Objective: To assess the effect of maintenance tocolysis in women who are at high or low risk for preterm delivery according to fetal fibronectin (fFN) status and cervical length (CL).
Study design: ...We compared the risk of preterm delivery in fFN pos and fFN neg women and in women with a CL <15 mm and ≥15 mm, by using the Cox regression. Differences between the effectiveness of maintenance tocolysis in high- and low-risk women were assessed by using an interaction term.
Results: 122 fFN tests were taken, of which 50 were fFN pos. CL was measured in 236 women, of whom 52 women had a CL <15 mm. The median gestational age at delivery was lower in fFN pos women; fFN pos women had a higher hazard for preterm delivery at any point of time (HR 4.7; 95% CI 2.9 to 7.6). Comparable results were seen for CL. Neither fFN status nor CL did alter the effect of maintenance tocolysis, which was ineffective in the total randomized group, on the risk of preterm delivery (p for interaction = 0.87 for fFN and 0.18 for CL).
Conclusion: Maintenance tocolytic therapy with nifedipine is ineffective and not dependent on fFN or CL status.
Comparison of the effect of oral contraceptives on hemostatic variables in venous thrombosis patients (thrombosis while using oral contraceptives) with the effect in healthy control subjects. Our aim ...was to assess whether some of these effects were more pronounced in women who had suffered thrombosis, i.e., whether these were "hemostatic hyperresponders".
A population-based case-control study, the Leiden Thrombophilia Study.
We investigated 99 pre-menopausal women, age 15-49 years, who had used oral contraceptives at the time of a first, objectively confirmed episode of deep-vein thrombosis. They were not pregnant, nor in puerperium, nor had had a recent miscarriage, and were not using injectable progestogens, nor suffering from inherited coagulation defects. The median time between occurrence of deep-vein thrombosis and venepuncture was 18 months, and 30 of the 99 women were still using oral contraceptives, while 69 had discontinued oral contraceptive use. In addition, a group of 153 control women (54 of them were oral contraceptive users and 99 were non-users) were studied. The following hemostatic variables were measured: APTT, factor VII, factor VIII, factor XII, fibrinogen, prothrombin, total antithrombin, normalised activated protein C sensitivity ratio (n-APC-sr), protein C, protein S and free protein S.
We found marked and significant effects of oral contraceptive use on the levels of several clotting factors, with an increase in factor VII, factor XII, protein C and a decrease in antithrombin, n-APC-sr and protein S. Less marked effects that were non-significant or only significant in either patients or controls, were an increase in factor VIII, fibrinogen and prothrombin and a decrease in the APTT and free protein S. In the former thrombosis patients several of these effects of oral contraceptives were more pronounced than in healthy women: specifically on factor VII, antithrombin, n-APC-sr and protein C.
Our results of the effects of oral contraceptives generally confirm previous reports in healthy volunteers. Our data also show that in former deep-vein thrombosis patients these effects are more pronounced. Apparently some women become "high hemostatic responders" when exposed to oral contraceptives, and they may be the women most vulnerable to its thrombogenic effects.
Recently, it has been described that elevated plasma levels of factor VIII are a strong risk factor for venous thrombosis. We analysed the data of the Leiden Thrombophilia Study, a population based ...case-control study on the causes of venous thrombosis, to verify whether the risk due to oral contraceptive use was higher in women with higher factor VIII levels. Furthermore we investigated the joint risk of high factor VIII levels and oral contraceptive use. We selected 155 premenopausal women with deep-vein thrombosis and 169 control subjects, aged 15-49, who were at the time of their thrombosis (or similar date in control) not pregnant, nor in the puerperium, did not have a recent miscarriage, and were not using injectable progestogens. Of the patients, 109 (70%) women had used oral contraceptives during the month preceding their deep-vein thrombosis, in contrast to 65 (38%) of the control subjects (index date), yielding an odds ratio for oral contraceptive use of 3.8 (95% CI 2.4-6.0). Of the women who suffered a deep-vein thrombosis 56 (36%) had high factor VIII levels (> or =150 IU/dl) as compared with 29 (17%) of the control subjects, yielding an odds ratio for high factor VIII of 4.0 (95% CI 2.0-8.0), relative to factor VIII levels <100 IU/dl. The joint effect of oral contraceptive use and high factor VIII resulted in an odds ratio of 10.3 (95% CI 3.7-28.9), comparing women who had both with women who had neither. We conclude that there is an increase in risk due to oral contraceptive use in women with higher factor VIII levels and that both factors have additive effects.
At present, women with threatened preterm labor before 32 weeks of gestation are, after transfer to a perinatal center, treated with tocolytics and corticosteroids. Many of these women are treated ...unnecessarily. Fibronectin is an accurate predictor for the occurrence of preterm birth among women with threatened preterm labor. We will assess whether triage of these women with fibronectin testing, cervical length or their combination is cost-effective.
We will investigate a prospective cohort of women referred to a perinatal centre for spontaneous threatened preterm labor between 24 and 34 weeks with intact membranes. All women will be tested for fibronectin and cervical length. Women with a cervical length <10 mm and women with a cervical length between 10-30 mm in combination with a positive fibronectin test will be treated with tocolytics according to local protocol. Women with a cervical length between 10-30 mm in combination with a negative fibronectin test will be randomised between treatment with nifedipine (intervention) and placebo (control) for 48 hours. Women with a cervical length > 30 mm will be managed according to local protocol. Corticosteroids may be given to all women at the discretion of the attending physician. Primary outcome measure will be delivery within 7 days. Secondary outcome measures will be neonatal morbidity and mortality, complications of tocolytics, costs and health related quality of life. The analysis will be according to the intention to treat principle. We anticipate the probability on preterm birth within 7 days in the group of women with a negative fibronectine test to be 5%. Two groups of 110 women will be needed to assure that in case of non-inferiority the difference in the proportion of preterm deliveries < 7 days will be within a prespecified boundary of 7.5% (one sided test, beta 0.2, alpha 0.05). Data obtained from women with a positive and negative fibronectin tests in both the cohort study and the trial will be integrated in a cost-effectiveness analysis that will assess economic consequences of the use of fibronectin.
This study will provide evidence for the use of fibronectin testing as safe and cost-effective method in a triage for threatened preterm labor.
Nederlands Trial Register (NTR) number 1857, http://www.trialregister.nl.
Please cite this paper as: Vijgen S, Koopmans C, Opmeer B, Groen H, Bijlenga D, Aarnoudse J, Bekedam D, van den Berg P, de Boer K, Burggraaff J, Bloemenkamp K, Drogtrop A, Franx A, de Groot C, ...Huisjes A, Kwee A, van Loon A, Lub A, Papatsonis D, van der Post J, Roumen F, Scheepers H, Stigter R, Willekes C, Mol B, Van Pampus M for the HYPITAT study group. An economic analysis of induction of labour and expectant monitoring in women with gestational hypertension or pre‐eclampsia at term (HYPITAT trial). BJOG 2010;117:1577–1585.
Objective To assess the economic consequences of labour induction compared with expectant monitoring in women with gestational hypertension or pre‐eclampsia at term.
Design An economic analysis alongside the Hypertension and Pre‐eclampsia Intervention Trial At Term (HYPITAT).
Setting Obstetric departments of six university and 32 teaching and district hospitals in the Netherlands.
Population Women diagnosed with gestational hypertension or pre‐eclampsia between 36+0 and 41+0 weeks of gestation, randomly allocated to either induction of labour or expectant monitoring.
Methods A trial‐based cost‐effectiveness analysis was performed from a societal perspective during a 1‐year time horizon.
Main outcome measures One‐year costs were estimated and health outcomes were expressed as the prevalence of poor maternal outcome defined as either maternal complications or progression to severe disease.
Results The average costs of induction of labour (n = 377) were €7077 versus €7908 for expectant monitoring (n = 379), with an average difference of −€831 (95% CI −€1561 to −€144). This 11% difference predominantly originated from the antepartum period: per woman costs were €1259 for induction versus €2700 for expectant monitoring. During delivery, more costs were generated following induction (€2190) compared with expectant monitoring (€1210). No substantial differences were found in the postpartum, follow‐up and for non‐medical costs.
Conclusion In women with gestational hypertension or mild pre‐eclampsia at term, induction of labour is less costly than expectant monitoring because of differences in resource use in the antepartum period. As the trial already demonstrated that induction of labour results in less progression to severe disease without resulting in a higher caesarean section rate, both clinical and economic consequences are in favour of induction of labour in these women.
Trial registration The trial has been registered in the clinical trial register as ISRCTN08132825.
Studies conducted in the first three decades after discovery of a link between venous thromboembolism and oral contraceptive users showed a relative risk of first thrombosis during oral contraceptive ...use of 2.9 (95% CI 0.5-17). In recent studies in which the sub-50 micrograms ethinyl estrodiol containing pills were investigated comparing current users with non-users, the RR is 3.8 for non-fatal deep VTE and 2.7 for superficial VTE, deep VTE and pulmonary embolism (PE) together and 2.1 for fatal VT and PE together. The association is attributed to the estrogenic component and not related to duration of pill use. The risk disappears once the pill has been stopped, and it is not elevated among past users. Smoking does not appear to be risk factor for VTE; obesity and varicose veins are, at the most, weak risk factors. Since a causal relationship between OC use and VTE is tempting, clues for unraveling the mechanism were sought in the hemostatic system. Studies of the coagulation system found changes in the activation of coagulation and fibrinolytic compartments, but within the normal range. An epidemiologic study showed that the risk of VTE among women using OCs is 30-fold increased by the presence of a mutation of factor V, called Factor V Leiden (5% prevalence in the Caucasian population). Selective screening for the mutated factor V should be limited to women with a personal or family history of VTE. Four epidemiologic studies showed a two-fold increase in risk of VTE with the use of OCs containing third-generation progestins (gestodene and desogestrel), relative to second-generations products (levonorgestrel). Biases cannot devaluate the conclusion that the increased risk of VTE in especially first-time and younger users of third-generation OCs is highly likely. The clinical consequence is therefore that second-generation OCs are the first choice in prescription to first-time users.
Objective: Recently, it has been proposed that hereditary coagulation abnormalities leading to an increased venous thrombosis risk may play a role in the development of preeclampsia. We tested this ...hypothesis in women who have had preeclampsia compared with matched control subjects.
Study Design: We conducted a case-control study of 163 women with preeclampsia during 1991-1996. Control subjects were matched for age and delivery date. Patients and control subjects were tested for the presence of factor V Leiden, prothrombin 20210A allele, protein C, protein S, and antithrombin deficiency. Logistic regression methods were used for data analysis.
Results: The prevalence of these genetic risk factors was similar in the patient group (12.9%) and the control group (12.9%; odds ratio, 1.0; 95% confidence interval, 0.5-3.9). Unexpectedly, we found a high prevalence of factor V Leiden in the control group (9.2%).
Conclusion: We found no differences in the prevalence of genetic risk factors of thrombosis in women with preeclampsia compared with control subjects. (Am J Obstet Gynecol 1999;181:975-80.)
Abstract
Objective
The aim of this study was to assess which characteristics and results of vaginal examination are predictive for delivery within 7 days, in women with threatened preterm labor ...after initial treatment.
Study Design
A secondary analysis of a randomized controlled trial on maintenance nifedipine includes women who remained undelivered after threatened preterm labor for 48 hours. We developed one model for women with premature prelabor rupture of membranes (PPROM) and one without PPROM. The predictors were identified by backward selection. We assessed calibration and discrimination and used bootstrapping techniques to correct for potential overfitting.
Results
For women with PPROM (model 1), nulliparity, history of preterm birth, and vaginal bleeding were included in the multivariable analysis. For women without PPROM (model 2), maternal age, vaginal bleeding, cervical length, and fetal fibronectin (fFN) status were in the multivariable analysis. Discriminative capability was moderate to good (
c
-statistic 0.68; 95% confidence interval CI 0.60–0.77 for model 1 and 0.89; 95% CI, 0.84–0.93 for model 2).
Conclusion
PPROM and vaginal bleeding in the current pregnancy are relevant predictive factors in all women, as are maternal age, cervical length, and fFN in women without PPROM and nulliparity, history of preterm birth in women with PPROM.
Preterm labour is the main cause of perinatal morbidity and mortality in the Western world. At present, there is evidence that tocolysis for 48 hours is useful in women with threatened preterm labour ...at least before 32 weeks. This allows transfer of the patient to a perinatal centre, and maximizes the effect of corticosteroids for improved neonatal survival. It is questionable whether treatment with tocolytics should be maintained after 48 hours.
The APOSTEL II trial is a multicentre placebo-controlled study. Pregnant women admitted for threatened preterm labour who have been treated with 48 hours corticosteroids and tocolysis will be eligible to participate in the trial between 26+0 and 32+2 weeks gestational age. They will be randomly allocated to nifedipine (intervention) or placebo (control) for twelve days or until delivery, whatever comes first.Primary outcome is a composite of perinatal death, and severe neonatal morbidity up to evaluation at 6 months after birth. Secondary outcomes are gestational age at delivery, number of days in neonatal intensive care and total days of the first 6 months out of hospital. In addition a cost-effectiveness analysis will be performed. Analysis will be by intention to treat. The power calculation is based on an expected 11% difference in adverse neonatal outcome. This implies that 406 women have to be randomised (two sided test, beta 0.2 at alpha 0.05).
This trial will provide evidence as to whether maintenance tocolysis reduces severe perinatal morbidity and mortality in women with threatened preterm labour before 32 weeks.
http://www.trialregister.nl, NTR 1336, date of registration: June 3rd 2008.
PDF
