A new microdialysis probe for continuous lactate measurement during fetal monitoring: Proof of concept in an animal model.

INTRODUCTION: Cardiotocography (CTG) is currently the most commonly used method for intrapartum fetal monitoring during labor. However, a high false-positive rate of fetal acidosis indicated by CTG leads to an increase in obstetric interventions. We developed a microdialysis probe that is integrated into a fetal scalp electrode allowing continuous measurement of lactate subcutaneously, thus giving instant information about the oxygenation status of the fetus. Our aim was to establish proof of concept in an animal model using a microdialysis probe to monitor lactate subcutaneously. MATERIAL AND METHODS: We performed an in vivo study in adult male wild-type Wistar rats. We modified electrodes used for CTG monitoring in human fetuses to incorporate a microdialysis membrane. Optimum flow rates for microdialysis were determined in vitro. For the in vivo experiment, a microdialysis probe was inserted into the skin on the back of the animal. De-oxygenation and acidosis were induced by lowering the inspiratory oxygen pressure. Oxygenation and heart rate were monitored. A jugular vein cannula was inserted to draw blood samples for analysis of lactate, pH, pco2 , and saturation. Lactate levels in dialysate were compared with plasma lactate levels. RESULTS: Baseline blood lactate levels were around 1 mmol/L. Upon de-oxygenation, oxygen saturation fell to below 40% for 1 h and blood lactate levels increased 2.5-fold. Correlation of dialysate lactate levels with plasma lactate levels was 0.89 resulting in an R2 of .78 in the corresponding linear regression. CONCLUSIONS: In this animal model, lactate levels in subcutaneous fluid collected by microdialysis closely reflected blood lactate levels upon transient de-oxygenation, indicating that our device is suitable for subcutaneous measurement of lactate. Microdialysis probe technology allows the measurement of multiple compounds in the dialysate, such as glucose, albumin, or inflammatory mediators, so this technique may offer the unique possibility to shed light on fetal physiology during the intrapartum period.

New diagnostic criteria for gestational diabetes mellitus and their impact on the number of diagnoses and pregnancy outcomes.

AIMS/HYPOTHESIS: Detection and management of gestational diabetes mellitus (GDM) are crucial to reduce the risk of pregnancy-related complications for both mother and child. In 2013, the WHO adopted new diagnostic criteria for GDM to improve pregnancy outcomes. However, the evidence supporting these criteria is limited. Consequently, these new criteria have not yet been endorsed in the Netherlands. The aim of this study was to determine the impact of these criteria on the number of GDM diagnoses and pregnancy outcomes. METHODS: Data were available from 10,642 women who underwent a 75 g OGTT because of risk factors or signs suggestive of GDM. Women were treated if diagnosed with GDM according to the WHO 1999 criteria. Data on pregnancy outcomes were obtained from extensive chart reviews from 4,431 women and were compared between women with normal glucose tolerance (NGT) and women classified into the following groups: (1) GDM according to WHO 1999 criteria; (2) GDM according to WHO 2013 criteria; (3) GDM according to WHO 2013 fasting glucose threshold, but not WHO 1999 criteria; and (4) GDM according to WHO 1999 2 h plasma glucose threshold (2HG), but not WHO 2013 criteria. RESULTS: Applying the new WHO 2013 criteria would have increased the number of diagnoses by 45% (32% vs 22%) in this population of women at higher risk for GDM. In comparison with women with NGT, women classified as having GDM based only on the WHO 2013 threshold for fasting glucose, who were not treated for GDM, were more likely to have been obese (46.1% vs 28.1%, p < 0.001) and hypertensive (3.3% vs 1.2%, p < 0.001) before pregnancy, and to have had higher rates of gestational hypertension (7.8% vs 4.9%, p = 0.003), planned Caesarean section (10.3% vs 6.5%, p = 0.001) and induction of labour (34.8% vs 28.0%, p = 0.001). In addition, their neonates were more likely to have had an Apgar score <7 at 5 min (4.4% vs 2.6%, p = 0.015) and to have been admitted to the Neonatology Department (15.0% vs 11.1%, p = 0.004). The number of large for gestational age (LGA) neonates was not significantly different between the two groups. Women potentially missed owing to the higher 2HG threshold set by WHO 2013 had similar pregnancy outcomes to women with NGT. These women were all treated for GDM with diet and 20.5% received additional insulin. CONCLUSIONS/INTERPRETATION: Applying the WHO 2013 criteria will have a major impact on the number of GDM diagnoses. Using the fasting glucose threshold set by WHO 2013 identifies a group of women with an increased risk of adverse outcomes compared with women with NGT. We therefore support the use of a lower fasting glucose threshold in the Dutch national guideline for GDM diagnosis. However, adopting the WHO 2013 criteria with a higher 2HG threshold would exclude women in whom treatment for GDM seems to be effective.

Pregnancy outcomes in women with gestational diabetes mellitus diagnosed according to the WHO-2013 and WHO-1999 diagnostic criteria: a multicentre retrospective cohort study.

BACKGROUND: The World Health Organization (WHO) adopted more stringent diagnostic criteria for GDM in 2013, to improve pregnancy outcomes. However, there is no global consensus on these new diagnostic criteria, because of limited evidence. The objective of the study was to evaluate maternal characteristics and pregnancy outcomes in two cohorts in the Netherlands applying different diagnostic criteria for GDM i.e. WHO-2013 and WHO-1999. METHODS: A multicenter retrospective study involving singleton GDM pregnancies in two regions, between 2011 and 2016. Women were diagnosed according to the WHO-2013 criteria in the Deventer region (WHO-2013-cohort) and according to the WHO-1999 criteria in the Groningen region (WHO-1999-cohort). After GDM diagnosis, all women were treated equally based on the national guideline. Maternal characteristics and pregnancy outcomes were compared between the two groups. RESULTS: In total 1386 women with GDM were included in the study. Women in the WHO-2013-cohort were older and had a higher pre-gestational body mass index. They were diagnosed earlier (24.9 [IQR 23.3-29.0] versus 27.7 [IQR 25.9-30.7] weeks, p = < 0.001) and less women were treated with additional insulin therapy (15.6% versus 43.4%, p = < 0.001). Rate of spontaneous delivery was higher in the WHO-2013-cohort (73.1% versus 67.4%, p = 0.032). The percentage large-for-gestational-age (LGA) neonates (birth weight > 90th percentile, corrected for sex, ethnicity, parity, and gestational age) was lower in the WHO-2013- cohort, but not statistical significant (16.5% versus 18.5%, p = 0.379). There were no differences between the cohorts regarding stillbirth, birth trauma, low Apgar score, and preeclampsia. CONCLUSIONS: Using the new WHO-2013 criteria resulted in an earlier GDM diagnosis, less women needed insulin treatment and more spontaneous deliveries occurred when compared to the cohort diagnosed with WHO-1999 criteria. No differences were found in adverse pregnancy outcomes.

Prediction of progression to severe disease in women with late preterm hypertensive disorders of pregnancy.

INTRODUCTION: If hypertensive disorders of pregnancy are diagnosed before term, the benefits of immediate delivery need to be weighed against the neonatal consequences of preterm delivery. If we are able to predict which women are at high risk of progression to severe disease, they could be targeted for delivery and maternal complications might be reduced. In addition, this may prevent unnecessary preterm births in women at low risk. MATERIAL AND METHODS: We developed a prediction model using data from the HYPITAT-II trail, which evaluated immediate delivery vs. expectant monitoring in women with non-severe hypertensive disorders of pregnancy between 34 and 37 weeks of gestation. Univariate and multivariate logistic regression analysis were used to identify relevant variables from clinical and laboratory parameters. The performance of the resulting prediction model was assessed by receiver operating characteristic analysis, calibration and bootstrapping, using the average predicted probabilities. RESULTS: We included 519 women, 115 (22.2%) of whom developed severe hypertensive disorders of pregnancy. The prediction model included: maternal age (odds ratio 0.92 per year), gestational age (odds ratio 0.87 per week), systolic blood pressure (odds ratio 1.05 per mmHg), the presence of chronic hypertension (odds ratio 2.4), platelet count (odds ratio 0.996), creatinine (odds ratio 1.02) and lactate dehydrogenase (odds ratio 1.003). The model showed good fit (p = 0.64), fair discrimination (area under the curve 0.76, 95% confidence interval 0.73-0.81, p < 0.001) and could stratify women in three risk groups of average, intermediate and high risk (predicted probabilities <0.22, <0.44 and >0.45, respectively). CONCLUSION: In women with non-severe hypertension in pregnancy near term, progression to severe disease can be predicted. This model requires external validation before it can be applied in practice.

Immediate delivery versus expectant monitoring for hypertensive disorders of pregnancy between 34 and 37 weeks of gestation (HYPITAT-II): an open-label, randomised controlled trial.

BACKGROUND: There is little evidence to guide the management of women with hypertensive disorders in late preterm pregnancy. We investigated the effect of immediate delivery versus expectant monitoring on maternal and neonatal outcomes in such women. METHODS: We did an open-label, randomised controlled trial, in seven academic hospitals and 44 non-academic hospitals in the Netherlands. Women with non-severe hypertensive disorders of pregnancy between 34 and 37 weeks of gestation were randomly allocated to either induction of labour or caesarean section within 24 h (immediate delivery) or a strategy aimed at prolonging pregnancy until 37 weeks of gestation (expectant monitoring). The primary outcomes were a composite of adverse maternal outcomes (thromboembolic disease, pulmonary oedema, eclampsia, HELLP syndrome, placental abruption, or maternal death), and neonatal respiratory distress syndrome, both analysed by intention-to-treat. This study is registered with the Netherlands Trial Register (NTR1792). FINDINGS: Between March 1, 2009, and Feb 21, 2013, 897 women were invited to participate, of whom 703 were enrolled and randomly assigned to immediate delivery (n=352) or expectant monitoring (n=351). The composite adverse maternal outcome occurred in four (1·1%) of 352 women allocated to immediate delivery versus 11 (3·1%) of 351 women allocated to expectant monitoring (relative risk [RR] 0·36, 95% CI 0·12-1·11; p=0·069). Respiratory distress syndrome was diagnosed in 20 (5·7%) of 352 neonates in the immediate delivery group versus six (1·7%) of 351 neonates in the expectant monitoring group (RR 3·3, 95% CI 1·4-8·2; p=0·005). No maternal or perinatal deaths occurred. INTERPRETATION: For women with non-severe hypertensive disorders at 34-37 weeks of gestation, immediate delivery might reduce the already small risk of adverse maternal outcomes. However, it significantly increases the risk of neonatal respiratory distress syndrome, therefore, routine immediate delivery does not seem justified and a strategy of expectant monitoring until the clinical situation deteriorates can be considered. FUNDING: ZonMw.

Neonatal and obstetric outcomes in diet- and insulin-treated women with gestational diabetes mellitus: a retrospective study.

BACKGROUND: To evaluate the neonatal and obstetric outcomes of pregnancies complicated by gestational diabetes mellitus (GDM). Screening and treatment - diet-only versus additional insulin therapy - were based on the 2010 national Dutch guidelines. METHODS: Retrospective study of the electronic medical files of 820 singleton GDM pregnancies treated between January 2011 and September 2014 in a university and non-university hospital. Pregnancy outcomes were compared between regular care treatment regimens -diet-only versus additional insulin therapy- and pregnancy outcomes of the Northern region of the Netherlands served as a reference population. RESULTS: A total of 460 women (56 %) met glycaemic control on diet-only and 360 women (44 %) required additional insulin therapy. Between the groups, there were no differences in perinatal complications (mortality, birth trauma, hyperbilirubinaemia, hypoglycaemia), small for gestational age, large for gestational age (LGA), neonate weighing >4200 g, neonate weighing ≥4500 g, Apgar score <7 at 5 min, respiratory support, preterm delivery, and admission to the neonatology department. Neonates born in the insulin-group had a lower birth weight compared with the diet-group (3364 vs. 3467 g, p = 0.005) and a lower gestational age at birth (p = 0.001). However, birth weight was not different between the groups when expressed in percentiles, adjusted for gestational age, gender, parity, and ethnicity. The occurrence of preeclampsia and gestational hypertension was comparable between the groups. In the insulin-group, labour was more often induced and more planned caesarean sections were performed (p = 0.001). Compared with the general obstetric population, the percentage of LGA neonates was higher in the GDM population (11.0 % vs.19.9 %, p = <0.001). CONCLUSIONS: Neonatal and obstetric outcomes were comparable either with diet-only or additional insulin therapy. However, compared with the general obstetric population, the incidence of LGA neonates was significantly increased in this GDM cohort.

Maternal and neonatal outcomes of pregnancy in women with chronic hypertension: a retrospective analysis of a national register.

INTRODUCTION: Pregnancies complicated by chronic hypertension are at increased risk of adverse pregnancy outcomes. To assess whether planned early delivery might prevent some of these adverse outcomes, we studied maternal and neonatal outcomes of pregnancy in women with chronic hypertension, including gestational-age-specific outcomes. MATERIAL AND METHODS: We performed a retrospective, population-based cohort study, using data from the Netherlands Perinatal Register. We included women with chronic hypertension and normotensive controls who delivered a singleton without congenital anomalies in 2002-2007. We calculated crude and adjusted odds ratios (OR) with 95% CI, compared delivery and ongoing pregnancy using moving averages, and used multiple Cox regression to adjust for differences in baseline characteristics and to examine adverse neonatal outcomes across subgroups of hypertensive disorder. Main outcome measures were composite adverse maternal and neonatal outcomes. RESULTS: We included 3457 (0.3%) women with chronic hypertension and 984 932 normotensive controls. Women with chronic hypertension had adverse maternal outcomes more often (28.7% vs. 6.6%, adjusted OR 5.7, 95% CI 5.3-6.2). Their offspring had an increased rate of neonatal morbidity (17.4% vs. 13.2%, adjusted OR 1.2, 95% CI 1.1-1.4) but not of severe adverse neonatal outcomes (2.5% vs. 2.2%, adjusted OR 0.8, 95% CI 0.6-1.0). The increased risk of adverse maternal outcomes for ongoing pregnancy remained stable around 17% at term. The risk of severe adverse neonatal outcomes for birth was at its lowest between 38 and 40 weeks, mainly in women with iatrogenic onset of delivery. CONCLUSIONS: Women with chronic hypertension are at increased risk of adverse maternal and neonatal outcomes compared with controls throughout pregnancy, including at term. Our results suggest that the optimal timing of delivery might be between 38 and 40 weeks of gestation, but prospective randomized studies should confirm this.

Epithelial-to-mesenchymal transition in fibrosis: collagen type I expression is highly upregulated after EMT, but does not contribute to collagen deposition.

The hallmark of fibrosis is an accumulation of fibrillar collagens, especially of collagen type I. There is considerable debate whether in vivo type II epithelial-to-mesenchymal transition (EMT) is involved in organ fibrosis. Lineage tracing experiments by various groups show opposing data concerning the relative contribution of epithelial cells to the pool of myofibroblasts. We hypothesized that EMT-derived cells might directly contribute to collagen deposition. To study this, EMT was induced in human epithelial lung and renal cell lines in vitro by means of TGF-ß1 stimulation, and we compared the collagen type I (COL1A1) expression levels of transdifferentiated cells with that of myofibroblasts obtained by TGF-ß1 stimulation of human dermal and lung fibroblasts. COL1A1 expression levels of transdifferentiated epithelial cells appeared to be at least one to two orders of magnitude lower than that of myofibroblasts. This was confirmed at immunohistochemical level: in contrast to myofibroblasts, collagen type I deposition by EMT-derived cells was not or hardly detectable. We postulate that, even when type II EMT occurs in vivo, the direct contribution of EMT-derived cells to collagen accumulation is rather limited.

Dotting the I's and crossing the T's: autonomy and/or beneficence? The 'fetus as a patient' in maternal-fetal surgery.

Chervenak and McCullough, authors of the most acknowledged ethical framework for maternal-fetal surgery, rely on the 'ethical-obstetrical' concept of the fetus as a patient in order to determine what is morally owed to fetuses by both physicians and the women who gestate them in the context of prenatal surgery. In this article, we reconstruct the argumentative structure of their framework and present an internal criticism. First, we analyse the justificatory arguments put forward by the authors regarding the moral status of the fetus qua patient. Second, we discuss the internal coherence and consistency of the moral obligations those authors derive from that concept. We claim that some of the dilemmas their approach is purported to avoid, such as the debate about the independent moral status of the fetus, and the foundation of the moral obligations of pregnant women (towards the fetuses they gestate) are not, all things considered, avoided. Chervenak and McCullough construct the obligations of physicians as obligations towards entities with equal moral status. But, at the same time, they assume that the woman has an independent moral status while the moral status of the fetus is dependent on the decision of the woman to present it to a physician for care. According to the logic of their own argumentation, Chervenak and McCullough implicitly admit a different moral status of the woman and the fetus, which will lead to different ascription of duties of the physician than those they ascribed.

Fathers with PTSD and depression in pregnancies complicated by preterm preeclampsia or PPROM.

PURPOSE: To assess prevalence and risk factors for posttraumatic stress disorder (PTSD) and depression in fathers after early preeclampsia (PE) or preterm premature rupture of membranes (PPROM). METHODS: Partners of patients hospitalized for PE or PPROM and partners of healthy controls completed PTSD (PSS-SR) and depression (BDI-II) questionnaires during pregnancy (t 1) and 6 weeks postpartum (t 2). 85 of the 187 eligible men participated (51 partners of patients, 34 partners of control) at t 1, and 66 men participated both time points. RESULTS: No significant differences were found between partners of patients and partners of controls in symptoms of PTSD and depression (t 1: p = 0.28 for PTSD and p = 0.34 for depression; t 2: p = 0.08 for PTSD and p = 0.31 for depression). For partners of patients, correlation between PTSD and depression sum-scores was 0.48 (p < 0.001) at t 1 and 0.86 (p < 0.001) at t 2. Within-couple correlation was low and not significant during pregnancy, but strong at postpartum (PSS-SR: r = 0.62, p < 0.001; BDI-II: r = 0.59, p < 0.001). Higher paternal age was associated with more symptoms of PTSD and depression postpartum in partners of patients. Symptoms of PTSD and depression during pregnancy predicted the occurrence of PTSD symptoms following childbirth in partners of patients. CONCLUSIONS: Symptoms of PTSD and depression occurred at a similar rate in partners of women with PE or PPROM and partners of healthy pregnant controls. Symptoms of PTSD and depression during pregnancy predicted the occurrence of PTSD symptoms following childbirth. Increased paternal age predicted more symptoms of PTSD and depression postpartum. At 6 weeks postpartum, a strong association was found between men and women in symptoms of PTSD and depression.

Functional outcome of very preterm-born and small-for-gestational-age children at school age.

BACKGROUND: Our aim was to determine functional outcome of very preterm-born and small-for-gestational-age (SGA) children as compared with matched controls at school age. METHODS: We included 28 very preterm SGA children (GA <32 wk, birth weight (BW) <10th percentile), born in 2000-2001. We also included 28 very preterm but appropriate-for-gestational-age (AGA) children, matched for GA, gender, and birth year, as controls. We assessed motor skills, intelligence quotient (IQ), attention, verbal memory, visual perception, visuomotor integration, executive functioning, and behavior of both sets of children at school age. RESULTS: The SGA children had a median GA of 29.7 wk and BW of 888 g, whereas the controls had a median GA of 29.4 wk and BW of 1,163 g. At 8.6 y, the median total IQ of the SGA children was 94 as compared with 95 in the controls (not significant). Performance IQ was significantly lower in SGA children (89 vs. 95, P = 0.043), whereas verbal IQ was not (95 vs. 95). Total motor skills (P = 0.048) and fine motor skills (P = 0.021) were worse in SGA children. Furthermore, SGA children scored lower on selective attention (P = 0.026) and visual perception (P = 0.025). Other scores did not differ significantly between groups. CONCLUSION: The differences we found between the groups were small. This suggests that the impaired functioning of very preterm-born SGA children is attributable to their having been born very preterm rather than to being SGA.

Prediction of progression to a high risk situation in women with gestational hypertension or mild pre-eclampsia at term.

OBJECTIVE: To evaluate whether progression to a high-risk situation is predictable in women with gestational hypertension (GH) or mild pre-eclampsia (PE) at term. METHODS: Women with a singleton pregnancy, a fetus in cephalic position, between 36 and 41 weeks of gestation, complicated by GH or mild PE that were managed expectantly, were selected from the HYPITAT trial. We evaluated the predictability of progression to a high-risk situation. Logistic regression was used to determine the predictive value of clinical characteristics or laboratory findings and to generate a prediction model for progression to a high-risk situation. The predictive value of this model was assessed with receiver-operating characteristic (ROC) analysis, calibration and internal validation. RESULTS: We included 703 women, of whom 244 (34.7%) had progression to a high-risk situation. After multivariable analysis, nulliparity (OR 1.87), maternal age (OR 1.05 per year), gestational age (OR 0.88 per week), previous abortion (OR 1.26), ethnicity (OR 2.05 for non-Caucasian ethnicity), diastolic (OR 1.04 per mmHg), systolic blood pressure (OR 1.02 per mmHg) and the laboratory parameters proteinuria, haemoglobin, platelets, uric acid and alanine aminotransferase were included in the final model. The area under the ROC curve of this model was 0.71 (95% CI, 0.67-0.74). Even though the goodness of fit was moderate (P=0.40), internal validation showed the model could hold in the overall population. CONCLUSION: In the prediction of progression to a high-risk situation, in women with GH or mild PE at term, a distinction can be made between women with a low risk and women with high risk.

Induction of labour versus expectant monitoring for gestational hypertension or mild pre-eclampsia after 36 weeks' gestation (HYPITAT): a multicentre, open-label randomised controlled trial.

BACKGROUND: Robust evidence to direct management of pregnant women with mild hypertensive disease at term is scarce. We investigated whether induction of labour in women with a singleton pregnancy complicated by gestational hypertension or mild pre-eclampsia reduces severe maternal morbidity. METHODS: We undertook a multicentre, parallel, open-label randomised controlled trial in six academic and 32 non-academic hospitals in the Netherlands between October, 2005, and March, 2008. We enrolled patients with a singleton pregnancy at 36-41 weeks' gestation, and who had gestational hypertension or mild pre-eclampsia. Participants were randomly allocated in a 1:1 ratio by block randomisation with a web-based application system to receive either induction of labour or expectant monitoring. Masking of intervention allocation was not possible. The primary outcome was a composite measure of poor maternal outcome--maternal mortality, maternal morbidity (eclampsia, HELLP syndrome, pulmonary oedema, thromboembolic disease, and placental abruption), progression to severe hypertension or proteinuria, and major post-partum haemorrhage (>1000 mL blood loss). Analysis was by intention to treat and treatment effect is presented as relative risk. This study is registered, number ISRCTN08132825. FINDINGS: 756 patients were allocated to receive induction of labour (n=377 patients) or expectant monitoring (n=379). 397 patients refused randomisation but authorised use of their medical records. Of women who were randomised, 117 (31%) allocated to induction of labour developed poor maternal outcome compared with 166 (44%) allocated to expectant monitoring (relative risk 0.71, 95% CI 0.59-0.86, p<0.0001). No cases of maternal or neonatal death or eclampsia were recorded. INTERPRETATION: Induction of labour is associated with improved maternal outcome and should be advised for women with mild hypertensive disease beyond 37 weeks' gestation. FUNDING: ZonMw.

Recurrence risk of preeclampsia in a linked population-based cohort: Effects of first pregnancy maximum diastolic blood pressure and gestational age.

OBJECTIVE: To estimate preeclampsia occurrence and recurrence risk in the 2nd pregnancy and analyze associated risk factors such as 1st pregnancy maximum diastolic blood pressure (maxDBP) and gestational age at delivery (GA). STUDY DESIGN: Linked cohort of 1st and 2nd pregnancies of 272,551 women from the Dutch Perinatal Registry collected between 2000 and 2007. We defined preeclampsia as hypertension (maxDBP ≥90 mmHg or documented hypertension) plus proteinuria (≥300 mg/24 h) and analyzed its 2nd pregnancy occurrence with logistic regression. Early and late onset preeclampsia were defined by delivery before and after the 34th week, respectively. RESULTS: Preeclampsia prevalences in the 1st and 2nd pregnancies were 2.5% and 0.9%, respectively. Women with prior preeclampsia had a 10.5% risk of recurrence. For women with term 1st pregnancies and maxDBP <80 mmHg, the 2nd pregnancy preeclampsia rate was 0.2% (95% CI 0.17%-0.23%), while for those whom presented maxDBP ≥110 mmHg it was 4.2% (95% CI 3.6%-4.8%). First pregnancy late onset preeclampsia was associated with increased preeclampsia recurrence risk proportional to 1st pregnancy maxDBP: in women with a maxDBP between 100 and 109 mmHg the recurrence risk was 8.3%, while for women with a maxDBP ≥110 mmHg this risk was 11% (difference 2.7%; 95% CI 1.0%-4.4%). In 1st pregnancy early onset preeclampsia corresponding rates were 14.8% and 19.3% (difference 4.5%; 95% CI -1.3%-9.7%). CONCLUSION: Preeclampsia recurrence risk is 10%. Preeclampsia risk in the 2nd pregnancy increases proportionally to 1st pregnancy maxDBP. Earlier onsets of 1st pregnancy preeclampsia further increase recurrence risk.

Fetal bladder wall regeneration with a collagen biomatrix and histological evaluation of bladder exstrophy in a fetal sheep model.

OBJECTIVES: To evaluate histological changes in an animal model for bladder exstrophy and fetal repair of the bladder defect with a molecular-defined dual-layer collagen biomatrix to induce fetal bladder wall regeneration. METHODS: In 12 fetal lambs the abdominal wall and bladder were opened by a midline incision at 79 days' gestation. In 6 of these lambs an uncorrected bladder exstrophy was created by suturing the edges of the opened bladder to the abdominal wall (group 1). The other 6 lambs served as a repair group, where a dual-layer collagen biomatrix was sutured into the bladder wall and the abdominal wall was closed (group 2). A caesarean section was performed at 140 days' gestation, followed by macroscopic and histological examination. RESULTS: Group 1 showed inflammatory and maturational changes in the mucosa, submucosa and detrusor muscle of all the bladders. In group 2, bladder regeneration was observed, with urothelial coverage, ingrowth of fibroblasts and smooth muscle cells, deposition of collagen, neovascularization and nerve fibre formation. This tissue replaced the collagen biomatrix. No structural changes of the bladder were seen in group 2. CONCLUSIONS: The animal model, as in group 1, for bladder exstrophy shows remarkable histological resemblance with the naturally occurring anomaly in humans. This model can be used to develop new methods to salvage or regenerate bladder tissue in bladder exstrophy patients. Fetal bladder wall regeneration with a collagen biomatrix is feasible in this model, resulting in renewed formation of urothelium, blood vessels, nerve fibres, ingrowth of smooth muscle cells and salvage of the native bladder.

Induction of labour versus expectant monitoring in women with pregnancy induced hypertension or mild preeclampsia at term: the HYPITAT trial.

BACKGROUND: Hypertensive disorders, i.e. pregnancy induced hypertension and preeclampsia, complicate 10 to 15% of all pregnancies at term and are a major cause of maternal and perinatal morbidity and mortality. The only causal treatment is delivery. In case of preterm pregnancies conservative management is advocated if the risks for mother and child remain acceptable. In contrast, there is no consensus on how to manage mild hypertensive disease in pregnancies at term. Induction of labour might prevent maternal and neonatal complications at the expense of increased instrumental vaginal delivery rates and caesarean section rates. METHODS/DESIGN: Women with a pregnancy complicated by pregnancy induced hypertension or mild preeclampsia at a gestational age between 36+0 and 41+0 weeks will be asked to participate in a multi-centre randomised controlled trial. Women will be randomised to either induction of labour or expectant management for spontaneous delivery. The primary outcome of this study is severe maternal morbidity, which can be complicated by maternal mortality in rare cases. Secondary outcome measures are neonatal mortality and morbidity, caesarean and vaginal instrumental delivery rates, maternal quality of life and costs. Analysis will be by intention to treat. In total, 720 pregnant women have to be randomised to show a reduction in severe maternal complications of hypertensive disease from 12 to 6%. DISCUSSION: This trial will provide evidence as to whether or not induction of labour in women with pregnancy induced hypertension or mild preeclampsia (nearly) at term is an effective treatment to prevent severe maternal complications. TRIAL REGISTRATION: The protocol is registered in the clinical trial register number ISRCTN08132825.

Lysosomal storage diseases in non-immune hydrops fetalis pregnancies.

BACKGROUND: At least 20 inborn errors of metabolism may cause hydrops fetalis. Most of these are lysosomal storage diseases. The study proposes a diagnostic flowchart for prenatal diagnosis of non-immune hydrops fetalis. METHODS: This study contains a series of 75 non-immune hydrops fetalis pregnancies. Mucopolysaccharides, oligosaccharides, neuraminic acid and 21 lysosomal enzymes were measured in amniotic fluid and cultured amniotic cells. RESULTS: The study gives reference values for mucopolysaccharides and neuraminic acid at various stages of gestation. Four definite and two probable lysosomal diagnoses were found among the 75 investigated cases (=5.3-8%). Fetal death was found to cause false positive values for mucopolysaccharides in amniotic fluid. In the galactosialidosis case, two novel mutations were found in the cathepsin A gene. CONCLUSIONS: Reference values for mucopolysaccharides and neuraminic acid depend on gestational age. In a relatively high percentage of the hydrops foetalis pregnancies, a lysosomal aetiology is found. This study provides a strategy to diagnose lysosomal diseases in hydrops fetalis pregnancies. Awareness of lysosomal storage diseases causing hydrops fetalis is useful as it gives an opportunity for risk evaluation, genetic counseling to parents and targeted prenatal diagnostics for ensuing pregnancies.