Cost-effectiveness of maternal immunization against neonatal invasive Group B Streptococcus in the Netherlands.

BACKGROUND: Neonatal invasive Group B Streptococcus (GBS) infection causes considerable disease burden in the Netherlands. Intrapartum antibiotic prophylaxis (IAP) prevents early-onset disease (EOD), but has no effect on late-onset disease (LOD). A potential maternal GBS vaccine could prevent both EOD and LOD by conferring immunity in neonates. OBJECTIVE: Explore under which circumstances maternal vaccination against GBS would be cost-effective as an addition to, or replacement for the current risk factor-based IAP prevention strategy in the Netherlands. METHODS: We assessed the maximum cost-effective price per dose of a trivalent (serotypes Ia, Ib, and III) and hexavalent (additional serotypes II, IV, and V) GBS vaccine in addition to, or as a replacement for IAP. To project the prevented costs and disease burden, a decision tree model was developed to reflect neonatal GBS disease and long-term health outcomes among a cohort based on 169,836 live births in the Netherlands in 2017. RESULTS: Under base-case conditions, maternal immunization with a trivalent vaccine would gain 186 QALYs and prevent more than €3.1 million in health care costs when implemented in addition to IAP. Immunization implemented as a replacement for IAP would gain 88 QALYs compared to the current prevention strategy, prevent €1.5 million in health care costs, and avoid potentially ~ 30,000 IAP administrations. The base-case results correspond to a maximum price of €58 per dose (vaccine + administration costs; using a threshold of €20,000/QALY). Expanding the serotype coverage to a hexavalent vaccine would only have a limited additional impact on the cost-effectiveness in the Netherlands. CONCLUSIONS: A maternal GBS vaccine could be cost-effective when implemented in addition to the current risk factor-based IAP prevention strategy in the Netherlands. Discontinuation of IAP would save costs and prevent antibiotic use, however, is projected to lead to a lower health gain compared to vaccination in addition to IAP.

Maternal vascular malperfusion in spontaneous preterm birth placentas related to clinical outcome of subsequent pregnancy.

INTRODUCTION: Spontaneous preterm birth (SPTB) has several causes and its pathophysiology remains unclear. In a significant proportion of SPTB, placental histology shows signs of maternal vascular malperfusion (MVM); commonly associated with hypertensive disorders of pregnancy (HD), fetal growth restriction (FGR) and placental abruption, together referred to as clinical ischemic placental diseases (IPD). We hypothesized that women with SPTB and placental MVM are at elevated risk for IPD in a subsequent pregnancy. METHODS: We included women with SPTB in our cohort and followed the subsequent ongoing pregnancy (n = 110). Histological placental characteristics in the index were reported according to new international guidelines, and related to the clinical outcome of the subsequent pregnancy. RESULTS: In the SPTB placentas, we observed MVM in 61.8% (n = 68). In the subsequent pregnancies in 19.1% (n = 21) at least one clinical sign of IPD was present (HD (12.7%), FGR (5.5%) or placental abruption (0.9%)). There was no significant difference in the prevalence of clinical IPD or recurrence of SPTB in the subsequent pregnancy between women with and without placental MVM in the index pregnancy, although our study was not powered to detect small differences. DISCUSSION: Women with a history of SPTB have an elevated risk of IPD in the subsequent pregnancy. MVM is present in a large proportion of SPTB placentas. The presence of placental MVM in the index pregnancy does not predict clinical IPD or recurrent SPTB in a subsequent pregnancy.

Evaluation of women's worries in different strategies for the prevention of early onset group B streptococcal disease in neonates.

OBJECTIVE: Early onset group B streptococcal (EOGBS) disease is an important cause of neonatal morbidity and mortality. EOGBS preventive strategies aim to reduce the risk of neonatal complications. Two new strategies to prevent EOGBS were implemented in two regions in the Netherlands: a risk-based and a combination strategy and were compared to the Dutch strategy in a third region. Little is known how women feel about preventive EOGBS strategies, the consequences for management during labour, side effects such as harm caused by over prescribing of antibiotics or anxiety caused by screening. Women's worries in pregnancy overall and on women's worries related to GBS regarding the different strategies were explored. METHODS: Design - Setting - Participants - Interventions (if appropriate) - Before implementation of the two new strategies, all three regions worked according to the Dutch strategy. Women completed the Cambridge worry scale and a newly developed worry scale aimed to detect GBS related worries at 35 weeks of pregnancy before (T0) and after (T1) implementation of new strategies. Analyses were performed to test whether women's overall worries in pregnancy and their GBS related worries differed between the three strategies. MEASUREMENTS AND FINDINGS: In total 1369 women participated, 519 before implementation (T0) and 850 during implementation (T1) of EOGBS preventive strategies. Mean overall worries in pregnancy and GBS related worries were low during the whole study period in all three regions. No differences were found in total mean GBS related worries between the three strategies during implementation (T1). When looking at the combined 10% highest CWS and/or GBS related worries during implementation the adjOR were 1.94 (95% CI 1.21-3.12) for the combination strategy, 2.09 (95% CI 1.42-3.08 for primiparity and 6.37 (95% CI 2.98-13.60) for having a different country of origin. KEY CONCLUSIONS: Overall women had minor GBS related worries in all EOGBS preventive strategies. Implementation of the combination strategy, primiparity and having a different country of origin are associated with the highest levels of overall worries in pregnancy and GBS related worries. IMPLICATIONS FOR PRACTICE: The low level of women's worries combined with limited effects and cost effectiveness of the three strategies suggests that the strategy with the least costs and lowest antibiotic use should be implemented. A more tailored approach seems needed to address the specific needs of primiparous women and of women from different countries of origin when implementing the combination strategy.

Adherence to three different strategies to prevent early onset GBS infection in newborns.

PROBLEM: Despite the introduction of preventive guidelines, no decrease in the incidence of early onset infection was observed. BACKGROUND: Early onset group B streptococcal (EOGBS) infection is an important cause of neonatal morbidity and mortality. AIM: Our study was conducted to determine adherence to three guideline-based group B streptococcus (GBS) preventive strategies. METHODS: A prospective experimental study clustered by obstetric collaboration region was performed between March 2013 and August 2014 among midwives, obstetricians and paediatricians in the Netherlands. At baseline, the three regions operated according to the Dutch preventive strategy (founded on the risk-based strategy) in order to prevent EOGBS infection, whereas in the study period they followed either the risk-based, the combination or the Dutch strategy. Adherence was measured prospectively per pregnant woman, using predefined core elements of each preventive strategy: identification of risk factors, maternal GBS screening, application of intrapartum antibiotic prophylaxis and observation of the child. Data about adherence to the core elements were collected from medical records, maternal questionnaires and laboratory test results. FINDINGS: In the three regions, a total of 121 care providers and 1562 women participated. We found an overall adherence of 90% to the risk-based strategy, 57% to the combination strategy and 89% to the Dutch strategy. Adherence to a strategy in case women had EOGBS risk factors was below 20% in all strategies. DISCUSSION: The majority of women with EOGBS risk factors did not receive the care prescribed by any of three preventive strategies and were not treated optimally. CONCLUSION: The risk-based and the Dutch strategy are the recommended strategies for implementation.

An innovative implementation strategy to improve the use of Dutch guidelines on hypertensive disorders in pregnancy: A randomized controlled trial.

OBJECTIVE: To evaluate the effectiveness of an innovative strategy to improve implementation of evidence-based guidelines on the management of hypertension in pregnancy compared to a common strategy of professional audit and feedback. DESIGN: Cluster randomized controlled trial (c-RCT). SETTING: Sixteen Dutch hospitals. POPULATION: All patients with a hypertensive disorder during pregnancy who were admitted to one of the participating hospitals between April 1st 2010 and May 1st 2011, were suitable for inclusion; the only exclusion criterion was the presence of lethal fetal abnormalities. METHODS: Hospitals were randomly assigned to either an innovative implementation strategy including a computerized decision support system (DSS) and professional audit and feedback or a minimal implementation strategy of audit and feedback only. MAIN OUTCOME MEASURES: Primary outcome measure was a combined rate of major maternal complications. Secondary outcome measures included process-related measures on guideline adherence, and patient-related outcomes. A process evaluation was performed alongside. RESULTS: No statistically significant difference was found in both the occurrence of major complications and most secondary outcome measures between the two groups. Process evaluation showed limited use of the computerized DSS, with a large variation between hospitals (0-49,5% of the eligible patients), but positive experiences of actual users. CONCLUSION: Using a computerized DSS for implementation of the clinical guidelines for the management of hypertension in pregnancy did not result in fewer major maternal and fetal complications. Limited use of the DSS in the innovative strategy group could be an explanation for the lack of effect.

Barriers and facilitators related to the uptake of four strategies to prevent neonatal early-onset group B haemolytic streptococcus disease: a qualitative study.

BACKGROUND: Actions to prevent early onset disease in neonates are based on different strategies including administering antibiotic prophylaxis during labour in case of 1) maternal GBS colonisation (screening strategy), 2) identified risk factors (risk-based strategy) or 3) a combination of these two conditions (maternal GBS colonisation and identified risk factors: combination strategy and the Dutch guideline). Low adherence to guidelines preventing EOGBS has been reported. Each strategy has drawbacks and clinical outcomes are affected by care providers' and women's adherence. The actual impact of any preventive strategy is the product of efficacy of the strategy and the level of implementation. In order to reduce neonatal death due to EOGBS by developing the optimal guideline, we analysed barriers and facilitators of current used strategies. METHODS: Focus group and personal interviews with care providers and women were performed. Impeding and enhancing factors in adherence to the preventive strategies were discussed and scored using the Measurement Instrument for Determinants of Innovations (MIDI) and analysed by two independent researchers. RESULTS: Overall, care providers identified 3.6 times more factors that would impede (n = 116) rather than facilitate (n = 32) adherence to the preventive strategies. 28% facilitative factors were reported in relation to the combination strategy and 86% impeding factors in relation to the Dutch guideline. The most preferred strategy was the combination strategy by 74% of the care providers and by 86% of the women. DISCUSSION: We obtained a detailed understanding of factors that influence adherence to preventive strategies. This insight can be used to develop implementation activities to improve the uptake of new strategies. TRIAL REGISTRATION: The trial is registered in the Dutch Trial Register NTR3965 .

Development and Measurement of Guidelines-Based Quality Indicators of Caesarean Section Care in the Netherlands: A RAND-Modified Delphi Procedure and Retrospective Medical Chart Review.

BACKGROUND: There is an ongoing discussion on the rising CS rate worldwide. Suboptimal guideline adherence may be an important contributor to this rise. Before improvement of care can be established, optimal CS care in different settings has to be defined. This study aimed to develop and measure quality indicators to determine guideline adherence and identify target groups for improvement of care with direct effect on caesarean section (CS) rates. METHOD: Eighteen obstetricians and midwives participated in an expert panel for systematic CS quality indicator development according to the RAND-modified Delphi method. A multi-center study was performed and medical charts of 1024 women with a CS and a stratified and weighted randomly selected group of 1036 women with a vaginal delivery were analysed. Quality indicator frequency and adherence were scored in 2060 women with a CS or vaginal delivery. RESULTS: The expert panel developed 16 indicators on planned CS and 11 indicators on unplanned CS. Indicator adherence was calculated, defined as the number of women in a specific obstetrical situation in which care was performed as recommended in both planned and unplanned CS settings. The most frequently occurring obstetrical situations with low indicator adherence were: 1) suspected fetal distress (frequency 17%, adherence 46%), 2) non-progressive labour (frequency 12%, CS performed too early in over 75%), 3) continuous support during labour (frequency 88%, adherence 37%) and 4) previous CS (frequency 12%), with adequate counselling in 15%. CONCLUSIONS: We identified four concrete target groups for improvement of obstetrical care, which can be used as a starting point to reduce CS rates worldwide.

Maternal allopurinol administration during suspected fetal hypoxia: a novel neuroprotective intervention? A multicentre randomised placebo controlled trial.

OBJECTIVE: To determine whether maternal allopurinol treatment during suspected fetal hypoxia would reduce the release of biomarkers associated with neonatal brain damage. DESIGN: A randomised double-blind placebo controlled multicentre trial. PATIENTS: We studied women in labour at term with clinical indices of fetal hypoxia, prompting immediate delivery. SETTING: Delivery rooms of 11 Dutch hospitals. INTERVENTION: When immediate delivery was foreseen based on suspected fetal hypoxia, women were allocated to receive allopurinol 500 mg intravenous (ALLO) or placebo intravenous (CONT). MAIN OUTCOME MEASURES: Primary endpoint was the difference in cord S100ß, a tissue-specific biomarker for brain damage. RESULTS: 222 women were randomised to receive allopurinol (ALLO, n=111) or placebo (CONT, n=111). Cord S100ß was not significantly different between the two groups: 44.5 pg/mL (IQR 20.2-71.4) in the ALLO group versus 54.9 pg/mL (IQR 26.8-94.7) in the CONT group (difference in median -7.69 (95% CI -24.9 to 9.52)). Post hoc subgroup analysis showed a potential treatment effect of allopurinol on the proportion of infants with a cord S100ß value above the 75th percentile in girls (ALLO n=5 (12%) vs CONT n=10 (31%); risk ratio (RR) 0.37 (95% CI 0.14 to 0.99)) but not in boys (ALLO n=18 (32%) vs CONT n=15 (25%); RR 1.4 (95% CI 0.84 to 2.3)). Also, cord neuroketal levels were significantly lower in girls treated with allopurinol as compared with placebo treated girls: 18.0 pg/mL (95% CI 12.1 to 26.9) in the ALLO group versus 32.2 pg/mL (95% CI 22.7 to 45.7) in the CONT group (geometric mean difference -16.4 (95% CI -24.6 to -1.64)). CONCLUSIONS: Maternal treatment with allopurinol during fetal hypoxia did not significantly lower neuronal damage markers in cord blood. Post hoc analysis revealed a potential beneficial treatment effect in girls. TRIAL REGISTRATION NUMBER: NCT00189007, Dutch Trial Register NTR1383.

Exploring perinatal shift-to-shift handover communication and process: an observational study.

RATIONALE, AIMS AND OBJECTIVES: Loss of situation awareness (SA) by health professionals during handover is a major threat to patient safety in perinatal care. SA refers to knowing what is going on around. Adequate handover communication and process may support situation assessment, a precursor of SA. This study describes current practices and opinions of perinatal handover to identify potential improvements. METHODS: Structured direct observations of shift-to-shift patient handovers (n = 70) in an academic perinatal setting were used to measure handover communication (presence and order of levels of SA: current situation, background, assessment and recommendation) and process (duration, interruptions/distractions, eye contact, active inquiry and reading information back). Afterwards, receivers' opinions of handover communication (n = 51) were measured by means of a questionnaire. RESULTS: All levels of SA were present in 7% of handovers, the current situation in 86%, the background in 99%, an assessment in 24% and a recommendation in 46%. In 77% of handovers the background was mentioned first, followed by the current situation. Forty-four per cent of handovers took 2 minutes or more per patient. In 52% distractions occurred, in 43% there was no active inquiry, in 32% no eye contact and in 97% information was not read back. The overall mean of the receivers' opinions of handover communication was 4.1 (standard deviation ± 0.7; scale 1-5, where 5 is excellent). CONCLUSIONS: Perinatal handovers are currently at risk for inadequate situation assessment because of variability and limitations in handover communication and process. However, receivers' opinions of handover communication were very positive, indicating a lack of awareness of patient safety threats during handover. Therefore, the staff's awareness of current limitations should be raised, for example through video reflection or simulation training.

Physical activity in overweight and obese pregnant women is associated with higher levels of proinflammatory cytokines and with reduced insulin response through interleukin-6.

OBJECTIVE Previously, we reported the positive association of moderate-to-vigorous physical activity (MVPA) with insulin sensitivity in overweight and obese pregnant women. We sought to assess whether these MVPA-induced changes in insulin sensitivity are mediated by changes in interleukin (IL)-6, IL-10, tumor necrosis factor (TNF)-α, and IL-1ß. RESEARCH DESIGN AND METHODS A prospective longitudinal study was conducted in 46 overweight and obese women at risk for gestational diabetes mellitus. Objective physical activity measurements and fasting blood samples were taken at 15, 24, and 32 weeks of pregnancy. At 24 and 32 weeks, a 100-g oral glucose test was performed in addition. Cytokines, C-reactive protein, and glucose and insulin levels were measured, and insulin sensitivity and first-phase insulin response were calculated. Relationships between the different parameters were assessed using linear regression models, adjusting for maternal age and BMI. RESULTS All cytokines were elevated in women with higher levels of MVPA at 15 weeks of gestation. Higher IL-6 was related to a lower first-phase insulin response (ß -810.5 [95% CI -1,524.5 to -96.5]; P = 0.03). TNF-α and IL-1ß had different effects in women with low MVPA (with low IL-6 levels) compared with more active women. CRP was not related to MVPA. CONCLUSIONS The association of MVPA with insulin sensitivity and first-phase insulin response may be (partly) mediated by IL-6, since this cytokine was related to reduced first-phase insulin response. The possible positive effects of the elevated cytokine profile in active obese pregnant women warrant further study.

Implementation of a cost-effective strategy to prevent neonatal early-onset group B haemolytic streptococcus disease in the Netherlands.

BACKGROUND: Early-onset Group B haemolytic streptococcus infection (EOGBS) is an important cause of neonatal morbidity and mortality in the first week of life. Primary prevention of EOGBS is possible with intra-partum antibiotic prophylaxis (IAP.) Different prevention strategies are used internationally based on identifying pregnant women at risk, either by screening for GBS colonisation and/or by identifying risk factors for EOGBS in pregnancy or labour. A theoretical cost-effectiveness study has shown that a strategy with IAP based on five risk factors (risk-based strategy) or based on a positive screening test in combination with one or more risk factors (combination strategy) was the most cost-effective approach in the Netherlands. IAP for all pregnant women with a positive culture in pregnancy (screening strategy) and treatment in line with the current Dutch guideline (IAP after establishing a positive culture in case of pre-labour rupture of membranes or preterm birth and immediate IAP in case of intra-partum fever, previous sibling with EOGBS or GBS bacteriuria), were not cost-effective. Cost-effectiveness was based on the assumption of 100% adherence to each strategy. However, adherence in daily practice will be lower and therefore have an effect on cost-effectiveness. METHOD/DESIGN: The aims are to: a.) implement the current Dutch guideline, the risk-based strategy and the combination strategy in three pilot regions and b.) study the effects of these strategies in daily practice. Regions where all the care providers in maternity care implement the allocated strategy will be randomised. Before the introduction of the strategy, there will be a pre-test (use of the current guideline) involving 105 pregnant women per region. This will be followed by a post-test (use of the allocated strategy) involving 315 women per region. The outcome measures are: 1.) adherence to the specific prevention strategy and the determinants of adherence among care providers and pregnant women, 2.) outcomes in pregnant women and their babies and 3.) the costs of each strategy in relation to the effects. DISCUSSION: This study will provide recommendations for the implementation of the most cost-effective prevention strategy for EOGBS in the Netherlands on the basis of feasibility in daily practice. TRIAL REGISTRATION: Dutch Trial Register, NTR3965.

Hypertensive disorders in pregnancy: a review of international guidelines.

International collaboration could facilitate systematic development of guidelines to regulate and improve clinical practice. Insight into existing international guidelines regarding hypertensive disorders in pregnancy (HDP) is essential. Aim was to evaluate the content and quality of international clinical guidelines on HDP. Quality was assessed with the internationally validated Appraisal of Guidelines for Research and Evaluation (AGREE II) Instrument. Six guidelines were identified. Quality was moderate to high. Major flaws were applicability, editorial independence and stakeholder involvement. Recommendations differed considerably, particularly their extensiveness. The number of international HDP guidelines is small and the extensiveness of their recommendations varies considerably.

Longitudinal relationship of physical activity with insulin sensitivity in overweight and obese pregnant women.

BACKGROUND: Physical activity (PA) initiated in the second half of pregnancy does not affect (or modify) insulin sensitivity in normal weight women. However, this might be different in obese women with lower insulin sensitivity. OBJECTIVE: To test the hypothesis that in overweight and obese women at risk for gestational diabetes, PA is related to improved maternal glucose and insulin metabolism in pregnancy. METHODS: A longitudinal study, with measurements at 15, 24, and 32 weeks of gestation, was conducted. Time spent in moderate-to-vigorous PA (MVPA) was measured objectively. In regression models, the relationship between time spent in MVPA at week 15 and changes in MVPA from 15 weeks to 24 or 32 weeks with fasting glucose, glycosylated hemoglobin, fasting insulin, insulin sensitivity, and insulin response at week 24 or 32 was assessed. RESULTS: In a group of 24 women, MVPA in early pregnancy was significantly associated with a reduced first- and second-phase insulin response at week 32. Women with larger decreases in MVPA throughout pregnancy had significantly higher fasting insulin levels, worse insulin sensitivity, increased first- and second-phase insulin response, and higher triglyceride levels in late pregnancy compared to women with smaller decreases in MVPA. Time spent in MVPA was not related to glucose or glycosylated hemoglobin levels. CONCLUSIONS: In our group of overweight and obese pregnant women, MVPA was associated with improved insulin sensitivity, insulin response, and decreased triglycerides at 32 weeks of pregnancy. This supports efforts for counseling obese women at risk for gestational diabetes in pregnancy to maintain their MVPA levels.

Cost-effectiveness of an exercise program during pregnancy to prevent gestational diabetes: results of an economic evaluation alongside a randomised controlled trial.

BACKGROUND: The prevalence of gestational diabetes mellitus (GDM) is increasing worldwide. GDM and the risks associated with GDM lead to increased health care costs and losses in productivity. The objective of this study is to evaluate whether the FitFor2 exercise program during pregnancy is cost-effective from a societal perspective as compared to standard care. METHODS: A randomised controlled trial (RCT) and simultaneous economic evaluation of the FitFor2 program were conducted. Pregnant women at risk for GDM were randomised to an exercise program to prevent high maternal blood glucose (n = 62) or to standard care (n = 59). The exercise program consisted of two sessions of aerobic and strengthening exercises per week. Clinical outcome measures were maternal fasting blood glucose levels, insulin sensitivity and infant birth weight. Quality of life was measured using the EuroQol 5-D and quality-adjusted life-years (QALYs) were calculated. Resource utilization and sick leave data were collected by questionnaires. Data were analysed according to the intention-to-treat principle. Missing data were imputed using multiple imputations. Bootstrapping techniques estimated the uncertainty surrounding the cost differences and incremental cost-effectiveness ratios. RESULTS: There were no statistically significant differences in any outcome measure. During pregnancy, total health care costs and costs of productivity losses were statistically non-significant (mean difference €1308; 95%CI €-229 - €3204). The cost-effectiveness analyses showed that the exercise program was not cost-effective in comparison to the control group for blood glucose levels, insulin sensitivity, infant birth weight or QALYs. CONCLUSION: The twice-weekly exercise program for pregnant women at risk for GDM evaluated in the present study was not cost-effective compared to standard care. Based on these results, implementation of this exercise program for the prevention of GDM cannot be recommended. TRIAL REGISTRATION: NTR1139.

Quality of guidelines on the management of diabetes in pregnancy: a systematic review.

BACKGROUND: Diabetes during pregnancy can lead to severe risks for both mother and fetus when it is not managed properly. The use of rigorously developed guidelines with a robust implementation process can have a positive influence on the management of diabetes during pregnancy. This study aims to compare recommendations and assess the quality of clinical guidelines on gestational diabetes mellitus (GDM) and pre-existing diabetes mellitus during pregnancy. METHODS: Guidelines were selected by searching PubMed, the Guideline Clearing House and Google. All guidelines developed since 2000 on diabetes during pregnancy in English or Dutch were considered. Recommendations of the guidelines were compared. Furthermore, the quality was assessed by two authors independently, using the AGREE instrument. RESULTS: Eight guidelines were included. According to the AGREE instrument, the quality of most guidelines was low. The domains editorial independence, stakeholder involvement and rigour of development had the lowest scores. Recommendations were mainly comparable on glycemic control, preconceptional counseling and prenatal care and labour. Differences between recommendations were found for screening on GDM and induction of labour. CONCLUSIONS: The quality of most guidelines concerning the management of diabetes during pregnancy needs to be improved. A more systematic approach in the development of these guidelines, more attention for updating procedures and piloting of the guidelines and involvement of target users and patients is recommended.

Identification of cases with adverse neonatal outcome monitored by cardiotocography versus ST analysis: secondary analysis of a randomized trial.

OBJECTIVE: To evaluate whether correct adherence to clinical guidelines might have led to prevention of cases with adverse neonatal outcome. DESIGN: Secondary analysis of cases with adverse outcome in a multicenter randomized clinical trial. SETTING: Nine Dutch hospitals. POPULATION: Pregnant women with a term singleton fetus in cephalic position. METHODS: Data were obtained from a randomized trial that compared monitoring by STAN® (index group) with cardiotocography (control group). In both trial arms, three observers independently assessed the fetal surveillance results in all cases with adverse neonatal outcome, to determine whether an indication for intervention was present, based on current clinical guidelines. MAIN OUTCOME MEASURES: Adverse neonatal outcome cases fulfilled one or more of the following criteria: (i) metabolic acidosis in umbilical cord artery (pH < 7.05 and base deficit in extracellular fluid >12 mmol/L); (ii) umbilical cord artery pH < 7.00; (iii) perinatal death; and/or (iv) signs of moderate or severe hypoxic ischemic encephalopathy. RESULTS: We studied 5681 women, of whom 61 (1.1%) had an adverse outcome (26 index; 35 control). In these women, the number of performed operative deliveries for fetal distress was 18 (69.2%) and 16 (45.7%), respectively. Reassessment of all 61 cases showed that there was a fetal indication to intervene in 23 (88.5%) and 19 (57.6%) cases, respectively. In 13 (50.0%) vs. 11 (33.3%) cases, respectively, this indication occurred more than 20 min before the time of delivery, meaning that these adverse outcomes could possibly have been prevented. CONCLUSIONS: In our trial, more strict adherence to clinical guidelines could have led to additional identification and prevention of adverse outcome.

Prediction of neonatal metabolic acidosis in women with a singleton term pregnancy in cephalic presentation.

We sought to predict neonatal metabolic acidosis at birth using antepartum obstetric characteristics (model 1) and additional characteristics available during labor (model 2). In 5667 laboring women from a multicenter randomized trial that had a high-risk singleton pregnancy in cephalic presentation beyond 36 weeks of gestation, we predicted neonatal metabolic acidosis. Based on literature and clinical reasoning, we selected both antepartum characteristics and characteristics that became available during labor. After univariable analyses, the predictors of the multivariable models were identified by backward stepwise selection in a logistic regression analysis. Model performance was assessed by discrimination and calibration. To correct for potential overfitting, we (internally) validated the models with bootstrapping techniques. Of 5667 neonates born alive, 107 (1.9%) had metabolic acidosis. Antepartum predictors of metabolic acidosis were gestational age, nulliparity, previous cesarean delivery, and maternal diabetes. Additional intrapartum predictors were spontaneous onset of labor and meconium-stained amniotic fluid. Calibration and discrimination were acceptable for both models (c-statistic 0.64 and 0.66, respectively). In women with a high-risk singleton term pregnancy in cephalic presentation, we identified antepartum and intrapartum factors that predict neonatal metabolic acidosis at birth.

Interventions for preventing gestational diabetes mellitus: a systematic review and meta-analysis.

BACKGROUND: The prevalence of gestational diabetes mellitus (GDM) is increasing worldwide. GDM is associated with increased risks for mother and child during pregnancy and in later life. The aim of this article is to systematically review literature on the effectiveness of interventions to prevent GDM. METHODS: Controlled trials found in PubMed, EMBASE, or CENTRAL were selected. The primary outcome was GDM, and relevant secondary outcomes were maternal fasting blood glucose and large-for-gestational age (LGA) or macrosomia. Data were combined in meta-analyses, and the quality of evidence for the effectiveness of the interventions was assessed in a GRADE approach. RESULTS: Nineteen studies evaluating six types of interventions were included. Dietary counseling significantly reduced GDM incidence compared to standard care. None of the interventions was effective in lowering maternal fasting blood glucose. Low glycemic index (LGI) diet advice and an exercise program significantly reduced the risk of macrosomia. The quality of evidence for these outcomes was low. CONCLUSIONS: The results indicate that there may be some benefits of dietary counseling, an LGI diet advice, or an exercise program. However, better-designed studies are required to generate higher quality evidence. At the moment, no strong conclusions can be drawn with regard to the best intervention for prevention of GDM.

Antenatal allopurinol for reduction of birth asphyxia induced brain damage (ALLO-Trial); a randomized double blind placebo controlled multicenter study.

BACKGROUND: Hypoxic-ischaemic encephalopathy is associated with development of cerebral palsy and cognitive disability later in life and is therefore one of the fundamental problems in perinatal medicine. The xanthine-oxidase inhibitor allopurinol reduces the formation of free radicals, thereby limiting the amount of hypoxia-reperfusion damage. In case of suspected intra-uterine hypoxia, both animal and human studies suggest that maternal administration of allopurinol immediately prior to delivery reduces hypoxic-ischaemic encephalopathy. METHODS/DESIGN: The proposed trial is a randomized double blind placebo controlled multicenter study in pregnant women at term in whom the foetus is suspected of intra-uterine hypoxia.Allopurinol 500 mg IV or placebo will be administered antenatally to the pregnant woman when foetal hypoxia is suspected. Foetal distress is being diagnosed by the clinician as an abnormal or non-reassuring foetal heart rate trace, preferably accompanied by either significant ST-wave abnormalities (as detected by the STAN-monitor) or an abnormal foetal blood scalp sampling (pH < 7.20).Primary outcome measures are the amount of S100B (a marker for brain tissue damage) and the severity of oxidative stress (measured by isoprostane, neuroprostane, non protein bound iron and hypoxanthine), both measured in umbilical cord blood. Secondary outcome measures are neonatal mortality, serious composite neonatal morbidity and long-term neurological outcome. Furthermore pharmacokinetics and pharmacodynamics will be investigated.We expect an inclusion of 220 patients (110 per group) to be feasible in an inclusion period of two years. Given a suspected mean value of S100B of 1.05 ug/L (SD 0.37 ug/L) in the placebo group this trial has a power of 90% (alpha 0.05) to detect a mean value of S100B of 0.89 ug/L (SD 0.37 ug/L) in the 'allopurinol-treated' group (z-test2-sided). Analysis will be by intention to treat and it allows for one interim analysis. DISCUSSION: In this trial we aim to answer the question whether antenatal allopurinol administration reduces hypoxic-ischaemic encephalopathy in neonates exposed to foetal hypoxia. TRIAL REGISTRATION NUMBER: Clinical Trials, protocol registration system: NCT00189007.

Therapeutic options of caesarean scar pregnancy: case series and literature review.

We describe our experience with the treatment of 4 caesarean scar pregnancies and provide an overview of current literature. Four women diagnosed with a caesarean scar pregnancy in our hospital between 1996 and 2007 were treated with local or systemic methotrexate and had a steady decline of the serum beta-hCG level. The uterus was preserved in all women and 3 of them had an uneventful subsequent pregnancy and delivery. We suggest that transcervical needle aspiration of amniotic fluid followed by intra-amniotic injection of methotrexate should be the treatment of choice, followed by surgical treatment only if methotrexate fails.