The CErebro Placental RAtio as indicator for delivery following perception of reduced fetal movements, protocol for an international cluster randomised clinical trial; the CEPRA study.

BACKGROUND: Routine assessment in (near) term pregnancy is often inaccurate for the identification of fetuses who are mild to moderately compromised due to placental insufficiency and are at risk of adverse outcomes, especially when fetal size is seemingly within normal range for gestational age. Although biometric measurements and cardiotocography are frequently used, it is known that these techniques have low sensitivity and specificity. In clinical practice this diagnostic uncertainty results in considerable 'over treatment' of women with healthy fetuses whilst truly compromised fetuses remain unidentified. The CPR is the ratio of the umbilical artery pulsatility index over the middle cerebral artery pulsatility index. A low CPR reflects fetal redistribution and is thought to be indicative of placental insufficiency independent of actual fetal size, and a marker of adverse outcomes. Its utility as an indicator for delivery in women with reduced fetal movements (RFM) is unknown. The aim of this study is to assess whether expedited delivery of women with RFM identified as high risk on the basis of a low CPR improves neonatal outcomes. Secondary aims include childhood outcomes, maternal obstetric outcomes, and the predictive value of biomarkers for adverse outcomes. METHODS: International multicentre cluster randomised trial of women with singleton pregnancies with RFM at term, randomised to either an open or concealed arm. Only women with an estimated fetal weight ≥ 10th centile, a fetus in cephalic presentation and normal cardiotocograph are eligible and after informed consent the CPR will be measured. Expedited delivery is recommended in women with a low CPR in the open arm. Women in the concealed arm will not have their CPR results revealed and will receive routine clinical care. The intended sample size based on the primary outcome is 2160 patients. The primary outcome is a composite of: stillbirth, neonatal mortality, Apgar score < 7 at 5 min, cord pH < 7.10, emergency delivery for fetal distress, and severe neonatal morbidity. DISCUSSION: The CEPRA trial will identify whether the CPR is a good indicator for delivery in women with perceived reduced fetal movements. TRIAL REGISTRATION: Dutch trial registry (NTR), trial NL7557 . Registered 25 February 2019.

Reduced growth velocity from the mid-trimester is associated with placental insufficiency in fetuses born at a normal birthweight.

BACKGROUND: Fetal growth restriction (FGR) due to placental insufficiency is a major risk factor for stillbirth. While small-for-gestational-age (SGA; weight < 10th centile) is a commonly used proxy for FGR, detection of FGR among appropriate-for-gestational-age (AGA; weight ≥ 10th centile) fetuses remains an unmet need in clinical care. We aimed to determine whether reduced antenatal growth velocity from the time of routine mid-trimester ultrasound is associated with antenatal, intrapartum and postnatal indicators of placental insufficiency among term AGA infants. METHODS: Three hundred and five women had biometry measurements recorded from their routine mid-trimester (20-week) ultrasound, at 28 and 36 weeks' gestation, and delivered an AGA infant. Mid-trimester, 28- and 36-week estimated fetal weight (EFW) and abdominal circumference (AC) centiles were calculated. The EFW and AC growth velocities between 20 and 28 weeks, and 20-36 weeks, were examined as predictors of four clinical indicators of placental insufficiency: (i) low 36-week cerebroplacental ratio (CPR; CPR < 5th centile reflects cerebral redistribution-a fetal adaptation to hypoxia), (ii) neonatal acidosis (umbilical artery pH < 7.15) after the hypoxic challenge of labour, (iii) low neonatal body fat percentage (BF%) reflecting reduced nutritional reserve and (iv) placental weight < 10th centile. RESULTS: Declining 20-36-week fetal growth velocity was associated with all indicators of placental insufficiency. Each one centile reduction in EFW between 20 and 36 weeks increased the odds of cerebral redistribution by 2.5% (odds ratio (OR) = 1.025, P = 0.001), the odds of neonatal acidosis by 2.7% (OR = 1.027, P = 0.002) and the odds of a < 10th centile placenta by 3.0% (OR = 1.030, P < 0.0001). Each one centile reduction in AC between 20 and 36 weeks increased the odds of neonatal acidosis by 3.1% (OR = 1.031, P = 0.0005), the odds of low neonatal BF% by 2.8% (OR = 1.028, P = 0.04) and the odds of placenta < 10th centile by 2.1% (OR = 1.021, P = 0.0004). Falls in EFW or AC of > 30 centiles between 20 and 36 weeks were associated with two-threefold increased relative risks of these indicators of placental insufficiency, while low 20-28-week growth velocities were not. CONCLUSIONS: Reduced growth velocity between 20 and 36 weeks among AGA fetuses is associated with antenatal, intrapartum and postnatal indicators of placental insufficiency. These fetuses potentially represent an important, under-recognised cohort at increased risk of stillbirth. Encouragingly, this novel fetal assessment would require only one additional ultrasound to current routine care, and adds to the potential benefits of routine 36-week ultrasound.

Roles of the underlying cause of delivery and gestational age on long-term child health.

BACKGROUND: Clinical conditions leading to delivery are heterogeneous. However, most studies examining the short- and long-term consequences of birth on child health only consider gestational age at delivery, not the underlying cause. OBJECTIVE: To examine the effect of both gestational age at delivery and underlying cause of delivery on child health outcomes. METHODS: This population-based retrospective cohort study of singleton infants born in Alberta (April 2004-March 2005) used linked administrative and perinatal data to identify birth subtypes by underlying cause (infection/inflammation (I/I), placental dysfunction (PD), both, or neither), gestational age at delivery, and child health outcomes (neonatal morbidity and mortality, paediatric complex chronic conditions, and neurodevelopmental disorders and disabilities). Poisson regression with robust variance was used to assess differences in the (adjusted) risk ratio (RR) of each outcome by gestational age, and by cause of delivery. The roles of gestational age and cause of delivery were examined using mediation analysis methods. RESULTS: A total of 38,192 children were included, with 66.7% experiencing neither I/I nor PD (I/I: 4.0%, PD: 27.5%, both: 1.8%). Infants born preterm had higher risk of all outcomes compared to those born at term and late-term. Infants with exposure to both causes had higher risk of all outcomes (neonatal morbidity, RR 8.96, 95% confidence interval [CI] 7.55, 10.63; paediatric complex chronic conditions, RR 3.94, 95% CI 3.08, 5.05; and neurodevelopmental disorders, RR 1.58, 95% CI 1.37, 1.84). The effect of underlying cause of delivery on child health outcomes was partially explained by gestational age, more in cases involving I/I than in those involving PD alone. CONCLUSIONS: Short- and long-term child health outcomes differ by the underlying cause leading to delivery, as well as the gestational age at delivery. Having a clearer prognosis for infants may promote the use of clinical interventions earlier for children at increased risk.

Association of abnormal placental perfusion with the risk of male hypospadias: a hospital-based retrospective cohort study.

BACKGROUND: The effect and extent of abnormal placental perfusion (APP) on the risk of male hypospadias are poorly understood. We compared the prevalence of male hypospadias in the offspring of women with APP and quantify the extent of the APP effect on the anomaly. METHODS: A hospital-based retrospective analysis of births from 2012 to 2016 was conducted in 2018. Women of singleton pregnancy and male infants born to them were included (N = 21,447). A multivariate analysis was performed to compare the prevalence of male hypospadias in infants exposed to APP with those that were not exposed to APP. RESULTS: Compared with the infants of women without APP, infants of women with APP showed an increased risk of male hypospadias (odds ratio, 2.40; 95% confidence interval, 1.09-5.29). The male hypospadias cumulative risk increased with the severity of APP. Infants exposed to severe APP had a significantly higher risk of male hypospadias than those without APP exposure (9.2 versus 1.7 per 1000 infants, P < 0.001). A path analysis indicated that 28.18-46.61% of the risk of hypospadias may be attributed to the effect of APP. CONCLUSIONS: Male hypospadias risk was associated with APP and increased with APP severity, as measured in the second trimester. APP had an important role in the development of the anomaly.

Does Pentaerytrithyltetranitrate reduce fetal growth restriction in pregnancies complicated by uterine mal-perfusion? Study protocol of the PETN-study: a randomized controlled multicenter-trial.

BACKGROUND: Affecting approximately 10% of pregnancies, fetal growth restriction (FGR), is the most important cause of perinatal mortality and morbidity. Impaired placental function and consequent mal-perfusion of the placenta is the leading cause of FGR. Although, screening for placental insufficiency based on uterine artery Doppler measurement is well established, there is no treatment option for pregnancies threatened by FGR. The organic nitrate pentaerithrityl tetranitrate (PETN) is widely used for the treatment of cardiovascular disease and has been shown to have protective effects on human endothelial cells. In a randomized placebo controlled pilot-study our group could demonstrate a risk reduction of 39% for the development of FGR, and FGR or death, by administering PETN to patients with impaired uterine artery Doppler at mid gestation. To confirm these results a prospective randomized placebo controlled double-blinded multicentre trial was now initiated. METHOD: The trial has been initiated in 14 centres in Germany. Inclusion criteria are abnormal uterine artery Doppler, defined by mean PI > 1.6, at 190 to 226 weeks of gestation in singleton pregnancies. Included patients will be monitored in 4-week intervals. Primary outcome measures are development of FGR (birth weight < 10th percentile), severe FGR (birth weight < 3rd centile) and perinatal death. Placental abruption, birth weight below the 3rd, 5th and 10th centile, development of FGR requiring delivery before 34 weeks` gestation, neonatal intensive care unit admission, and spontaneous preterm delivery < 34 weeks` and 37 weeks` gestation will be assessed as secondary endpoints. Patient enrolment was started in August 2017. Results are expected in 2020. DISCUSSION: During the past decade therapeutic agents with possible perfusion optimizing potential have been evaluated in clinical trials to treat FGR. Meta-analysis and sub-analysis of trials targeting preeclampsia revealed ASS to have a potential in reducing FGR. Phosphodiesterase-type-5 inhibitors have recently been tested in a worldwide RCT for therapy of established FGR, failing to show an effect on neonatal outcome. The ongoing multicenter trial will, by confirming our previous results, finally provide a therapeutic option in cases at risk for FGR. TRIAL REGISTRATION: DRKS00011374 registered at September 29th, 2017 and NCT03669185 , registered September 13th, 2018.

The sFlt-1/PlGF ratio values within the <38, 38-85 and >85 brackets as compared to perinatal outcomes.

Background Soluble fms-like tyrosine kinase-1 (sFlt-1) and placental growth factor (PlGF) are used as markers of preeclampsia. The aim of this paper was to assess the correlations between the sFlt-1/PlGF ratio values within the <38, 38-85 and >85 brackets and perinatal outcomes in pregnancies that require determination of these markers. Methods A total of 927 pregnant patients between 18 and 41 weeks' gestation suspected of or confirmed with any form of placental insufficiency (preeclampsia, intrauterine growth restriction [IUGR], gestational hypertension, HELLP syndrome, placental abruption) were included in the study. In each of the patients, the sFlt-1/PlGF ratio was calculated. Patients were divided into three groups according to the sFlt-1/PlGF ratio brackets of <38, 38-85 and >85. Results Significantly worse perinatal outcomes were found in the sFlt-1/PlGF >85 group, primarily with lower cord blood pH, neonatal birth weight and shorter duration of gestation. Statistically significant correlations between the values of these markers and the abovementioned perinatal effects were found. Conclusion An sFlt-1/PlGF ratio value of >85 suggests that either preeclampsia or one of the other placental insufficiency forms may occur, which is associated with lower cord blood pH, newborn weight and earlier delivery. Determining the disordered angiogenesis markers and calculating the sFlt-1/PlGF ratio in pregnancies complicated by placental insufficiency may lead to better diagnosis, therapeutic decisions and better perinatal outcomes.

A placenta clinic approach to the diagnosis and management of fetal growth restriction.

Effective detection and management of fetal growth restriction is relevant to all obstetric care providers. Models of best practice to care for these patients and their families continue to evolve. Since much of the disease burden in fetal growth restriction originates in the placenta, the concept of a multidisciplinary placenta clinic program, managed primarily within a maternal-fetal medicine division, has gained popularity. In this context, fetal growth restriction is merely one of many placenta-related disorders that can benefit from an interdisciplinary approach, incorporating expertise from specialist perinatal ultrasound and magnetic resonance imaging, reproductive genetics, neonatal pediatrics, internal medicine subspecialties, perinatal pathology, and nursing. The accurate diagnosis and prognosis for women with fetal growth restriction is established by comprehensive clinical review and detailed sonographic evaluation of the fetus, combined with uterine artery Doppler and morphologic assessment of the placenta. Diagnostic accuracy for placenta-mediated fetal growth restriction may be enhanced by quantification of maternal serum biomarkers including placenta growth factor alone or combined with soluble fms-like tyrosine kinase-1. Uterine artery Doppler is typically abnormal in most instances of early-onset fetal growth restriction and is associated with coexistent preeclampsia and underlying maternal vascular malperfusion pathology of the placenta. By contrast, rare but potentially more serious underlying placental diagnoses, such as massive perivillous fibrinoid deposition, chronic histiocytic intervillositis, or fetal thrombotic vasculopathy, may be associated with normal uterine artery Doppler waveforms. Despite minor variations in placental size, shape, and cord insertion, placental function remains, largely normal in the general population. Consequently, morphologic assessment of the placenta is not currently incorporated into current screening programs for placental complications. However, placental ultrasound can be diagnostic in the context of fetal growth restriction, for example in Breus' mole and triploidy, which in turn may enhance diagnosis and management. Several examples are illustrated in our figures and supplementary videos. Recent advances in the ability of multiparameter screening and intervention programs to reduce the risk of severe preeclampsia will likely increase efforts to deliver similar improvements for women at risk of fetal growth restriction. Placental pathology is important because the underlying pathologies associated with fetal growth restriction have a wide range of recurrence risks. Rare conditions such as massive perivillous fibrinoid deposition or chronic histolytic intervillositis may recur in >50% of subsequent pregnancies. Postpartum care in a placenta-focused program can provide effective counseling for modifiable maternal risk factors, and can assist in planning future pregnancy care based on the pathologic basis of fetal growth restriction.

Monitoring of Hemostasis and Management of Anticoagulant Thromboprophylaxis in Pregnant Women with Increased Risk of Fetal Loss.

Physiological prothrombotic changes during pregnancy and the postpartum period, along with other preexisting maternal risk factors, increase the risk of both venous thromboembolism (VTE) and adverse pregnancy outcomes. Pregnancy complications that develop due to placental insufficiency as a result of inappropriate activation of coagulation are present in more than 5% of pregnancies and can contribute to significant maternal morbidity and mortality. Therefore, anticoagulant prophylaxis in women with congenital and acquired thrombophilic conditions should be actively considered. According to the Guidelines of American College of Chest Physicians, the use of low-molecular-weight heparin is suggested for prophylaxis of VTE and pregnancy complications in high-risk pregnant women. However, personalized refinements of such thromboprophylaxis remains unspecified, despite the necessity of better targeted recommendations for life-threatening conditions. We, therefore, review the possibilities of longitudinal monitoring and comprehensive assessment of changes in hemostasis in the group of high-risk pregnant women, which can then be used for early prediction and individualization of the optimal anticoagulant thromboprophylaxis of pregnancy complications. Simultaneously, we present our single-center experience with such monitoring and our first series of results.

Imaging of activated complement using ultrasmall superparamagnetic iron oxide particles (USPIO)--conjugated vectors: an in vivo in utero non-invasive method to predict placental insufficiency and abnormal fetal brain development.

In the current study, we have developed a magnetic resonance imaging-based method for non-invasive detection of complement activation in placenta and foetal brain in vivo in utero. Using this method, we found that anti-complement C3-targeted ultrasmall superparamagnetic iron oxide (USPIO) nanoparticles bind within the inflamed placenta and foetal brain cortical tissue, causing a shortening of the T2* relaxation time. We used two mouse models of pregnancy complications: a mouse model of obstetrics antiphospholipid syndrome (APS) and a mouse model of preterm birth (PTB). We found that detection of C3 deposition in the placenta in the APS model was associated with placental insufficiency characterised by increased oxidative stress, decreased vascular endothelial growth factor and placental growth factor levels and intrauterine growth restriction. We also found that foetal brain C3 deposition was associated with cortical axonal cytoarchitecture disruption and increased neurodegeneration in the mouse model of APS and in the PTB model. In the APS model, foetuses that showed increased C3 in their brains additionally expressed anxiety-related behaviour after birth. Importantly, USPIO did not affect pregnancy outcomes and liver function in the mother and the offspring, suggesting that this method may be useful for detecting complement activation in vivo in utero and predicting placental insufficiency and abnormal foetal neurodevelopment that leads to neuropsychiatric disorders.

Mid-pregnancy fetal growth, uteroplacental Doppler indices and maternal demographic characteristics: role in prediction of stillbirth.

INTRODUCTION: To evaluate the relative value of mid trimester fetal growth, uterine artery Doppler indices and maternal demographics in prediction of stillbirth. MATERIAL AND METHODS: Retrospective cohort study; 23 894 singleton pregnancies routinely scanned between 19 and 24 weeks' gestation. Maternal characteristics included age, body mass index, ethnicity and medical history. Fetal biometry indices, birthweight and uterine artery pulsatility index values were converted to percentiles and multivariable logistic regression analysis was performed. The predictive accuracy was assessed using receiver operating characteristic curves analysis. The main outcome was prediction of preterm and term stillbirths. RESULTS: Non-Caucasian ethnicity, femur length centile and uterine artery pulsatility index were significantly associated with the risk of stillbirth (all p < 0.01). The detection rate of screening by maternal factors alone was 19% for all stillbirths, and 12 and 14% for term and preterm stillbirth at a 10% false positive rate, respectively. Using femur length centile alone, the detection rates were 27 and 23%, respectively. Uterine artery pulsatility index alone was able to predict 24 and 31% of term and preterm stillbirths. Screening by combining maternal factors, femur length centile and uterine artery Doppler detected 27 and 35% of term and preterm stillbirths at a 10% false positive rate. CONCLUSIONS: Second trimester ultrasound assessment offers an opportunity to identify pregnancies at the highest risk of stillbirth occurring as a consequence of placental dysfunction. This information may be useful to improve pregnancy outcome by identifying women who may benefit from increased ultrasound surveillance and/or timely intervention.

Placental involvement by non-Hodgkin lymphoma in a Crohn disease patient on long-term thiopurine therapy.

We report the first published case of aggressive diffuse large B-cell (non-Hodgkin) lymphoma in a 35-year-old pregnant woman who had Crohn disease and was taking long-term thiopurine therapy: the patient developed placental insufficiency, and there was intrauterine fetal death.

[Energy Metabolism in the Placenta and the Role of Disturbances in the Development of Placental Insufficiency at an Exacerbation of Cytomegalovirus Infection].

Objective: Determine the characteristics of placental energy metabolism and to establish its role in the development of placental insufficiency at an exacerbation of cytomegalovirus (CMV) infection in 25­28 weeks of gestation. Methods: In a prospective study of the case-control type included pregnant, delivery on term of 37­38 weeks. The sample of 50 pregnant women, including 25 CMV-seropositive with exacerbation of CMV infection at 25­28 weeks of gestation and with the titer of IgG antibodies to CMV 1: 1600 at the time of the study and 25 CMV-seronegative women the same pregnancy. The study was conducted at the obstetric department of pathology of pregnancy and laboratory «Etiopathogenesis mechanisms and recovery processes with non-specific lung diseases¼ Far Eastern Scientific Center of Physiology and Pathology of Respiration together with the urban maternity ward at City Hospital in the period from 2014 to 2015. The activity of pyruvate dehydrogenase, α-ketoglutarate dehydrogenase and a dehydrogenase lipoic acid was determined by histochemical methods on cryostat sections of fresh frozen tissue placenta by the method of R. Lilly. Evaluation of the intensity of histochemical reactions carried out by the program cytophotometry Scion. The morphology of the placenta was studied in paraffin sections stained with hematoxylin Böhmer-eosin, van Gieson's picrofuchsin and alcian blue by Steedman. Results: Exacerbation of CMV infection at 25­28 weeks of gestation leads to a decrease in the intensity of the histochemical reaction of pyruvate dehydrogenase in 2.4 times, lipoic acid dehydrogenase ­ in 2.9 times, and α-ketoglutarate dehydrogenase ­ in 1.5 times in the syncytiotrophoblast villous placenta. The placental morphological structure study showed villi in a state of death or necrotic changes, as well as increasing the number of avascular immature villi. In the maternal part of the placenta were marked constriction clearances, hypertrophy of muscle and connective tissue layers blood vessels. Conclusion: The findings suggest that the exacerbation of CMV infection at 25­28 weeks of pregnancy causes a decrease in the intensity of energy metabolism in the placenta by suppressing the activity of the enzymes α-ketoglutarate dehydrogenase and pyruvate dehydrogenase complex, which is accompanied by disturbances of the morphological structure of the placental barrier, the development of placental insufficiency.

The 4G/4G polymorphism of the plasminogen activator inhibitor-1 (PAI-1) gene as an independent risk factor for placental insufficiency, which triggers fetal hemodynamic centralization.

OBJECTIVE: To describe a case report of 4G/4G polymorphism of the plasminogen activator inhibitor-1 (PAI-1) gene as an independent risk factor for placental insufficiency. DESIGN: Case report. SETTING: Department of Public Health, State University of Ceará (UECE), Fortaleza-CE, Brazil. CASE REPORT: Hereditary hypofibrinolysis, which is mediated by 4G/4G homozygosity for the PAI-1 gene, is an independent risk factor for pregnancy complications, probably acting through thrombotic induction of placental insufficiency. We report a case of a low risk pregnancy, which separately presented placental insufficiency and fetal centralization at the beginning of the third trimester, without any other clinical manifestations during pregnancy. However, immediately after childbirth, the patient had a deep vein thrombosis of a lower limb. The anatomopathological examination of the placenta showed old and recent placental infarcts. Homozygosity for the 4G allele of PAI-1 gene was subsequently diagnosed as the sole probable causal factor.

Decrease of the incidence of renin-angiotensin-system inhibitor induced oligohydramnios-sequence in Germany in 2011.

AIM: to assess whether the incidence of angiotensin II-receptor type 1 antagonist (AT1-antagonist)­ or ACE-inhibitor induced cases of oligohydramnios sequence (OHS) in 2011 was reduced after intensive alerts as to the causal association between AT1-antagonist /ACE-inhibitor and OHS in the German medical literature. METHOD: 3 sources of information were used: A nationwide active surveillance of OHS in German paediatric hospitals (ESPED); Embryotox, (Berlin Institute for Clinical Teratology and Drug Risk Assessment in Pregnancy) and screening of pubmed (AT1-antagonist/ACE-inhibitor induced OHS). RESULTS: 45 cases of OHS were identified, no case due to maternal AT1-antagonist/ACE-inhibitor treatment. Causes for OHS were: premature rupture of membranes (PPROM) (n = 28), congenital anomalies of fetal kidneys and urinary tract(CAKUT (n = 15), placental insufficiency (n = 1),unknown cause (n = 1). Mortality until discharge was 37.8 % (32.1 % PPROM, 57.1 % CAKUT). Embryotox identified 3 exposures to AT1-antagonists in pregnancy, no case was associated with OHS. The pubmed search did not identify any case of OHS related to AT1-antagonist/ACE-inhibitor in pregnancy in Germany in 2011. CONCLUSION: Treatment of pregnant women with ACE inhibitors or AT1-antagonists still occurs but no cases of AT1-antagonist- or ACE-inhibitor induced OHS were reported in 2011 in Germany most likely due to repeated published alerts underlining the importance of consequent education. OHS remains a serious condition with high mortality despite modern intensive care.

[PREDICTORS OF FORMATION OF NEW FORMS--OF BRONCHOPULMONARY DYSPLASIA AT THE PRENATAL STAGE].

The analysis of history in 116 premature infants, of which 74 children formed a new form of bronchopulmionary dysplasia. The analysis revealed that predictors of the formation of new forms of bronchopulmonary dysplasia are the pregnant woman, accompanied by hypoxia (jeopardy throughout pregnancy, fetoplacental insufficiency, hypotension, pregnancy, anemia) or infectious inflammation (presence of IgG to a pregnant ureaplasma, chorioamnionitis, polyhydramnios).

Placental pathology lesions: International Society for Ultrasound in Obstetrics and Gynecology vs Society for Maternal-Fetal Medicine fetal growth restriction definitions.

BACKGROUND: Research on the definition of fetal growth restriction (FGR) has focused on predicting adverse perinatal outcomes. A significant limitation of this approach is that the individual outcomes of interest could be related to the condition and the treatment. Evaluation of outcomes that reflect the pathophysiology of FGR may overcome this limitation. OBJECTIVE: To compare the diagnostic performance of the FGR definitions established by the International Society for Ultrasound in Obstetrics and Gynecology (ISUOG) and the Society for Maternal-Fetal Medicine (SMFM) to predict placental histopathological findings associated with placental insufficiency and a composite adverse neonatal outcome (ANeO). STUDY DESIGN: In this retrospective cohort study of singleton pregnancies, the ISUOG and the SMFM guidelines were used to identify pregnancies with FGR and a corresponding control group. The primary outcome was the prediction of placental histopathological findings associated with placental insufficiency, defined as lesions associated with maternal vascular malperfusion (MVM). A composite ANeO (ie, umbilical artery pH≤7.1, Apgar score at 5 minutes ≤4, neonatal intensive care unit admission, hypoglycemia, respiratory distress syndrome requiring mechanical ventilation, intrapartum fetal distress requiring expedited delivery, and perinatal death) was investigated as a secondary outcome. Sensitivity, specificity, positive and negative predictive values, and the areas under the receiver-operating-characteristics curves were determined for each FGR definition. Logistic regression models were used to assess the association between each definition and the studied outcomes. A subgroup analysis of the diagnostic performance of both definitions stratifying the population in early and late FGR was also performed. RESULTS: Both societies' definitions showed a similar diagnostic performance as well as a significant association with the primary (ISUOG adjusted odds ratio 3.01 [95% confidence interval 2.42, 3.75]; SMFM adjusted odds ratio 2.85 [95% confidence interval 2.31, 3.51]) and secondary outcomes (ISUOG adjusted odds ratio 1.95 [95% confidence interval 1.56, 2.43]; SMFM adjusted odds ratio 2.12 [95% confidence interval 1.70, 2.65]). Furthermore, both FGR definitions had a limited discriminatory capacity for placental histopathological findings of MVM and the composite ANeO (area under the receiver-operating-characteristics curve ISUOG 0.63 [95% confidence interval 0.61, 0.65], 0.59 [95% confidence interval 0.56, 0.61]; area under the receiver-operating-characteristics SMFM 0.63 [95% confidence interval 0.61, 0.66], 0.60 [95% confidence interval 0.57, 0.62]). CONCLUSION: The ISUOG and the SMFM FGR definitions have limited discriminatory capacity for placental histopathological findings associated with placental insufficiency and a composite ANeO. El resumen está disponible en Español al final del artículo.

Fetal assessment for anesthesiologists: are you evaluating the other patient?

Suboptimal communication between anesthesiologists and obstetricians can be associated with unintended poor maternal and neonatal outcomes, especially for emergency cesarean deliveries. Obstetricians use the results of antepartum and intrapartum fetal assessments to assess fetal well-being and to make decisions about the timing and method of delivery. Because abnormal results may lead to the need for urgent or emergency cesarean deliveries, these decisions may directly impact anesthetic care. Lack of familiarity with fetal assessments and the significance of the results may thus hinder the communication necessary for optimal patient care. In this review article, we discuss the current antepartum and intrapartum fetal assessment modalities, including the nonstress test, biophysical profile, Doppler velocimetry, electronic fetal heart rate monitoring, fetal electrocardiogram (STAN-ST waveform analysis), and fetal pulse oximetry. The physiologic basis behind these modalities and the available evidence regarding their utility in clinical practice are also reviewed. The 2008 National Institute of Child Health and Human Development workshop report on electronic fetal monitoring categories, which are incorporated into the American College of Obstetricians and Gynecologists guidelines for intrapartum care, is examined. The implications of test interpretation to the practice of obstetric anesthesiology is also discussed. Anesthesia provider understanding of fetal assessment modalities is essential in improving communication with obstetricians and improving the planning of cesarean deliveries for high-risk obstetric patients.

Nanomedicines: An approach to treat placental insufficiency and the current challenges.

INTRODUCTION: Preeclampsia and fetal growth restriction are common pregnancy complications that significantly impact perinatal health and offspring development later in life. The origin of these complex syndromes overlap in placental insufficiency. Progress in developing treatments for maternal, placental or fetal health is mainly limited by the risk of maternal and fetal toxicity. Nanomedicines are a promising approach to safely treat pregnancy complications since they can regulate drug interaction with the placenta to enhance efficacy of the treatment while minimizing exposure of the fetus. METHODS: This narrative review discusses the current developments and challenges of nanomedicines during pregnancy with a focus on preclinical models of placenta insufficiency syndromes. Firstly, we outline the safety requirements and potential therapeutic maternal and placental targets. Secondly, we review the prenatal therapeutic effects of the nanomedicines that have been tested in experimental models of placental insufficiency syndromes. RESULTS: The majority of liposomes and polymeric drug delivery system show promising results regarding the prevention of trans-placental passage nanomedicines in uncomplicated and complicated pregnancies. The others two studied classes, quantum dots and silicon nanoparticles, have been investigated to a limited extent in placental insufficiency syndromes. Characteristics of the nanoparticles such as charge, size, and timing of administration have been shown to influence the trans-placental passage. The few available preclinical therapeutic studies on placental insufficiency syndromes predominantly show beneficial effects of nanomedicines on both maternal and fetal health, but demonstrate contradicting results on placental health. Interpretation of results in this field is complicated by the fact that results are influenced by the choice of animal species and model, gestational age, placental maturity and integrity, and nanoparticle administration route. CONCLUSION: Nanomedicines form a promising therapeutic approach during (complicated) pregnancies mainly by reducing fetal toxicity and regulating drug interaction with the placenta. Different nanomedicines have been proven to effectively prevent trans-placental passage of encapsulated agents. This can be expected to dramatically reduce risks for fetal adverse effects. Furthermore, a number of these nanomedicines positively impacted maternal and fetal health in animal models for placental insufficiency. Demonstrating that effective drug concentrations can be reached in the target tissue. While these first animal studies are encouraging, more research is needed to better understand the influence of the pathophysiology of this multi-factorial disease before implementation in clinical practice can be considered. Therefore, extensive evaluation of safety and efficacy of these targeted nanoparticles is needed within multiple animal, in vitro, and/or ex vivo models. This may be complemented by diagnostic tools to assess the disease status to identify the best time to initiate treatment. Together these investigations should contribute to building confidence in the safety of nanomedicines for treating mother and child, as safety has, understandably, the highest priority in this sensitive patient groups.

Temporal patterns in count-to-ten fetal movement charts and their associations with pregnancy characteristics: a prospective cohort study.

BACKGROUND: Fetal movement counting has long been suggested as a screening tool to identify impaired placental function. However, quantitative limits for decreased fetal movement perform poorly for screening purposes, indicating the need for methodological refinement. We aimed to identify the main individual temporal patterns in fetal movement counting charts, and explore their associations with pregnancy characteristics. METHODS: In a population-based prospective cohort in Norway, 2009-2011, women with singleton pregnancies counted fetal movements daily from pregnancy week 24 until delivery using a modified "count-to-ten" procedure. To account for intra-woman correlation of observations, we used functional data analysis and corresponding functional principal component analysis to identify the main individual temporal patterns in fetal movement count data. The temporal patterns are described by continuous functional principal component (FPC) curves, with an individual score on each FPC for each woman. These scores were later used as outcome variables in multivariable linear regression analyses, with pregnancy characteristics as explanatory variables. RESULTS: Fetal movement charts from 1086 pregnancies were included. Three FPC curves explained almost 99% of the variation in the temporal data, with the first FPC, representing the individual overall counting time, accounting for 91% alone. There were several statistically significant associations between the FPCs and various pregnancy characteristics. However, the effects were small and of limited clinical value. CONCLUSIONS: This statistical approach for analyzing fetal movement counting data successfully captured clinically meaningful individual temporal patterns and how these patterns vary between women. Maternal body mass index, gestational age and placental site explained little of the variation in the temporal fetal movement counting patterns. Thus, a perceived decrease in fetal movement should not be attributed to a woman's basic pregnancy characteristics, but assessed as a potential marker of risk.

Fetal cardiac function: technical considerations and potential research and clinical applications.

Fetal echocardiography was initially used to detect structural anomalies but has more recently also been proposed to assess fetal cardiac function. This review summarizes technical issues and limitations in fetal cardiac function evaluation, as well as its potential research and clinical applications. Functional echocardiography has been demonstrated to select high-risk populations and to be associated with outcome in several fetal conditions including intrauterine growth restriction, twin-to-twin transfusion syndrome, maternal diabetes, and congenital diaphragmatic hernia. Fetal heart evaluation is challenging due to the smallness and high heart rate of the fetus and restricted access to the fetus far from the transducer. Due to these limitations and differences in cardiac function which are related to fetal maturation, cardiovascular parameters should be validated in the fetus and used with caution. Despite these precautions, in expert hands and with appropriate ultrasound equipment, evaluation of cardiac function is feasible in most fetuses. Functional fetal echocardiography is a promising tool that may soon be incorporated into clinical practice. Research is warranted to further refine the contribution of fetal cardiac assessment to the diagnosis, monitoring, or prediction of outcomes in various fetal conditions.