Publications by authors named "Robert Aardenburg"

21 Publications

  • Page 1 of 1

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

J Perinat Med 2021 Mar 6;49(3):357-363. Epub 2020 Nov 6.

Maastricht University Medical Centre, Obstetrics and Gynaecology, Maastricht, Netherlands.

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.
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http://dx.doi.org/10.1515/jpm-2020-0308DOI Listing
March 2021

External validation and clinical utility of prognostic prediction models for gestational diabetes mellitus: A prospective cohort study.

Acta Obstet Gynecol Scand 2020 07 14;99(7):891-900. Epub 2020 Feb 14.

Department of Epidemiology, Care and Public Health Research Institute (CAPHRI), Maastricht University, Maastricht, The Netherlands.

Introduction: We performed an independent validation study of all published first trimester prediction models, containing non-invasive predictors, for the risk of gestational diabetes mellitus. Furthermore, the clinical potential of the best performing models was evaluated.

Material And Methods: Systemically selected prediction models from the literature were validated in a Dutch prospective cohort using data from Expect Study I and PRIDE Study. The predictive performance of the models was evaluated by discrimination and calibration. Clinical utility was assessed using decision curve analysis. Screening performance measures were calculated at different risk thresholds for the best model and compared with current selective screening strategies.

Results: The validation cohort included 5260 women. Gestational diabetes mellitus was diagnosed in 127 women (2.4%). The discriminative performance of the 12 included models ranged from 68% to 75%. Nearly all models overestimated the risk. After recalibration, agreement between the observed outcomes and predicted probabilities improved for most models.

Conclusions: The best performing prediction models showed acceptable performance measures and may enable more personalized medicine-based antenatal care for women at risk of developing gestational diabetes mellitus compared with current applied strategies.
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http://dx.doi.org/10.1111/aogs.13811DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7317858PMC
July 2020

External Validation and Clinical Usefulness of First Trimester Prediction Models for the Risk of Preeclampsia: A Prospective Cohort Study.

Fetal Diagn Ther 2019 18;45(6):381-393. Epub 2018 Jul 18.

Department of Epidemiology, Care and Public Health Research Institute (CAPHRI), Maastricht University, Maastricht, The Netherlands.

Introduction: This study assessed the external validity of all published first trimester prediction models for the risk of preeclampsia (PE) based on routinely collected maternal predictors. Moreover, the potential utility of the best-performing models in clinical practice was evaluated.

Material And Methods: Ten prediction models were systematically selected from the literature. We performed a multicenter prospective cohort study in the Netherlands between July 1, 2013, and December 31, 2015. Eligible pregnant women completed a web-based questionnaire before 16 weeks' gestation. The outcome PE was established using postpartum questionnaires and medical records. Predictive performance of each model was assessed by means of discrimination (c-statistic) and a calibration plot. Clinical usefulness was evaluated by means of decision curve analysis and by calculating the potential impact at different risk thresholds.

Results: The validation cohort contained 2,614 women of whom 76 developed PE (2.9%). Five models showed moderate discriminative performance with c-statistics ranging from 0.73 to 0.77. Adequate calibration was obtained after refitting. The best models were clinically useful over a small range of predicted probabilities.

Discussion: Five of the ten included first trimester prediction models for PE showed moderate predictive performance. The best models may provide more benefit compared to risk selection as used in current guidelines.
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http://dx.doi.org/10.1159/000490385DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6604271PMC
January 2020

Prediction models for the risk of spontaneous preterm birth based on maternal characteristics: a systematic review and independent external validation.

Acta Obstet Gynecol Scand 2018 Aug 9;97(8):907-920. Epub 2018 May 9.

Department of Epidemiology, Care and Public Health Research Institute (CAPHRI), Maastricht University, Maastricht, The Netherlands.

Introduction: Prediction models may contribute to personalized risk-based management of women at high risk of spontaneous preterm delivery. Although prediction models are published frequently, often with promising results, external validation generally is lacking. We performed a systematic review of prediction models for the risk of spontaneous preterm birth based on routine clinical parameters. Additionally, we externally validated and evaluated the clinical potential of the models.

Material And Methods: Prediction models based on routinely collected maternal parameters obtainable during first 16 weeks of gestation were eligible for selection. Risk of bias was assessed according to the CHARMS guidelines. We validated the selected models in a Dutch multicenter prospective cohort study comprising 2614 unselected pregnant women. Information on predictors was obtained by a web-based questionnaire. Predictive performance of the models was quantified by the area under the receiver operating characteristic curve (AUC) and calibration plots for the outcomes spontaneous preterm birth <37 weeks and <34 weeks of gestation. Clinical value was evaluated by means of decision curve analysis and calculating classification accuracy for different risk thresholds.

Results: Four studies describing five prediction models fulfilled the eligibility criteria. Risk of bias assessment revealed a moderate to high risk of bias in three studies. The AUC of the models ranged from 0.54 to 0.67 and from 0.56 to 0.70 for the outcomes spontaneous preterm birth <37 weeks and <34 weeks of gestation, respectively. A subanalysis showed that the models discriminated poorly (AUC 0.51-0.56) for nulliparous women. Although we recalibrated the models, two models retained evidence of overfitting. The decision curve analysis showed low clinical benefit for the best performing models.

Conclusions: This review revealed several reporting and methodological shortcomings of published prediction models for spontaneous preterm birth. Our external validation study indicated that none of the models had the ability to predict spontaneous preterm birth adequately in our population. Further improvement of prediction models, using recent knowledge about both model development and potential risk factors, is necessary to provide an added value in personalized risk assessment of spontaneous preterm birth.
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http://dx.doi.org/10.1111/aogs.13358DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6099449PMC
August 2018

Homeostatic model assessment of beta cell function predicting abnormal oral glucose tolerance testing in pregnancy: a systematic review and meta-analysis.

Gynecol Endocrinol 2017 Dec 28;33(12):911-917. Epub 2017 Aug 28.

a Department of Obstetrics and Gynecology , Maastricht University Medical Center , Maastricht , The Netherlands.

Background: Gestational diabetes mellitus (GDM) complicates 1-14% of pregnancies and relates to increased risk of adverse obstetric outcomes. Currently GDM is diagnosed using an oral glucose tolerance test (OGTT), which is burdensome and time intensive.

Objective: To compare current literature on whether the homeostatic model assessment beta cell function (HOMA-β) is an accurate predictor of an abnormal OGTT in pregnant women.

Methods: Pubmed, Cochrane and Embase were searched. Included studies evaluated pregnant women at risk for GDM using the homeostatic model assessment of beta cell function (HOMA-β) for the assessment of beta cell function and the OGTT. Studies with animals, non-pregnant women, women with type 2 diabetes and post-partum diabetes were excluded. The QUADAS-2 criteria were used to assess the methodological quality of studies.

Results: A total of 12 studies were included, reporting on 7292 women. Seven studies showed a difference in beta cell function between women with impaired glucose tolerance compared to healthy pregnant women. HOMA-β is significantly lower in impaired glucose tolerance (p < 0.001).

Conclusions: Although HOMA-β is lower in women with abnormal OGTT in pregnancy, given the high degree of heterogeneity of studies, we do not propagate HOMA-β as a sole diagnostic tool replacing OGTT to diagnose GDM.
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http://dx.doi.org/10.1080/09513590.2017.1369516DOI Listing
December 2017

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

Acta Obstet Gynecol Scand 2017 Feb 3;96(2):158-165. Epub 2017 Jan 3.

Scientific Institute for Quality of Healthcare (IQ healthcare), Radboud University Nijmegen Medical Center, Nijmegen, the Netherlands.

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-R 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.
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http://dx.doi.org/10.1111/aogs.13059DOI Listing
February 2017

Prediction of postpartum hemorrhage in women with gestational hypertension or mild preeclampsia at term.

Acta Obstet Gynecol Scand 2014 Apr;93(4):399-407

Department of Obstetrics and Gynecology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.

Objective: To assess whether postpartum hemorrhage can be predicted in women with gestational hypertension or mild preeclampsia at term.

Design: A cohort study in which we used data from our multicentre randomized controlled trial (HYPITAT trial).

Setting: The study was conducted in 38 hospitals in the Netherlands between 2005 and 2008.

Population: Women with gestational hypertension or mild preeclampsia at term (n = 1132).

Methods: An antepartum model (model A) and an antepartum/intrapartum model (model B) were created using logistic regression. The predictive capacity of the models was assessed with receiver operating characteristic analysis and calibration.

Main Outcome Measure: Postpartum hemorrhage, defined as blood loss >1000 mL within 24 h after delivery.

Results: Postpartum hemorrhage occurred in 118 (10.4%) women. Maternal age (odds ratio 1.03), prepregnancy body mass index (odds ratio 0.96), and women with preeclampsia (odds ratio 1.5) were independent antepartum prognostic variables of postpartum hemorrhage. Intrapartum variables incorporated in the model were gestational age at delivery (odds ratio 1.2), duration of dilatation stage (odds ratio 1.1), and episiotomy (odds ratio 1.5). Model A and model B showed moderate discrimination, with areas under the receiver operating characteristic curve of 0.59 (95% confidence interval 0.53-0.64) and 0.64 (95% confidence interval 0.59-0.70), respectively. Calibration was moderate for model A (Hosmer-Lemeshow p = 0.26) but better for model B (Hosmer-Lemeshow p = 0.36). The rates of postpartum hemorrhage ranged from 4% (lowest 10%) to 22% (highest 10%).

Conclusion: In the assessment of performance of a prediction model, calibration is more important than discriminative capacity. Our prediction model shows that for women with gestational hypertension or mild preeclampsia at term, distinction between low and high risk of developing postpartum hemorrhage is possible when antepartum and intrapartum variables are combined.
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http://dx.doi.org/10.1111/aogs.12352DOI Listing
April 2014

SIMPLE: implementation of recommendations from international evidence-based guidelines on caesarean sections in the Netherlands. Protocol for a controlled before and after study.

Implement Sci 2013 Jan 3;8. Epub 2013 Jan 3.

GROW-School for Oncology and Developmental Biology, Department of Obstetrics and Gynaecology, Maastricht University Medical Centre, Maastricht, The Netherlands.

Background: Caesarean section (CS) rates are rising worldwide. In the Netherlands, the most significant rise is observed in healthy women with a singleton in vertex position between 37 and 42 weeks gestation, whereas it is doubtful whether an improved outcome for the mother or her child was obtained. It can be hypothesized that evidence-based guidelines on CS are not implemented sufficiently. Therefore, the present study has the following objectives: to develop quality indicators on the decision to perform a CS based on key recommendations from national and international guidelines; to use the quality indicators in order to gain insight into actual adherence of Dutch gynaecologists to guideline recommendations on the performance of a CS; to explore barriers and facilitators that have a direct effect on guideline application regarding CS; and to develop, execute, and evaluate a strategy in order to reduce the CS incidence for a similar neonatal outcome (based on the information gathered in the second and third objectives).

Methods: An independent expert panel of Dutch gynaecologists and midwives will develop a set of quality indicators on the decision to perform a CS. These indicators will be used to measure current care in 20 hospitals with a population of 1,000 women who delivered by CS, and a random selection of 1,000 women who delivered vaginally in the same period. Furthermore, by interviewing healthcare professionals and patients, the barriers and facilitators that may influence the decision to perform a CS will be measured. Based on the results, a tailor-made implementation strategy will be developed and tested in a controlled before-and-after study in 12 hospitals (six intervention, six control hospitals) with regard to effectiveness, experiences, and costs.

Discussion: This study will offer insight into the current CS care and into the hindering and facilitating factors influencing obstetrical policy on CS. Furthermore, it will allow definition of patient categories or situations in which a tailor-made implementation strategy will most likely be meaningful and cost effective, without negatively affecting the outcome for mother and child.

Trial Registration: http://www.clinicaltrials.gov: NCT01261676.
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http://dx.doi.org/10.1186/1748-5908-8-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3547819PMC
January 2013

Is it useful to measure C-reactive protein and leukocytes in patients with prelabor rupture of membranes?

Am J Perinatol 2010 Aug 1;27(7):543-7. Epub 2010 Mar 1.

Department of Obstetrics and Gynecology, Máxima Medical Center, Veldhoven, The Netherlands.

Neonatal infection is the main complication of prelabor rupture of membranes (PROM). We studied the accuracy of measuring C-reactive protein (CRP) and leukocytes in maternal serum to predict neonatal infection. We performed a retrospective cohort study in two hospitals in the Netherlands between 2003 and 2006. We included consecutive women hospitalized for PROM. In both hospitals, CRP and leukocytes were measured routinely in maternal serum every 2 days until delivery. End points considered were clinical neonatal infection and proven neonatal sepsis. The accuracy of CRP and leukocytes was assessed using receiver operating characteristic (ROC) analysis. We included 299 women with PROM, 12 of whom had a twin pregnancy. Gestational age at inclusion varied between 26 weeks and 0 days and 41 weeks and 5 days with a median of 37 weeks and 3 days. In 47 women (16%), the neonate developed a clinical infection. The areas under the ROC curve of CRP and leukocytes in the prediction of clinical neonatal infection were 0.61 and 0.62, respectively. Of the 47 infected neonates, six neonates (2%) had a proven neonatal sepsis. In the mothers of these septic neonates, maternal CRP did not rise above 50 mg/L and leukocyte values varied between 9.8 and 25.8 x 10 (9)/L. In women with PROM, CRP and leukocytes should not be measured routinely.
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http://dx.doi.org/10.1055/s-0030-1248941DOI Listing
August 2010

Blunted autonomic response to volume expansion in formerly preeclamptic women with low plasma volume.

Reprod Sci 2009 Jan;16(1):105-12

Department of Obstetrics and Gynecology, Radboud University Nijmegen Medical Centre, Nijmegen, Netherlands.

Objective: We hypothesize that low plasma volume in normotensive formerly preeclamptic women reflects reduced venous storage capacity. To test this hypothesis, we compared circulatory and autonomic responses to acute volume loading between women with low and those with normal plasma volume.

Methods: In 24 normotensive formerly preeclamptic women at least 6 months postpartum, we administered 500 mL of iso-oncotic fluid by constant intravenous infusion in 30 minutes, while recording changes in heart rate, blood pressure, cardiac output, and measuring active plasma renin and alpha-atrial natriuretic peptide concentrations. We estimated arterial sympathetic control, cardiac autonomic regulatory balance, and baroreflex sensitivity using spectral analysis. Intergroup and intragroup changes were analyzed nonparametrically.

Results: 17 women (71%) had low plasma volume and 7 (29%) had normal plasma volume. Plasma volume expansion induced comparable changes in blood pressure, heart rate, baroreflex sensitivity, and active plasma renin concentration in low plasma volume and normal plasma volume. Cardiac output and alpha-atrial natriuretic peptide increased in low plasma volume but not in normal plasma volume. Volume expansion reduced sympathetic activity ( from 2.41 to 1.76 mm Hg(2), P = .03) in normal plasma volume but not in low plasma volume ( from 2.72 to 2.48 mm Hg(2), P > .05).

Conclusion: The sympathoinhibitory response to volume expansion is diminished in low plasma volume, which suggests that cardiovascular reflex function is impaired. We speculate that this defect contributes to circulatory maladaptation to pregnancy, sympathetic dominance, and the development of gestational hypertensive disease.
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http://dx.doi.org/10.1177/1933719108324136DOI Listing
January 2009

Imperforate hymen: a cause of abdominal pain in female adolescents.

BMJ Case Rep 2009 26;2009. Epub 2009 May 26.

Orbis Medical Centre, Obstetrics and Gynaecology, PO Box 5500, Sittard, 6130 MB, The Netherlands.

A 16-year-old girl presented with primary amenorrhea and had had cyclical abdominal pain for almost a year. At examination we observed a painful mass in the lower abdomen and normal secondary sex characteristics. Perineal examination showed a bluish bulging hymen. Transabdominal ultrasonography revealed a dense mass in the pelvis measuring about 12×11 cm. We diagnosed an imperforate hymen with haematocolpos and haematometra. The hymen was opened surgically and a large quantity of menstrual blood was drained from the vagina and uterus. Postoperative recovery was normal without any pain. The patient now menstruates regularly. An imperforate hymen occurs in 0.05% of women. It is important to be aware of this while examining a female adolescent presenting with cyclical abdominal pain and primary amenorrhea. Late discovery of an imperforate hymen may lead to pain, infections, hydronephrosis and endometriosis with subfertility as a possible consequence.
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http://dx.doi.org/10.1136/bcr.08.2008.0722DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3029536PMC
November 2011

Endothelium-dependent vasodilatation in formerly preeclamptic women correlates inversely with body mass index and varies independently of plasma volume.

Reprod Sci 2007 Dec;14(8):765-70

Department of Obstetrics and Gynecology, University of Maastricht, Maatricht, The Netherlands.

Endothelial dysfunction and a subnormal plasma volume predispose to preeclampsia. The authors determine whether endothelium-dependent vasodilatation is lower in formerly preeclamptic women, explore whether endothelial dysfunction coincides with low plasma volume, and determine if endothelial dysfunction correlates with circulating endothelial stressors. In formerly preeclamptic women and controls, the authors estimated changes in forearm blood flow after arterial occlusion. They measured plasma volume, blood pressure, and circulating variables. To identify factors associated with endothelial function, the authors used Spearman correlation and regression analysis. Endothelial function did not differ between patients and controls and did not correlate with plasma volume; however, it did correlate negatively with body mass index and positively with arterial compliance. Analysis suggested a negative impact of metabolic syndrome on endothelial function. In formerly preeclamptic women, endothelial function is comparable to controls and varies independently of plasma volume. In patients, endothelial function does vary with features of the metabolic syndrome.
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http://dx.doi.org/10.1177/1933719107308336DOI Listing
December 2007

A low plasma volume in formerly preeclamptic women predisposes to the recurrence of hypertensive complications in the next pregnancy.

J Soc Gynecol Investig 2006 Dec 23;13(8):598-603. Epub 2006 Oct 23.

Departments of Obstetrics and Gynecology, University Hospital Maastricht, Maastricht, The Netherlands.

Background: Formerly preeclamptic women with a subnormal plasma volume (PV) have an increased risk to develop a hypertensive disorder in a subsequent pregnancy as compared to women with normal PV. In the current study we tested the hypothesis that formerly preeclamptic women who develop recurrent disease in their next pregnancy differ from their counterparts with an uneventful next pregnancy by a lower pre-pregnant PV, a lower venous capacitance, smaller rises in these indices in early pregnancy, a lower renal adaptive response, and a lower response to mild exercise.

Patients And Methods: We enrolled 33 formerly preeclamptic women in this study. Only 14 conceived within the study period, with seven of them developing a recurrent hypertensive disorder in their next pregnancy (RECUR), while seven had an uneventful next pregnancy (NORM). Before pregnancy and at 12 weeks of gestational age, we compared the following variables between these subgroups: PV, venous capacitance, effective renal plasma flow (ERPF), glomerular filtration rate (GFR), and the responses in stroke volume (SV) and heart rate (HR) to mild exercise. To estimate venous capacitance, we infused 500 mL of a modified gelatine solution in 30 minutes while recording the change in cardiac output (pulse contour analysis). The ratio of percent change in blood volume to percent change in cardiac output in response to a standardized small volume load provides an estimate for venous capacitance.

Results: RECUR differed from NORM by a 20% lower pre-pregnant PV (P <.02) and venous capacitance (0.29 [0.11-0.55] vs 0.86 [0.64-2.03] P = .002). NORM and RECUR were comparable with respect to pregnancy-induced rise in PV, renal hemodynamics and function, and response to mild exercise at 12 weeks. Newborn weight correlated positively with pre-pregnancy PV (R(2) = 0.53 and P = .04).

Conclusion: Formerly preeclamptic women with a recurrent hypertensive disorder in their next pregnancy differed from their counterparts with an uneventful next pregnancy by a lower pre-pregnant PV and a lower venous capacitance, the latter two indices correlating also inversely with the incidence of fetal growth restriction. The preserved acute response to volume-related stimuli in women with a low pre-pregnant PV supports the view that the predisposition of low pre-pregnant PV to adverse pregnancy outcome may result from a concomitant, PV-dependent change setpoint and/or gain in the stimulus/response interrelation of the volume regulatory system.
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http://dx.doi.org/10.1016/j.jsgi.2006.07.008DOI Listing
December 2006

Low plasma volume coincides with sympathetic hyperactivity and reduced baroreflex sensitivity in formerly preeclamptic patients.

J Soc Gynecol Investig 2006 Jan;13(1):48-52

Department of Obstetrics and Gynecology, University Hospital Maastricht, Maastricht, The Netherlands.

Background: Preeclampsia is associated with enhanced sympathetic activity as well as subnormal plasma volume. Meanwhile, in over 50% of these complicated pregnancies, the subnormal plasma volume has been found to persist for a prolonged period after pregnancy. The objective of this study is to test the hypothesis that in normotensive formerly-preeclamptic women, persistence of a subnormal plasma volume coincides with enhanced sympathetic activity and with it, an altered autonomic control of blood pressure.

Methods: Forty-eight formerly-preeclamptic women participated in this study. After measurement of their plasma volume by iodine 125-albumin indicator dilution, they were subdivided into a group with a normal plasma volume (plasma volume > 48 ml/kg lean body mass) and a group with a subnormal plasma volume (< or = 48 ml/kg lean body mass). We performed spectral analysis on their beat-to-beat blood pressure and heart rate recordings and compared both groups using non-parametric tests.

Results: Formerly-preeclamptic women with a subnormal plasma volume had a higher sympathetic activity (P = .001) and a lower baroreflex sensitivity (P = .04) than their counterparts with a normal plasma volume.

Conclusion: In normotensive formerly-preeclamptic women, a subnormal plasma volume coincides with a higher sympathetic activity in the blood pressure regulation and lower baroreflex sensitivity. Whether these alterations in the autonomic control mechanisms are a cause or effect of the subnormal plasma volume remains to be elucidated.
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http://dx.doi.org/10.1016/j.jsgi.2005.11.003DOI Listing
January 2006

Vascular expression of adrenomedullin is increased in Wistar rats during early pregnancy.

Eur J Obstet Gynecol Reprod Biol 2005 Nov;123(1):35-40

Department of Obstetrics and Gynecology, Research Institute Growth and Development (GROW), University Hospital Maastricht-AZM, PO Box 5800, 6202 AZ Maastricht, The Netherlands.

Objective: Circulating levels of adrenomedullin (ADM)--a vasodilator peptide with long-lasting effects--increase in the course of pregnancy. Neither the site nor the concomitant rate of ADM synthesis in pregnancy is known. The aim of this study was to test the hypothesis that the rise in plasma levels of ADM during pregnancy is paralleled by increased gene expression and protein levels in the vascular bed.

Study Design: We determined in cardiovascular and reproductive tissues of non-pregnant (n=10) and 10-days pregnant (n=10) Wistar rats ADM gene expression by semi-quantitative RT-PCR (normalized to GAPDH). As a support for the mRNA data, protein concentrations were measured by both ELISA and Western blot analysis. Finally, ADM in these tissues was localized by immunohistochemical staining. Statistical analysis was carried out by applying Mann-Whitney U-test.

Results: ADM mRNA levels in the abdominal aorta, renal artery and the kidney were increased during pregnancy. In addition, immunohistochemical staining in the kidney, uterus, abdominal aorta, renal, uterine and superior mesenteric artery was more intense as compared to non-pregnant rats. However, we observed lower concentrations of tissue ADM protein in pregnant rats, indicating an increased release of the hormone by the producing cells.

Conclusion: Vascular ADM gene expression is increased in the first half of rat pregnancy. This coincides and may be functionally related to the institution of a high flow/low resistance circulation in pregnancy.
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http://dx.doi.org/10.1016/j.ejogrb.2005.02.014DOI Listing
November 2005

Formerly preeclamptic women with a subnormal plasma volume are unable to maintain a rise in stroke volume during moderate exercise.

J Soc Gynecol Investig 2005 Dec 29;12(8):599-603. Epub 2005 Sep 29.

Department of Obstetrics and Gynecology, University Hospital Maastricht, Maastricht, The Netherlands.

Introduction: In formerly preeclamptic women with a low plasma volume, the recurrence rate of preeclampsia is higher than in women with a normal prepregnant plasma volume. In a recent study, we demonstrated that the low plasma volume subgroup also had a subnormal venous capacitance. In the present study, we determined the impact of subnormal plasma volume on the hemodynamic response to moderate exercise.

Patients And Methods: We performed this study in the follicular phase of the menstrual cycle, in 31 formerly preeclamptic women with a subnormal plasma volume (low-PV) and eight parous controls. The exercise consisted of 60 minutes of cycling in the supine position at 35% of the individualized maximum capacity. Before, during, and after cycling, we measured the percentage change in heart rate, stroke volume, and cardiac output. Before and after exercise, we measured the effective renal plasma flow (ERPF, para-amino-hippurate [PAH] clearance), glomerular filtration rate (GFR, inulin clearance), circulating levels of alpha-atrial natriuretic peptide (alpha-ANP), and active plasma renin concentration (APRC).

Results: The response to exercise of formerly preeclamptic women with a subnormal plasma volume differed from that in controls by a lack of rise in stroke volume, a smaller rise in cardiac output and alpha-ANP, and a greater fall in GFR. The responses in heart rate, ERPF, and APRC did not differ between the two groups.

Conclusion: The response to moderate exercise of formerly preeclamptic women with a subnormal plasma volume differs from that in healthy parous controls with a normal plasma volume and suggests a lower capacity to raise venous return in conditions of a higher demand for systemic flow. The lower capacity to raise venous return in these conditions is associated with more cardiovascular drift. The physiologic consequence is a lower aerobic endurance performance during moderate exercise.
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http://dx.doi.org/10.1016/j.jsgi.2005.08.005DOI Listing
December 2005

Maternal nonpregnant vascular function correlates with subsequent fetal growth.

Am J Obstet Gynecol 2005 Feb;192(2):504-12

Department of Obstetrics and Gynecology,University Hospital Maastricht and University Hospital Nijmegen, Nijmegen, The Netherlands.

Objective: Evidence is accumulating that fetal growth is influenced by preexisting maternal disorder(s) hampering endothelial function. We tested the hypothesis that in nonpregnant normotensive, formerly preeclamptic women, vascular function predicts the development of fetal growth restriction.

Methods: In 60 formerly preeclamptic women, we measured central hemodynamic and vascular and clotting function mid follicular phase during the menstrual cycle. Inclusion for final analysis required besides normotension, a subsequent singleton pregnancy, established within 1 year after the prepregnant evaluation and ongoing beyond 16 weeks' gestation. In the ongoing pregnancy we determined birth weight and birth weight percentile.

Results: Among 60 formerly preeclamptic women, 45 (75%) were normotensive. Thirty-one (69%) participants succeeded in establishing an ongoing pregnancy within 1 year and were included for final analysis. Of the 31 subsequent pregnancies, 8 (26%) were complicated by fetal growth restriction. Prepregnant left and right uterine artery pulsatility index (PI) correlated inversely with carotid artery compliance ( r = 0.57, P = .005, r = 0.62, P = .002) and venous compliance ( r = 0.49, P = .02 and r = 0.45, P = .04, respectively). The latter, in turn, correlates with plasma volume ( r = 0.63, P = .001) and total peripheral vascular resistance index ( r = -0.45, P = .02). Finally, prepregnant left and right uterine artery PI correlated inversely with subsequent achieved fetal growth ( r = -0.68, P < .0001 and r = -0.58, P = .001, respectively).

Conclusion: In nonpregnant normotensive, formerly preeclamptic women, an elevated uterine artery PI predisposes to subsequent restriction in fetal growth.
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http://dx.doi.org/10.1016/j.ajog.2004.08.035DOI Listing
February 2005

Pre-pregnant prediction of recurrent preeclampsia in normotensive thrombophilic formerly preeclamptic women receiving prophylactic antithrombotic medication.

J Soc Gynecol Investig 2005 Feb;12(2):112-7

Department of Obstetrics and Gynecology, University Medical Center Nijmegen St. Radboud, Nijmegen.

Background: Both hemodynamic abnormalities and thrombophilia predispose to pregnancy-associated vascular complications such as fetal growth restriction, stillbirth, preeclampsia, and placental abruption. Antithrombotic treatment may reduce the risk for these events. In this study we tested the hypothesis that in normotensive thrombophilic formerly preeclamptic women certain alterations in hemodynamic function as measured under nonpregnant conditions predict the development of hypertensive disorders and/or fetal growth restriction in the subsequent pregnancy.

Methods: In 350 nondiabetic formerly preeclamptic women, we measured in the follicular phase of the menstrual cycle at least 5 months postpartum central hemodynamic, metabolic, and hemostatic variables. In the subsequent ongoing pregnancy we determined fetal outcome variables and the incidence of maternal vascular complications. In addition to a normotensive thrombophilic profile, inclusion for final analysis required a subsequent singleton pregnancy, established within 1 year following the pre-pregnant evaluation and ongoing beyond 16 weeks' gestation. As a consequence, 47 normotensive thrombophilic formerly preeclamptic women could be included for final analysis. All formerly preeclamptic participants received aspirin throughout pregnancy. Additionally, those with thrombophilia or hyperhomocysteinemia were treated with low molecular weight heparin and with pyridoxine and folic acid supplementation, respectively.

Results: Among 350 formerly preeclamptic women, 266 (76%) were normotensive and 84 (24%) hypertensive. About half (140/266) of normotensive formerly preeclamptic participants were thrombophilic. One hundred eighteen formerly preeclamptic participants succeeded in establishing an ongoing pregnancy within 1 year. From this subset of formerly preeclamptic women, 47 were normotensive thrombophilic; 23 remained normotensive (THROMB), whereas 24 developed at least gestational hypertension (COMPLITHROMB). Participants in the latter subgroup were more obese than those remaining normotensive. In addition, this former subset of women had a higher vascular resistance index, and a lower plasma volume and cardiac index. With respect to fetal outcome, COMPLITHROMB gave birth to an infant with a lower birth weight relative to THROMB. Preeclampsia with or without the hemolysis, elevated liver enzymes, and low platelets (HELLP) syndrome recurred in 26% of the participants in the whole thrombophilic group, in which a low pre-pregnant plasma volume and a raised vascular resistance predisposed for recurrent hypertensive disorders.

Conclusion: Pre-pregnant hemodynamic, metabolic, and clotting variables in formerly preeclamptic women can predict hypertension in the subsequent pregnancy.
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http://dx.doi.org/10.1016/j.jsgi.2004.10.009DOI Listing
February 2005

A subnormal plasma volume in formerly preeclamptic women is associated with a low venous capacitance.

J Soc Gynecol Investig 2005 Feb;12(2):107-11

Department of Obstetrics and Gynecology, University Hospital Maastricht, Maastricht, The Netherlands.

Objective: Pregnancy induces a smaller rise in plasma volume in formerly preeclamptic women with a pre-existent subnormal plasma volume than in their counterparts with a normal plasma volume. These women also have a three times higher recurrence rate of pregnancy-induced hypertensive disorders. In this study we tested the hypothesis that a subnormal plasma volume in these women is related to a lower capacitance of their venous compartment.

Methods: In 31 nonpregnant formerly preeclamptic women with a subnormal plasma volume and eight parous controls, we infused intravenously 500 mL of a modified gelatin solution over 30 minutes. Before and after infusion we measured the circulating levels of alpha-atrial natriuretic peptide (alpha-ANP) and active plasma renin concentration (APRC). During volume loading, we recorded the change in heart rate, stroke volume, and cardiac output using pulse contour analysis. We measured the ratio of percent change in blood volume and percent change in cardiac output during volume loading as a marker for venous capacitance.

Results: During volume loading, patients differed from controls by a larger rise in alpha-ANP, pulse rate, and cardiac output, and by a lower estimated venous capacitance. The concomitant response of stroke volume and APRC did not differ appreciably between groups.

Conclusion: Formerly preeclamptic women with a subnormal plasma volume differ from controls with a normal plasma volume by a reduced venous capacitance. These results support our hypothesis that, in these women, a subnormal plasma volume indicates the presence of a subnormal venous capacitance.
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http://dx.doi.org/10.1016/j.jsgi.2004.09.002DOI Listing
February 2005

Low plasma volume following pregnancy complicated by pre-eclampsia predisposes for hypertensive disease in a next pregnancy.

BJOG 2003 Nov;110(11):1001-6

Department of Obstetrics and Gynaecology, University Maastricht, The Netherlands.

Objective: A large number of women with a history of pre-eclampsia/HELLP have a low plasma volume at least six months postpartum. The objective of this study was to determine whether a low plasma volume in formerly pre-eclamptic women and HELLP patients is associated with an increased risk for recurrent hypertensive complications in a next pregnancy.

Design: Prospective observational study.

Setting: Tertiary obstetric centre.

Sample: Formerly pre-eclamptic women and controls.

Methods: In 316 women with a history of pre-eclampsia and/or HELLP, we measured, plasma volume along with haemodynamic, metabolic and haemostatic variables at least six months postpartum. A group of 22 healthy parous controls was used as a reference. After standardising plasma volume for body mass index, women were subdivided into normotensive and normal plasma volume (n = 199), normotensive and low plasma volume (n = 76) and hypertensive (n = 41) subgroups, which were compared for demography, clinical parameters and course of a next pregnancy.

Main Outcome Measures: Recurrent hypertensive disease of pregnancy.

Results: Relative to the normal plasma volume subgroup, normotensive women in the low plasma volume subgroup have a higher body mass index, a lower total vascular compliance and a shorter estimated systemic circulation time. They have a higher HOMA index and higher fasting triglyceride levels. In normotensive and hypertensive former patients alike, low plasma volume is associated with a higher recurrence of hypertensive complications in a next pregnancy compared with normotensive women with normal plasma volume.

Conclusion: Low plasma volume in normotensive women with a history of pre-eclampsia and/or HELLP is associated with overweight, reduced vascular compliance and insulin resistance and a predisposition for recurrent pre-eclampsia and HELLP syndrome in a next pregnancy.
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November 2003

Hemodynamic changes in pseudopregnancy in chronically instrumented, conscious rats are preserved after hysterectomy.

Pflugers Arch 2002 Jan 31;443(3):427-31. Epub 2001 Oct 31.

Department of Obstetrics and Gynecology, Academic Hospital Maastricht, PO Box 5800, 6201 AZ Maastricht, The Netherlands.

Hemodynamic changes in early-pregnant and pseudopregnant rats are comparable, indicating that the trophoblast does not contribute to these changes. It is unclear whether the presence of the uterus is needed for the normal early-pregnancy hemodynamic adaptation. In this study we tested the hypothesis that uterine factors do not contribute to the systemic hemodynamic changes in early pseudopregnancy. To this end, we studied systemic hemodynamics in conscious pseudopregnant rats subjected to a hysterectomy, and compared these results with those obtained in a control group of pseudopregnant rats. The animals were studied on days 4, 8, 12 and 19 postmating. On day 8 of pseudopregnancy, cardiac output has increased by 23+/-7% in the hysterectomized group and 15+/-5% in the control group. In both groups this rise in cardiac output was entirely accomplished by a rise in stroke volume, by 28+/-8% and 19+/-5%, respectively. Mean arterial pressure did not change appreciably. Therefore, total peripheral resistance also decreased in both groups (17+/-6%) by day 8. After day 12 the hemodynamic parameters returned to baseline. We conclude that systemic hemodynamic changes in hysterectomized pseudopregnant rats closely resemble those in intact pseudopregnant rats. Therefore, the uterus does not seem to play a role in these changes. This supports the hypothesis that only hormones from ovarian origin trigger the initial hemodynamic adaptation to early pregnancy.
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http://dx.doi.org/10.1007/s004240100664DOI Listing
January 2002
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