Patient preferences for disposable and reusable vaginal specula and their willingness to compromise in the era of climate change: A cross-sectional study.

OBJECTIVE: To evaluate patient satisfaction on gynaecological examination with metal, plastic and biobased plastic vaginal specula, and to investigate whether patients are willing to compromise on comfort for a more sustainable healthcare system. DESIGN: Cross-sectional study: population-based survey. SETTING: Gynaecological outpatient clinics in five Dutch hospitals. POPULATION: Patients during general gynaecology consultation hours. METHODS: A survey containing two questions about patient demographics, four about comfort and five about sustainability and healthcare was distributed. MAIN OUTCOME MEASURES: Comfort score (scale 1-10). SECONDARY OUTCOMES: (1) temperature, size and ease of insertion, (2) willingness to compromise for a more sustainable healthcare system. RESULTS: In all, 196 patients completed the survey. Biobased plastic vaginal specula scored significantly higher on comfort than the metal ones (mean 8.03 ± 1.65 versus 7.26 ± 1.51 respectively; P < 0.001). The biobased plastic vaginal speculum is significantly the most comfortable on temperature, whereas the metal speculum is the least comfortable (P < 0.007). Most patients are willing to compromise on comfort or are open to the reuse of disposables to contribute to a more sustainable healthcare. The majority of patients (77%) urge healthcare organisations to combat climate change. CONCLUSIONS: There is a small but statistically significant difference in favour of a biobased plastic speculum regarding comfort score, although it might be questioned whether this is clinically relevant. Furthermore, patients are willing to compromise on comfort for a more sustainable healthcare, which should be a contributing factor in speculum selection.

Placenta Pathology From Term Born Neonates With Normal or Adverse Outcome.

BACKGROUND: The incidence of umbilical cord or placental parenchyma abnormalities associated with mortality or morbidity of term infants is lacking. METHODS: Placentas of 55 antepartum stillbirths (APD), 21 intrapartum stillbirths (IPD), 12 neonatal deaths (ND), and 80 admissions to a level 3 neonatal intensive care unit (NS) were studied and compared with 439 placentas from neonates from normal term pregnancies and normal outcome after vaginal delivery (NPVD) and with 105 placentas after an elective caesarian sections (NPEC). RESULTS: NPVD and NPEC placentas showed no or one abnormality in 70% and placentas from stillbirth showed two or more abnormalities in 80% of cases. APD placentas more frequently had a low weight and less formation of terminal villi. Hypercoiling was more often present in all study groups. Severe chronic villitis was almost exclusively present in APD placentas. Chorioamnionitis was significantly more frequent in APD, IPD and NS placentas and funisitis was more often observed in IPD and NS placentas. CONCLUSION: Multiple placental abnormalities are significantly more frequent in placentas from term neonates with severe perinatal morbidity and mortality. These placental abnormalities are thought to be associated with disturbed oxygen transfer or with inflammation.

Implementation of a first-trimester prognostic model to improve screening for gestational diabetes mellitus.

BACKGROUND: Improvement in the accuracy of identifying women who are at risk to develop gestational diabetes mellitus (GDM) is warranted, since timely diagnosis and treatment improves the outcomes of this common pregnancy disorder. Although prognostic models for GDM are externally validated and outperform current risk factor based selective approaches, there is little known about the impact of such models in day-to-day obstetric care. METHODS: A prognostic model was implemented as a directive clinical prediction rule, classifying women as low- or high-risk for GDM, with subsequent distinctive care pathways including selective midpregnancy testing for GDM in high-risk women in a prospective multicenter birth cohort comprising 1073 pregnant women without pre-existing diabetes and 60 obstetric healthcare professionals included in nine independent midwifery practices and three hospitals in the Netherlands (effectiveness-implementation hybrid type 2 study). Model performance (c-statistic) and implementation outcomes (acceptability, adoption, appropriateness, feasibility, fidelity, penetration, sustainability) were evaluated after 6 months by indicators and implementation instruments (NoMAD; MIDI). RESULTS: The adherence to the prognostic model (c-statistic 0.85 (95%CI 0.81-0.90)) was 95% (n = 1021). Healthcare professionals scored 3.7 (IQR 3.3-4.0) on implementation instruments on a 5-point Likert scale. Important facilitators were knowledge, willingness and confidence to use the model, client cooperation and opportunities for reconfiguration. Identified barriers mostly related to operational and organizational issues. Regardless of risk-status, pregnant women appreciated first-trimester information on GDM risk-status and lifestyle advice to achieve risk reduction, respectively 89% (n = 556) and 90% (n = 564)). CONCLUSIONS: The prognostic model was successfully implemented and well received by healthcare professionals and pregnant women. Prognostic models should be recommended for adoption in guidelines.

Associations between periconceptional lifestyle behaviours and adverse pregnancy outcomes.

BACKGROUND: While the potential adverse outcomes of prenatal exposure to unhealthy lifestyle are widely evidenced, little is known about these exposures in the periconception period. We investigated the associations between lifestyle behaviours and adverse pregnancy outcomes with a unique distinction between preconceptional- and prenatal lifestyle behaviours. METHODS: A secondary analysis took place within a prospective multicentre cohort study in the Netherlands, including 3,684 pregnant women. Baseline characteristics and preconceptional and first trimester lifestyle behaviours were assessed through a self-administered questionnaire in the first trimester. Adverse pregnancy outcomes (hypertensive disorders in pregnancy (HDP), small for gestational age (SGA), gestational diabetes (GDM) and spontaneous preterm birth (sPTB)) were reported by healthcare professionals. Data were collected between 2012 and 2014 and analysed using multivariate logistic regression. RESULTS: Women who are overweight, and especially obese, have the highest odds of developing any adverse pregnancy outcome (adjusted odds ratio (aOR) 1.61 (95 % Confidence Interval (CI) 1.31-1.99) and aOR 2.85 (95 %CI 2.20-3.68), respectively), particularly HDP and GDM. Women who prenatally continued smoking attained higher odds for SGA (aOR 1.91 (95 %CI 1.05-1.15)) compared to the reference group, but these odds decreased when women prenatally quit smoking (aOR 1.14 (95 %CI 0.59-2.21)). Women who did not use folic acid supplements tended to have a higher odds of developing adverse pregnancy outcomes (aOR 1.28 (95 %CI 0.97-1.69)), while women who prenatally started folic acid supplements did not (aOR 1.01 (95 %CI 0.82-1.25)). CONCLUSIONS: Our results indicate that smoking cessation, having a normal body mass index (BMI) and initiating folic acid supplements preconceptionally may decrease the risk of adverse pregnancy outcomes. Therefore, intervening as early as the preconception period could benefit the health of future generations.

External validation of a prediction model on vaginal birth after caesarean in a The Netherlands: a prospective cohort study.

OBJECTIVES: Discussing the individual probability of a successful vaginal birth after caesarean (VBAC) can support decision making. The aim of this study is to externally validate a prediction model for the probability of a VBAC in a Dutch population. METHODS: In this prospective cohort study in 12 Dutch hospitals, 586 women intending VBAC were included. Inclusion criteria were singleton pregnancies with a cephalic foetal presentation, delivery after 37 weeks and one previous caesarean section (CS) and preference for intending VBAC. The studied prediction model included six predictors: pre-pregnancy body mass index, previous vaginal delivery, previous CS because of non-progressive labour, Caucasian ethnicity, induction of current labour, and estimated foetal weight ≥90th percentile. The discriminative and predictive performance of the model was assessed using receiver operating characteristic curve analysis and calibration plots. RESULTS: The area under the curve was 0.73 (CI 0.69-0.78). The average predicted probability of a VBAC according to the prediction model was 70.3% (range 33-92%). The actual VBAC rate was 71.7%. The calibration plot shows some overestimation for low probabilities of VBAC and an underestimation of high probabilities. CONCLUSIONS: The prediction model showed good performance and was externally validated in a Dutch population. Hence it can be implemented as part of counselling for mode of delivery in women choosing between intended VBAC or planned CS after previous CS.

Significant reduction in umbilical artery metabolic acidosis after implementation of intrapartum ST waveform analysis of the fetal electrocardiogram.

BACKGROUND: Although the evidence regarding the benefit of using ST waveform analysis of the fetal electrocardiogram is conflicting, ST waveform analysis is considered as adjunct to identify fetuses at risk for asphyxia in our center. Most randomized controlled trials and meta-analyses have not shown a significant decrease in umbilical metabolic acidosis, while some observational studies have shown a gradual decrease of this outcome over a longer period of time. Observational studies can give more insight into the effect of implementation of the ST technology in daily clinical practice. OBJECTIVE: To evaluate the change in frequency of perinatal intervention and adverse neonatal outcome after the implementation of ST waveform analysis of the fetal electrocardiogram from 2000 to 2013. STUDY DESIGN: This retrospective longitudinal study was conducted in a tertiary referral center. A total of 19,664 medium- and high-risk singleton pregnancies with fetuses in cephalic presentation, a gestational age of ≥36 weeks, and the intention to deliver vaginally were included. ST waveform analysis of the fetal electrocardiogram was implemented in the year 2000 and by 2010 all deliveries were monitored using this technology. Data were collected on the following perinatal outcomes: fetal blood sampling, mode of delivery, umbilical cord blood gases, Apgar scores, neonatal encephalopathy, and perinatal death. Longitudinal trend analysis was used to detect changes over time in all deliveries monitored by cardiotocography either alone or in adjunct to ST waveform analysis of the fetal electrocardiogram. Logistic regression was used to correct for possible confounders. RESULTS: The umbilical artery metabolic acidosis rate declined from 2.5% (average rate of 2000 + 2001 + 2002) to 0.4% (average of 2011 + 2012 + 2013) (P < .001), which represents an 84% decrease. This decrease largely occurred between 2006 and 2008, during the Dutch randomized trial on fetal electrocardiogram ST waveform analysis. At this time, approximately 20% of deliveries were monitored using this method. Furthermore, there were significant reductions in fetal blood sampling rate (P < .001). Overall cesarean and vaginal instrumental deliveries decreased significantly (P < .001), but not for fetal distress. There were no changes in the Apgar scores. The incidence of neonatal encephalopathy was significantly lower in the second part of the study (odds ratio 0.39, 95% confidence interval 0.17-0.89). CONCLUSION: There was an 84% decrease in the incidence of umbilical artery metabolic acidosis in all deliveries between 2000 and 2013. The neonatal encephalopathy rate, fetal blood sampling rate, and the total number of cesarean and vaginal instrumental deliveries also decreased.

Fetal electrocardiography ST-segment analysis for intrapartum monitoring: a critical appraisal of conflicting evidence and a way forward.

BACKGROUND: In the past century, some areas of obstetric including intrapartum care have been slow to benefit from the dramatic advances in technology and medical care. Although fetal heart rate monitoring (cardiotocography) became available a half century ago, its interpretation often differs between institutions and countries, its diagnostic accuracy needs improvement, and a technology to help reduce the unnecessary obstetric interventions that have accompanied the cardiotocography is urgently needed. STUDY DESIGN: During the second half of the 20th century, key findings in animal experiments captured the close relationship between myocardial glycogenolysis, myocardial workload, and ST changes, thus demonstrating that ST waveform analysis of the fetal electrocardiogram can provide information on oxygenation of the fetal myocardium and establishing the physiological basis for the use of electrocardiogram in intrapartum fetal surveillance. RESULTS: Six randomized controlled trials, 10 meta-analyses, and more than 20 observational studies have evaluated the technology developed based on this principle. Nonetheless, despite this intensive assessment, differences in study protocols, inclusion criteria, enrollment rates, clinical guidelines, use of fetal blood sampling, and definitions of key outcome parameters, as well as inconsistencies in randomized controlled trial data handling and statistical methodology, have made this voluminous evidence difficult to interpret. Enormous resources spent on randomized controlled trials have failed to guarantee the generalizability of their results to other settings or their ability to reflect everyday clinical practice. CONCLUSION: The latest meta-analysis used revised data from primary randomized controlled trials and data from the largest randomized controlled trials from the United States to demonstrate a significant reduction of metabolic acidosis rates by 36% (odds ratio, 0.64; 95% confidence interval, 0.46-0.88) and operative vaginal delivery rates by 8% (relative risk, 0.92; 95% confidence interval, 0.86-0.99), compared with cardiotocography alone.

Identification of barriers and facilitators for optimal cesarean section care: perspective of professionals.

BACKGROUND: The cesarean section (CS) rate has increased over recent decades with poor guideline adherence as a possible cause. The objective of this study was to explore barriers and facilitators for delivering optimal care as described in clinical practice guidelines. METHODS: Key recommendations from evidence-based guidelines were used as a base to explore barriers and facilitators for delivering optimal CS care in The Netherlands. Both focus group and telephone interviews among 29 different obstetrical professionals were performed. Transcripts from the interviews were analysed. Barriers and facilitators were identified and categorised in six domains according to the framework developed by Grol: the guideline recommendations (I), the professional (II), the patient (III), the social context (IV), the organizational context (V) and the financial/legislation context (VI). RESULTS: Most barriers were found in the professional and organizational domain. Barriers mentioned by healthcare professionals were disagreement with specific guideline recommendations, and hesitation to allow women to be part of the decision making process. Other barriers are lack of adequately trained personal staff, lack of collaboration between professionals, and lack of technical equipment. CONCLUSIONS: Clear facilitators and barriers for guideline adherence were identified in all domains. Several barriers may be addressed by using decision aids on mode of birth or prediction models to individualise care in women in whom both planned vaginal birth and CS are equal options. In women with an intended vaginal birth, adequate staffing and the availability of both fetal blood sampling and epidural analgesia are important.

Perspectives, preferences and needs regarding early prediction of preeclampsia in Dutch pregnant women: a qualitative study.

BACKGROUND: To improve early risk-identification in pregnancy, research on prediction models for common pregnancy complications is ongoing. Therefore, it was the aim of this study to explore pregnant women's perceptions, preferences and needs regarding prediction models for first trimester screening for common pregnancy complications, such as preeclampsia, to support future implementation. METHOD: Ten focus groups (of which five with primiparous and five with multiparous women) were conducted (n = 45). Six focus groups were conducted in urban regions and four in rural regions. All focus group discussions were audio taped and NVIVO was used in order to facilitate the thematic analysis conducted by the researchers. RESULTS: Women in this study had a positive attitude towards first trimester screening for preeclampsia using prediction models. Reassurance when determined as low-risk was a major need for using the test. Self-monitoring, early recognition and intensive monitoring were considered benefits of using prediction models in case of a high-risk. Women acknowledged that high-risk determination could cause (unnecessary) anxiety, but it was expected that personal and professional interventions would level out this anxiety. CONCLUSION: Women in this study had positive attitudes towards preeclampsia screening. Self-monitoring, together with increased alertness of healthcare professionals, would enable them to take active actions to improve pregnancy outcomes. This attitude enhances the opportunities for prevention, early recognition and treatment of preeclampsia and probably other adverse pregnancy outcomes.

Practice variation of vaginal birth after cesarean and the influence of risk factors at patient level: a retrospective cohort study.

INTRODUCTION: Large practice variation exists in mode of delivery after cesarean section, suggesting variation in implementation of contemporary guidelines. We aim to evaluate this practice variation and to what extent this can be explained by risk factors at patient level. MATERIAL AND METHODS: This retrospective cohort study was performed among 17 Dutch hospitals in 2010. Women with one prior cesarean section without a contraindication for a trial of labor were included. We used multivariate logistic regression analysis to develop models for risk factor adjustments. One model was derived to adjust the elective repeat cesarean section rates; a second model to adjust vaginal birth after cesarean rates. Standardized rates of elective repeat cesarean section and vaginal birth after cesarean per hospital were compared. Pseudo-R2 measures were calculated to estimate the percentage of practice variation explained by the models. Secondary outcomes were differences in practice variation between hospital types and the correlation between standardized elective repeat cesarean section and vaginal birth after cesarean rates. RESULTS: In all, 1068 women had a history of cesarean section, of whom 71% were eligible for inclusion. A total of 515 women (67%) had a trial of labor, of whom 72% delivered vaginally. The elective repeat cesarean section rate at hospital level ranged from 6 to 54% (mean 29.8, standard deviation 11.8%). Vaginal birth after cesarean rates ranged from 50 to 90% (mean 71.8%, standard deviation 11.1%). More than 85% of this practice variation could not be explained by risk factors at patient level. CONCLUSION: A large practice variation exists in elective repeat cesarean section and vaginal birth after cesarean rates that can only partially be explained by risk factors at patient level.

Which Factors Contribute to False-Positive, False-Negative, and Invalid Results in Fetal Fibronectin Testing in Women with Symptoms of Preterm Labor?

Objective We assessed the influence of external factors on false-positive, false-negative, and invalid fibronectin results in the prediction of spontaneous delivery within 7 days. Methods We studied symptomatic women between 24 and 34 weeks' gestational age. We performed uni- and multivariable logistic regression to estimate the effect of external factors (vaginal soap, digital examination, transvaginal sonography, sexual intercourse, vaginal bleeding) on the risk of false-positive, false-negative, and invalid results, using spontaneous delivery within 7 days as the outcome. Results Out of 708 women, 237 (33%) had a false-positive result; none of the factors showed a significant association. Vaginal bleeding increased the proportion of positive fetal fibronectin (fFN) results, but was significantly associated with a lower risk of false-positive test results (odds ratio [OR], 0.22; 95% confidence intervals [CI], 0.12-0.39). Ten women (1%) had a false-negative result. None of the investigated factors was significantly associated with a significantly higher risk of false-negative results. Twenty-one tests (3%) were invalid; only vaginal bleeding showed a significant association (OR, 4.5; 95% CI, 1.7-12). Conclusion The effect of external factors on the performance of qualitative fFN testing is limited, with vaginal bleeding as the only factor that reduces its validity.

Prognostic models in obstetrics: available, but far from applicable.

Health care provision is increasingly focused on the prediction of patients' individual risk for developing a particular health outcome in planning further tests and treatments. There has been a steady increase in the development and publication of prognostic models for various maternal and fetal outcomes in obstetrics. We undertook a systematic review to give an overview of the current status of available prognostic models in obstetrics in the context of their potential advantages and the process of developing and validating models. Important aspects to consider when assessing a prognostic model are discussed and recommendations on how to proceed on this within the obstetric domain are given. We searched MEDLINE (up to July 2012) for articles developing prognostic models in obstetrics. We identified 177 papers that reported the development of 263 prognostic models for 40 different outcomes. The most frequently predicted outcomes were preeclampsia (n = 69), preterm delivery (n = 63), mode of delivery (n = 22), gestational hypertension (n = 11), and small-for-gestational-age infants (n = 10). The performance of newer models was generally not better than that of older models predicting the same outcome. The most important measures of predictive accuracy (ie, a model's discrimination and calibration) were often (82.9%, 218/263) not both assessed. Very few developed models were validated in data other than the development data (8.7%, 23/263). Only two-thirds of the papers (62.4%, 164/263) presented the model such that validation in other populations was possible, and the clinical applicability was discussed in only 11.0% (29/263). The impact of developed models on clinical practice was unknown. We identified a large number of prognostic models in obstetrics, but there is relatively little evidence about their performance, impact, and usefulness in clinical practice so that at this point, clinical implementation cannot be recommended. New efforts should be directed toward evaluating the performance and impact of the existing models.

Absolute first trimester cell-free DNA levels and their associations with adverse pregnancy outcomes.

OBJECTIVE: To study associations of first trimester cell-free fetal DNA levels (in this paper referred to as cell-free placental DNA (cfpDNA) levels) and preeclampsia (PE), pregnancy-induced hypertension (PIH), gestational diabetes (GDM) and spontaneous preterm birth (sPB). METHOD: A nested case-control study was conducted in first trimester samples (gestational age 8+0 -13+6 weeks). A total of 226 cases and 301 controls were included. CfpDNA levels were quantified in male-bearing pregnancies using real-time DYS14-PCRs on DNA isolated from maternal serum. CfpDNA multiples of the median (MoMs) were calculated based on associations with patient characteristics (body mass index, parity, ethnicity and smoking). Associations between MoMs and adverse outcomes were studied. RESULTS: Cell-free placental DNA levels were negatively associated with body mass index (ß = -0.297, p < 0.001) and smoking (ß = -0.163, p = 0.006). MoMs were lower in women who later developed PIH (n = 84, p = 0.009) or GDM (n = 56, p = 0.037). There was no association between cfpDNA MoMs and PE (n = 37, p = 0.15) or sPB (n = 49, p = 0.19). CfpDNA was positively correlated with pregnancy-associated plasma protein A (r = 0.426, p < 0.001) but not with placental growth factor (r = 0.059, p = 0.179). CONCLUSION: Adjusted first trimester cfpDNA levels are associated with PIH and GDM but probably not with PE or sPB. © 2016 John Wiley & Sons, Ltd.

Evaluation of strategies regarding management of imminent preterm delivery before 32 weeks of gestation: a regional cohort study among 1375 women in the Netherlands.

OBJECTIVE: To evaluate the management of imminent preterm delivery with respect to prescription of antenatal corticosteroids (ACS) and referral to a tertiary center. STUDY DESIGN: A retrospective cohort study existing of 1 perinatal center and 9 referring hospitals. All women who received their first dose of ACS in 1 of the 10 hospitals between 24+0 and 32+0 weeks of gestation and/or delivered before 32 weeks of gestation from 2005 until 2010. Patients were identified using the electronic database of hospital pharmacies. Main outcome measures were time interval from administration to delivery for different indications and number of women who were not referred in time to a tertiary center. RESULTS: In total, 1375 women received ACS. Main indications were suspected preterm labor (44.7%), preterm prelabor rupture of membranes (15.9%), maternal indication (12.8%), fetal indication (9.2%) and vaginal blood loss (8.4%). Overall, 467 (34.0%) women delivered ≤7 days after ACS administration; 8.7% of women with vaginal blood loss and 54.5% of women with maternal indication. Among the 931 women who received ACS in the secondary hospitals, 452 (48.5%) women were referred to a tertiary hospital and 89 (6.5%) women delivered in a secondary hospital with a gestational age of less than 32 weeks. CONCLUSION: One-third of all women receiving ACS delivered within 7 days and half of the women who received ACS in a secondary hospital were referred to a tertiary center. There seems to be room for improvement regarding the timing of ACS administration and subsequently referral to a tertiary center.

The added predictive value of biphasic events in ST analysis of the fetal electrocardiogram for intrapartum fetal monitoring.

OBJECTIVE: To study the predictive value of biphasic ST-events for interventions for suspected fetal distress and adverse neonatal outcome, when using ST-analysis of the fetal electrocardiogram (FECG) for intrapartum fetal monitoring. DESIGN: Prospective cohort study. SETTING: Three academic hospitals in Sweden. POPULATION: Women in labor with a high-risk singleton fetus in cephalic position beyond 36 weeks of gestation. METHODS: In women in labor who were monitored with conventional cardiotocography, ST-waveform analysis was recorded and concealed. Traces with biphasic ST-events of the FECG (index) were compared with traces without biphasic events of the FECG. The ability of biphasic events to predict interventions for suspected fetal distress and adverse outcome was assessed using univariable and multivariable logistic regression analyses. MAIN OUTCOME MEASURES: Interventions for suspected fetal distress and adverse outcome (defined as presence of metabolic acidosis (i.e. umbilical cord pH <7.05 and base deficit in extracellular fluid >12 mmol), umbilical cord pH <7.00, 5-min Apgar score <7, admittance to neonatal intensive care unit or perinatal death). RESULTS: Although the presence of biphasic events of the FECG was associated with more interventions for fetal distress and an increased risk of adverse outcome compared with cases with no biphasic events, the presence of significant (i.e. intervention advised according to cardiotocography interpretation) biphasic events showed no independent association with interventions for fetal distress [odds ratio (OR) 1.71, 95% confidence interval (CI) 0.65-4.50] or adverse outcome (OR 1.96, 95% CI 0.74-5.24). CONCLUSION: The presence of significant biphasic events did not discriminate in the prediction of interventions for fetal distress or adverse outcome. Therefore, biphasic events in relation to ST-analysis monitoring during birth should be omitted if future studies confirm our findings.

Pharmacokinetics of nifedipine slow-release during sustained tocolysis.

OBJECTIVE: The pharmacokinetics of nifedipine as a tocolytic agent has not been studied in great detail in pregnant women and has instead focused on immediate release tablets and gastrointestinal therapeutic system (GITS) tablets. The aim of this study was to determine nifedipine slow-release half-life and distribution volume in pregnant women and to compare these with pharmacokinetic parameters of nifedipine in non-pregnant subjects described in the literature. MATERIALS: This is a study parallel to a trial studying women with threatened preterm labor between 26 + 0 and 32 + 2 weeks after initial tocolysis and a completed course of corticosteroids, who were randomly allocated to maintenance nifedipine (slow-release tablets 20 mg 4 times daily) or placebo. Exclusion criteria for the pharmacokinetic study were contra-indications for nifedipine, impaired liver function, and concomitant intake of inhibitors or inducers of the cytochrome P450 3A4 isoenzyme. Blood samples for measuring nifedipine plasma concentrations were drawn at t = 0, t = 12 hours, t = 24 hours, t = 48 hours, t = 72 hours, t = 7 days, and t = 9 days. METHODS: Pharmacokinetic parameters were estimated using iterative two-stage Bayesian population pharmacokinetic analysis by MWPharm© software. The study was designed to establish a correlation between body weight and nifedipine plasma level. RESULTS: The pharmacokinetic parameters of nifedipine slow-release tablets were determined from the data of 8 pregnant women. Nifedipine slow-release had a half-life of 2 - 5 hours, a mean distribution volume of 6.2 ± 1.9 L/kg (calculated while using a fixed biological availability of 0.45 taken from the literature due to lack of intravenous data in this population) compared to a half-life of 6 - 11 hours, and a distribution volume of 1.2 - 1.3 L/kg described in non-pregnant subjects in the literature. None of the women delivered during study medication. Study medication was continued for the duration of the pharmacokinetic study (9 days) in all women. A correlation between nifedipine plasma levels and maternal body weight was not demonstrated. This may have been caused by lack of power. CONCLUSION: Pregnant subjects in this study, using nifedipine slow-release tablets, showed a larger volume of distribution and a shorter elimination half-life than for non-pregnant subjects as published in the literature.

Randomized comparison of nifedipine and placebo in fibronectin-negative women with symptoms of preterm labor and a short cervix (APOSTEL-I Trial).

OBJECTIVE: To evaluate whether tocolysis with nifedipine can be omitted in women with symptoms of preterm labor, a shortened cervix, and negative fetal fibronectin test. STUDY DESIGN: A randomized noninferiority trial was performed in all Dutch perinatal centers. Women with symptoms of preterm labor between 24 and 34 weeks, intact membranes, cervical length between 10 and 30 mm, and negative fibronectin test were randomly allocated to nifedipine (80 mg/day) or placebo. The primary outcome was delivery within 7 days. Secondary outcomes were severe neonatal morbidity and mortality. We also followed all eligible nonrandomized women. RESULTS: We allocated 37 women to nifedipine and 36 women to placebo. In the nifedipine group, three women (8.1%) delivered within 7 days, compared with one woman (2.8%) in the placebo group (difference -5.3%; one-sided 95% confidence limit 4.5%). Median gestational age at delivery were respectively 37 + 0 (interquartile range [IQR] 34 + 6 to 38 + 5) and 38 + 2 (IQR 37 + 0 to 39 + 6) weeks (p = 0.008). In the nifedipine group, three pregnancies (8.1%) had a poor outcome; there were no poor outcomes in the placebo group. We observed similar trends in eligible nonrandomized women. CONCLUSION: In symptomatic women with preterm labor, a shortened cervix, and negative fibronectin test, placebo treatment is not inferior to tocolysis with nifedipine.

Economic analysis comparing induction of labor and expectant management in women with preterm prelabor rupture of membranes between 34 and 37 weeks (PPROMEXIL trial).

OBJECTIVE: To compare the costs of induction of labor and expectant management in women with preterm prelabor rupture of membranes (PPROM). DESIGN: Economic analysis based on a randomized clinical trial. SETTING: Obstetric departments of eight academic and 52 non-academic hospitals in the Netherlands. POPULATION: Women with PPROM near term who were not in labor 24 h after PPROM. METHODS: A cost-minimization analysis was done from a health care provider perspective, using a bottom-up approach to estimate resource utilization, valued with unit-costs reflecting actual costs. MAIN OUTCOME MEASURES: Primary health outcome was the incidence of neonatal sepsis. Direct medical costs were estimated from start of randomization to hospital discharge of mother and child. RESULTS: Induction of labor did not significantly reduce the probability of neonatal sepsis [2.6% vs. 4.1%, relative risk 0.64 (95% confidence interval 0.25-1.6)]. Mean costs per woman were €8094 for induction and €7340 for expectant management (difference €754; 95% confidence interval -335 to 1802). This difference predominantly originated in the postpartum period, where the mean costs were €5669 for induction vs. €4801 for expectant management. Delivery costs were higher in women allocated to induction than in women allocated to expectant management (€1777 vs. €1153 per woman). Antepartum costs in the expectant management group were higher because of longer antepartum maternal stays in hospital. CONCLUSIONS: In women with pregnancies complicated by PPROM near term, induction of labor does not reduce neonatal sepsis, whereas costs associated with this strategy are probably higher.

Placental pathology in full-term infants with hypoxic-ischemic neonatal encephalopathy and association with magnetic resonance imaging pattern of brain injury.

OBJECTIVE: To investigate the relationship between placental pathology and pattern of brain injury in full-term infants with neonatal encephalopathy after a presumed hypoxic-ischemic insult. STUDY DESIGN: The study group comprised full-term infants with neonatal encephalopathy subsequent to presumed hypoxia-ischemia with available placenta for analysis who underwent cerebral magnetic resonance imaging (MRI) within the first 15 days after birth. Macroscopic and microscopic characteristics of the placenta were assessed. The infants were classified according to the predominant pattern of brain injury detected on MRI: no injury, predominant white matter/watershed injury, predominant basal ganglia and thalami (BGT) injury, or white matter/watershed injury with BGT involvement. Maternal and perinatal clinical factors were recorded. RESULTS: Placental tissue was available for analysis in 95 of 171 infants evaluated (56%). Among these 95 infants, 34 had no cerebral abnormalities on MRI, 27 had white matter/watershed injury, 18 had BGT injury, and 16 had white matter/watershed injury with BGT involvement. Chorioamnionitis was a common placental finding in both the infants without injury (59%) and those with white matter/BGT injury (56%). On multinomial logistic regression analysis, white matter/watershed injury with and without BGT involvement was associated with decreased placental maturation. Hypoglycemia was associated with an increased risk of the white matter/BGT injury pattern (OR,5.4; 95% CI, 1.4-21.4). The BGT injury pattern was associated with chronic villitis (OR, 12.7; 95% CI, 2.4-68.7). A placental weight <10th percentile appeared to be protective against brain injury, especially for the BGT pattern (OR, 0.1; 95% CI, 0.01-0.7). CONCLUSION: Placental weight <10th percentile was mainly associated with normal cerebral MRI findings. Decreased placental maturation and hypoglycemia <2.0 mmol/L were associated with increased risk of white matter/watershed injury with or without BGT involvement. Chronic villitis was associated with BGT injury irrespective of white matter injury.