLUSIONS: A bolus dose of 6 g magnesium sulfate was well tolerated and without any serious side effects in either mother or infant. Most of our women reached the targeted concentration range of serum magnesium levels after infusion was completed. Their infants had magnesium levels within acceptable levels, regardless of gestational week or mother's body mass index.

Term breech presentation-Intended cesarean section versus intended vaginal delivery-A systematic review and meta-analysis.

INTRODUCTION: Three per cent of all infants are born in breech presentation, still the preferred way to deliver them remains controversial. The objective of this systematic review was to assess the safety for the mother and child depending on intended mode of delivery when the baby is in breech position at term. MATERIAL AND METHODS: The population (P) was pregnant women with a child in breech presentation, from gestational week 34+0 . The intervention (I) was the intention to deliver by cesarean section, the comparison (C) was the intention to deliver vaginally. Outcomes (O) were perinatal mortality, perinatal morbidity, maternal mortality, maternal morbidity, conversion of delivery mode, and the mother's experience. Systematic literature searches were performed. We included randomized trials, cohort studies with more than 500 women/group and case series for more than 15 000 women published between 1990 and October 2021, written in English or the Nordic languages. The certainty of evidence was assessed using the GRADE approach and data were pooled in meta-analyses. PROSPERO registration number: CRD42020209546. RESULTS: Thirty-two articles were included (with 530 604 women). The certainty of evidence was moderate or low because the study designs were mostly retrospective cohort studies. The only randomized trial showed reduced risk of perinatal mortality for planned cesarean section, risk ratio (RR) 0.27 (95% confidence interval [CI] 0.08-0.97, 2078 women, low certainty of evidence), stillbirths excluded. A meta-analysis of cohort studies resulted in a similar estimate, RR 0.36 (95% CI 0.25-0.51, 21 studies, 388 714 women, low certainty of evidence). We also found reduced risk for outcomes representing perinatal morbidity 0-28 days: 5-min Apgar score less than 7 in one randomized controlled trial: RR 0.27 (95% CI 0.12-0.58, 2033 women, moderate certainty of evidence), and in a meta-analysis: RR 0.1 (95% CI 0.14-0.26, 18 studies, 217 024 women, moderate certainty of evidence); APGAR score less than 4 at 5 min: RR 0.39 (95% CI 0.19-0.81, five studies, 44 498 women, low certainty of evidence); and pH less than 7.0: RR 0.23 (95% CI 0.12-0.43, four studies, 13 440 women, low certainty of evidence). Outcomes for the mother were similar in the groups except for reduced risk for experience of urinary incontinence in the group of planned cesarean section: RR 0.62 (95% CI 0.41-0.93, one study, 1940 women, low certainty of evidence). The conversion rate from planned vaginal delivery to emergency cesarean section ranged from 16% to 51% (median 41.8%, 10 studies, 50 763 women, moderate certainty of evidence). CONCLUSIONS: Intended cesarean section may reduce the risk of perinatal mortality and perinatal as well as some maternal morbidity compared with intended vaginal delivery. It is uncertain whether there is any difference in maternal mortality. The conversion rate from intended vaginal delivery to emergency cesarean section is high.

Challenges imposed by the COVID-19 pandemic on the Obstetrics and Gynecology residency program: a mixed-methods Swedish survey in the COPE Staff cohort study.

BACKGROUND: To outline how the training program and work situation of residents in Obstetrics and Gynecology (OB-GYN) was affected by the pandemic and to illuminate how residents experienced these changes. METHODS: As part of the COVID-19 in Pregnancy and Early Childhood Staff (COPE Staff) cohort study, between January and May 2021, all participating residents were invited to answer a 28-question online Resident Survey focusing on their specialist education, work situation and experiences during the COVID-19 pandemic. Descriptive statistics were given in percentages for categorical variables and means and standard deviations (SD) for continuous variables. Univariate comparative analyses were performed with the use of the Pearson's Chi-2-test for dichotomous data. The association between residents' worry about the quality and length of their specialist training, with extra clinical hours and transfer to other healthcare institutions were assessed by multivariate logistic regression. Free text responses were analyzed by content analysis. RESULTS: Of the 162 participating OB-GYN residents, 69% expressed concern that the pandemic would have a negative impact on their training. Ninety-five (95%) reported cancellation/postponement of educational activities, 70% performed fewer surgeries and 27% had been transferred to other healthcare institutions where about half reported having gained more general knowledge as a physician. Working extra clinical hours was reported by 69% (7.4 ± 5.3 hours per week) and 14% had considered changing their profession due to the pandemic. Senior residents, compared to junior residents, more often experienced cancelled/postponed clinical rotations (30% vs 15%, P=0.02) and reported performing fewer surgeries (P=0.02). The qualitative analysis highlighted the lack of surgical procedural training as a major concern for residents. CONCLUSION: The COVID-19 pandemic has strongly impacted the training program and work situation of OB-GYN residents in Sweden. Residents were concerned over the negative impact of the pandemic on their training program and senior residents reported more missed educational opportunities as compared to junior residents. Program directors, head of institutions and clinical supervisors can use the problem areas pinpointed by this study to support residents and compensate for missed educational opportunities. While hands-on-training and operating time cannot be compensated for, the authors hope that the findings of the study can help develop new strategies to minimize the negative impact of the current and future pandemics on resident education and work situation.

Prenatal detection of congenital heart disease - results of a Swedish screening program 2013-2017.

BACKGROUND: This report evaluates results of a screening program on prenatal detection of congenital heart defects in a geographical cohort of western Sweden between January 1st, 2013 and June 31st, 2017. During the study period 88,230 children were born in VGR. METHODS: Retrospective data on pregnant women from the Västra Götaland region that were referred to fetal cardiologists in Gothenburg were retrieved. To determine prenatal detection rate, all neonates who underwent surgery or catheter intervention for a critical congenital heart defect born between January 1st, 2014 and December 31st, 2016 were included. The four-chamber view was implemented into the routine scan in 2009 and implementation of the ISUOG guidelines, including the outflow tracts, started in the region in 2015. RESULTS: 113 fetuses received a prenatal diagnosis of a major congenital heart defect. 89% of these were referred because of a suspected cardiac malformation and 88% were diagnosed before 22 completed weeks. 59% of the patients diagnosed before 22 completed weeks opted for termination of pregnancy. During 2014-2016, 61 fetuses had a prenatal diagnosis of a critical congenital heart defect and a further 47 were diagnosed after birth, hence 56% were diagnosed prenatally, 82% for those which had a combination with an extracardiac abnormality and/or chromosomal aberration compared to 50% if an isolated critical congenital heart defect was diagnosed. For single ventricle cardiac defects such as hypoplastic left heart syndrome, double inlet left ventricle and tricuspid atresia, the detection rate was 100%. The detection rate for transposition of the great arteries and coarctation of the aorta was 9 and 18% respectively. CONCLUSIONS: 56% of all fetuses with a critical congenital heart defect were diagnosed prenatally during 2014-2016 and approximately 53% of all major congenital heart defects 2013-2017 as compared to 13.8% in 2009 in the same region. An increased focus towards the fetal heart in the routine scan improved the prenatal detection rate of major congenital heart defects. The detection of congenital heart defects affecting the four-chamber view seems sufficient, but more training is needed to improve the quality of the examination of the outflow tracts.

Efficacy and safety of oral misoprostol vs transvaginal balloon catheter for labor induction: An observational study within the SWEdish Postterm Induction Study (SWEPIS).

INTRODUCTION: Induction of labor is increasing. A common indication for induction of labor is late term and postterm pregnancy at 41 weeks or more. We aimed to evaluate if there are any differences regarding efficacy, safety, and women's childbirth experience between oral misoprostol and transvaginal balloon catheter for cervical ripening in women with a low-risk singleton pregnancy and induction of labor at 41+0 to 42+0 to 1 weeks of gestation. MATERIAL AND METHODS: In this observational study, based on data from the Swedish Postterm Induction Study (SWEPIS), a multicenter randomized controlled trial, a total of 1213 women with a low-risk singleton pregnancy at 41 to 42 weeks of gestation were induced with oral misoprostol (n = 744) or transvaginal balloon catheter (n = 469) at 15 Swedish delivery hospitals. The primary efficacy outcome was vaginal delivery within 24 h and primary safety outcomes were neonatal and maternal composite adverse outcomes. Secondary outcomes included time to vaginal delivery and mode of delivery. Women's childbirth experience was assessed with the Childbirth Experience Questionnaire (CEQ 2.0) and visual analog scale. We present crude and adjusted mean differences and relative risks (RR) with 95% CI. Adjustment was performed for a propensity score based on delivery hospital and baseline characteristics including Bishop score. RESULTS: Vaginal delivery within 24 h was significantly lower in the misoprostol group compared with the balloon catheter group (46.5% [346/744] vs 62.7% [294/469]; adjusted RR 0.76 95% CI 0.640.89]). Primary neonatal and maternal safety outcomes did not differ between groups (neonatal composite 3.5% [36/744] vs 3.2% [15/469]; adjusted RR 0.77 [95% CI 0.31-1.89]; maternal composite 2.3% [17/744] vs 1.9% [9/469]; adjusted RR 1.70 [95% CI 0.58-4.97]). Adjusted mean time to vaginal delivery was increased by 3.8 h (95% CI 1.3-6.2 h) in the misoprostol group. Non-operative vaginal delivery and cesarean delivery rates did not differ. Women's childbirth experience was positive overall and similar in both groups. CONCLUSIONS: Induction of labor with oral misoprostol compared with a transvaginal balloon catheter was associated with a lower probability of vaginal delivery within 24 h and a longer time to vaginal delivery. However, primary safety outcomes, non-operative vaginal delivery, and women's childbirth experience were similar in both groups. Therefore, both methods can be recommended in women with low-risk postdate pregnancies.

Neuroprotective exendin-4 enhances hypothermia therapy in a model of hypoxic-ischaemic encephalopathy.

Hypoxic-ischaemic encephalopathy remains a global health burden. Despite medical advances and treatment with therapeutic hypothermia, over 50% of cooled infants are not protected and still develop lifelong neurodisabilities, including cerebral palsy. Furthermore, hypothermia is not used in preterm cases or low resource settings. Alternatives or adjunct therapies are urgently needed. Exendin-4 is a drug used to treat type 2 diabetes mellitus that has also demonstrated neuroprotective properties, and is currently being tested in clinical trials for Alzheimer's and Parkinson's diseases. Therefore, we hypothesized a neuroprotective effect for exendin-4 in neonatal neurodisorders, particularly in the treatment of neonatal hypoxic-ischaemic encephalopathy. Initially, we confirmed that the glucagon like peptide 1 receptor (GLP1R) was expressed in the human neonatal brain and in murine neurons at postnatal Day 7 (human equivalent late preterm) and postnatal Day 10 (term). Using a well characterized mouse model of neonatal hypoxic-ischaemic brain injury, we investigated the potential neuroprotective effect of exendin-4 in both postnatal Day 7 and 10 mice. An optimal exendin-4 treatment dosing regimen was identified, where four high doses (0.5 µg/g) starting at 0 h, then at 12 h, 24 h and 36 h after postnatal Day 7 hypoxic-ischaemic insult resulted in significant brain neuroprotection. Furthermore, neuroprotection was sustained even when treatment using exendin-4 was delayed by 2 h post hypoxic-ischaemic brain injury. This protective effect was observed in various histopathological markers: tissue infarction, cell death, astrogliosis, microglial and endothelial activation. Blood glucose levels were not altered by high dose exendin-4 administration when compared to controls. Exendin-4 administration did not result in adverse organ histopathology (haematoxylin and eosin) or inflammation (CD68). Despite initial reduced weight gain, animals restored weight gain following end of treatment. Overall high dose exendin-4 administration was well tolerated. To mimic the clinical scenario, postnatal Day 10 mice underwent exendin-4 and therapeutic hypothermia treatment, either alone or in combination, and brain tissue loss was assessed after 1 week. Exendin-4 treatment resulted in significant neuroprotection alone, and enhanced the cerebroprotective effect of therapeutic hypothermia. In summary, the safety and tolerance of high dose exendin-4 administrations, combined with its neuroprotective effect alone or in conjunction with clinically relevant hypothermia make the repurposing of exendin-4 for the treatment of neonatal hypoxic-ischaemic encephalopathy particularly promising.

Risk of uterine rupture in multiparous women after induction of labor with prostaglandin: A national population-based cohort study.

OBJECTIVE: To assess whether, after induction of labor with prostaglandin, multiparous (≥2 para) women have an increased risk of uterine rupture compared with nulliparous or uniparous women. METHODS: This was a retrospective population-based cohort study including women who underwent induction with prostaglandin in all maternity wards in Sweden between May 1996 and December 2019 (n = 56 784). The study cohort was obtained by using data from the Swedish Medical Birth Register, which contains information from maternity and delivery records. The main outcome measure was uterine rupture. RESULTS: Overall, multiparous women induced with prostaglandin had an increased risk of uterine rupture compared with nulliparous women (adjusted odds ratio [OR], 3.33 [95% confidence interval (CI), 1.38-8.04]; P < 0.007). Multiparous women with no previous cesarean section (CS) induced with prostaglandin had more than three times higher risk of uterine rupture (crude OR, 3.55 [95% Cl, 1.48-8.53]; P = 0.005) compared with nulliparous women and four times higher risk compared with uniparous women (OR, 4.10 [95% CI, 1.12-15.00]; P < 0.033). Multiparous women with previous CS had a decreased risk of uterine rupture compared with uniparous women with one previous CS (crude OR, 0.41 [95% Cl, 0.21-0.78]; P = 0.007). CONCLUSION: Our study implies that multiparity in women with no previous CS is a risk factor for uterine rupture when induced with prostaglandin. This should be taken into consideration when deciding on the appropriate method of induction.

Inflammatory and cardiovascular markers in placenta following SARS-CoV-2 infection during pregnancy: A Swedish prospective cohort study.

INTRODUCTION: Maternal SARS-CoV-2 infection can affect pregnancy outcome, but the placental response to and the effect of timing of infection is not well studied. The aim of this study was to investigate the placental levels of inflammatory and cardiovascular markers in pregnancies complicated by SARS-CoV-2 infection compared to non-infected pregnancies, and to investigate whether there was an association between time point of infection during pregnancy and placental inflammatory and cardiovascular protein levels. METHODS: Placental samples from a prospectively recruited pregnancy cohort of SARS-CoV-2-infected (n = 53) and non-infected (n = 50) women were analysed for 177 inflammatory and cardiovascular proteins, using an antibody-based proximity extension assay. In the SARS-CoV-2-infected group, half of the women were infected before 20 weeks of gestation, and five women were hospitalised for severe SARS-CoV-2 infection. Single-protein analyses were performed with linear mixed effects models, followed by Benjamini-Hochberg correction for multiple testing. Multi-protein analyses were performed using principal component analysis and machine learning algorithms. RESULTS: The perinatal outcomes and the placental levels of inflammatory or cardiovascular proteins in women with SARS-CoV-2 infection were similar to those in non-infected women. There were no differences in inflammatory or cardiovascular protein levels between early and late pregnancy SARS-CoV-2 infection, nor any linear correlations between protein levels and gestational age at time of infection. DISCUSSION: Women with SARS-CoV-2 infection during pregnancy without clinical signs of placental insufficiency have no changes in inflammatory or cardiovascular protein patterns in placenta at time of birth regardless of the timing of the infection.

Neuro-Specific and Immuno-Inflammatory Biomarkers in Umbilical Cord Blood in Neonatal Hypoxic-Ischemic Encephalopathy.

OBJECTIVES: The aim of the study was to evaluate neuronal injury and immuno-inflammatory biomarkers in umbilical cord blood (UCB) at birth, in cases with perinatal asphyxia with or without hypoxic-ischemic encephalopathy (HIE), compared with healthy controls and to assess their ability to predict HIE. STUDY DESIGN: In this case-control study, term infants with perinatal asphyxia were recruited at birth. UCB was stored at delivery for batch analysis. HIE was diagnosed by clinical Sarnat staging at 24 h. Glial fibrillary acidic protein (GFAP), the neuronal biomarkers tau and neurofilament light protein (NFL), and a panel of cytokines were analyzed in a total of 150 term neonates: 50 with HIE, 50 with asphyxia without HIE (PA), and 50 controls. GFAP, tau, and NFL concentrations were measured using ultrasensitive single-molecule array (Simoa) assays, and a cytokine screening panel was applied to analyze the immuno-inflammatory and infectious markers. RESULTS: GFAP, tau, NFL, and several cytokines were significantly higher in newborns with moderate and severe HIE compared to a control group and provided moderate prediction of HIE II/III (AUC: 0.681-0.827). Furthermore, the levels of GFAP, tau, interleukin-6 (IL-6), and interleukin-8 (IL-8) were higher in HIE II/III cases compared with cases with PA/HIE I. IL-6 was also higher in HIE II/III compared with HIE I cases. CONCLUSIONS: Biomarkers of brain injury and inflammation were increased in umbilical blood in cases with asphyxia. Several biomarkers were higher in HIE II/III versus those with no HIE or HIE I, suggesting that they could assist in the prediction of HIE II/III.

Maternal liver-related symptoms during pregnancy in primary sclerosing cholangitis.

Background & Aims: Although worsening liver-related symptoms during pregnancy can occur in primary sclerosing cholangitis (PSC), there are insufficient data to effectively counsel patients on their pre-conception risk and no clear recommendations on monitoring and management during pregnancy. We aimed to describe maternal liver-related symptoms in pregnancy, both before and after PSC diagnosis, and explore factors associated with worsening symptoms and liver-related outcomes. Methods: We conducted a multicentre retrospective observational study of females with PSC and known pregnancy with live birth, via the International PSC Study Group. We included 450 patients from 12 European centres. Data included clinical variables, liver-related symptoms (pruritus and/or cholangitis) during pregnancy, and liver biochemistry. A composite primary endpoint of transplant-free survival from time of PSC diagnosis was used. Results: There were 266 pregnancies in 178 patients following PSC diagnosis. Worsening liver-related symptoms were reported in 66/228 (28.9%) pregnancies; they had a reduced transplant-free survival (p = 0.03), which retained significance on multivariate analysis (hazard ratio 3.02, 95% CI 1.24-7.35; p = 0.02).Abnormal biochemistry and/or liver-related symptoms (pruritus and/or cholangitis) were noted during pregnancy before PSC diagnosis in 21/167 (12.6%) patients. They had a reduced transplant-free survival from pregnancy (p = 0.01), which did not retain significance in a multivariable model (hazard ratio 1.10, 95% CI 0.43-2.85; p = 0.84). Conclusions: Liver-related symptoms are frequently encountered during pregnancies before the diagnosis of PSC, and pregnancy may expose the pre-clinical phase of PSC in some patients. Worsening liver-related symptoms were seen in a third of our cohort with known PSC during pregnancy; and this subgroup had a poorer prognosis, which may be related to more advanced liver disease at time of pregnancy and/or a more severe disease phenotype. Impact and implications: Patients with PSC can develop worsening of their liver-related symptoms during pregnancy; however, risk factors for this and the long-term implications are not known. We identified that there is a significant risk of these symptoms in pregnancy, both before and after PSC has been diagnosed, particularly in patients with elevated alkaline phosphatase. Furthermore, our findings suggest that worsening symptoms during pregnancy may be associated with adverse long-term clinical outcomes of liver transplantation and death in patients with known PSC. This may be related to the presence of more advanced liver disease at time of pregnancy. This information can be used to counsel patients with PSC before conception and identify patients who need close follow-up after delivery.

Safety, effectiveness, women's experience, and economic costs of outpatient induction in women with uncomplicated pregnancies: A systematic review and meta-analyses.

BACKGROUND: Induction of labor is increasing worldwide, and some countries have started to introduce outpatient induction in low-risk women. OBJECTIVES: To assess current knowledge concerning the safety, efficacy, women's experience, and economic costs of outpatient induction compared with inpatient induction. SEARCH STRATEGY: Multiple databases were last searched on October 19, 2021. Studies were selected according to our pre-specified inclusion, selection, and exclusion criteria. SELECTION CRITERIA: PICO; P-women with low-risk pregnancy planned for induction of labor. I-Outpatient induction C-Inpatient induction O-Outcomes according to the core outcome set for induction of labor (COSIOL). DATA COLLECTION AND ANALYSIS: Pooled in meta-analyses. The certainty of evidence was assessed using the GRADE system. MAIN RESULTS: The 20 included studies, including 7956 women, showed an overall low incidence of adverse events and indicated comparable results for inpatient and outpatient induction, but the studies were underpowered for safety-related outcomes. Women's experiences of outpatient induction were mostly positive. Based on three studies, the economic costs consequence is inconclusive. CONCLUSIONS: Due to early randomization, heterogenic study design, and underpowered studies regarding safety outcome, the certainty of evidence is very low. It is uncertain whether outpatient induction affects the risk for neonatal and maternal complications.

The COPE Staff study: Study description and initial report regarding job satisfaction, work-life conflicts, stress, and burnout among Swedish maternal and neonatal healthcare workers during the COVID-19 pandemic.

OBJECTIVE: To describe the study design of the COPE Staff cohort study on working conditions for maternal and neonatal healthcare workers (MNHCWs), and present baseline data regarding job satisfaction, work-life conflicts, stress, and burnout. METHODS: Between January and April 2021, 957 MNHCWs (administrative and medical staff) completed a baseline survey. Average levels of job satisfaction, work-life conflicts, stress, and burnout, and associations to perceived workload were assessed. RESULTS: The average levels of job satisfaction, work-life conflicts, stress, and burnout were 68.6 (95% confidence interval [CI] 64.3-72.8), 42.6 (95% CI 37.3-48.0), 42.0 (95% CI 37.7-46.3), and 1.9 (95% CI 1.6-2.2), respectively. The respondents scoring above critical values indicating clinical burnout ranged between 3% and 18%, respectively, for the four burnout sub-dimensions. Women reported significantly higher levels of stress and burnout. Younger participants had lower job satisfaction and higher levels of work-life conflicts, stress, and burnout. Higher perceived workload was significantly associated with lower job satisfaction levels and higher levels of work-life conflicts, stress, and burnout. CONCLUSIONS: Our results indicate associations between MNHCWs perceived workload and job satisfaction, work-life conflicts, stress, and burnout during the COVID-19 pandemic. Eighteen percent scored above critical values for exhaustion.

Working conditions for healthcare workers at a Swedish university hospital infectious disease department during the COVID-19 pandemic: barriers and facilitators to maintaining employee wellbeing.

Background: Healthcare workers (HCWs) at infectious disease departments have held the frontline during the COVID-19 pandemic. This study aimed to identify barriers and facilitators to maintaining the employees' wellbeing that may be used to increase preparedness for future pandemics within ID Departments. Methods: In September 2020, a web-based survey on demographics and work environment was distributed to all HCWs at the Infectious Disease Department at Sahlgrenska University Hospital. Results were compared with a pre-COVID-19 survey from October 2019. A quantitative analysis of the overall effects of the pandemic on the working conditions of HCWs was conducted; in addition, a qualitative content analysis of open-ended responses was performed. Results: In total, 222 and 149 HCWs completed the pre-COVID-19 and COVID-19 surveys (84 and 54% response rate), respectively. Overall, we found significant changes regarding increased workload, lack of emotional support in stressful work situations, and inability to recover after shifts. These factors correlated both with younger age and concern of becoming infected. The open-ended answers (n = 103, 69%) revealed five generic categories (Workload; Organizational support; Worry and ethical stress; Capability; and Cooperation and unity) with a total of 14 identified factors representing plausible individual and organizational-level barriers or facilitators to sustained employee wellbeing. Conclusion: Younger HCWs as well as those expressing worries about contracting the infection were found to be particularly affected during the COVID-19 pandemic and these groups may require additional support in future outbreaks. Factors both increasing and decreasing the pandemic-induced negative health consequences for HCWs were identified; this knowledge may be utilized in the future.

Genetic inhibition of caspase-2 reduces hypoxic-ischemic and excitotoxic neonatal brain injury.

OBJECTIVE: Perinatal brain injury is a major cause of neurodevelopmental handicaps. Multiple pathways of oxidant stress, inflammation, and excitotoxicity lead to cell damage and death, including caspase-dependent apoptosis. Caspase-2 (Casp2; Nedd-2, Ich-1) is a developmentally regulated initiator caspase, which poorly cleaves other caspases but can initiate mitochondrial outer membrane permeabilization. We have investigated if Casp2 could mediate perinatal ischemic brain damage. METHODS: Casp2 expression in human neonatal brains and developmental patterns in rats and mice were evaluated. Casp2-deficient (Casp2(-/-)), wild-type (WT), and heterozygous (Casp2(+/-)) newborn C57BL/6 mice were subjected to hypoxia-ischemia (unilateral carotid occlusion + exposure to 10% oxygen for 50 minutes) or intracerebral injection of the excitotoxic N-methyl-D-aspartate-receptor agonist ibotenate. In addition, Casp2 specific siRNAs were preinjected into the brain of WT newborn mice 24 hours before ibotenate treatment. Brain tissues were examined by immunohistochemical staining (cresyl violet, MAP2, NF68, Casp2, Casp3) and Western blotting. Lesion volumes and injury in the cortical plates and white matter were quantified together with activated Casp3. RESULTS: Casp2 is highly expressed in the neonatal brain. Casp2-deficient mice subjected to hypoxia-ischemia at postnatal day 9 present significantly lower cerebral infarction, reduced white matter injury, and reduced Casp3 activation in the thalamus and hippocampus. Both Casp2(-/-) mice and siRNA-administered WT mice conferred reduction of gray and white matter injury after excitotoxic insult at postnatal day 5. Casp3 activation was also found reduced in Casp2-deficient mice subjected to excitotoxicity. INTERPRETATION: These data suggest for the first time a role of Casp2 in neonatal brain damage.

Combined effect of hypothermia and caspase-2 gene deficiency on neonatal hypoxic-ischemic brain injury.

INTRODUCTION: [corrected] Hypoxia-ischemia (HI) injury in term infants develops with a delay during the recovery phase, opening up a therapeutic window after the insult. Hypothermia is currently an established neuroprotective treatment in newborns with neonatal encephalopathy (NE), saving one in nine infants from developing neurological deficits. Caspase-2 is an initiator caspase, a key enzyme in the route to destruction and, therefore, theoretically a potential target for a pharmaceutical strategy to prevent HI brain damage. METHODS: The aim of this study was to explore the neuroprotective efficacy of hypothermia in combination with caspase-2 gene deficiency using the neonatal Rice-Vannucci model of HI injury in mice. RESULTS: HI brain injury was moderately reduced in caspase-2(-/-) mice as compared with wild-type (WT) mice. Five hours of hypothermia (33 °C ) vs. normothermia (36 °C) directly after HI provided additive protection overall (temperature P = 0.0004, caspase-2 genotype P = 0.0029), in the hippocampus and thalamus, but not in other gray matter regions or white matter. Delayed hypothermia initiated 2 h after HI in combination with caspase-2 gene deficiency reduced injury in the hippocampus, but not in other brain areas. DISCUSSION: In conclusion, caspase-2 gene deficiency combined with hypothermia provided enhanced neuroprotection as compared with hypothermia alone.