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Background: Phase-rectified signal averaging, an innovative signal processing technique, can be used to investigate quasi-periodic oscillations in noisy, nonstationary signals that are obtained from fetal heart rate. Phase-rectified signal averaging is currently the best method to predict survival after myocardial infarction in adult cardiology. Application of this method to fetal medicine has established significantly better identification than with short-term variation by computerized cardiotocography of growth-restricted fetuses., Objective: The aim of this study was to determine the longitudinal progression of phase-rectified signal averaging indices in severely growth-restricted human fetuses and the prognostic accuracy of the technique in relation to perinatal and neurologic outcome., Study Design: Raw data from cardiotocography monitoring of 279 human fetuses were obtained from 8 centers that took part in the multicenter European "TRUFFLE" trial on optimal timing of delivery in fetal growth restriction. Average acceleration and deceleration capacities were calculated by phase-rectified signal averaging to establish progression from 5 days to 1 day before delivery and were compared with short-term variation progression. The receiver operating characteristic curves of average acceleration and deceleration capacities and short-term variation were calculated and compared between techniques for short- and intermediate-term outcome., Results: Average acceleration and deceleration capacities and short-term variation showed a progressive decrease in their diagnostic indices of fetal health from the first examination 5 days before delivery to 1 day before delivery. However, this decrease was significant 3 days before delivery for average acceleration and deceleration capacities, but 2 days before delivery for short-term variation. Compared with analysis of changes in short-term variation, analysis of (delta) average acceleration and deceleration capacities better predicted values of Apgar scores <7 and antenatal death (area under the curve for prediction of antenatal death: delta average acceleration capacity, 0.62 [confidence interval, 0.19-1.0]; delta short-term variation, 0.54 [confidence interval, 0.13-0.97]; P=.006; area under the curve for prediction Apgar <7: average deceleration capacity <24 hours before delivery, 0.64 [confidence interval, 0.52-0.76]; short-term variation <24 hours before delivery, 0.53 [confidence interval, 0.40-0.65]; P=.015). Neither phase-rectified signal averaging indices nor short-term variation showed predictive power for developmental disability at 2 years of age (Bayley developmental quotient, <95 or <85)., Conclusion: The phase-rectified signal averaging method seems to be at least as good as short-term variation to monitor progressive deterioration of severely growth-restricted fetuses. Our findings suggest that for short-term outcomes such as Apgar score, phase-rectified signal averaging indices could be an even better test than short-term variation. Overall, our findings confirm the possible value of prospective trials based on phase-rectified signal averaging indices of autonomic nervous system of severely growth-restricted fetuses., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Objective: Women with a history of preeclampsia are at increased risk for future cardiovascular disease. Determination of cardiovascular biomarkers may be useful to understand the pathophysiological mechanism of cardiovascular disease development in these women., Methods: We performed an analysis in the Preeclampsia Risk EValuation in FEMales study, a retrospective cohort consisting of 339 women with a history of early preeclampsia and 332 women after normotensive pregnancy. Women attended a follow-up visit ten years after the index pregnancy. A subset of 8 different cardiovascular biomarkers was investigated, reflecting inflammatory, metabolic, thrombotic and endothelial function markers. Associations between PE and these novel biomarkers were analyzed by linear regression analysis and adjusted for traditional cardiovascular risk factors., Results: Mean age of 671 women of the PREVFEM cohort was 39 years and women were on average 10 years post index pregnancy. Women post preeclampsia had significantly higher levels of SE-selectin (adjusted difference 4.55, 99%CI 0.37; 8.74) and PAPPA (adjusted difference 19.08; 99%CI 13.18; 24.99), whereas ApoB (adjusted difference -0.23 99%CI -0.32; -0.14) was inversely associated with preeclampsia, compared to women with a previous normotensive pregnancy. Adiponectin, leptin, sICAM-1, sVCAM-1 and PAI-1 were not different between both groups., Conclusion: We demonstrated an independent association of preeclampsia with SE-selectin and PAPPA (markers of vascular dysfunction), which may contribute to future cardiovascular events in women post preeclampsia. However, ApoB (an apolipoprotein) was significantly lower and could point at a protective mechanism in our PE study women., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Objective: To develop a multivariable prognostic model for the risk of preterm delivery in women with multiple pregnancy that includes cervical length measurement at 16 to 21 weeks' gestation and other variables., Methods: We used data from a previous randomized trial. We assessed the association between maternal and pregnancy characteristics including cervical length measurement at 16 to 21 weeks' gestation and time to delivery using multivariable Cox regression modelling. Performance of the final model was assessed for the outcomes of preterm and very preterm delivery using calibration and discrimination measures., Results: We studied 507 women, of whom 270 (53%) delivered < 37 weeks (preterm) and 66 (13%) < 32 weeks (very preterm). Women with cervical length < 30 mm delivered more often preterm (hazard ratio 1.9; 95% CI 0.7 to 4.8). Other independently contributing predictors were previous preterm delivery, monochorionicity, smoking, educational level, and triplet pregnancy. Prediction models for preterm and very preterm delivery had a c-index of 0.68 (95% CI 0.63 to 0.72) and 0.68 (95% CI 0.62 to 0.75), respectively, and showed good calibration., Conclusion: In women with a multiple pregnancy, the risk of preterm delivery can be assessed with a multivariable model incorporating cervical length and other predictors.

Objective: There are few prospective cohorts of delayed-interval delivery for twin and triplet pregnancies. Nonetheless, the procedure is an option to improve perinatal outcome., Study Design: A standard protocol was designed before candidates for delayed interval were managed by the 2 authors from 1991 to 2007. Perinatal as maternal outcomes were evaluated up to 1 year., Results: In 93 twin and 34 triplet pregnancies, the inclusion criteria were fulfilled; in 45 twin and 8 triplet pregnancies, there were contraindications to prolong pregnancy; and in 10 twin and 26 triplet pregnancies, asynchronous delivery was not possible because of immediate delivery of the remaining multiples. Thus, the procedure was performed in only 41% (38/93) of twin and 35% (12/34) of triplet pregnancies admitted with threatening early delivery. Among twin pregnancies, the mean delay was 19 (1-107) days. When the first delivery was less than 25 weeks, no first twin but 9 of 18 second twins (50%) survived (P < .001). Survival rate of first twins born beyond 25 weeks was 13 of 20 (65%) compared with 19 of 20 (95%) (P = .03) in corresponding second twins. In 7 of 12 triplet pregnancies with the first born less than 25 weeks, 2 of 14 remaining triplets survived after an interval of 118 days. Beyond 25 weeks, 3 of 5 first and 4 of 10 remaining triplets survived after intervals of 2-13 days (P = n.s.). Delay between second and third triplet was never longer than 2 days. Frequent maternal complications were chorioamnionitis (22%), postpartum hemorrhage, retained placenta (10%), and abruption (6%)., Conclusion: Our study provides data to assist physicians in the informed consent process when asynchronous delivery is considered and feasible.

Background: The majority of women with a history of preeclampsia have either an underlying thrombophilic disorder or a vascular disorder. In this study, we tested the hypothesis that only the latter condition predisposes for abnormal hemodynamic adaptation to pregnancy., Methods: Thirty-seven formerly preeclamptic subjects were subdivided into a hypertensive (HYPERT, N = 10), a normotensive thrombophilic (THROMB, N = 13) and a normotensive nonthrombophilic subgroup (NONTHROMB, N = 14). In these women and in 10 normal parous controls, the following variables were measured at least five-months postpartum at day 5 (+/-2) of the menstrual cycle and again at five- and seven-weeks amenorrhea in the next pregnancy: mean arterial pressure, heart rate, cardiac output, central cardiovascular dimensions, plasma volume, glomerular filtration rate, effective renal plasma flow, 17-beta estradiol, progesterone, the hormones of the renin-angiotensin-aldosterone (RAAS) axis, catecholamines and alpha-atrial natriuretic peptide., Results: The early pregnancy rise in cardiac output, renal variables, RAAS activity, and plasma volume was comparable in all groups. However, the HYPERT and NONTHROMB subgroups differed from controls by a lower plasma volume in the prepregnant state. In addition, only the women in these two subgroups responded to pregnancy by a rise in circulating alpha-atrial natriuretic peptide. In addition, at seven weeks, in the subjects belonging to the HYPERT and NONTHROMB subgroups, plasma volume was the lowest and correlated inversely with the concomitant circulating level of alpha-atrial natriuretic peptide., Conclusion: The hemodynamic adaptation to pregnancy in the HYPERT and NONTHROMB subgroups differs from that in THROMB and controls by an early pregnancy rise in alpha-atrial natriuretic peptide. As a consequence, the early pregnancy plasma volume expansion in the NONTHROMB and HYPERT subgroups is less than in normal parous controls.

Objective: Among women with a history of preeclampsia the prevalence of hemodynamic and clotting disorders is elevated. In this study we tested the hypothesis that the normal cyclic variation in hemodynamic and renal function parameters with the menstrual cycle that is seen among healthy women would be preserved in women with a history of preeclampsia irrespective of whether they had an underlying hemodynamic or clotting disorder., Study Design: We compared the hemodynamic and volume cyclic variations during the menstrual cycle among women with a history of preeclampsia (n = 39) with those among healthy parous control women (control group, n = 10). The participants with a history of preeclampsia were subdivided into groups of women with hypertension with or without thrombophilia (hypertension group, n = 10), women with a normotension and a thrombophilic disorder (thrombophilia group, n = 17), and women without either of these abnormalities (symptom-free group, n = 12). We measured > or =5 months post partum, once during the follicular phase of the menstrual cycle (day 5 +/- 2) and once during the luteal phase (day 22 +/- 2), the following variables: body weight and length, mean arterial pressure, heart rate, cardiac output, plasma volume, glomerular filtration rate, effective renal plasma flow, and concentrations of renal volume homeostatic hormones, reproductive hormones, and catecholamines. From the measured data we calculated body mass index, cardiac index, left ventricular work, total peripheral and renal vascular resistances, effective renal blood flow, and renal filtration fraction., Results: The hypertension group differed from the control group in having higher baseline (follicular phase) values for cardiac output, cardiac output, left ventricular work, renal vascular resistance, and atrial natriuretic peptide and norepinephrine levels. The symptom-free group differed from the control group in having a lower baseline plasma volume and higher baseline cardiac output and left ventricular work values. Women in the thrombophilia group were comparable to those in the control group with respect to baseline hemodynamic and renal function variables except for a higher renal vascular work value. In the control group heart rate, plasma volume, effective renal plasma volume, effective renal blood flow, and concentrations of renin-angiotensin-aldosterone system hormones and norepinephrine were increased during the luteal phase with respect to values during the follicular phase, whereas the renal vascular resistance and atrial natriuretic peptide values were decreased. In the three subgroups of women with a history of preeclampsia this cyclic pattern with the menstrual cycle was preserved for most of these parameters., Conclusion: Although baseline hemodynamic and volume status among women with a history of preeclampsia differed from that among healthy parous control subjects, the cyclic variation with the menstrual cycle was largely preserved.

Objective: Most women with a pregnancy complicated by preeclampsia have either hypertension or a disorder with a thrombophilic phenotype or both of these. In this study we evaluated whether hemodynamic variables and volume homeostasis in a subgroup of normotensive women with a history of preeclampsia with normal clotting function (defined as the symptom-free subgroup) were comparable with those in a healthy parous control group., Study Design: In a group of 58 subjects with a history of preeclampsia and a group of 11 healthy parous control subjects we measured the following variables > or = 5 months post partum at day 5 +/- 2 of the menstrual cycle: body weight and length, mean arterial pressure, heart rate, cardiac output, plasma volume, glomerular filtration rate, effective renal plasma flow, and plasma concentrations of volume regulatory hormones, clotting factors, antiphospholipid antibodies, and homocysteine before and after a methionine load. From the measured data we calculated body mass index, body surface area, cardiac index, left ventricular work, total peripheral and renal vascular resistances, effective renal blood flow, and renal filtration fraction., Results: Among women with a history of preeclampsia 26 were normotensive with thrombophilia (45%), 14 had hypertension (24%), and 18 were normotensive without thrombophilia (31%). These last symptom-free subjects with a history of preeclampsia were more obese than were control subjects. They also had higher cardiac output and left ventricular work and a lower plasma volume than the healthy parous control subjects. Thus they resemble the second subgroup of subjects (subjects with hypertension and a history of preeclampsia) rather than the control subjects. The hemodynamic and renal functions in the subgroup of subjects with a history of preeclampsia with normotension and thrombophilia were similar to those in healthy parous control subjects., Conclusion: On the basis of this study we conclude that hemodynamic parameters and volume homeostasis in the symptom-free subgroup of women with a history of preeclampsia are different from those in healthy parous control subjects. Hemodynamic parameters and volume homeostasis in this subgroup resemble those of women with hypertension and a history of preeclampsia. We therefore propose the classification of these symptom-free subjects with a history of preeclampsia as having "latent" hypertension.

Objective: An open, randomized, prospective, multicenter trial was conducted to compare the efficacy and safety of intravenous ketanserin, a selective serotonin 2 receptor blocker, with that of intravenous dihydralazine in the management of severe early-onset (<32 weeks' gestation) preeclampsia. End points of this study were blood pressure control and maternal outcome., Study Design: Patients with a diastolic blood pressure >110 mm Hg were randomly assigned to receive either ketanserin (n = 22) or dihydralazine (n = 22) as initial therapy. Plasma volume expansion preceded antihypertensive treatment, which was administered according to a fixed schedule., Results: The reductions in blood pressure with the 2 drugs were similar; however, adequate blood pressure control was reached significantly earlier with ketanserin (84 +/&#95; 63 vs 171 +/- 142 minutes, P = .017). Occurrence of maternal complications was significantly lower among patients who received ketanserin than among patients who received dihydralazine (n = 6 vs n = 18, P =.0007). A significant difference in favor of ketanserin was noted in daily fluid balance., Conclusion: Antihypertensive efficacies of ketanserin and dihydralazine were comparable, but significantly fewer maternal complications were noted among the patients receiving ketanserin. Ketanserin is an attractive alternative in the management of severe early-onset preeclampsia.

Objective: The objective was to test the hypothesis that women with a recent history of preeclampsia have abnormalities in renal hemodynamics and volume status., Study Design: We studied a group of 26 primiparous women with history of preeclampsia and a group of 12 parous women with a history of uneventful pregnancies (control group). At least 4 months post partum we compared the following variables between these groups: effective renal plasma flow, glomerular filtration rate, plasma volume, plasma concentration of active renin, plasma concentration of angiotensin II, plasma concentration of aldosterone, and plasma concentration of atrial natriuretic peptide., Results: Both plasma volume and plasma concentration of atrial natriuretic peptide were lower in the formerly preeclamptic group. Compared with the control subjects, the formerly preeclamptic group also had a lower effective renal plasma flow, a higher filtration fraction, and a higher renal vascular resistance. Intergroup differences in plasma concentration of active renin, plasma concentration of angiotensin II and plasma concentration of aldosterone were small and inconsistent., Conclusions: Women with history of preeclampsia are relatively hypovolemic and tend to have lower effective renal plasma flow and higher renal vascular resistance and filtration fraction than do control subjects. These findings support the hypothesis that otherwise healthy women with a history of preeclampsia show abnormalities in their volume status and renal hemodynamics, irrespective of their blood pressure.

A case is reported in which fetal monitoring during vaginal delivery of triplets was performed with the MT 430 actocardiotocograph. This method provides optimal monitoring of multiple pregnancies because the fetal heart rate tracings of three fetuses, together with recordings of fetal movements and uterine contractions, can be visualized on one display.

In 16 normal pregnancies the relationship between foramen ovale flow velocity waveforms and fetal behavioral states at 37 to 38 weeks' gestation was studies with Doppler techniques. Foramen ovale flow velocity waveforms are characterized by a typical systolic/diastolic component. Average flow velocity was statistically significantly increased in behavioral state 2F (active sleep) as compared with state 1F (quiet sleep), which was mainly determined by an increase in flow velocity during the end-systolic and passive atrial filling phase. The increase in the average flow velocity at the foramen ovale level during active sleep suggests a redistribution of blood flow at the cardiac level, resulting in an increased right-to-left shunt.

A test is needed that would accurately predict favorable neonatal lung performance in the presence of prolonged severe oligohydramnios caused by ruptured membranes so that optimal obstetric care can be provided. We propose such a test that is based on the degree of modulation of fetal ductal blood flow velocity by fetal breathing movements after maternal glucose loading. In a prospective cross-sectional study of 49 normal pregnancies (50 fetuses) between 25 and 38 weeks an exponential increase in breathing-related ductal blood flow velocity modulation was observed with advancing gestational age, reflecting the developing pulmonary vascular bed. Fetal ductal flow velocity waveforms were also recorded in 13 cases of prolonged severe oligohydramnios after ruptured membranes before 28 weeks' gestation. Normal ductal blood flow velocity modulation values were associated with normal neonatal lung performance, whereas reduced ductal blood flow velocity modulation values were associated with pulmonary hypoplasia. Fetal breathing-related ductal flow velocity modulation appears to be a promising predictor of neonatal lung performance.

In 13 normal pregnancies at 27-28 weeks of gestation the blood flow velocity waveform at the lower thoracic level of the fetal descending aorta was studied in relation to fetal heart rate pattern (FHRP), fetal eye movements (FEM) and fetal body movements (FBM). State parameter combinations in which high fetal heart rate (FHR) variability was present, were associated with a significant reduction in pulsatility index (PI) as compared with periods in which low FHR variability was present, irrespective of FEM and FBM, indicating a reduced peripheral vascular resistance. At 27-28 weeks of gestation FHR variability and PI might be linked to baroreceptor sensitivity. PI values derived from combinations FHRP-A, FEM(-), FBM(-) and FHRP-B, FEM(+), FBM(+) showed a significant inverse relationship (P less than 0.05) with FHR. FHR and FHR variability should be taken into account when studying flow velocity waveforms in the fetal descending aorta at 27-28 weeks of gestation.

Flow velocity waveforms in the fetal internal carotid artery during fetal behavioural state 2F were compared with blood gas and acid-base data from fetal scalp blood samples immediately following artificial rupture of the membranes in 17 normal term pregnancies. The pulsatility index in the fetal internal carotid artery was positively related to PO2 and base excess suggesting that also under physiological conditions fetal cerebral vascular resistance may respond to changes in fetal oxygenation.

In 12 patients with intrauterine growth retardation (IUGR), the relationship between the blood flow velocity waveform at the lower thoracic level of the fetal descending aorta and fetal behavioural states at 37-38 wk of gestation was studied. A significant inverse relationship (P less than 0.001) was established between pulsatility index (PI) and fetal heart rate (FHR) in state 1F and 2F. The PI as a measure of peripheral vascular resistance, demonstrated a marked increase compared to normal pregnancy. There is a virtual overlap of PI values originating from state 1F and 2F according to the classification by Nijhuis et al. (J.G. Nijhuis, H.F.R. Prechtl, C.B. Martin, Jr. and R.S.G.M. Bots (1982) Early Hum. Dev. 6, 177-195). The peripheral vasoconstriction present in IUGR seems to overrule state dependent PI fluctuations. The marked rise in PI, particularly at lower FHR and the constancy of PI in relation to fetal behavioural states can be considered vascular adaptations, which are instrumental in the centralization of the fetal circulation, with the aim of favouring blood supply to the brain, heart and adrenals during IUGR.

In 16 normal pregnancies the relationship between the blood flow velocity waveform and fetal behavioral states at 37 to 38 weeks' gestation was studied. Whereas behavioral state independency was established for the acceleration time, peak flow velocity demonstrated a statistically significant reduction during active sleep, compared with quiet sleep. These data reflect reduced ductal flow and suggest a redistribution in the left-ventricular and right-ventricular output in favor of the left side of the heart during active sleep. Peak flow velocities in the fetal ductus arteriosus were independent of fetal heart rate.

In 13 normal pregnancies, the relationship between the blood flow velocity waveform at the lower thoracic level of the fetal descending aorta and fetal behavioural states at 37-38 weeks of gestation was studied. The pulsatility index (PI), as a measure of peripheral vascular resistance, was significantly lower during state 2F compared to state 1F according to the classification by Nijhuis et al. (Nijhuis, J.G. et al. (1982) Early Hum. Dev., 6, 177-195), suggesting an increased perfusion of the fetal skeletal musculature to meet the energy demand needed for the raised muscular activity during state 2F; A significant inverse relationship (P less than 0.001) was established between PI and FHR in state 2F; this was mainly determined by a significant rise in end-diastolic flow velocity (P less than 0.02). Both the behavioural state and FHR should be taken into account when evaluating flow velocity waveforms in the fetal descending aorta during the latter weeks of pregnancy.