Cost-effectiveness of diagnostic testing strategies including cervical-length measurement and fibronectin testing in women with symptoms of preterm labor.

OBJECTIVE: To evaluate the cost-effectiveness of combining cervical-length (CL) measurement and fetal fibronectin (fFN) testing in women with symptoms of preterm labor between 24 and 34 weeks' gestation. METHODS: This was a model-based cost-effectiveness analysis evaluating seven test-treatment strategies based on CL measurement and/or fFN testing in women with symptoms of preterm labor from a societal perspective, in which neonatal outcomes and costs were weighted. Estimates of disease prevalence, test accuracy and costs were based on two recently performed nationwide cohort studies in The Netherlands. RESULTS: Strategies using fFN testing and CL measurement separately to predict preterm delivery are associated with higher costs and incidence of adverse neonatal outcomes compared with strategies that combine both tests. Additional fFN testing when CL is 15-30 mm was considered cost effective, leading to a cost saving of €3919 per woman when compared with a treat-all strategy, with a small deterioration in neonatal health outcomes, namely one additional perinatal death and 21 adverse outcomes per 10 000 women with signs of preterm labor (incremental cost-effectiveness ratios €39 million and €1.9 million, respectively). Implementing this strategy in The Netherlands, a country with about 180 000 deliveries annually, could lead to an annual cost saving of between €2.4 million and €7.6 million, with only a small deterioration in neonatal health outcomes. CONCLUSION: In women with symptoms of preterm labor at 24-34 weeks' gestation, performing additional fFN testing when CL is between 15 and 30 mm is a viable and cost-saving strategy. Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd.

Pilot study demonstrates that placental histology can provide an additional tool for diagnosing early-onset neonatal sepsis.

AIM: We explored whether placental histology could help to diagnose early-onset neonatal sepsis (EONS), guide clinical decision-making 48 hours after birth and reduce antibiotic use. METHODS: This study comprised 109 infants born at less than 32 weeks of gestation, who were admitted to the neonatal intensive care unit of Isala, Zwolle, The Netherlands, between January 2013 and December 2013. EONS was defined as clinical symptoms plus raised serial C-reactive protein (CRP) >10 mg/L and a positive (proven EONS) or a negative (suspected EONS) blood culture. Placentas were studied for a histological inflammatory response and scored according to Redline's criteria. RESULTS: A histological inflammatory response was seen in 15/88 (17%) placentas and this occurred significantly more often in infants with a high suspicion of EONS (p < 0.05). No histological inflammatory response was seen if maternal risk factors for EONS were absent, despite a raised CRP level. Based on placental histology, the duration of antibiotic therapy was reduced from more than five days to 48 hours in 20/27 infants (74%). CONCLUSION: Histological examination of the placenta helped to diagnose EONS and guide clinical decision-making 48 hours after birth and led to a clinically relevant reduction in antibiotic use.

Maintenance tocolysis with nifedipine in threatened preterm labour: 2-year follow up of the offspring in the APOSTEL II trial.

OBJECTIVE: To evaluate long-term effects of maintenance tocolysis with nifedipine on neurodevelopmental outcome of the infant. DESIGN, SETTING AND POPULATION: Follow up of infants of women who participated in a multicentre randomised controlled trial on maintenance tocolysis with nifedipine versus placebo. METHODS: Two years after the APOSTEL II trial on maintenance tocolysis with nifedipine versus placebo, we asked participants to complete the Ages and Stages Questionnaire. MAIN OUTCOME MEASURES: Infant development was measured in five domains. Developmental delay was defined as a score of ≤1 SD in one or more developmental domains. We performed exploratory subgroup analysis in women with preterm prolonged rupture of the membranes, and in women with a cervical length <10 mm at study entry. RESULTS: Of the 276 women eligible for follow up, 135 (52.5%) returned the questionnaire, encompassing data of 170 infants. At 2 years of age, infants of women with nifedipine maintenance tocolysis compared with placebo had a higher overall incidence of fine motor problems (22.2 versus 7.6%, OR 3.43, 95% CI 1.29-9.14, P = 0.01), and a lower incidence of poor problem-solving (21.1 versus 29.1%, OR 0.27, 95% CI 0.08-0.95, P = 0.04). CONCLUSIONS: This follow-up study revealed no clear benefit of nifedipine maintenance tocolysis at 2 years of age. As short-term adverse perinatal outcome was not reduced in the original APOSTEL II trial, we conclude that maintenance tocolysis does not appear to be beneficial at this time. TWEETABLE ABSTRACT: No clear benefit of nifedipine maintenance tocolysis in preterm labour on 2-year infant outcome.

Quantitative fetal fibronectin testing in combination with cervical length measurement in the prediction of spontaneous preterm delivery in symptomatic women.

OBJECTIVE: To evaluate whether in symptomatic women, the combination of quantitative fetal fibronectin (fFN) testing and cervical length (CL) improves the prediction of preterm delivery (PTD) within 7 days compared with qualitative fFN and CL. DESIGN: Post hoc analysis of frozen fFN samples of a nationwide cohort study. SETTING: Ten perinatal centres in the Netherlands. POPULATION: Symptomatic women between 24 and 34 weeks of gestation. METHODS: The risk of PTD <7 days was estimated in predefined CL and fFN strata. We used logistic regression to develop a model including quantitative fFN and CL, and one including qualitative fFN (threshold 50 ng/ml) and CL. We compared the models' capacity to identify women at low risk (<5%) for delivery within 7 days using a reclassification table. MAIN OUTCOME MEASURES: Spontaneous delivery within 7 days after study entry. RESULTS: We studied 350 women, of whom 69 (20%) delivered within 7 days. The risk of PTD in <7 days ranged from 2% in the lowest fFN group (<10 ng/ml) to 71% in the highest group (>500 ng/ml). Multivariable logistic regression showed an increasing risk of PTD in <7 days with rising fFN concentration [10-49 ng/ml: odds ratio (OR) 1.3, 95% confidence interval (95% CI) 0.23-7.0; 50-199 ng/ml: OR 3.2, 95% CI 0.79-13; 200-499 ng/ml: OR 9.0, 95% CI 2.3-35; >500 ng/ml: OR 39, 95% CI 9.4-164] and shortening of the CL (OR 0.86 per mm, 95% CI 0.82-0.90). Use of quantitative fFN instead of qualitative fFN resulted in reclassification of 18 (5%) women from high to low risk, of whom one (6%) woman delivered within 7 days. CONCLUSION: In symptomatic women, quantitative fFN testing does not improve the prediction of PTD within 7 days compared with qualitative fFN testing in combination with CL measurement in terms of reclassification from high to low (<5%) risk, but it adds value across the risk range. TWEETABLE ABSTRACT: Quantitative fFN testing adds value to qualitative fFN testing with CL measurement in the prediction of PTD.

Carbetocin in comparison with oxytocin in several dosing regimens for the prevention of uterine atony after elective caesarean section in the Netherlands.

PURPOSE: The aim of the study was to compare the prophylactic effects of carbetocin with those of oxytocin for the prevention of uterine atony in patients undergoing elective caesarean section (CS) in the Netherlands. The primary endpoint was the need for additional uterotonic medication. METHODS: Each of the five participating Dutch hospitals treated 50-100 term patients with 100 µg of intravenous carbetocin on prescription. Each centre retrieved charts of 250 patients treated with oxytocin according to the hospital's policy for the prevention of uterine atony (oxytocin bolus 5 IU, bolus 10 IU or bolus 5 IU followed by 10 IU in 2 h). RESULTS: In the carbetocin group 462 subjects were included and in the oxytocin group 1,122. The proportion of subjects needing additional uterotonic treatment was 3.1 % (95 % CI 1.7-5.1 %) after carbetocin and 7.2 % (5.8-8.9 %) after oxytocin; relative risk 0.41 (0.19-0.85); p = 0.0110. Carbetocin was most effective compared with the oxytocin 5 IU bolus subgroup with less need for additional uterotonic medication (3.1 vs. 9.3 %, p = 0.0067) and blood transfusions (2.2 vs. 3.6 %, p = 0.0357). CONCLUSIONS: Compared with oxytocin, prophylaxis of uterine atony with carbetocin after an elective CS diminished the need for additional uterotonics by more than 50 %.

Effect of 17-alpha hydroxyprogesterone caproate on cervical length in twin pregnancies.

OBJECTIVES: Previous studies on singleton pregnancies have indicated that progestogens may reduce the rate of cervical shortening during pregnancy. The aim of this study was to investigate whether treatment with 17-alpha hydroxyprogesterone caproate (17-OHPC) has an effect on cervical shortening in twin pregnancies. METHODS: This was a secondary analysis of patients who had participated in a multicenter randomized clinical trial on the effectiveness of 17-OHPC in preventing preterm birth in multiple pregnancies (the AMPHIA-trial). We included all trial participants with a twin gestation who had undergone repeat cervical length measurements during pregnancy. We performed a separate analysis of women with repeat measurements in centers where this was standard protocol for multiple pregnancies. The rate of cervical shortening for both the 17-OHPC group and the placebo group was analyzed using a linear mixed model. RESULTS: Of the 671 patients who participated in the trial, 282 (42%) had a twin pregnancy and underwent two or more cervical length measurements. Of these women, 140 were monitored in centers where repeat measurements were standard protocol. We observed an overall reduction of cervical length from 44.3 mm at 14-18 weeks to 30.0 mm at 30-34 weeks' gestation. In the 17-OHPC group, cervical length decreased by 1.04 mm each gestational week, while this was 1.11 mm per week for the placebo group (P = 0.6). For the overall group, each 10% decrease in cervical length led to an increase in the risk of preterm birth (hazard ratio, 1.14; 95% CI, 1.08-1.21). CONCLUSION: In women with a twin pregnancy, there is progressive shortening of the cervix during pregnancy, regardless of 17-OHPC use.

Neurodevelopmental outcomes at five years after early-onset fetal growth restriction: Analyses in a Dutch subgroup participating in a European management trial.

OBJECTIVE: The objective of this study is to explore developmental outcomes at five years after early-onset fetal growth restriction (FGR). STUDY DESIGN: Retrospective data analysis of prospective follow-up of patients of three Dutch centres, who participated in a twenty centre European randomized controlled trial on timing of delivery in early-onset FGR. Developmental outcome of very preterm infants born after extreme FGR is assessed at (corrected) age of five. RESULTS: Seventy-four very preterm FGR children underwent follow-up at the age of five. Mean gestational age at birth was 30 weeks and birth weight was 910 g, 7% had a Bayley score <85 at two years. Median five years' FSIQ was 97, 16% had a FSIQ < 85, and 35% had one or more IQ scores <85. Motor score ≤ 7 on movement ABC-II (M-ABC-II-NL) was seen in 38%. Absent or reversed end-diastolic flow, gestational age at delivery, birthweight and neonatal morbidity were related to an FSIQ < 85. Any abnormal IQ scale score was related to birthweight, male sex and severity of FGR, and abnormal motor score to male sex and bronchopulmonary dysplasia (BPD). CONCLUSIONS: Overall, median cognitive outcome at five years was within normal range, but 35% of the children had any abnormal IQ score at age five, depending on the IQ measure, and motor impairment was seen in 38% of the children. GA at delivery, birthweight, EDF prior to delivery and neonatal morbidity were the most important risk factors for cognitive outcomes.

[Tertiary obstetric care: the aims of the planning decree on perinatal care of 2001 have not yet been achieved]. / Derdelijns verloskundige zorg: doelstellingen van het 'planningsbesluit bijzondere perinatologische zorg' uit 2001 nog niet gehaald.

OBJECTIVE: To compare the actual situation in tertiary perinatal care in the Netherlands with the objectives laid down in the 2001 decree on perinatal care by the Dutch Ministry of Health, Welfare and Sport. DESIGN: Descriptive, retrospective. METHOD: Data on tertiary perinatal care, the transfer or refusal of women with very endangered pregnancies and the personnel of obstetric high care (OHC) units in 2006 were compared with the targets laid down in the planning decree on perinatal care and in a report by the Dutch Health Council from 2000. Parameters of tertiary perinatal care output were the number of admissions, and the number of beds in OHC units and neonatal intensive care units (NICU). RESULTS: In 2006, 128 of the 250 beds intended for OHC had been obtained. The degree of capacity utilisation was 94%, while the norm is 80%. 312 women were transferred due to lack of capacity of OHC units and NICU. The number of staff, specialised physicians as well as nurses, was considerably lower than the planned capacity. But training for obstetric perinatologists and OHC nurses was given. CONCLUSION: The targets for the number of beds for tertiary obstetric care and associated medical personnel have not been achieved as yet. As a consequence, the number of transfers is still too high. The funding of OHC units is not attuned to the complexity of tertiary perinatal care. Closer supervision of the execution of the planning decree and an adequate financing system are needed to achieve the objectives of the planning decree in the next 3 years.

Hemodynamic changes with paradoxical blood flow in expectant management of abruptio placentae.

BACKGROUND: Because the early diagnosis of abruption often is missed or misinterpreted, emergency situations frequently do not permit adequate management. CASE: A woman of 26-weeks' gestation was transferred with symptoms and laboratory findings typical for abruption. Ultrasound, including Doppler, revealed a subchorionic hematoma, pathologic blood flow in the uterine arteries, low pulsatility index values in the fetal cerebral and umbilical arteries (paradoxical blood flow), and high maximal velocities in the fetal aorta. Repeated Doppler and laboratory examinations revealed a gradual restoration to normal of the arterial uterine blood flow pattern, of paradoxical blood flow, aortic maximal velocities, and laboratory values. CONCLUSION: Serial Doppler measurements considering the paradoxical pattern illustrate pathophysiologic mechanisms of abruption that may assist in deciding whether to deliver immediately or to continue intense surveillance.

Cerebral and umbilical arterial blood flow velocity waveforms in normal and growth-retarded pregnancies.

A combined sector and pulsed Doppler system was used to study the pulsatility index in the fetal internal carotid artery and umbilical artery in 156 normal pregnancies and 42 cases of intrauterine growth retardation (birth weight below the tenth percentile). All pregnancies were in the third trimester. In normal pregnancies, there was a gestational age-related fall in pulsatility index for both the umbilical artery and the umbilical artery/internal carotid artery ratio. No such fall was established for the pulsatility index in the internal carotid artery. In growth-retarded pregnancies, raised pulsatility index values in the umbilical artery were associated with reduced pulsatility index values in the internal carotid artery, suggesting the presence of a "brain-sparing" effect. When fetal causes of growth retardation were excluded, the sensitivities of the pulsatility index in the internal carotid artery, the umbilical artery, and for the umbilical artery/internal carotid artery ratio were 65, 83, and 88% at the 1 standard deviation (SD) cutoff level; and 48, 60, and 70% at the 2 SD cutoff level. Growth-retarded fetuses with structural or chromosomal defects had normal pulsatility index values in the internal carotid artery.

Minimal enteral feeding, fetal blood flow pulsatility, and postnatal intestinal permeability in preterm infants with intrauterine growth retardation.

OBJECTIVE: To study the effect of minimal enteral feeding (MEF) on intestinal permeability and feeding tolerance in preterm infants with intrauterine growth retardation (gestational age < 37 weeks, birth weight for gestational age p < 10). Furthermore, to determine whether fetal blood flow pulsatility or intestinal permeability predict feeding tolerance in these infants. DESIGN: Randomised controlled trial. METHODS: Within 48 hours of birth, infants were randomised to MEF or no enteral feeding (NEF) for five days in addition to parenteral feeding. Intestinal permeability was measured by the sugar absorption test before (SAT1) and after (SAT2) the study. The sugar absorption test measured the urinary lactulose/mannitol (LM) ratio after oral ingestion of a solution (375 mosm) containing mannitol and lactulose. Charts of all infants were assessed for measures of feeding tolerance. Fetal blood flow pulsatility index (U/C ratio) was measured within the seven days before birth. RESULTS: Of the 56 infants enrolled, 42 completed the study: 20 received MEF and 22 NEF. The decrease in LM ratio (LM ratio 1 - LM ratio 2) was not significantly different between the two groups (0.25 v 0.11; p = 0.14). Feeding tolerance, growth, and incidence of necrotising enterocolitis were not significantly different between the two groups. Neither the U/C nor the LM ratio 1 predicted feeding tolerance. CONCLUSIONS: The results suggest that MEF of preterm infants with intrauterine growth retardation has no effect on the decrease in intestinal permeability after birth. Neither fetal blood flow pulsatility nor intestinal permeability predicts feeding tolerance.

The relationship between fetal heart rate and Doppler blood flow velocity waveforms.

The degree of fetal heart rate dependency of pulsatility index measurements in the fetal descending aorta, internal carotid artery, and umbilical artery was studied relative to quiet and active sleep states in normal and growth-retarded fetuses at 37-38 weeks of gestation. In all vessels an inverse relationship between pulsatility index and heart rate was established. The degree of this inverse relationship varies proportionally with the level of peripheral vascular resistance in the vessels studied.

Flow velocity waveforms in the fetal internal carotid artery relative to fetal blood gas and acid-base measurements in normal pregnancy.

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.

The blood flow velocity waveform in the fetal descending aorta: its relationship to fetal behavioural states in normal pregnancy at 37-38 weeks.

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.

The blood flow velocity waveform in the fetal descending aorta; its relationship to behavioural states in the growth-retarded fetus at 37-38 weeks of gestation.

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.

The blood flow velocity waveform in the fetal descending aorta; its relationship to fetal heart rate pattern, eye and body movements in normal pregnancy at 27-28 weeks of gestation.

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.

Lack of agreement between central venous pressure and pulmonary capillary wedge pressure in preeclampsia.

OBJECTIVE: To establish if agreement exists between central venous pressure (CVP) and pulmonary capillary wedge pressure (PCWP) measurements in severe hypertension in pregnancy as analyzed by tests of bias, precision, and 95% limits of agreement. METHODS: In a prospective study, CVP and PCWP data in 30 patients were collected by means of a pulmonary artery catheter from initiation of therapy until delivery. Patients with a diastolic blood pressure of more than 110 mm Hg were included. Correlation and agreement between CVP and PCWP before and after treatment were evaluated. RESULTS: The correlation coefficient (r) for CVP-PCWP data in 30 untreated patients was r = 0.64 (p = 0.0002) and for 256 pairs of posttreatment data, it was r = 0.53 (p < 0.0001). Linear regression and correlation for each individual patient in 29 patients with more than 3 measurements showed a significant correlation (p < 0.05) in 19 patients (66%). Correlation was poor (p > 0.05) in 10 patients (34%). The mean difference between PCWP and CVP was 3.5 +/- 2.6 mm Hg (limits of agreement: -1.6 to 8.7) in untreated patients. The mean difference between PCWP and CVP for 256 pairs of data derived posttreatment was 4.9 +/- 3.8 mm Hg (limits of agreement: -2.7 to 12. 5). CONCLUSION: Invasive measurements of CVP and PCWP were found to agree poorly. Until a reliable noninvasive method is available to measure left ventricular preload, PCWP is the measurement of choice when invasive hemodynamic monitoring is necessary in patients with severe preeclampsia.

Recurrence rate of pre-eclampsia in women with thrombophilia influenced by low-molecular-weight heparin treatment?

OBJECTIVES: (1) To assess the recurrence rate of pre-eclampsia in women with this history before 34 weeks of pregnancy and thrombophilia. (2) To evaluate the effects of low-molecular-weight heparin (LMWH) on pregnancy outcome. METHODS: In a multicentre retrospective study subsequent pregnancies of women with a history of pre-eclampsia necessitating birth before 34 weeks and thrombophilia were analysed. Of 58 women, 26 received LMWH and aspirin (ASA) and 32 ASA (22) or no (10) medication in their subsequent pregnancies. RESULTS: In eight women treated with LMWH and ASA and in 16 women receiving ASA or no medication pre-eclampsia recurred in the subsequent pregnancy. (OR 0.55, 95% CI 0.15-1.31) There were no significant differences in birth weight or gestational age between both groups. CONCLUSIONS: The recurrence rate of pre-eclampsia in women with thrombophilic disorders is high in this small retrospective study. No positive effect was found for LMWH treatment. A multicentred randomised study has been started to reach an adequate number of patients to evaluate the influence of LMWH treatment.

Uncomplicated pregnancy and puerperium after puerperal cerebral venous thrombosis.

In this report we describe an uncomplicated pregnancy and puerperium in a 34 year old patient who had a previous puerperal superior sagittal sinus thrombosis. Heparin was given 3 weeks antepartum and oral anticoagulants 3 months postpartum.

Gray scale ultrasound for the investigation of early pregnancy.

73 early gestations (6-14 wk) were investigated with gray scale ultrasound. 7 of them ended in spontaneous first-trimester abortion, and in all of these the findings were characteristic for spontaneous interruption of pregnancy. The remaining 66 continued to term. Regression analysis was performed with respect to the diameter of the gestation sac, the fetal crown-rump length, and the placental surface and thickness. The method is considered appropriate for the diagnosis of early abortion and the study of placental morphology and morphometry. On the basis of the results obtained with gray scale techniques, various concepts derived from B-scan observations (e.g. implantation locus and early twin observation) will have to be corrected.