It is with sadness that we received the message that Karel Maršál passed away on March 6, 2023. Karel Maršál, MD, PhD, Professor Emeritus at Lund University and Director of the WHO Collaborating Center in Lund, was born in Prague, former Czechoslovakia, in 1943. After completing his undergraduate studies at Charles University in Prague, he and his fiancée Lida moved as political refugees to Sweden in 1968. They came to Malmö General Hospital in 1973, where Karel gained his specialty in obstetrics and gynecology. Already then, Malmö was a nursery for research on fetal physiology and monitoring, and Karel was soon involved. He defended his PhD thesis, “Ultrasonic Measurements of Fetal Breathing Movements in Man”, at Lund University in 1977. With the introduction of Doppler ultrasonography to measure blood flow velocity, an era of prolific research commenced, leading to a growing international collaboration under Karel's leadership. In a series of PhD theses, normal fetal circulation was mapped to form the basis for the clinical assessment of the compromised fetus, and for studying the effects of medications and smoking during pregnancy. Experimental work on fetal lambs added further insights into circulatory pathophysiology. The introduction of routine ultrasound in Malmö in 1972 paved the way for identifying and studying fetal growth restriction and its underlying circulatory changes, today a major clinical field. Karel was the Head of the Perinatal Division at the University Hospital in Malmö and his personality as an enthusiastic, persevering, and meticulous scientist earned him a professorship in Malmö in 1991. In 1997, Karel moved to Lund to become Professor in Obstetrics and Gynecology, and later head of the clinical department. In 1995, he became Honorary Professor at Charles University in Prague, Czech Republic. He also served as Director of the undergraduate program of the Medical School at Lund University and as Chief Medical Officer in the county of Skåne, Sweden. Karel was the main tutor of 21 PhD students and co-tutor of another 14 research students. He published 354 original papers, 132 book chapters and reviews, and 14 textbooks. He was editor or co-editor of the Journal of Maternal and Fetal Investigation, of Fetal and Maternal Medicine Review, and of Seminars in Fetal and Neonatal Medicine, and was a member of the editorial board of 10 international scientific journals. His primary areas of experience and research were in perinatology, obstetrics, fetal monitoring, obstetric and gynecologic ultrasound, Doppler ultrasound, fetal physiology, ultrasound safety, and obstetric quality assurance. Throughout the years, Karel's research was supported by numerous grants, among them from the prestigious Swedish Research Council. He was the principal investigator in numerous national and international multicenter studies, such as the EXPRESS study on extremely preterm infants in Sweden, and he was national coordinator for Sweden in three EU studies. Karel served as president of the International Society of Ultrasound in Obstetrics and Gynecology, he was an honorary member of various national and international institutions and a board member of European Federation of Societies for Ultrasound in Medicine and Biology, World Federation for Ultrasound in Medicine and Biology, and other societies. In the past, he was the main organizer of 15 international scientific congresses, including two world congresses on ultrasound in obstetrics and gynecology. He received several prestigious awards, such as the Ian Donald Gold Medal and the Haackert Gold Medal in Prenatal Medicine. Karel was elected Doctor Honoris Causae at universities in Olomouc, Czech Republic, and Poznan, Poland. He was course leader of 38 national and international postgraduate courses in perinatal medicine, obstetrics, ultrasound, and obstetric Doppler ultrasound. His last participation in such an event was in February 2023. Karel's wife, Lida, gave him unending support throughout his career. Had Karel not injured his leg in a skiing accident, their paths may never have crossed. He had to take a break from medical school, and when he returned to his studies, he and Lida became classmates. Innumerable mothers and children all over the globe have benefited from Karel's ground-breaking scientific work, leadership, and deeds. His 50-year career as a clinician, scientist, teacher, coach, role model, and—most of all—the best friend of the unborn baby is now at an end. Among his friends and co-workers, he will be vividly remembered as a quietly jovial, sharp-witted gentleman with a human perspective and a friendly attitude toward each of us. He is sorely missed.

Fetal growth restriction is associated with adverse perinatal outcome and the clinical management of these pregnancies is a challenge. The aim of this study was to investigate the potential of cerebroplacental ratio (CPR) to predict adverse perinatal outcome in high-risk pregnancies in the third trimester. Another aim was to study whether the CPR has better predictive value than its components, middle cerebral artery (MCA) pulsatility index (PI) and umbilical artery (UA) PI. The study was a retrospective cohort study including 1573 singleton high-risk pregnancies with Doppler examinations performed at 32 +0 to 40 +6 gestational weeks at Lund University Hospital and the University Hospital of Malmö between 29 December 1994 and 31 December 2017. Receiver operating characteristics (ROC) curves were used to investigate the predictive value of the gestational age-specific z -scores for CPR, UA PI and MCA PI, respectively, for the primary outcome “perinatal asphyxia/mortality” and the secondary outcomes “birthweight small for gestational age (SGA)” and two composite outcomes: “appropriate for gestational age/large for gestational age liveborn infants with neonatal morbidity” and “SGA liveborn infants with neonatal morbidity.” The performance in predicting perinatal asphyxia/mortality was poor for all three variables and did not differ significantly. The ROC area under curve (AUC) was 0.56, 0.55 and 0.53 for CPR, UA PI and MCA PI z -scores, respectively. The ROC AUC for CPR z -scores to predict SGA was 0.73, significantly higher than that for either UA PI or MCA PI ( P  < .001). The ability of CPR and the MCA PI to predict appropriate for gestational age/large for gestational age infant morbidity and SGA infant morbidity was similar and significantly better than UA PI ( P  < .001). In the present study, none of the three Doppler measures proved to be useful in predicting perinatal asphyxia and mortality. CPR and MCA PI were equally good in predicting neonatal morbidity, especially in SGA pregnancies, and both were significantly better predictors than the UA PI. CPR had a high predictive value for SGA at birth, better than that of its two components, UA PI and MCA PI.

Introduction Fetal growth restriction is associated with adverse perinatal outcome and the clinical management of these pregnancies is a challenge. The aim of this study was to investigate the potential of cerebroplacental ratio (CPR) to predict adverse perinatal outcome in high-risk pregnancies in the third trimester. Another aim was to study whether the CPR has better predictive value than its components, middle cerebral artery (MCA) pulsatility index (PI) and umbilical artery (UA) PI. Material and methods The study was a retrospective cohort study including 1573 singleton high-risk pregnancies with Doppler examinations performed at 32(+0) to 40(+6) gestational weeks at Lund University Hospital and the University Hospital of Malmo between 29 December 1994 and 31 December 2017. Receiver operating characteristics (ROC) curves were used to investigate the predictive value of the gestational age-specific z-scores for CPR, UA PI and MCA PI, respectively, for the primary outcome "perinatal asphyxia/mortality" and the secondary outcomes "birthweight small for gestational age (SGA)" and two composite outcomes: "appropriate for gestational age/large for gestational age liveborn infants with neonatal morbidity" and "SGA liveborn infants with neonatal morbidity." Results The performance in predicting perinatal asphyxia/mortality was poor for all three variables and did not differ significantly. The ROC area under curve (AUC) was 0.56, 0.55 and 0.53 for CPR, UA PI and MCA PI z-scores, respectively. The ROC AUC for CPR z-scores to predict SGA was 0.73, significantly higher than that for either UA PI or MCA PI (P < .001). The ability of CPR and the MCA PI to predict appropriate for gestational age/large for gestational age infant morbidity and SGA infant morbidity was similar and significantly better than UA PI (P < .001). Conclusions In the present study, none of the three Doppler measures proved to be useful in predicting perinatal asphyxia and mortality. CPR and MCA PI were equally good in predicting neonatal morbidity, especially in SGA pregnancies, and both were significantly better predictors than the UA PI. CPR had a high predictive value for SGA at birth, better than that of its two components, UA PI and MCA PI.

Purpose To investigate the predictive capacity of a new method for sound spectrum analysis of Doppler signals recorded from the umbilical artery in high-risk pregnancies. Material and Methods The retrospective study comprised 127 pregnant women with various pregnancy complications between 23 and 39 gestational weeks. Umbilical artery blood flow velocity waveforms were recorded with Doppler ultrasound and characterized by pulsatility index (PI) and blood flow class (BFC). Doppler audio signals were stored on a digital video recorder and the sound frequency at the energy level 15 dB below its peak (MAX(peak)-15 dB) was estimated off-line. The prediction of probability for composite adverse pregnancy outcome (operative delivery for fetal distress, admission to neonatal intensive care unit, perinatal death) was evaluated using the area under the curve (AUC) of the receiver operating characteristics (ROC) curve. Results With increasing umbilical artery BFC, the MAXpeak15 dB frequencies decreased (p < 0.0001) and the PI increased (p < 0.0001). The ROC AUCs for adverse outcome for MAXpeak-15 dB and for PI were 0.842 and 0.836 (p = 0.88), respectively. For the combination of MAX(peak)-15 dB and PI, the corresponding AUC was 0.894, significantly higher than that of PI (p < 0.03) and of MAX(peak)-15 dB (p < 0.05). Conclusion Umbilical artery Doppler sound spectrum analysis might be a useful supplement to PI in the clinical evaluation of fetoplacental circulation.

The aim of this thesis was to develop an objective method for evaluation of umbilical artery circulation based on auditory perception of the Doppler sound signals. Study I. The operator listened to synthetically produced sound signals from continuous flow. The human ear was most sensitive to sound frequencies in the lower range from this type of flow. Study II. Doppler signals were recorded from the umbilical artery of sheep fetuses. An objective sound measure, MAXpeak-15dB (the frequency band where the energy level had decreased by 15 dB from its maximum level) was identified and found to correlate well with the sonographer’s subjective grading and with the traditional waveform analysis. Studies III and IV. Fetoplacental and uteroplacental circulation was investigated before and after treatment with corticosteroids of women at risk for preterm birth. A transient decrease in pulsatility index (PI) in the umbilical artery and ductus venosus occurred after steroid treatment. MAXpeak-15dB increased significantly after corticosteroids parallel with a decrease in PI and was more sensitive to the changes in flow. Study V. MAXpeak-15dB was applied on umbilical artery Doppler signals in high-risk pregnancies and was found to show similar results as the traditional PI in predicting the probability of composite adverse pregnancy outcome. Receiver operating characteristic curves were used with an area under curve (AUC) of 0.842 for MAXpeak-15dB and 0.836 for PI. When the two parameters were combined the predictive performance was improved (AUC 0.894). MAXpeak-15dB might thus provide additional clinically useful information on the hemodynamics of fetoplacental circulation. (Less)

Analysis of umbilical artery flow velocity waveforms characterized by pulsatility index (PI) is used to evaluate fetoplacental circulation in high-risk pregnancies. However, an experienced sonographer may be able to further differentiate between various timbres of Doppler audio signals. Recently, we have developed a method for objective audio signal characterization; the method has been tested in an animal model. In the present pilot study, the method was for the first time applied to human pregnancies. Doppler umbilical artery velocimetry was performed in 13 preterm fetuses before and after two doses of 12 mg betamethasone. The auditory measure defined by the frequency band where the spectral energy had dropped 15 dB from its maximum level (MAX peak-15 dB ), increased two days after betamethasone administration ( p  = 0.001) parallel with a less pronounced decrease in PI ( p  = 0.04). The new auditory parameter MAX peak-15 dB reflected the changes more sensitively than the PI did.

Analysis of umbilical artery flow velocity waveforms characterized by pulsatility index (PI) is used to evaluate fetoplacental circulation in high-risk pregnancies. However, an experienced sonographer may be able to further differentiate between various timbres of Doppler audio signals. Recently, we have developed a method for objective audio signal characterization; the method has been tested in an animal model. In the present pilot study, the method was for the first time applied to human pregnancies. Doppler umbilical artery velocimetry was performed in 13 preterm fetuses before and after two doses of 12 mg betamethasone. The auditory measure defined by the frequency band where the spectral energy had dropped 15 dB from its maximum level (MAXpeak-15 dB ), increased two days after betamethasone administration (p = 0.001) parallel with a less pronounced decrease in PI (p = 0.04). The new auditory parameter MAXpeak-15 dB reflected the changes more sensitively than the PI did.

OBJECTIVE:An experienced sonographer can by listening to the Doppler audio signals perceive various timbres that distinguish different types of umbilical artery flow despite an unchanged pulsatility index (PI). Our aim was to develop an objective measure of the Doppler audio signals recorded from fetoplacental circulation in a sheep model.METHODS:Various degrees of pathological flow velocity waveforms in the umbilical artery, similar to those in human complicated pregnancies, were induced by microsphere embolization of the placental bed (embolization model, 7 lamb fetuses, 370 Doppler recordings) or by fetal hemodilution (anemia model, 4 lamb fetuses, 184 recordings). A subjective 11-step operator auditory scale (OAS) was related to conventional Doppler parameters, PI and time average mean velocity (TAM), and to sound frequency analysis of Doppler signals (sound frequency with the maximum energy content [MAXpeak] and frequency band at maximum level minus 15 dB [MAXpeak-15 dB] over several heart cycles).RESULTS:WE FOUND A NEGATIVE CORRELATION BETWEEN THE OAS AND PI: median Rho -0.73 (range -0.35- -0.94) and -0.68 (range -0.57- -0.78) in the two lamb models, respectively. There was a positive correlation between OAS and TAM in both models: median Rho 0.80 (range 0.58-0.95) and 0.90 (range 0.78-0.95), respectively. A strong correlation was found between TAM and the results of sound spectrum analysis; in the embolization model the median r was 0.91 (range 0.88-0.97) for MAXpeak and 0.91 (range 0.82-0.98) for MAXpeak-15 dB. In the anemia model, the corresponding values were 0.92 (range 0.78-0.96) and 0.96 (range 0.89-0.98), respectively.CONCLUSION:Audio-spectrum analysis reflects the subjective perception of Doppler sound signals in the umbilical artery and has a strong correlation to TAM-velocity. This information might be of importance for clinical management of complicated pregnancies as an addition to conventional Doppler parameters.

Objective: To relate Doppler velocimetry findings in fetoplacental and uteroplacental circulation to placental histomorphology. Material and methods: In 14 uncomplicated and 31 high-risk pregnancies Doppler velocimetry was performed in umbilical artery and vein, and in maternal uterine veins and arteries during the second half of gestation. Histopathology of the placentas was examined, especially for signs of ischemia and inflammation. Results: All fetuses in uncomplicated pregnancies had normal flow velocity waveforms in umbilical artery; in the high-risk group, 18 fetuses had abnormal flow (increased PI or absent/reverse end-diastolic flow). The latter group had more often high ischemic score and infarctions in the placenta than found in pregnancies with normal umbilical artery flow (p < 0.001 and p = 0.02, respectively). Similarly, the abnormal uterine artery flow pattern (uterine artery score 3–4) occurred more often with high ischemic score and placenta infarctions (p < 0.001 and p < 0.001, respectively). No significant associations were found between the uterine venous flow type and placental ischemia. Conclusion: Placental ischemic morphological changes were associated with Doppler ultrasound signs of increased resistance to arterial blood flow, both on the fetal and maternal sides of the placenta. No significant relation to the uterine venous flow velocities was found.