Cardiac Doppler in poorly controlled gestational diabetics and its link to markers of intra-uterine hypoxia and adverse outcome.

The aim of the study was to investigate foetal cardiac function using the modified myocardial performance index (Mod-MPI) in poorly controlled gestational diabetics and its link with intrauterine markers for hypoxia and to an adverse outcome. In a prospective, cross sectional study, 44 consecutive women with severe or poorly controlled gestational diabetic pregnancies in their third trimester on insulin therapy were recruited and matched with 44 women with normal pregnancies which served as the control group. Using Doppler echocardiography the foetal Mod-MPI was calculated. The foetal Mod-MPI was significantly higher in the diabetic group compared to the controls indicating significant myocardial dysfunction. The Mod-MPI served as an excellent marker of adverse outcomes. Foetal myocardial function was significantly impaired in poorly controlled gestational diabetics and there was a significant link of Mod-MPI to intrauterine markers of hypoxia, as well as to an adverse outcome. Mod-MPI has the potential to improve foetal surveillance in gestational diabetes.IMPACT STATEMENTWhat is already known on this subject? Abnormal foetal cardiac function, as reflected in the modified myocardial performance index, has been reported to be significantly increased in foetuses of poorly controlled diabetics managed on insulin.What do the results of this study add? There is a significant link between abnormal foetal cardiac function to intrauterine markers of hypoxia, as well as to an adverse outcome; and that development of myocardial dysfunction could be one of the main mechanisms, inducing foetal compromise in poorly controlled gestational diabetes.What are the implications of these findings for clinical practice and/or further research? This study explores an interesting concept of foetal pathophysiology in gestational diabetes, namely the concept of "pseudo-hypoxia" in a foetus of a gestational diabetic mother, and this intrauterine "hypoxic stress" in turn leading to myocardial dysfunction. The Mod-MPI, a clinical marker for cardiac dysfunction, can therefore be used in the clinical setting to track a deteriorating metabolic state.

Is obesity in pregnancy associated with signs of chronic fetal hypoxia?

INTRODUCTION: The prevalence of obesity in pregnancy is increasing worldwide. Maternal obesity increases risks of severe fetal and neonatal complications. The underlying pathophysiological mechanisms are unclear. One possible contributing factor could be chronic fetal hypoxia. The aim of this study was to compare placentas from women with and without obesity with respect to placental lesions, which could reflect compensatory mechanisms in response to chronic fetal hypoxia as well as lesions possibly leading to chronic fetal hypoxia. In addition, levels of erythropoietin in cord blood were compared between offspring of lean and obese women. MATERIAL AND METHODS: This cohort study included 180 women with uneventful, full-term, singleton pregnancies, out of which 91 lean women had a body mass index (BMI) of 18.5-24.9 kg/m2 and 89 women had obesity (BMI ≥30 kg/m2 ). Women were recruited at Södersjukhuset between 16 October 2018 and 2 December 2019. Placentas were investigated by two senior perinatal pathologists, who were blinded for maternal BMI. Cord blood was analyzed for levels of erythropoietin. RESULTS: Levels of erythropoietin in cord blood increased with maternal BMI (P = .01, ß = 0.97, 95% CI 0.27-1.68). There was no difference between placentas of obese and lean women in number of placental lesions reflecting chronic fetal hypoxia or in lesions that could possibly lead to chronic fetal hypoxia. CONCLUSIONS: This study of term and uneventful pregnancies demonstrated a positive association between maternal obesity and concentrations of erythropoietin in cord blood at birth. This finding supports the hypothesis of chronic fetal hypoxia as a risk factor for complications in the pregnancies of obese women. There were no differences in lesions associated with hypoxia between placentas of obese and lean women.

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.

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.

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.

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.

Amniotic Fluid Embolism: A Rare Complication of Second-Trimester Amniocentesis.

Amniotic fluid embolism occurring following diagnostic amniocentesis is extremely rare. Only 2 cases have been reported in the English literature over the past 55 years, the most recent one approximately 3 decades ago. We present a case of amniocentesis at 24 weeks' gestation that was performed as part of an evaluation of abnormal fetal ultrasound findings. Immediately following amniotic fluid aspiration, maternal hemodynamic collapse occurred, initially diagnosed and treated as anaphylactic shock. Shortly after initial therapy, coagulopathy was noted and amniotic fluid syndrome suspected. Rapid response restored maternal hemodynamic stability; however, the fetus had suffered fatal damage.

Sympathetic neural activation does not mediate heart rate variability during repeated brief umbilical cord occlusions in near-term fetal sheep.

Changes in fetal heart rate variability (FHRV) and ST segment elevation (measured as the T/QRS ratio) are used to evaluate fetal adaptation to labour. The sympathetic nervous system (SNS) is an important contributor to FHRV under healthy normoxic conditions, and is critical for rapid support of blood pressure during brief labour-like asphyxia. However, although it has been assumed that SNS activity contributes to FHRV during labour; this has never been tested, and it is unclear whether the SNS contributes to the rapid increase in T/QRS ratio during brief asphyxia. Thirteen chronically instrumented fetal sheep at 0.85 of gestation received either chemical sympathectomy with 6-hydroxydopamine (6-OHDA; n = 6) or sham treatment (control; n = 7), followed 4-5 days later by 2 min episodes of complete umbilical cord occlusion repeated every 5 min for up to 4 h, or until mean arterial blood pressure fell to <20 mmHg for two successive occlusions. FHRV was decreased before occlusions in the 6-OHDA group (P < 0.05) and 2-4.5 h during recovery after occlusions (P < 0.05) compared to the control group. During each occlusion there was a rapid increase in T/QRS ratio. Between successive occlusions the T/QRS ratio rapidly returned to baseline, and FHRV increased above baseline in both groups (P < 0.05), with no significant effect of sympathectomy on FHRV or T/QRS ratio. In conclusion, these data show that SNS activity does not mediate the increase in FHRV between repeated episodes of brief umbilical cord occlusion or the transient increase in T/QRS ratio during occlusions.

Neutralizing anti-interleukin-1ß antibodies modulate fetal blood-brain barrier function after ischemia.

We have previously shown that increases in blood-brain barrier permeability represent an important component of ischemia-reperfusion related brain injury in the fetus. Pro-inflammatory cytokines could contribute to these abnormalities in blood-brain barrier function. We have generated pharmacological quantities of mouse anti-ovine interleukin-1ß monoclonal antibody and shown that this antibody has very high sensitivity and specificity for interleukin-1ß protein. This antibody also neutralizes the effects of interleukin-1ß protein in vitro. In the current study, we hypothesized that the neutralizing anti-interleukin-1ß monoclonal antibody attenuates ischemia-reperfusion related fetal blood-brain barrier dysfunction. Instrumented ovine fetuses at 127 days of gestation were studied after 30 min of carotid occlusion and 24h of reperfusion. Groups were sham operated placebo-control- (n=5), ischemia-placebo- (n=6), ischemia-anti-IL-1ß antibody- (n=7), and sham-control antibody- (n=2) treated animals. Systemic infusions of placebo (0.154M NaCl) or anti-interleukin-1ß monoclonal antibody (5.1±0.6 mg/kg) were given intravenously to the same sham or ischemic group of fetuses at 15 min and 4h after ischemia. Concentrations of interleukin-1ß protein and anti-interleukin-1ß monoclonal antibody were measured by ELISA in fetal plasma, cerebrospinal fluid, and parietal cerebral cortex. Blood-brain barrier permeability was quantified using the blood-to-brain transfer constant (Ki) with α-aminoisobutyric acid in multiple brain regions. Interleukin-1ß protein was also measured in parietal cerebral cortices and tight junction proteins in multiple brain regions by Western immunoblot. Cerebral cortical interleukin-1ß protein increased (P<0.001) after ischemia-reperfusion. After anti-interleukin-1ß monoclonal antibody infusions, plasma anti-interleukin-1ß monoclonal antibody was elevated (P<0.001), brain anti-interleukin-1ß monoclonal antibody levels were higher (P<0.03), and interleukin-1ß protein concentrations (P<0.03) and protein expressions (P<0.001) were lower in the monoclonal antibody-treated group than in placebo-treated-ischemia-reperfusion group. Monoclonal antibody infusions attenuated ischemia-reperfusion-related increases in Ki across the brain regions (P<0.04), and Ki showed an inverse linear correlation (r= -0.65, P<0.02) with anti-interleukin-1ß monoclonal antibody concentrations in the parietal cortex, but had little effect on tight junction protein expression. We conclude that systemic anti-interleukin-1ß monoclonal antibody infusions after ischemia result in brain anti-interleukin-1ß antibody uptake, and attenuate ischemia-reperfusion-related interleukin-1ß protein up-regulation and increases in blood-brain barrier permeability across brain regions in the fetus. The pro-inflammatory cytokine, interleukin-1ß, contributes to impaired blood-brain barrier function after ischemia in the fetus.

Did antepartum hypoxic insult caused by fetal vessel thrombosis influence the procalcitonin level in umbilical blood? A case report.

We report a case of marked elevation of the procalcitonin level in umbilical blood and neonatal blood at birth. The mother did not perceive fetal motion. Antepartum fetal heart rate monitoring showed a loss of variability and absence of acceleration. No fetal breathing movement, fetal movement, or fetal tone were observed by ultrasonography. The female neonate was delivered by cesarean section at 25 weeks of gestation, with birthweight 774 g. The umbilical arterial pH value at birth was 7.29. Mild elevation in interleukin-6 and tumor necrosis factor-α in umbilical blood were observed. Cytochrome c showed a high level in umbilical and neonatal blood at birth. Placental histopathology revealed multiple fetal vessel thrombosis in the large stem villi and chorionic vessels. The neonate showed no infectious signs throughout the neonatal period. Computed tomography at 3 months of age revealed atrophy in the cerebrum and cerebellum. At 1 year after birth, the infant showed spastic quadriplegia. In this case, antepartum asphyxia due to fetal vessel thrombosis may have influenced the elevation of procalcitonin level in umbilical blood and neonatal blood at birth.

Obstetric litigation: the importance of the quality of clinical files and its influence on expertise conclusions.

To appreciate the Portuguese circumstances concerning situations of obstetric medico-legal conflicts and to evaluate the influence of the quality of files in expert conclusions, an analysis of all cases of obstetric medical responsibility from 2001-11 was carried out. File quality was evaluated by absence or insufficiency of clinical information supplied, by poor quality of document copies and by the registered incongruities among all the health professionals involved. Clinical files sent for forensic analysis were defective in most cases (89.5%). In about 11% of cases, expert opinion was inconclusive as a result of the poor quality of the clinical files sent for technical and scientific analysis. This situation is particularly serious in cases where the reason for the dispute was asphyxia, traumatic lesions of the newborn following instrumented delivery or shoulder dystocia and maternal sequelae, where the lack or absence of information, and poor quality copies were significantly associated with inconclusive opinions.

[Mechanisms of hypoxia development during pregnancy and the disorder of fetus blood supply at cytomegalovirus infection].

OBJECTIVE: Our aim was to study the mechanisms of hypoxia development at pregnancy associated with cytomegalovirus infection (CMVI). METHODS: 30 parturient women with CMVI relapse at the 25-28 weeks of pregnancy and their newborns were examined. Cytochrome C, Hsp-70, p53, Bcl-2 and caspase-3 in placenta homogenate were found out with serologic methods, the morphology of erythrocytes with cytophotometry, erythrocytes membrane proteins with disc-electrophoresis method, TBA-active products with V.B. Gavrilov's method, superoxide dismutase activity with spectrophotometry, 2.3-diphosphoglyceric acid (2.3 DPG) with I.S. Luganov's method, erythrocytes membrane microviscosity with fluorimethric method, oxyhemoglobin and methemoglobin with Evelyn and Malloy' method, and erythrocytes deformability with M. T. Lutsenko's method. RESULTS: In blood erythrocytes of CMV-seropositive parturient women there was the decrease of cytoskeleton proteins: α- and ß-spectrine was 1.14 times less, ankyrin was 1.62 times less, band 4. 1 protein was 1.29 times less; there was 1.87 times increase of antigen-binding glycophorin, 1.37 times growth of TBA-active products and 1.35 times drop of superoxide dismutase activity; the deformability index was 9.5 times less, 2.3 DPG was 1.22 times less and oxyhemoglobin was 1.06 times less. In placenta homogenate Bcl-2 was 1.5 times less, Hsp-70 was 2.5 times more, p53 was 6.1 times more, cytochrome C was 1.76 times more, caspase-3 was 3.86 times more. In umbilical cord blood erythrocytes 2.3 DPG was 1.3 times more and oxyhemoglobin was 1.06 times less. CONCLUSION: The obtained data proves that CMVI relapse at 25-28 weeks of pregnancy causes the disorder of morphofunctional state of mother's blood erythrocytes and their ability to oxygenation, the development offetoplacental barrier, the decrease offetus oxygen blood supply and the development of intrauterine hypoxia.

Perinatal asphyxia in monochorionic versus dichorionic twins: incidence, risk factors and outcome.

OBJECTIVE: To estimate the incidence, risk factors, severity and outcome after perinatal asphyxia in monochorionic (MC) versus dichorionic (DC) twins. METHODS: We included all consecutive near-term MC and DC twins with perinatal asphyxia admitted to our neonatal ward between 2004 and 2013 and compared the perinatal characteristics and neonatal outcome between both groups. RESULTS: The incidence of perinatal asphyxia in MC and DC twin infants was 4.0 (11/272) and 4.0% (8/200; p = 1.00). In contrast to DC twins, asphyxia in MC twins was strongly associated with acute exsanguination and anemia at birth; 64% (7/11) in MC twins and 0% (0/8) in DC twins (p < 0.01). Median hemoglobin level at birth in the MC and DC groups was 11.5 and 18.6 g/dl, respectively (p < 0.01). CONCLUSIONS: Perinatal asphyxia in MC twins is often associated with severe anemia at birth due to acute hemorrhage through the placental vascular anastomoses.

Successful management of fetal hypoxia due to amniotic banding at 26 weeks of pregnancy: A case report of a rare survival.

BACKGROUND: Amniotic banding is a rare condition that can lead to structural limb anomalies, fetal distress and adverse obstetric outcomes. The main hypothesis for its etiology is a rupture of the amniotic membrane in early pregnancy, with the formation of tightly entangling strands around the fetus. These strands can constrict, incise, and subsequently amputate limb parts, the neck or head. More rarely, the amniotic banding can affect the umbilical cord, leading to fetal distress or potential intra-uterine fetal demise. OBJECTIVE: We present a unique case of a 26-week pregnant woman who attended a polyclinical consultation due to reduced fetal movements with concerning cardiotocography (CTG) findings. A review of the literature about amniotic banding of the umbilical cord was conducted as well, identifying diagnostic and interventional options for the obstetrician's practice. STUDY DESIGN: This is a case report, alongside a review of the literature. RESULTS: The CTG indicated fetal distress, prompting an emergency caesarean section (C-section). Upon delivery, the neonate exhibited signs of amniotic band sequence, with distal phalangeal defects on the right hand and severe constriction of the umbilical cord caused by amniotic strands, the latter precipitating fetal hypoxia. Direct ultrasound diagnosis remains a challenge in the absence of limb amputation, yet indirect signs such as distal limb or umbilical doppler flow abnormalities and distal limb edema may be suggestive of amniotic banding. MRI is proposed as an adjuvant diagnostic tool yet does not present a higher detection rate compared to ultrasound. Fetoscopic surgery to perform lysis of the amniotic strands with favorable outcome has been described in literature. CONCLUSION: This case presents the first reported survival of an extremely preterm fetus in hypoxic distress as a cause of amniotic banding of the umbilical cord, with a rare degree of incidental timing. Ultrasound diagnosis remains the gold standard. Obstetrical vigilance is warranted, with fetal rescue proven to be feasible.

Heart rate-mediated blood pressure control in preterm fetal sheep under normal and hypoxic-ischemic conditions.

BACKGROUND: The understanding of hypoxemia-induced changes in baroreflex function is limited and may be studied in a fetal sheep experiment before, during, and after standardized hypoxic conditions. METHODS: Preterm fetal lambs were instrumented at 102 d gestation (term: 146 d). At 106 d, intrauterine hypoxia--ischemia was induced by 25 min of umbilical cord occlusion (UCO). Baroreflex-related fluctuations were calculated at 30-min intervals during the first week after UCO by transfer function (cross-spectral) analysis between systolic blood pressure (SBP) and R-R interval fluctuations, estimated in the low-frequency (LF, 0.04-0.15 Hz) band. LF transfer gain (baroreflex sensitivity) and delay (s) reflect the baroreflex function. RESULTS: Baseline did not differ in LF transfer gain and delay between controls and the UCO group. In controls, LF gain showed postnatal increase. By contrast, LF gain gradually decreased in the UCO group, resulting in significantly lower values 4-7 d after UCO. In the UCO group, LF delay increased and differed significantly from controls. CONCLUSION: Our results show that intrauterine hypoxia-ischemia results in reduced baroreflex sensitivity over a period of 7 d, indicating limited efficacy to buffer BP changes by adapting heart rate. Cardiovascular dysregulation may augment already present cerebral damage after systemic hypoxia-ischemia in the reperfusion period.

Invited review: heat stress effects during late gestation on dry cows and their calves.

In dairy cattle, late gestation is a critical period for fetal growth and physiological transition into the next lactation. Environmental factors, such as temperature and light, exert dramatic effects on the production, health, and well-being of animals during this period and after parturition. The aim of this review was to introduce effects of heat stress during late gestation on dairy cattle, and discuss the biological mechanisms that underlie the observed production and health responses in the dam and her fetus. Relative to cooled cows, cows that are heat stressed during late gestation have impaired mammary growth before parturition and decreased milk production in the subsequent lactation. In response to higher milk yield, cows cooled prepartum undergo a series of homeorhetic adaptations in early lactation to meet higher demand for milk synthesis compared with heat-stressed cows, but no direct effect of environmental heat stress on metabolism exists during the dry period. Prepartum cooling improves immune status of transition cows and evidence suggests that altered prolactin signaling in immune cells mediates the effects of heat stress on immune function. Late-gestation heat stress compromises placental development, which results in fetal hypoxia, malnutrition, and eventually fetal growth retardation. Maternal heat stress may also have carryover effects on the postnatal growth of offspring, but direct evidence is still lacking. Emerging evidence suggests that offspring from prepartum heat-stressed cows have compromised passive immunity and impaired cell-mediated immune function compared with those from cooled cows.

[Placental pathology of uteroplacental vascular deficiency]. / Anatomie pathologique de l'insuffisance vasculaire utéroplacentaire.

The indications of the pathological examination of the placenta are mainly represented by uteroplacental vascular deficiency. The clinical context is often evocative, but it can sometimes be solely an intra-uterine growth retardation or an unexplained in utero fetal death. So, the pathological lesions of this uteroplacental vascular deficiency must be well-known to be correctly interpreted, for none of these lesions is truly specific. The pathological diagnosis is based on a group of macroscopic and microscopic arguments. Various physiopathological mechanisms, often imperfectly known, can be at the origin of an uteroplacental vascular insufficiency, but in the current position, the pathological examination does not allow etiopathogenic orientation. The development of the trophoblastic biopsies gives us access to a new material which, in parallel with the cytogenetic analysis, often allows us, in front of an unexplained intra-uterine growth retardation, to direct the diagnosis towards uteroplacental vascular insufficiency. The histological analysis of the chorionic villous sampling taken precociously during pathological pregnancies is thus a major diagnostic contribution. But especially, this analysis gives access to new information which, in the near future, will enable us to better define the pathological evolution of the lesions of hypoxic chorionic villous and to contribute to a better knowledge of this pathology which, under many aspects, still conceals many mysteries.