Fetal intelligent navigation echocardiography (FINE) has superior performance compared to manual navigation of the fetal heart by non-expert sonologists.

OBJECTIVES: Manual and intelligent navigation (i.e. fetal intelligent navigation echocardiography or FINE) by the operator are two methods to obtain standard fetal cardiac views from spatiotemporal image correlation (STIC) volumes. The objective was to compare the performance between manual and intelligent navigation (FINE) of the fetal heart by non-expert sonologists. METHODS: In this prospective observational study, ten sonologists underwent formal training on both navigational methods. Subsequently, they were tested on their ability to obtain nine cardiac views from five STIC volumes of normal fetal hearts (19-28 gestational weeks) using such methods. The following parameters were determined for both methods: (1) success rate of obtaining nine cardiac views; (2) mean time to obtain nine cardiac views per sonologist; and (3) maximum number of cardiac views successfully obtained for each STIC volume. RESULTS: All fetal cardiac images obtained from 100 STIC volumes (50 for each navigational method) were reviewed by an expert in fetal echocardiography. Compared to manual navigation, FINE was associated with a significantly: (1) higher success rate of obtaining eight (excluding the abdomen view) appropriate cardiac views (92-100% vs. 56-88%; all p<0.05); (2) shorter mean time (minute:seconds) to obtain nine cardiac views (2:11 ± 0:37 vs. 15:49 ± 7:44; p<0.0001); and (3) higher success rate of obtaining all nine cardiac views for a given STIC volume (86 vs. 14%; p<0.001). CONCLUSIONS: When performed by non-expert sonologists, intelligent navigation (FINE) had a superior performance compared to manual navigation of the normal fetal heart. Specifically, FINE obtained appropriate fetal cardiac views in 92-100% of cases.

The etiology of preeclampsia.

Preeclampsia is one of the "great obstetrical syndromes" in which multiple and sometimes overlapping pathologic processes activate a common pathway consisting of endothelial cell activation, intravascular inflammation, and syncytiotrophoblast stress. This article reviews the potential etiologies of preeclampsia. The role of uteroplacental ischemia is well-established on the basis of a solid body of clinical and experimental evidence. A causal role for microorganisms has gained recognition through the realization that periodontal disease and maternal gut dysbiosis are linked to atherosclerosis, thus possibly to a subset of patients with preeclampsia. The recent reports indicating that SARS-CoV-2 infection might be causally linked to preeclampsia are reviewed along with the potential mechanisms involved. Particular etiologic factors, such as the breakdown of maternal-fetal immune tolerance (thought to account for the excess of preeclampsia in primipaternity and egg donation), may operate, in part, through uteroplacental ischemia, whereas other factors such as placental aging may operate largely through syncytiotrophoblast stress. This article also examines the association between gestational diabetes mellitus and maternal obesity with preeclampsia. The role of autoimmunity, fetal diseases, and endocrine disorders is discussed. A greater understanding of the etiologic factors of preeclampsia is essential to improve treatment and prevention.

Toward a new taxonomy of obstetrical disease: improved performance of maternal blood biomarkers for the great obstetrical syndromes when classified according to placental pathology.

BACKGROUND: The major challenge for obstetrics is the prediction and prevention of the great obstetrical syndromes. We propose that defining obstetrical diseases by the combination of clinical presentation and disease mechanisms as inferred by placental pathology will aid in the discovery of biomarkers and add specificity to those already known. OBJECTIVE: To describe the longitudinal profile of placental growth factor (PlGF), soluble fms-like tyrosine kinase-1 (sFlt-1), and the PlGF/sFlt-1 ratio throughout gestation, and to determine whether the association between abnormal biomarker profiles and obstetrical syndromes is strengthened by information derived from placental examination, eg, the presence or absence of placental lesions of maternal vascular malperfusion. STUDY DESIGN: This retrospective case cohort study was based on a parent cohort of 4006 pregnant women enrolled prospectively. The case cohort of 1499 pregnant women included 1000 randomly selected patients from the parent cohort and all additional patients with obstetrical syndromes from the parent cohort. Pregnant women were classified into six groups: 1) term delivery without pregnancy complications (n=540; control); 2) preterm labor and delivery (n=203); 3) preterm premature rupture of the membranes (n=112); 4) preeclampsia (n=230); 5) small-for-gestational-age neonate (n=334); and 6) other pregnancy complications (n=182). Maternal plasma concentrations of PlGF and sFlt-1 were determined by enzyme-linked immunosorbent assays in 7560 longitudinal samples. Placental pathologists, masked to clinical outcomes, diagnosed the presence or absence of placental lesions of maternal vascular malperfusion. Comparisons between mean biomarker concentrations in cases and controls were performed by utilizing longitudinal generalized additive models. Comparisons were made between controls and each obstetrical syndrome with and without subclassifying cases according to the presence or absence of placental lesions of maternal vascular malperfusion. RESULTS: 1) When obstetrical syndromes are classified based on the presence or absence of placental lesions of maternal vascular malperfusion, significant differences in the mean plasma concentrations of PlGF, sFlt-1, and the PlGF/sFlt-1 ratio between cases and controls emerge earlier in gestation; 2) the strength of association between an abnormal PlGF/sFlt-1 ratio and the occurrence of obstetrical syndromes increases when placental lesions of maternal vascular malperfusion are present (adjusted odds ratio [aOR], 13.6 vs 6.7 for preeclampsia; aOR, 8.1 vs 4.4 for small-for-gestational-age neonates; aOR, 5.5 vs 2.1 for preterm premature rupture of the membranes; and aOR, 3.3 vs 2.1 for preterm labor (all P<0.05); and 3) the PlGF/sFlt-1 ratio at 28 to 32 weeks of gestation is abnormal in patients who subsequently delivered due to preterm labor with intact membranes and in those with preterm premature rupture of the membranes if both groups have placental lesions of maternal vascular malperfusion. Such association is not significant in patients with these obstetrical syndromes who do not have placental lesions. CONCLUSION: Classification of obstetrical syndromes according to the presence or absence of placental lesions of maternal vascular malperfusion allows biomarkers to be informative earlier in gestation and enhances the strength of association between biomarkers and clinical outcomes. We propose that a new taxonomy of obstetrical disorders informed by placental pathology will facilitate the discovery and implementation of biomarkers as well as the prediction and prevention of such disorders.

Population-Level Study on Fetal Deaths and Preterm Births during SARS-CoV-2 Pandemic in the State of Michigan.

OBJECTIVE: The aim of the study is to explore the effect of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic on preterm birth at different gestational ages and fetal death in the state of Michigan. STUDY DESIGN: Data on live births and fetal deaths in the state of Michigan from March to November in the years 2017 through 2020 were obtained from Michigan Department of Health and Human Services (MDHHS). Preterm birth rate, fetal death rate (per 1,000 live births) overall and stratified by race and maternal comorbidities during the period of pandemic (March-November 2020) were compared with the same period (March-November) in the prepandemic years (2017-2019). RESULTS: Of 328,879 live births and 1,470 fetal deaths during the study period, 77,983 live births and 242 fetal deaths were reported in 2020. Compared with prepandemic years, fetal death rate per 1,000 live births was significantly lower in 2020 (3.1 vs. 4.7 [2017], 5.2 [2018], 4.4 [2019], p-value <0.001). The adjusted risk for fetal death in 2020 was decreased (odds ratio [OR] = 0.64 [95% confidence interval (CI): 0.56-0.74], p <0.0001), compared with prepandemic years. Fetal death was significantly associated with African-American race, pregnancy hypertension and prepregnancy diabetes. No significant difference in the proportion of preterm births (<37 weeks' gestation) was noted between pandemic and prepandemic years (9.9 vs. 10.0%, p = 0.50). There was no significant difference in the risk of preterm birth across gestational age strata (<28, 28-316/7, 32-366/7, 37-416/7, and >42 weeks) between pandemic and prepandemic years on multinomial analysis. Significant associations with preterm birth across all years included African American race, lower level of maternal education, pregnancy-induced hypertension, chronic hypertension, prepregnancy diabetes, congenital anomalies, previous preterm birth, and prolonged rupture of membranes >12 hours. CONCLUSION: Fetal death rate was significantly lower whereas preterm births remained unchanged during pandemic in comparison with prepandemic years in the state of Michigan. KEY POINTS: · A decrease in fetal death rate was noted during SARS CoV-2 pandemic in the State of Michigan.. · Overall state-wide rates of preterm birth did not change in 2020, compared to previous years.. · Significant risk factors associated with preterm birth and fetal deaths did not differ between prepandemic and pandemic years..

Personalized assessment of cervical length improves prediction of spontaneous preterm birth: a standard and a percentile calculator.

BACKGROUND: A sonographic short cervix (length <25 mm during midgestation) is the most powerful predictor of preterm birth. Current clinical practice assumes that the same cervical length cutoff value should apply to all women when screening for spontaneous preterm birth, yet this approach may be suboptimal. OBJECTIVE: This study aimed to (1) create a customized cervical length standard that considers relevant maternal characteristics and gestational age at sonographic examination and (2) assess whether the customization of cervical length evaluation improves the prediction of spontaneous preterm birth. STUDY DESIGN: This retrospective analysis comprises a cohort of 7826 pregnant women enrolled in a longitudinal protocol between January 2006 and April 2017 at the Detroit Medical Center. Study participants met the following inclusion criteria: singleton pregnancy, ≥1 transvaginal sonographic measurements of the cervix, delivery after 20 weeks of gestation, and available relevant demographics and obstetrical history information. Data from women without a history of preterm birth or cervical surgery who delivered at term without progesterone treatment (N=5188) were used to create a customized standard of cervical length. The prediction of the primary outcome, spontaneous preterm birth at <37 weeks of gestation, was assessed in a subset of pregnancies (N=7336) that excluded cases with induced labor before 37 weeks of gestation. Area under the receiver operating characteristic curve and sensitivity at a fixed false-positive rate were calculated for screening at 20 to 23 6/7, 24 to 27 6/7, 28 to 31 6/7, and 32 to 35 6/7 weeks of gestation in asymptomatic patients. Survival analysis was used to determine which method is better at predicting imminent delivery among symptomatic women. RESULTS: The median cervical length remained fundamentally unchanged until 20 weeks of gestation and subsequently decreased nonlinearly with advancing gestational age among women who delivered at term. The effects of parity and maternal weight and height on the cervical length were dependent on the gestational age at ultrasound examination (interaction, P<.05 for all). Parous women had a longer cervix than nulliparous women, and the difference increased with advancing gestation after adjusting for maternal weight and height. Similarly, maternal weight was nonlinearly associated with a longer cervix, and the effect was greater later in gestation. The sensitivity at a 10% false-positive rate for prediction of spontaneous preterm birth at <37 weeks of gestation by a short cervix ranged from 29% to 40% throughout pregnancy, yet it increased to 50%, 50%, 53%, and 54% at 20 to 23 6/7, 24 to 27 6/7, 28 to 31 6/7, and 32 to 35 6/7 weeks of gestation, respectively, for a low, customized percentile (McNemar test, P<.001 for all). When a cervical length <25 mm was compared to the customized screening at 20 to 23 6/7 weeks of gestation by using a customized percentile cutoff value that ensured the same negative likelihood ratio for both screening methods, the customized approach had a significantly higher (about double) positive likelihood ratio in predicting spontaneous preterm birth at <33, <34, <35, <36, and <37 weeks of gestation. Among symptomatic women, the difference in survival between women with a customized cervical length percentile of ≥10th and those with a customized cervical length percentile of <10th was greater than the difference in survival between women with a cervical length ≥25 mm and those with a cervical length <25 mm. CONCLUSION: Compared to the use of a cervical length <25 mm, a customized cervical length assessment (1) identifies more women at risk of spontaneous preterm birth and (2) improves the distinction between patients at risk for impending preterm birth in those who have an episode of preterm labor.

Cardiac Measurements of Size and Shape in Fetuses With Absent or Reversed End-Diastolic Velocity of the Umbilical Artery and Perinatal Survival and Severe Growth Restriction Before 34 Weeks' Gestation.

OBJECTIVES: The purpose of this study was to evaluate the end-diastolic size and shape of the 4-chamber view as well as the right ventricle (RV) and left ventricle (LV) in growth-restricted fetuses before 34 weeks' gestation with absent or reversed end-diastolic velocity of the umbilical artery and compare the results between those with perinatal deaths and those who survived the neonatal period. METHODS: Forty-nine fetuses with growth restriction and absent or reversed end-diastolic velocity of the umbilical artery were studied. The size, shape, and sphericity index of the 4-chamber view, RV, and LV were assessed. The number and percentage of fetuses with z score values of less than -1.65 and greater than 1.65 were computed. RESULTS: Of the 49 fetuses, there were 13 perinatal deaths (27%) and 36 (63%) neonatal survivors. Measurements that were unique for neonatal survivors were an increased RV apical transverse width and decreased measurements of the following: LV and RV widths, LV and RV areas, as well as RV sphericity indices. CONCLUSIONS: Fetuses with a smaller RV and LV size and area and those with a globular-shaped RV were at significantly lower risk for perinatal death.

Bacteria in the amniotic fluid without inflammation: early colonization vs. contamination.

OBJECTIVES: Intra-amniotic infection, defined by the presence of microorganisms in the amniotic cavity, is often accompanied by intra-amniotic inflammation. Occasionally, laboratories report the growth of bacteria or the presence of microbial nucleic acids in amniotic fluid in the absence of intra-amniotic inflammation. This study was conducted to determine the clinical significance of the presence of bacteria in amniotic fluid samples in the absence of intra-amniotic inflammation. METHODS: A retrospective cross-sectional study included 360 patients with preterm labor and intact membranes who underwent transabdominal amniocentesis for evaluation of the microbial state of the amniotic cavity as well as intra-amniotic inflammation. Cultivation techniques were used to isolate microorganisms, and broad-range polymerase chain reaction coupled with electrospray ionization mass spectrometry (PCR/ESI-MS) was utilized to detect the nucleic acids of bacteria, viruses, and fungi. RESULTS: Patients whose amniotic fluid samples evinced microorganisms but did not indicate inflammation had a similar perinatal outcome to those without microorganisms or inflammation [amniocentesis-to-delivery interval (p=0.31), spontaneous preterm birth before 34 weeks (p=0.83), acute placental inflammatory lesions (p=1), and composite neonatal morbidity (p=0.8)]. CONCLUSIONS: The isolation of microorganisms from a sample of amniotic fluid in the absence of intra-amniotic inflammation is indicative of a benign condition, which most likely represents contamination of the specimen during the collection procedure or laboratory processing rather than early colonization or infection.

Disorders of placental villous maturation are present in one-third of cases with spontaneous preterm labor.

OBJECTIVES: Spontaneous preterm labor is an obstetrical syndrome accounting for approximately 65-70% of preterm births, the latter being the most frequent cause of neonatal death and the second most frequent cause of death in children less than five years of age worldwide. The purpose of this study was to determine and compare to uncomplicated pregnancies (1) the frequency of placental disorders of villous maturation in spontaneous preterm labor; (2) the frequency of other placental morphologic characteristics associated with the preterm labor syndrome; and (3) the distribution of these lesions according to gestational age at delivery and their severity. METHODS: A case-control study of singleton pregnant women was conducted that included (1) uncomplicated pregnancies (controls, n=944) and (2) pregnancies with spontaneous preterm labor (cases, n=438). All placentas underwent histopathologic examination. Patients with chronic maternal diseases (e.g., chronic hypertension, diabetes mellitus, renal disease, thyroid disease, asthma, autoimmune disease, and coagulopathies), fetal malformations, chromosomal abnormalities, multifetal gestation, preeclampsia, eclampsia, preterm prelabor rupture of the fetal membranes, gestational hypertension, gestational diabetes mellitus, and HELLP (hemolysis, elevated liver enzymes and low platelet count) syndrome were excluded from the study. RESULTS: Compared to the controls, the most prevalent placental lesions among the cases were the disorders of villous maturation (31.8% [106/333] including delayed villous maturation 18.6% [62/333] vs. 1.4% [6/442], q<0.0001, prevalence ratio 13.7; and accelerated villous maturation 13.2% [44/333] vs. 0% [0/442], q<0.001). Other lesions in decreasing order of prevalence included hypercapillarized villi (15.6% [68/435] vs. 3.5% [33/938], q<0.001, prevalence ratio 4.4); nucleated red blood cells (1.1% [5/437] vs. 0% [0/938], q<0.01); chronic inflammatory lesions (47.9% [210/438] vs. 29.9% [282/944], q<0.0001, prevalence ratio 1.6); fetal inflammatory response (30.1% [132/438] vs. 23.2% [219/944], q<0.05, prevalence ratio 1.3); maternal inflammatory response (45.5% [195/438] vs. 36.1% [341/944], q<0.01, prevalence ratio 1.2); and maternal vascular malperfusion (44.5% [195/438] vs. 35.7% [337/944], q<0.01, prevalence ratio 1.2). Accelerated villous maturation did not show gestational age-dependent association with any other placental lesion while delayed villous maturation showed a gestational age-dependent association with acute placental inflammation (q-value=0.005). CONCLUSIONS: Disorders of villous maturation are present in nearly one-third of the cases of spontaneous preterm labor.

Clinical chorioamnionitis at term X: microbiology, clinical signs, placental pathology, and neonatal bacteremia - implications for clinical care.

OBJECTIVES: Clinical chorioamnionitis at term is considered the most common infection-related diagnosis in labor and delivery units worldwide. The syndrome affects 5-12% of all term pregnancies and is a leading cause of maternal morbidity and mortality as well as neonatal death and sepsis. The objectives of this study were to determine the (1) amniotic fluid microbiology using cultivation and molecular microbiologic techniques; (2) diagnostic accuracy of the clinical criteria used to identify patients with intra-amniotic infection; (3) relationship between acute inflammatory lesions of the placenta (maternal and fetal inflammatory responses) and amniotic fluid microbiology and inflammatory markers; and (4) frequency of neonatal bacteremia. METHODS: This retrospective cross-sectional study included 43 women with the diagnosis of clinical chorioamnionitis at term. The presence of microorganisms in the amniotic cavity was determined through the analysis of amniotic fluid samples by cultivation for aerobes, anaerobes, and genital mycoplasmas. A broad-range polymerase chain reaction coupled with electrospray ionization mass spectrometry was also used to detect bacteria, select viruses, and fungi. Intra-amniotic inflammation was defined as an elevated amniotic fluid interleukin-6 (IL-6) concentration ≥2.6 ng/mL. RESULTS: (1) Intra-amniotic infection (defined as the combination of microorganisms detected in amniotic fluid and an elevated IL-6 concentration) was present in 63% (27/43) of cases; (2) the most common microorganisms found in the amniotic fluid samples were Ureaplasma species, followed by Gardnerella vaginalis; (3) sterile intra-amniotic inflammation (elevated IL-6 in amniotic fluid but without detectable microorganisms) was present in 5% (2/43) of cases; (4) 26% of patients with the diagnosis of clinical chorioamnionitis had no evidence of intra-amniotic infection or intra-amniotic inflammation; (5) intra-amniotic infection was more common when the membranes were ruptured than when they were intact (78% [21/27] vs. 38% [6/16]; p=0.01); (6) the traditional criteria for the diagnosis of clinical chorioamnionitis had poor diagnostic performance in identifying proven intra-amniotic infection (overall accuracy, 40-58%); (7) neonatal bacteremia was diagnosed in 4.9% (2/41) of cases; and (8) a fetal inflammatory response defined as the presence of severe acute funisitis was observed in 33% (9/27) of cases. CONCLUSIONS: Clinical chorioamnionitis at term, a syndrome that can result from intra-amniotic infection, was diagnosed in approximately 63% of cases and sterile intra-amniotic inflammation in 5% of cases. However, a substantial number of patients had no evidence of intra-amniotic infection or intra-amniotic inflammation. Evidence of the fetal inflammatory response syndrome was frequently present, but microorganisms were detected in only 4.9% of cases based on cultures of aerobic and anaerobic bacteria in neonatal blood.

Placental delayed villous maturation is associated with evidence of chronic fetal hypoxia.

Background Normal development of the human placenta, referred to as villous tree maturation, entails formation of the vasculosyncytial membranes. These structures develop by the approximation of syncytiotrophoblasts with the villous capillary endothelium and constitute the most efficient sites of gaseous exchange in the placenta. Defective maturation of the villous tree can lead to deficient vasculosyncytial membranes, implicated in the high incidence of hypoxic complications. Hypoxia, in turn, can stimulate production of erythropoietin, whereby increased fetal plasma or amniotic fluid concentrations of this hormone reflect fetal hypoxemia. The current study was undertaken to determine whether delayed villous maturation is associated with changes in amniotic fluid erythropoietin concentrations. Methods Placental histologic examination was performed using hematoxylin and eosin. Subsequent to histologic assessment of delayed villous maturation, the diagnosis was confirmed with CD-15 immunohistochemistry. The controls (n = 61) were pregnancies without villous maturation abnormalities, and cases (n = 5) were pregnancies with delayed villous maturation. Amniotic fluid erythropoietin concentrations were measured using a specific immunoassay. Results Concentrations of erythropoietin in the amniotic fluid (1) of controls were less than the limit of detection and (2) of cases with delayed villous maturation were significantly higher than those of controls (P-value = 0.048). Conclusion Delayed villous maturation is associated with higher concentrations of amniotic fluid erythropoietin.

Disorders of placental villous maturation in fetal death.

Objective The aims of this study were to ascertain the frequency of disorders of villous maturation in fetal death and to also delineate other placental histopathologic lesions in fetal death. Methods This was a retrospective observational cohort study of fetal deaths occurring among women between January 2004 and January 2016 at Hutzel Women's Hospital, Detroit, MI, USA. Cases comprised fetuses with death beyond 20 weeks' gestation. Fetal deaths with congenital anomalies and multiple gestations were excluded. Controls included pregnant women without medical/obstetrical complications and delivered singleton, term (37-42 weeks) neonate with 5-min Apgar score ≥7 and birthweight between the 10th and 90th percentiles. Results Ninety-two percent (132/143) of placentas with fetal death showed placental histologic lesions. Fetal deaths were associated with (1) higher frequency of disorders of villous maturation [44.0% (64/143) vs. 1.0% (4/405), P < 0.0001, prevalence ratio, 44.6; delayed villous maturation, 22% (31/143); accelerated villous maturation, 20% (28/143); and maturation arrest, 4% (5/143)]; (2) higher frequency of maternal vascular malperfusion lesions [75.5% (108/143) vs. 35.7% (337/944), P < 0.0001, prevalence ratio, 2.1] and fetal vascular malperfusion lesions [88.1% (126/143) vs. 19.7% (186/944), P < 0.0001, prevalence ratio, 4.5]; (3) higher frequency of placental histologic patterns suggestive of hypoxia [59.0% (85/143) vs. 9.3% (82/942), P < 0.0001, prevalence ratio, 6.8]; and (4) higher frequency of chronic inflammatory lesions [53.1% (76/143) vs. 29.9% (282/944), P < 0.001, prevalence ratio 1.8]. Conclusion This study demonstrates that placentas of women with fetal death were 44 times more likely to present disorders of villous maturation compared to placentas of those with normal pregnancy. This suggests that the burden of placental disorders of villous maturation lesions is substantial.

Dual-Imaging Modality Approach to Evaluate Cerebral Hemodynamics in Growth-Restricted Fetuses: Oxygenation and Perfusion.

OBJECTIVE: To evaluate a dual-imaging modality approach to obtain a combined estimation of venous blood oxygenation (SνO2) using susceptibility-weighted magnetic resonance imaging (SWI-MRI), and blood perfusion using power Dopp-ler ultrasound (PDU) and fractional moving blood volume (FMBV) in the brain of normal growth and growth-restricted fetuses. METHODS: Normal growth (n = 33) and growth-restricted fetuses (n = 10) from singleton pregnancies between 20 and 40 weeks of gestation were evaluated. MRI was performed and SνO2 was calculated using SWI-MRI data obtained in the straight section of the superior sagittal sinus. Blood perfusion was estimated using PDU and FMBV from the frontal lobe in a mid-sagittal plane of the fetal brain. The association between fetal brain SνO2 and FMBV, and the distribution of SνO2 and FMBV values across gestation were calculated for both groups. RESULTS: In growth-restricted fetuses, the brain SνO2 values were similar, and the FMBV values were higher across gestation as compared to normal growth fetuses. There was a significantly positive association between SνO2 and FMBV values (slope = 0.38 ± 0.12; r = 0.7; p = 0.02) in growth-restricted fetuses. In normal growth fetuses, SνO2 showed a mild decreasing trend (slope = -0.7 ± 0.4; p = 0.1), whereas FMBV showed a mild increasing trend (slope = 0.2 ± 0.2; p = 0.2) with advancing gestation, and a mild but significant negative association (slope = -0.78 ± 0.3; r = -0.4; p = 0.04) between these two estimates. CONCLUSION: Combined MRI (SWI) and ultrasound (FMBV) techniques showed a significant association between cerebral blood oxygenation and blood perfusion in normal growth and growth-restricted fetuses. This dual-imaging approach could contribute to the early detection of fetal "brain sparing" and brain oxygen saturation changes in high-risk pregnancies.

Quantitative susceptibility mapping in the human fetus to measure blood oxygenation in the superior sagittal sinus.

OBJECTIVES: To present the feasibility of performing quantitative susceptibility mapping (QSM) in the human fetus to evaluate the oxygenation (SvO2) of cerebral venous blood in vivo. METHODS: Susceptibility weighted imaging (SWI) data were acquired from healthy pregnant subjects (n = 21, median = 31.3 weeks, interquartile range = 8.8 weeks). The susceptibility maps were generated from the SWI-phase images using a modified QSM processing pipeline, optimised for fetal applications. The processing pipeline is as follows: (1) mild high-pass filtering followed by quadratic fitting of the phase images to eliminate background phase variations; (2) manual creation of a fetal brain mask that includes the superior sagittal sinus (SSS); (3) inverse filtering of the resultant masked phase images using a truncated k-space approach with geometric constraint. Further, the magnetic susceptibility, ∆χv and corresponding putative SvO2 of the SSS were quantified from the generated susceptibility maps. Systematic error in the measured SvO2 due to the modified pipeline was also studied through simulations. RESULTS: Simulations showed that the systematic error in SvO2 when using a mask that includes a minimum of 5 voxels around the SSS and five slices remains < 3% for different orientations of the vessel relative to the main magnetic field. The average ∆χv in the SSS quantified across all gestations was 0.42 ± 0.03 ppm. Based on ∆χv, the average putative SvO2 in the SSS across all fetuses was 67% ± 7%, which is in good agreement with published studies. CONCLUSIONS: This in vivo study demonstrates the feasibility of using QSM in the human fetal brain to estimate ∆χv and SvO2. KEY POINTS: • A modified quantitative susceptibility mapping (QSM) processing pipeline is tested and presented for the human fetus. • QSM is feasible in the human fetus for measuring magnetic susceptibility and oxygenation of venous blood in vivo. • Blood magnetic susceptibility values from MR susceptometry and QSM agree with each other in the human fetus.

Mechanisms of death in structurally normal stillbirths.

Objectives To investigate mechanisms of in utero death in normally formed fetuses by measuring amniotic fluid (AF) biomarkers for hypoxia (erythropoietin [EPO]), myocardial damage (cardiac troponin I [cTnI]) and brain injury (glial fibrillary acidic protein [GFAP]), correlated with risk factors for fetal death and placental histopathology. Methods This retrospective, observational cohort study included intrauterine deaths with transabdominal amniocentesis prior to induction of labor. Women with a normal pregnancy and an indicated amniocentesis at term were randomly selected as controls. AF was assayed for EPO, cTnI and GFAP using commercial immunoassays. Placental histopathology was reviewed, and CD15-immunohistochemistry was used. Analyte concentrations >90th centile for controls were considered "raised". Raised AF EPO, AF cTnI and AF GFAP concentrations were considered evidence of hypoxia, myocardial and brain injury, respectively. Results There were 60 cases and 60 controls. Hypoxia was present in 88% (53/60), myocardial damage in 70% (42/60) and brain injury in 45% (27/60) of fetal deaths. Hypoxic fetuses had evidence of myocardial injury, brain injury or both in 77% (41/53), 49% (26/53) and 13% (7/53) of cases, respectively. Histopathological evidence for placental dysfunction was found in 74% (43/58) of these cases. Conclusion Hypoxia, secondary to placental dysfunction, was found to be the mechanism of death in the majority of fetal deaths among structurally normal fetuses. Ninety-one percent of hypoxic fetal deaths sustained brain, myocardial or both brain and myocardial injuries in utero. Hypoxic myocardial injury was an attributable mechanism of death in 70% of the cases. Non-hypoxic cases may be caused by cardiac arrhythmia secondary to a cardiac conduction defect.

Quantitative Flow Imaging in Human Umbilical Vessels In Utero Using Nongated 2D Phase Contrast MRI.

BACKGROUND: Volumetric assessment of afferent blood flow rate provides a measure of global organ perfusion. Phase-contrast magnetic resonance imaging (PCMRI) is a reliable tool for volumetric flow quantification, but given the challenges with motion and lack of physiologic gating signal, such studies, in vivo on the human placenta, are scant. PURPOSE: To evaluate and apply a nongated (ng) PCMRI technique for quantifying blood flow rates in utero in umbilical vessels. STUDY TYPE: Prospective study design. STUDY POPULATION: Twenty-four pregnant women with median gestational age (GA) 30 4/7 weeks and interquartile range (IQR) 8 1/7 weeks. FIELD STRENGTH/SEQUENCE: All scans were performed on a 3.0T Siemens Verio system using the ng-PCMRI technique. ASSESSMENT: The GA-dependent increase in umbilical vein (UV) and arterial (UA) flow was compared to previously published values. Systematic error to be expected from ng-PCMRI, in the context of pulsatile UA flow and partial voluming, was studied through Monte-Carlo simulations, as a function of resolution and number of averages. STATISTICAL TESTS: Correlation between the UA and UV was evaluated using a generalized linear model. RESULTS: Simulations showed that ng-PCMRI measurement variance reduced by increasing the number of averages. For vessels on the order of 2 voxels in radius, partial voluming led to 10% underestimation in the flow. In fetuses, the average flow rates in UAs and UV were measured to be 203 ± 80 ml/min and 232 ± 92 ml/min and the normalized average flow rates were 140 ± 59 ml/min/kg and 155 ± 57 ml/min/kg, respectively. Excellent correlation was found between the total arterial flow vs. corresponding venous flow, with a slope of 1.08 (P = 0.036). DATA CONCLUSION: Ng-PCMRI can provide accurate volumetric flow measurements in utero in the human umbilical vessels. Care needs to be taken to ensure sufficiently high-resolution data are acquired to minimize partial voluming-related errors. LEVEL OF EVIDENCE: 2 Technical Efficacy Stage 1 J. Magn. Reson. Imaging 2017.

Individualized growth assessment: conceptual framework and practical implementation for the evaluation of fetal growth and neonatal growth outcome.

Fetal growth abnormalities can pose significant consequences on perinatal morbidity and mortality of nonanomalous fetuses. The most widely accepted definition of fetal growth restriction is an estimated fetal weight less than the 10th percentile for gestational age according to population-based criteria. However, these criteria do not account for the growth potential of an individual fetus, nor do they effectively separate constitutionally small fetuses from ones that are malnourished. Furthermore, conventional approaches typically evaluate estimated fetal weight at a single time point, rather than using serial scans, to evaluate growth. This article provides a conceptual framework for the individualized growth assessment of a fetus/neonate based on measuring second-trimester growth velocity of fetal size parameters to estimate growth potential. These estimates specify size models that generate individualized third-trimester size trajectories and predict birth characteristics. Comparisons of measured and predicted values are used to separate normally growing fetuses from those with growth abnormalities. This can be accomplished with individual anatomical parameters or sets of parameters. A practical and freely available software (Individualized Growth Assessment Program) has been developed to allow implementation of this approach for clinical and research purposes.

A new customized fetal growth standard for African American women: the PRB/NICHD Detroit study.

BACKGROUND: The assessment of fetal growth disorders requires a standard. Current nomograms for the assessment of fetal growth in African American women have been derived either from neonatal (rather than fetal) biometry data or have not been customized for maternal ethnicity, weight, height, and parity and fetal sex. OBJECTIVE: We sought to (1) develop a new customized fetal growth standard for African American mothers; and (2) compare such a standard to 3 existing standards for the classification of fetuses as small (SGA) or large (LGA) for gestational age. STUDY DESIGN: A retrospective cohort study included 4183 women (4001 African American and 182 Caucasian) from the Detroit metropolitan area who underwent ultrasound examinations between 14-40 weeks of gestation (the median number of scans per pregnancy was 5, interquartile range 3-7) and for whom relevant covariate data were available. Longitudinal quantile regression was used to build models defining the "normal" estimated fetal weight (EFW) centiles for gestational age in African American women, adjusted for maternal height, weight, and parity and fetal sex, and excluding pathologic factors with a significant effect on fetal weight. The resulting Perinatology Research Branch/Eunice Kennedy Shriver National Institute of Child Health and Human Development (hereinafter, PRB/NICHD) growth standard was compared to 3 other existing standards--the customized gestation-related optimal weight (GROW) standard; the Eunice Kennedy Shriver National Institute of Child Health and Human Development (hereinafter, NICHD) African American standard; and the multinational World Health Organization (WHO) standard--utilized to screen fetuses for SGA (<10th centile) or LGA (>90th centile) based on the last available ultrasound examination for each pregnancy. RESULTS: First, the mean birthweight at 40 weeks was 133 g higher for neonates born to Caucasian than to African American mothers and 150 g higher for male than female neonates; maternal weight, height, and parity had a positive effect on birthweight. Second, analysis of longitudinal EFW revealed the following features of fetal growth: (1) all weight centiles were about 2% higher for male than for female fetuses; (2) maternal height had a positive effect on EFW, with larger fetuses being affected more (2% increase in the 95th centile of weight for each 10-cm increase in height); and (3) maternal weight and parity had a positive effect on EFW that increased with gestation and varied among the weight centiles. Third, the screen-positive rate for SGA was 7.2% for the NICHD African American standard, 12.3% for the GROW standard, 13% for the WHO standard customized by fetal sex, and 14.4% for the PRB/NICHD customized standard. For all standards, the screen-positive rate for SGA was at least 2-fold higher among fetuses delivered preterm than at term. Fourth, the screen-positive rate for LGA was 8.7% for the GROW standard, 9.2% for the PRB/NICHD customized standard, 10.8% for the WHO standard customized by fetal sex, and 12.3% for the NICHD African American standard. Finally, the highest overall agreement among standards was between the GROW and PRB/NICHD customized standards (Cohen's interrater agreement, kappa = 0.85). CONCLUSION: We developed a novel customized PRB/NICHD fetal growth standard from fetal data in an African American population without assuming proportionality of the effects of covariates, and without assuming that these effects are equal on all centiles of weight; we also provide an easy-to-use centile calculator. This standard classified more fetuses as being at risk for SGA compared to existing standards, especially among fetuses delivered preterm, but classified about the same number of LGA. The comparison among the 4 growth standards also revealed that the most important factor determining agreement among standards is whether they account for the same factors known to affect fetal growth.

Imaging putative foetal cerebral blood oxygenation using susceptibility weighted imaging (SWI).

OBJECTIVE: To evaluate the magnetic susceptibility, ∆χ v , as a surrogate marker of venous blood oxygen saturation, S v O 2, in second- and third-trimester normal human foetuses. METHODS: Thirty-six pregnant women, having a mean gestational age (GA) of 31 2/7 weeks, underwent magnetic resonance imaging (MRI). Susceptibility-weighted imaging (SWI) data from the foetal brain were acquired. ∆χ v of the superior sagittal sinus (SSS) was quantified using MR susceptometry from the intra-vascular phase measurements. Assuming the magnetic property of foetal blood, ∆χ do , is the same as that of adult blood, S v O 2 was derived from the measured Δχ v . The variation of ∆χ v and S v O 2, as a function of GA, was statistically evaluated. RESULTS: The mean ∆χ v in the SSS in the second-trimester (n = 8) and third-trimester foetuses (n = 28) was found to be 0.34± 0.06 ppm and 0.49 ±0.05 ppm, respectively. Correspondingly, the derived S v O 2 values were 69.4% ±3.27% and 62.6% ±3.25%. Although not statistically significant, an increasing trend (p = 0.08) in Δχ v and a decreasing trend (p = 0.22) in S v O 2 with respect to advancing gestation was observed. CONCLUSION: We report cerebral venous blood magnetic susceptibility and putative oxygen saturation in healthy human foetuses. Cerebral oxygen saturation in healthy human foetuses, despite a slight decreasing trend, does not change significantly with advancing gestation. KEY POINTS: • Cerebral venous magnetic susceptibility and oxygenation in human foetuses can be quantified. • Cerebral venous oxygenation was not different between second- and third-trimester foetuses. • Foetal cerebral venous oxygenation does not change significantly with advancing gestation.

Fetal Intelligent Navigation Echocardiography (FINE) Detects 98% of Congenital Heart Disease.

OBJECTIVE: Fetal intelligent navigation echocardiography (FINE) is a novel method that automatically generates and displays 9 standard fetal echocardiographic views in normal hearts by applying intelligent navigation technology to spatiotemporal image correlation (STIC) volume data sets. The main objective was to determine the sensitivity and specificity of FINE in the prenatal detection of congenital heart disease (CHD). METHODS: A case-control study was conducted in 50 fetuses with a broad spectrum of CHD (cases) and 100 fetuses with normal hearts (controls) in the second and third trimesters. Using 4-dimensional ultrasound with STIC technology, volume data sets were acquired. After all identifying information was removed, the data sets were randomly distributed to a different investigator for analysis using FINE. The sensitivity and specificity for the prenatal detection of CHD, as well as positive and negative likelihood ratios were determined. RESULTS: The diagnostic performance of FINE for the prenatal detection of CHD was: sensitivity of 98% (49 of 50), specificity of 93% (93 of 100), positive likelihood ratio of 14, and negative likelihood ratio of 0.02. Among cases with confirmed CHD, the diagnosis with use of FINE completely matched the final diagnosis in 74% (37 of 50); minor discrepancies were seen in 12% (6 of 50), and major discrepancies were seen in 14% (7 of 50). CONCLUSIONS: This is the first time the sensitivity and specificity of the FINE method in fetuses with normal hearts and CHD in the second and third trimesters has been reported. Because FINE identifies a broad spectrum of CHD with 98% sensitivity, this method could be used prenatally to screen for and diagnose CHD.

The frequency and type of placental histologic lesions in term pregnancies with normal outcome.

Objective To determine the frequency and type of histopathologic lesions in placentas delivered by women with a normal pregnancy outcome. Methods This retrospective cohort study included placental samples from 944 women with a singleton gestation who delivered at term without obstetrical complications. Placental lesions were classified into the following four categories as defined by the Society for Pediatric Pathology and by our unit: (1) acute placental inflammation, (2) chronic placental inflammation, (3) maternal vascular malperfusion and (4) fetal vascular malperfusion. Results (1) Seventy-eight percent of the placentas had lesions consistent with inflammatory or vascular lesions; (2) acute inflammatory lesions were the most prevalent, observed in 42.3% of the placentas, but only 1.0% of the lesions were severe; (3) acute inflammatory lesions were more common in the placentas of women with labor than in those without labor; (4) chronic inflammatory lesions of the placenta were present in 29.9%; and (5) maternal and fetal vascular lesions of malperfusion were detected in 35.7% and 19.7%, respectively. Two or more lesions with maternal or fetal vascular features consistent with malperfusion (high-burden lesions) were present in 7.4% and 0.7%, respectively. Conclusion Most placentas had lesions consistent with inflammatory or vascular lesions, but severe and/or high-burden lesions were infrequent. Mild placental lesions may be interpreted either as acute changes associated with parturition or as representative of a subclinical pathological process (intra-amniotic infection or sterile intra-amniotic inflammation) that did not affect the clinical course of pregnancy.