Antoinette C. Bolte

Use of recombinant activated factor VII in primary postpartum hemorrhage - The northern European registry 2000-2004

OBJECTIVE: To collect data from nine European countries for cases of obstetric hemorrhage between 2000 and 2004 in which recombinant activated factor VII (rFVIIa) was used. METHODS: The cases were identified through national surveys. Standardized case report forms included sociodemographic details, past medical and obstetric history, and details of the progress and management of labor in which the postpartum hemorrhage occurred. Clinicians were asked to describe subjectively the effect of rFVIIa administration using two mutually exclusive categories: 1) bleeding reduced or 2) bleeding unchanged or worse. RESULTS: A total of 113 forms were returned (88%) with 97 (86%) classified as treatment, and 16 (14%) as “secondary prophylaxis.” Clinicians noted improvements after a single dose for 80% of women in the treatment group, and for 75% in the secondary “prophylaxis” group. However, rFVIIa failed in 15 cases (13.8%). Few serious adverse events were noted related to rFVIIa administration; there were four cases of thromboembolism, one myocardial infarction, and one skin rash. CONCLUSION: Clinical reports and hematologic data suggest improvement for more than 80% of women after rFVIIa administration and few adverse effects. LEVEL OF EVIDENCE: II

Effect of Maintenance Tocolysis With Nifedipine in Threatened Preterm Labor on Perinatal Outcomes A Randomized Controlled Trial

IMPORTANCE In threatened preterm labor, maintenance tocolysis with nifedipine, after an initial course of tocolysis and corticosteroids for 48 hours, may improve perinatal outcome. OBJECTIVE To determine whether maintenance tocolysis with nifedipine will reduce adverse perinatal outcomes due to premature birth. DESIGN, SETTING, AND PARTICIPANTS APOSTEL-II (Assessment of Perinatal Outcome with Sustained Tocolysis in Early Labor) is a double-blind, placebo-controlled trial performed in 11 perinatal units including all tertiary centers in The Netherlands. From June 2008 to February 2010, women with threatened preterm labor between 26 weeks (plus 0 days) and 32 weeks (plus 2 days) gestation, who had not delivered after 48 hours of tocolysis and a completed course of corticosteroids, were enrolled. Surviving infants were followed up until 6 months after birth (ended August 2010). INTERVENTION Randomization assigned 406 women to maintenance tocolysis with nifedipine orally (80 mg/d; n = 201) or placebo (n = 205) for 12 days. Assigned treatment was masked from investigators, participants, clinicians, and research nurses. MAIN OUTCOME MEASURES Primary outcome was a composite of adverse perinatal outcomes (perinatal death, chronic lung disease, neonatal sepsis, intraventricular hemorrhage >grade 2, periventricular leukomalacia >grade 1, or necrotizing enterocolitis). Analyses were completed on an intention-to-treat basis. RESULTS Mean (SD) gestational age at randomization was 29.2 (1.7) weeks for both groups. Adverse perinatal outcome was not significantly different between groups: 11.9% (24/201; 95% CI, 7.5%-16.4%) for nifedipine vs 13.7% (28/205; 95% CI, 9.0%-18.4%) for placebo (relative risk, 0.87; 95% CI, 0.53-1.45). CONCLUSIONS AND RELEVANCE In patients with threatened preterm labor, nifedipine-maintained tocolysis did not result in a statistically significant reduction in adverse perinatal outcomes when compared with placebo. Although the lower than anticipated rate of adverse perinatal outcomes in the control group indicates that a benefit of nifedipine cannot completely be excluded, its use for maintenance tocolysis does not appear beneficial at this time. TRIAL REGISTRATION trialregister.nl Identifier: NTR1336.

Predictive value of cervical length measurement and fibronectin testing in threatened preterm labor

OBJECTIVE: To estimate the performance of combining cervical length measurement with fetal fibronectin testing in predicting delivery in women with symptoms of preterm labor. METHODS: We conducted a prospective nationwide cohort study in all 10 perinatal centers in The Netherlands. Women with symptoms of preterm labor between 24 and 34 weeks of gestation with intact membranes were included. In all women, qualitative fibronectin testing (0.050-microgram/mL cutoff) and cervical length measurement were performed. Logistic regression was used to predict spontaneous preterm delivery within 7 days after testing. A risk less than 5%, corresponding to the risk for women with a cervical length of at least 25 mm, was considered as low risk. RESULTS: Between December 2009 and August 2012, 714 women were enrolled. Fibronectin results and cervical length were available for 665 women, of whom 80 (12%) delivered within 7 days. Women with a cervical length of at least 30 mm or with a cervical length between 15 and 30 mm with a negative fibronectin result were at low risk (less than 5%) of spontaneous delivery within 7 days. Fibronectin testing in case of a cervical length between 15 and 30 mm additionally classified 103 women (15% of the cohort) as low risk and 36 women (5% of the cohort) as high risk. CONCLUSION: Cervical length measurement, combined with fetal fibronectin testing in case of a cervical length between 15 and 30 mm, improves identification of women with a low risk to deliver spontaneously within 7 days. LEVEL OF EVIDENCE: II

Pathophysiology of preeclampsia and the role of serotonin

Hypertensive disorders constitute the most common medical complications of pregnancy. In normal pregnancy, impressive physiological changes take place in the maternal cardiovascular system. Morphological changes are the result of invasion of migratory trophoblast cells into the walls of the spiral arteries. After destruction of elastic, muscular and neural tissue in the media, the trophoblast cells get incorporated into the vessel wall and the endothelial lining of the spiral arteries is restored. The physiological changes create a low-resistance, low-pressure, high-flow system with the absence of maternal vasomotor control. Biochemical adaptations in maternal vasculature include changes in the prostaglandin system, the renin-angiotensin-aldosteron system and the kallikrein-kinin system. In preeclampsia, physiological changes in the spiral arteries are confined to the decidual portion of the arteries. Myometrial segments remain anatomically intact and fail to dilate. In addition, the adrenergic nerve supply is left intact. The cause of this impaired endovascular trophoblast invasion is not yet elucidated. But in combination with the imbalance between vasodilator and vasoconstrictor eicosanoids, it gives rise to reduced perfusion of the intervillous space. In the absence of an adequate production of antiaggregatory prostacyclin (PGI(2)), nitric oxide, or both, surface-mediated platelet activation is supposed to occur on the surface of the spiral arteries. Because platelets are the principal source of circulating serotonin, the increased platelet aggregation in preeclampsia causes an increase in serotonin levels. Interaction of serotonin with serotonin(1)- or serotonin(2)-receptors depends on the state of the endovascular trophoblast or endothelium in the spiral arteries and has opposite effects with regard to vasodilating and vasoconstrictive influences.

Peri-partum reference ranges for ROTEM® thromboelastometry

BACKGROUND Post-partum haemorrhage (PPH) causes rapidly developing deficiencies in clotting factors and contributes to substantial maternal morbidity and mortality. Rotational thromboelastometry (ROTEM(®)) is increasingly used as a point of care coagulation monitoring device in patients with massive haemorrhage; however, there are limited data on reference ranges in the peri-partum period. These are required due to the haemostatic changes in pregnancy. METHODS In a Dutch multi-centre trial, 161 subjects were included; blood samples were obtained during labour (T1) and within 1 h of delivery (T2). Reference ranges of ROTEM(®) INTEM, EXTEM, FIBTEM, and APTEM were set and correlation with laboratory results was investigated using the guidelines of the International Federation of Clinical Chemistry. RESULTS Reference ranges were obtained for clotting time (CT), clot formation time (CFT), α-angle, clot firmness at 10 and 20 min (A10, A20), maximum clot firmness (MCF), and maximum lysis (ML). These were comparable from centre to centre, and between T1 and T2. Reference ranges T1: EXTEM: CT 31-63 s, CFT 41-120 s, and MCF 42-78 mm. INTEM CT 109-225 s, CFT 40-103, and MCF 63-78 mm. FIBTEM CT 31-79 s and MCF 13-45 mm. APTEM CT 33-62 s, CFT 42-118, and MCF 61-79 mm. CONCLUSIONS Reference values for ROTEM(®) parameters are reported. The previously published correlation between FIBTEM parameters and plasma fibrinogen levels by the Clauss method is confirmed. Further research is needed to define threshold values for haemostatic therapy in the course of PPH. Clinical trial registration NTR 2515 (http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=2515).

Pharmacological and surgical therapy for primary postpartum hemorrhage.

Early postpartum hemorrhage remains a significant cause of maternal morbidity and mortality. Postpartum hemorrhage is most commonly due to uterine atony and often responds to medical treatments such as administration of uterotonic drugs, alone or in combination with uterine massage or bimanual compression. As the incidence of cesarean section continues to rise, the problem of placenta previa and accreta is likely to become more common. For first-line management of postpartum hemorrhage adequate blood and fluid replacement is mandatory. In recent years new therapeutic measures to control the bleeding have gained attention. Although, these newer therapies focus on avoiding the need for emergency hysterectomy and preservation of reproductive function, reports of subsequent pregnancies are still scarce. Established management options are shortly reviewed and novel medical and surgical treatments are more extensively discussed.

Management and monitoring of severe preeclampsia

Preeclampsia is associated with increased maternal and perinatal morbidity and mortality. Preeclampsia is more than pregnancy-induced hypertension. The hypertension is only one manifestation of an underlying multifactorial, multisystem disorder, initiated early in pregnancy. In established severe disease there is volume contraction, reduced cardiac output, enhanced vascular reactivity, increased vascular permeability and platelet consumption. Medical treatment of severe hypertension in pregnancy is required. The more controversial issues are the role of pharmacological treatment in conservative management of severe preeclampsia aiming at prolongation of pregnancy, the ability of such therapy to modify the course of the underlying systemic disorder and the effects on fetal and maternal outcome. This paper presents an overview concerning the current developments in management and monitoring of severe preeclampsia. Controversial topics such as the role of plasma volume expansion in preeclampsia, expectant versus aggressive management of severe preeclampsia remote from term, and pharmacological interventions in the management of eclampsia and the HELLP syndrome are addressed.

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.

Pharmacological treatment of severe hypertension in pregnancy and the role of serotonin2-receptor blockers

Hypertensive disorders of pregnancy are the leading cause of maternal and perinatal mortality and morbidity in developing and developed countries. The etiology of preeclampsia is still unknown. Delivering the baby is the only definite treatment. The benefits of acute pharmacological control of severe hypertension prior to and/or post-delivery are generally accepted. Most drugs commonly used in the management of severe hypertension in pregnancy have significant maternal and/or neonatal adverse side effects. Furthermore, some are not effective to acutely lower the blood pressure in patients with a hypertensive crisis. Until recently not one of the commonly used antihypertensive drugs has been tailored to the pathophysiology of severe preeclampsia, being a clinical syndrome characterized by endothelial cell dysfunction, vasospasm and platelet aggregation. Ketanserin, a serotonin(2)-receptor blocker, is a drug that appears to be tailored for treating this pregnancy-associated enthothelial cell dysfunction. The results of several prospective trials show that there is a definite place for serotonin(2)-receptor blockers in the treatment of pregnancy-induced hypertensive disorders. This review provides a summary on the more established drugs as well as on some of the newer antihypertensive drugs used in pregnancy with emphasis on the existing experience with ketanserin.

TNF-receptor levels in preeclampsia--results of a longitudinal study in high-risk women

Objective. Tumor necrosis factor-alpha (TNF-α) is thought to play a role in immune activation in preeclampsia. The objective of this study was to establish if soluble TNF-receptor I (sTNF-rI) levels relate to the onset and severity of preeclampsia. Methods. Maternal plasma sTNF-rI levels were studied throughout pregnancy in 68 women with a history of severe preeclampsia or intra-uterine growth restriction (IUGR), and primigravidas with chronic hypertension. Data are presented as mean (SD) in ng/ml. Results. In the second trimester there was a significant difference in sTNF-rI levels between preeclamptic pregnancies with and without IUGR (means 1.33 (0.20) and 1.11 (0.15) respectively, p < 0.005). In severe preeclampsia with delivery before 34 weeks of gestation, sTNF-rI levels were higher than in mild preeclampsia in the second and third trimesters (means 1.40 (0.16) vs. 1.16 (0.19), p < 0.02 and 1.82 (0.47) vs. 1.42 (0.22), p < 0.05, respectively). Conclusion. sTNF-rI levels were higher in preeclampsia with fetal involvement, suggesting that increased TNF-α production in preeclampsia is related to impaired placentation rather than to the maternal syndrome.