Proposed cutoff for fetal scalp blood lactate in intrapartum fetal surveillance based on neonatal outcomes: a large prospective observational study.

OBJECTIVE: Determination of lactate in fetal scalp blood (FBS) during labour has been recognised since the 1970s. The internationally accepted cutoff of >4.8 mmol/l indicating fetal acidosis is exclusive for the point-of-care device (POC) LactatePro™, which is no longer in production. The aim of this study was to establish a new cutoff for scalp lactate based on neonatal outcomes with the use of the StatstripLactate® /StatstripXpress® Lactate system, the only POC designed for hospital use. DESIGN: Observational study. SETTING: January 2016 to March 2020 labouring women with indication for FBS were prospectively included from seven Swedish and one Australian delivery unit. POPULATION: Inclusion criteria: singleton pregnancy, vertex presentation, ≥35+0 weeks of gestation. METHOD: Based on the optimal correlation between FBS lactate and cord pH/lactate, only cases with ≤25 minutes from FBS to delivery were included in the final calculations. MAIN OUTCOME MEASURES: Metabolic acidosis in cord blood defined as pH <7.05 plus BDecf >10 mmol/l and/or lactate >10 mmol/l. RESULTS: A total of 3334 women were enrolled of whom 799 were delivered within 25 minutes. The areas under the receiver operating characteristics curves (AUC) and corresponding optimal cutoff values were as follows; metabolic acidosis AUC 0.87 (95% CI 0.77-0.97), cutoff 5.7 mmol/l; pH <7.0 AUC 0.83 (95% CI 0.68-0.97), cutoff 4.6 mmol/l; pH <7.05 plus BDecf ≥12 mmol/l AUC 0.97 (95% CI 0.92-1), cutoff 5.8 mmol/l; Apgar score <7 at 5 minutes AUC 0.74 (95% CI 0.63-0.86), cutoff 5.2 mmol/l; and pH <7.10 plus composite neonatal outcome AUC 0.76 (95% CI 0.67-0.85), cutoff 4.8 mmol/l. CONCLUSION: A scalp lactate level <5.2 mmol/l using the StatstripLactate® /StatstripXpress® system will safely rule out fetal metabolic acidosis. TWEETABLE ABSTRACT: Scalp blood lactate <5.2 mmol/l using the StatstripLactate® /StatstripXpress system has an excellent ability to rule out fetal acidosis.

Maternal Oxygen Supplementation Compared With Room Air for Intrauterine Resuscitation: A Systematic Review and Meta-analysis.

Importance: Supplemental oxygen is commonly administered to pregnant women at the time of delivery to prevent fetal hypoxia and acidemia. There is mixed evidence on the utility of this practice. Objective: To compare the association of peripartum maternal oxygen administration with room air on umbilical artery (UA) gas measures and neonatal outcomes. Data Sources: Ovid MEDLINE, Embase, Scopus, ClinicalTrials.gov, and Cochrane Central Register of Controlled Trials were searched from February 18 to April 3, 2020. Search terms included labor or obstetric delivery and oxygen therapy and fetal blood or blood gas or acid-base imbalance. Study Selection: Studies were included if they were randomized clinical trials comparing oxygen with room air at the time of scheduled cesarean delivery or labor in patients with singleton, nonanomalous pregnancies. Studies that did not collect paired umbilical cord gas samples or did not report either UA pH or UA Pao2 results were excluded. Data Extraction and Synthesis: Data were extracted by 2 independent reviewers. The analysis was stratified by the presence or absence of labor at the time of randomization. Data were pooled using random-effects models. Main Outcomes and Measures: The primary outcome for this review was UA pH. Secondary outcomes included UA pH less than 7.2, UA Pao2, UA base excess, 1- and 5-minute Apgar scores, and neonatal intensive care unit admission. Results: The meta-analysis included 16 randomized clinical trials (n = 1078 oxygen group and n = 974 room air group). There was significant heterogeneity among the studies (I2 = 49.88%; P = .03). Overall, oxygen administration was associated with no significant difference in UA pH (weighted mean difference, 0.00; 95% CI, -0.01 to 0.01). Oxygen use was associated with an increase in UA Pao2 (weighted mean difference, 2.57 mm Hg; 95% CI, 0.80-4.34 mm Hg) but no significant difference in UA base excess, UA pH less than 7.2, Apgar scores, or neonatal intensive care unit admissions. Umbilical artery pH values remained similar between groups after accounting for the risk of bias, type of oxygen delivery device, and fraction of inspired oxygen. After stratifying by the presence or absence of labor, oxygen administration in women undergoing scheduled cesarean delivery was associated with increased UA Pao2 (weighted mean difference, 2.12 mm Hg; 95% CI, 0.09-4.15 mm Hg) and a reduction in the incidence of UA pH less than 7.2 (relative risk, 0.63; 95% CI, 0.43-0.90), but these changes were not noted among those in labor (Pao2: weighted mean difference, 3.60 mm Hg; 95% CI, -0.30 to 7.49 mm Hg; UA pH<7.2: relative risk, 1.34; 95% CI, 0.58-3.11). Conclusions and Relevance: This systematic review and meta-analysis suggests that studies to date showed no association between maternal oxygen and a clinically relevant improvement in UA pH or other neonatal outcomes.

Cinnamaldehyde mitigates placental vascular dysfunction of gestational diabetes and protects from the associated fetal hypoxia by modulating placental angiogenesis, metabolic activity and oxidative stress.

Gestational diabetes mellitus (GDM) is a major pregnancy-related disorder with an increasing prevalence worldwide. GDM is associated with altered placental vascular functions and has severe consequences for fetal growth. There is no commonly accepted medication for GDM due to safety considerations. Actions of the currently limited therapeutic options focus exclusively on lowering the blood glucose level without paying attention to the altered placental vascular reactivity and remodelling. We used the fat-sucrose diet/streptozotocin (FSD/STZ) rat model of GDM to explore the efficacy of cinnamaldehyde (Ci; 20 mg/kg/day), a promising antidiabetic agent for GDM, and glyburide/metformin-HCl (Gly/Met; 0.6 + 100 mg/kg/day), as a reference drug for treatment of GDM, on the placenta structure and function at term pregnancy after their oral intake one week before mating onward. Through genome-wide transcriptome, biochemical, metabolome, metal analysis and histopathology we obtained an integrated understanding of their effects. GDM resulted in maternal and fetal hyperglycemia, fetal hyperinsulinemia and placental dysfunction with subsequent fetal anemia, hepatic iron deficiency and high serum erythropoietin level, reflecting fetal hypoxia. Differentially-regulated genes were overrepresented for pathways of angiogenesis, metabolic transporters and oxidative stress. Despite Ci and Gly/Met effectively alleviated the maternal and fetal glycemia, only Ci offered substantial protection from GDM-associated placental vasculopathy and prevented the fetal hypoxia. This was explained by Ci's impact on the molecular regulation of placental angiogenesis, metabolic activity and redox signaling. In conclusion, Ci provides a dual impact for the treatment of GDM at both maternal and fetal levels through its antidiabetic effect and the direct placental vasoprotective action. Lack of Gly/Met effectiveness to restore it's impaired functionality demonstrates the vital role of the placenta in developing efficient medications for GDM.

Interpretation of Fetal Heart Rate Monitoring in the Clinical Context.

Use of intrapartum fetal heart rate (FHR) monitoring has had limited success in preventing hypoxic injury to neonates. One of the most common limitations of FHR interpretation is the failure to consider chronic and acute clinical factors that may increase the risk of evolving acidemia. This manuscript reviews common clinical factors that may affect the FHR and should be considered when determining the need for early intervention based on changes in the FHR.

Interventions for Intrapartum Fetal Heart Rate Abnormalities.

Intrapartum fetal heart rate (FHR) decelerations may represent interrupted oxygen transfer to the fetus. In many cases, these interruptions are transient and do not result in progressive fetal acidemia with risk for asphyxia and neurological compromise. When significant FHR decelerations are present, reversible causes of reduced fetal oxygen delivery should be considered and corrective measures should be undertaken to optimize oxygenation. In this review, we describe potential intrapartum causes of reduced fetal oxygen delivery and the efficacy of common interventions for an abnormal FHR tracing.

Physiology of Fetal Heart Rate Monitoring.

Fetal heart tracings (FHTs) are useful as a window into the oxygenation status of the fetal brain. Patterns in the FHT reflect the oxygen status of the fetal brain. Fetal adaptive response to progressive hypoxemia and acidosis are detectable and produce recognizable patterns in the fetal heart rate. The basic physiology and adaptive responses that regulate the fetal heart rate and physiological fetal adaptations to stress as reflected in the FHTs are described. Mechanisms of oxygen delivery to the fetus including ways in which those mechanisms can be disrupted are reviewed.

Identification of the Fetus at Risk for Metabolic Acidemia Using Continuous Fetal Heart Rate Monitoring.

The fetal heart rate can be used to assess the current metabolic state of the fetus and predict the risk of the evolution of metabolic acidemia through the course of labor. In this chapter, we will present the pathophysiology of the development of fetal acidemia and provide an organized approach to identifying the risk of worsening acidemia using changes noted in the fetal heart rate pattern to allow for interventions that might alter this course.

The impact of a national cardiotocography education program on neonatal and maternal outcomes: A historical cohort study.

INTRODUCTION: Studies indicate an association between errors in cardiotocography (CTG) management and hypoxic brain injuries among newborns. Continuing professional education is recommended. We aimed to examine whether the implementation of a national interprofessional CTG education program in Denmark was associated with a decrease in risk of fetal hypoxia measured by umbilical cord pH < 7.00, 5-minute Apgar score <7 or neonatal therapeutic hypothermia. As a secondary aim, we assessed whether the educational intervention was associated with an increase in operative deliveries. MATERIAL AND METHODS: We conducted a historical cohort study from 2009 to 2015 including all intended vaginal deliveries with liveborn singletons in cephalic presentation and gestational age ≥37 weeks. Data were retrieved from the Medical Birth Register and the National Patient Register. The study period was divided in three: pre-implementation (2009-2012), implementation (2013) and post-implementation (2014-2015). Using logistic regression we estimated odds ratios (OR) of fetal hypoxia outcomes using the pre-implementation period as reference. Analyses were adjusted for potential maternal, neonatal and delivery-associated confounders. Missing data were accounted for by multiple imputation. RESULTS: In all, 331 282 deliveries were included. Overall risks of pH < 7.00, Apgar score <7 and therapeutic hypothermia were respectively 0.45%, 0.58% and 0.06%. Adjusted OR in the post-implementation period were 1.12 (95% confidence interval [CI] 1.00-1.26), 0.99 (95% CI 0.90-1.10) and 1.34 (95% CI 0.99-1.82) for the three outcomes, respectively. The pH missingness equaled 12.4%. Odds of emergency cesarean section was unaltered, whereas the odds of assisted vaginal delivery decreased by 14% (0.86, 95% CI 0.84-0.89). CONCLUSIONS: Healthcare professionals are considered the weakest link of CTG technology. We did not find that increasing healthcare professionals' CTG interpretation skills affected the risk of fetal hypoxia. Missing data for pH values were substantial and represent a limitation of the study. We cannot with certainty rule out that missingness masked a true effect of the intervention. Our study indicates that assisted vaginal deliveries can be decreased without an increased risk of fetal hypoxia. Dilution of effect in a complex clinical setting, rare outcomes, insufficient intervention and a possible overestimation of the impact of errors in CTG management might explain the lack of effect.

Arterio-venous blood gas Δvalues for validation of umbilical cord blood samples at birth are not only biased by sample mix ups but also affected by clinical factors.

INTRODUCTION: Traditional validation of umbilical cord blood samples with positive veno-arterial ΔpH and arterio-venous ΔpCO2 values confirms the source of samples, whereas negative Δvalues represent mix-up of samples. To investigate whether this is true, the distributions of V-A ΔpO2 and A-V Δlactate were also explored and related to clinical characteristics. In addition, different cord blood sampling techniques were evaluated. MATERIAL AND METHODS: Register study with cord blood acid-base and clinical data from 27 233 newborns. Clinical characteristics were related to positive, zero and negative Δvalues. Blood samplings from unclamped and double-clamped cords were compared. A two-sided P < 0.05 was considered significant. RESULTS: ΔpH and ΔpCO2 values distributed into positive, around zero, and negative sub-populations, with significant differences in pH and clinical characteristics between sub-populations. No such sub-populations were distinguished for ΔpO2 and Δlactate. The 2.5th and 5th ΔpH percentiles were 0.013 and 0.022, respectively, and for ΔpCO2 0.30 and 0.53 kPa. Applying 5th percentile criteria resulted in 3.5% of "approved" cases showing a ΔpO2  ≤ 0. Puncture and sampling of the unclamped cord resulted in significantly better sample quality. CONCLUSIONS: Unphysiological negative ΔpO2 values occurred despite correct validation with traditional criteria. Δlactate cannot be used for validation because both positive and negative values are physiological. Positive/around zero/negative ΔpH and ΔpCO2 sub-populations were associated with significant differences in pH and clinical characteristics, indicating that defective sampling and sample handling are not the sole explanations for negative Δvalues. Prompt puncture and sampling of the unclamped cord resulted in best sample quality.

Prediction of adverse perinatal outcome by cerebroplacental ratio in women undergoing induction of labor.

OBJECTIVE: To investigate the performance of screening for adverse perinatal outcome by the cerebroplacental ratio (CPR) measured within 24 h prior to induction of labor. METHODS: This was a prospective observational study of 1902 singleton pregnancies undergoing induction of labor at ≥ 37 weeks' gestation. Doppler ultrasound was used to measure the pulsatility index (PI) in the umbilical artery (UA) and fetal middle cerebral artery (MCA) within 24 h before induction of labor. The measured UA-PI and MCA-PI and their ratio were converted to multiples of the median after adjustment for gestational age. Univariable and multivariable logistic regression analysis was used to determine whether CPR improved the prediction of adverse perinatal outcome provided by maternal characteristics, medical history and obstetric factors. The detection rate (DR) and false-positive rate (FPR) of screening by CPR were estimated for Cesarean section for presumed fetal distress and adverse neonatal outcome, which included umbilical arterial or venous cord blood pH ≤ 7 and ≤ 7.1, respectively, 5-min Apgar score < 7, admission to the neonatal intensive care unit for > 24 h or hypoxic ischemic encephalopathy. RESULTS: A combination of maternal and pregnancy characteristics, including age, weight, racial origin, previous obstetric history, pre-eclampsia, gestational age at delivery and amniotic fluid volume, identified 39% of pregnancies requiring Cesarean section for fetal distress at a FPR of 10%; addition of CPR did not improve the performance of screening. In screening for adverse neonatal outcome by a combination of parity and CPR, the DR was 17% at a FPR of 10%. CONCLUSION: Low CPR, measured within 24 h prior to induction of labor, is associated with increased risk of Cesarean section for fetal distress and adverse neonatal outcome, but the performance of CPR for such surrogate measures of fetal hypoxic morbidity is poor. Copyright © 2018 ISUOG. Published by John Wiley & Sons Ltd.

Improvement of maternal and fetal outcomes in women with sickle cell disease treated with early prophylactic erythrocytapheresis.

BACKGROUND: The desire for pregnancy in sickle cell disease (SCD) women has become a true challenge for hematologists, requiring a multidisciplinary approach. Erythrocytapheresis (ECP) is an important therapeutic tool in SCD, but only limited data on starting time and the effects of ECP during pregnancy are available. STUDY DESIGN AND METHODS: This is a double-center retrospective cross-sectional study on a total of 46 single pregnancies in SCD women from January 2008 to June 2017. ECP was started at 10.7 ± 5.2 weeks of gestation, and prophylactic enoxaparin (4,000 U daily) was introduced due to the reported high prevalence of thromboembolic events in pregnant SCD women. RESULTS: The alloimmunization ratio was 2.1 per 1,000 and the alloimmunization rate was 5.6%. In early ECP-treated SCD women, no severe vaso-occlusive crisis, sepsis or severe infection, or preeclampsia or eclampsia were observed. We found normal umbilical arterial impedance during pregnancy, suggesting an optimal uteroplacental function in early ECP-treated SCD women. This was also supported by the improvement in newborn birthweights compared to previous studies. In our cohort, three SCD women were started later on ECP (20-25 weeks), and gestation ended with late fetal loss. Placenta pathology documented SCD-related damage and erythroblasts in placental vessels, indicating fetal hypoxia. CONCLUSIONS: Collectively, our data generate a rationale to support a larger clinical trial of early ECP program in SCD pregnancy.

Fetal heart rate short term variation during labor in relation to scalp blood lactate concentration.

INTRODUCTION: Fetal heart rate short term variation (STV) decreases with severe chronic hypoxia in the antenatal period. However, only limited research has been done on STV during labor. We have tested a novel algorithm for a valid baseline estimation and calculated STV. To explore the value of STV during labor, we compared STV with fetal scalp blood (FBS) lactate concentration, an early marker in the hypoxic process. MATERIAL AND METHODS: Software was developed which estimates baseline frequency using a novel algorithm and thereby calculates STV according to Dawes and Redman in up to four 30-minute blocks prior to each FBS. Cardiotocography traces from 1070 women in labor who had had FBS performed on 2134 occasions were analyzed. RESULTS: In acidemic cases (lactate >4.8 mmol/L; Lactate Pro™), median STV 30 minutes prior to FBS was 7.10 milliseconds compared with 6.09 milliseconds in the preacidemic (4.2-4.8 mmol/L) and 5.23 milliseconds in the normal (<4.2 mmol/L) groups (P < .05). There was a positive correlation between lactate and STV (rho = 0.16-0.24; P < .05). Median lactate concentration in cases with STV <3.0 milliseconds (n = 160) was 2.3 mmol/L. When 2 FBS were performed within 60 minutes the change rate of lactate correlated to STV (rho = 0.33; P < .001). Cases with increasing lactate concentration had a median STV of 5.29 milliseconds vs 4.41 milliseconds in those with decreasing lactate (P < .001). CONCLUSIONS: In the early stages of intrapartum hypoxia, STV increases, contrary to findings regarding chronic hypoxia in the antenatal period. The increase in the adrenergic surge is a likely explanation.

Neutralizing anti-interleukin-1ß antibodies reduce ischemia-related interleukin-1ß transport across the blood-brain barrier in fetal sheep.

Hypoxic ischemic insults predispose to perinatal brain injury. Pro-inflammatory cytokines are important in the evolution of this injury. Interleukin-1ß (IL-1ß) is a key mediator of inflammatory responses and elevated IL-1ß levels in brain correlate with adverse neurodevelopmental outcomes after brain injury. Impaired blood-brain barrier (BBB) function represents an important component of hypoxic-ischemic brain injury in the fetus. In addition, ischemia-reperfusion increases cytokine transport across the BBB of the ovine fetus. Reducing pro-inflammatory cytokine entry into brain could represent a novel approach to attenuate ischemia-related brain injury. We hypothesized that infusions of neutralizing IL-1ß monoclonal antibody (mAb) reduce IL-1ß transport across the BBB after ischemia in the fetus. Fetal sheep were studied 24-h after 30-min of carotid artery occlusion. Fetuses were treated with placebo- or anti-IL-1ß mAb intravenously 15-min and 4-h after ischemia. Ovine IL-1ß protein expressed from IL-1ß pGEX-2T vectors in Escherichia coli (E. coli) BL-21 cells was produced, purified, and radiolabeled with 125I. BBB permeability was quantified using the blood-to-brain transfer constant (Ki) with 125I-radiolabeled-IL-1ß. Increases in anti-IL-1ß mAb were observed in the brain of the mAb-treated group (P<0.001). Blood-to-brain transport of 125I-IL-1ß was lower (P<0.04) across brain regions in the anti-IL-1ß mAb-treated than placebo-treated ischemic fetuses. Plasma 125I-IL-1ß counts were higher (P<0.001) in the anti-IL-1ß mAb- than placebo-treated ischemic fetuses. Systemic infusions of anti-IL-1ß mAb reduce IL-1ß transport across the BBB after ischemia in the ovine fetus. Our findings suggest that conditions associated with increases in systemic pro-inflammatory cytokines and neurodevelopmental impairment could benefit from an anti-cytokine therapeutic strategy.

Macrosomia.

Fetal macrosomia is defined as birth weight >4000 g and is associated with several maternal and fetal complications such as maternal birth canal trauma, shoulder dystocia, and perinatal asphyxia. Early identification of risk factors could allow preventive measures to be taken to avoid adverse perinatal outcomes. Prenatal diagnosis is based on two-dimensional ultrasound formulae, but accuracy is low, particularly at advanced gestation. Three-dimensional ultrasound could be an alternative to soft tissue monitoring, allowing better prediction of birth weight than two-dimensional ultrasound. In this article, we describe the definition, risk factors, diagnosis, prevention, ultrasound monitoring, prenatal care, and delivery in fetal macrosomia cases.

Neonatal outcomes after introduction of a national intrapartum fetal surveillance education program: a retrospective cohort study.

OBJECTIVE: To determine the impact of a multidisciplinary fetal surveillance education program (FSEP) on term neonatal outcomes. METHODS: A retrospective cohort study of term neonatal outcomes before (1998-2004) and after (2005-2010) introduction of a FSEP. Clinical data was collected for all term infants admitted to a neonatal intensive care unit (NICU) in Australia between 1998 and 2010. Infants with congenital abnormalities were excluded. Neonatal mortality and severe neonatal morbidity (admission to a NICU, respiratory support, hypoxic encephalopathy) were compared before and after the FSEP was introduced. The rates of operative delivery during this time were assessed. RESULTS: There were 3 512 596 live term births between 1998 and 2010. The intrapartum hypoxic death rate at term decreased from 2.02 to 1.07 per 10 000 total births. More neonates were admitted to NICU after 2005 (10.6 versus 14.6 per 10 000 live births), however fewer babies admitted to the neonatal unit had Apgar scores < 5 at five minutes (55.1-45.5%, RR 0.82, 95% CI 0.7-0.87); and rates of hypoxic ischemic encephalopathy fell from 36% to 30% (RR 0.83, 95% CI 0.76-0.90). There was no increase in rates of emergency in labour caesarean sections (11.7% pre versus 11.1% post, RR 0.95, 95% CI 0.95-0.96). CONCLUSIONS: Introduction of a national FSEP was associated with increased neonatal admissions but a reduction in intrapartum hypoxia, without increasing emergency caesarean section rates.

Preventing deaths from complications of labour and delivery.

The process of labour and delivery remains an unnecessary and preventable cause of death of women and babies around the world. Although the rates of maternal and perinatal death are declining, there are large disparities between rich and poor countries, and sub-Saharan Africa has not seen the scale of decline as seen elsewhere. In many areas, maternity services remain sparse and under-equipped, with insufficient and poorly trained staff. Priorities for reducing the mortality burden are provision of safe caesarean section, prevention of sepsis and appropriate care of women in labour in line with the current best practices, appropriately and affordably delivered. A concern is that large-scale recourse to caesarean delivery has its own dangers and may present new dominant causes for maternal mortality. An area of current neglect is newborn care. However, innovative training methods and appropriate technologies offer opportunities for affordable and effective newborn resuscitation and follow-up management in low-income settings.