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author:("frank, Arie")
1.  Measuring Client Experiences in Maternity Care under Change: Development of a Questionnaire Based on the WHO Responsiveness Model 
PLoS ONE  2015;10(2):e0117031.
Maternity care is an integrated care process, which consists of different services, involves different professionals and covers different time windows. To measure performance of maternity care based on clients' experiences, we developed and validated a questionnaire.
Methods and Findings
We used the 8-domain WHO Responsiveness model, and previous materials to develop a self-report questionnaire. A dual study design was used for development and validation. Content validity of the ReproQ-version-0 was determined through structured interviews with 11 pregnant women (≥28 weeks), 10 women who recently had given birth (≤12 weeks), and 19 maternity care professionals. Structured interviews established the domain relevance to the women; all items were separately commented on. All Responsiveness domains were judged relevant, with Dignity and Communication ranking highest. Main missing topic was the assigned expertise of the health professional. After first adaptation, construct validity of the ReproQ-version-1 was determined through a web-based survey. Respondents were approached by maternity care organizations with different levels of integration of services of midwives and obstetricians. We sent questionnaires to 605 third trimester pregnant women (response 65%), and 810 women 6 weeks after delivery (response 55%). Construct validity was based on: response patterns; exploratory factor analysis; association of the overall score with a Visual Analogue Scale (VAS), known group comparisons. Median overall ReproQ score was 3.70 (range 1–4) showing good responsiveness. The exploratory factor analysis supported the assumed domain structure and suggested several adaptations. Correlation of the VAS rating and overall ReproQ score (antepartum, postpartum) supported validity (r = 0.56; 0.59, p<0.001 Spearman's correlation coefficient). Pre-stated group comparisons confirmed the expected difference following a good vs. adverse birth outcome. Fully integrated organizations performed slightly better (median = 3.78) than less integrated organizations (median = 3.63; p<0.001). Participation rate of women with a low educational level and/or a non-western origin was low.
The ReproQ appears suitable for assessing quality of maternity care from the clients' perspective. Recruitment of disadvantaged groups requires additional non-digital approaches.
PMCID: PMC4324965  PMID: 25671310
2.  Nifedipine versus atosiban in the treatment of threatened preterm labour (Assessment of Perinatal Outcome after Specific Tocolysis in Early Labour: APOSTEL III-Trial) 
Preterm birth is the most common cause of neonatal morbidity and mortality. Postponing delivery for 48 hours with tocolytics to allow for maternal steroid administration and antenatal transportation to a centre with neonatal intensive care unit facilities is the standard treatment for women with threatening preterm delivery in most centres. However, there is controversy as to which tocolytic agent is the drug of first choice. Previous trials have focused on tocolytic efficacy and side effects, and are probably underpowered to detect clinically meaningfull differences in neonatal outcome. Thus, the current evidence is inconclusive to support a balanced recommendation for clinical practice. This multicenter randomised clinical trial aims to compare nifedipine and atosiban in terms of neonatal outcome, duration of pregnancy and maternal side effects.
The Apostel III trial is a nationwide multicenter randomised controlled study. Women with threatened preterm labour (gestational age 25 – 34 weeks) defined as at least 3 contractions per 30 minutes, and 1) a cervical length of ≤ 10 mm or 2) a cervical length of 11-30 mm and a positive Fibronectin test or 3) ruptured membranes will be randomly allocated to treatment with nifedipine or atosiban. Primary outcome is a composite measure of severe neonatal morbidity and mortality. Secondary outcomes will be time to delivery, gestational age at delivery, days on ventilation support, neonatal intensive care (NICU) admittance, length admission in neonatal intensive care, total days in hospital until 3 months corrected age, convulsions, apnoea, asphyxia, proven meningitis, pneumothorax, maternal side effects and costs. Furthermore, an economic evaluation of the treatment will be performed. Analysis will be by intention to treat principle. The power calculation is based on an expected 10% difference in the prevalence of adverse neonatal outcome. This implies that 500 women have to be randomised (two sided test, β 0.2 at alpha 0.05).
This trial will provide evidence on the optimal drug of choice in acute tocolysis in threatening preterm labour.
Trial registration
Clinical trial registration: NTR2947, date of registration: June 20th 2011.
PMCID: PMC3944539  PMID: 24589124
Preterm birth; Tocolytics; Nifedipine; Atosiban; Outcome; Drug safety
3.  Cardiovascular risk estimation in women with a history of hypertensive pregnancy disorders at term: a longitudinal follow-up study 
Cardiovascular disease is associated with major morbidity and mortality in women in the Western world. Prediction of an individual cardiovascular disease risk in young women is difficult. It is known that women with hypertensive pregnancy complications have an increased risk for developing cardiovascular disease in later life and pregnancy might be used as a cardiovascular stress test to identify women who are at high risk for cardiovascular disease. In this study we assess the possibility of long term cardiovascular risk prediction in women with a history of hypertensive pregnancy disorders at term.
In a longitudinal follow-up study, between June 2008 and November 2010, 300 women with a history of hypertensive pregnancy disorders at term (HTP cohort) and 94 women with a history of normotensive pregnancies at term (NTP cohort) were included. From the cardiovascular risk status that was known two years after index pregnancy we calculated individual (extrapolated) 10-and 30-year cardiovascular event risks using four different risk prediction models including the Framingham risk score, the SCORE score and the Reynolds risk score. Continuous data were analyzed using the Student’s T test and Mann–Whitney U test and categorical data by the Chi-squared test. A poisson regression analysis was performed to calculate the incidence risk ratios and corresponding 95% confidence intervals for the different cardiovascular risk estimation categories.
After a mean follow-up of 2.5 years, HTP women had significantly higher mean (SD) extrapolated 10-year cardiovascular event risks (HTP 7.2% (3.7); NTP 4.4% (1.9) (p<.001, IRR 5.8, 95% CI 1.9 to 19)) and 30-year cardiovascular event risks (HTP 11% (7.6); NTP 7.3% (3.5) (p<.001, IRR 2.7, 95% CI 1.6 to 4.5)) as compared to NTP women calculated by the Framingham risk scores. The SCORE score and the Reynolds risk score showed similar significant results.
Women with a history of gestational hypertension or preeclampsia at term have higher predicted (extrapolated) 10-year and 30-year cardiovascular event risks as compared to women with a history of uncomplicated pregnancies. Further large prospective studies have to evaluate whether hypertensive pregnancy disorders have to be included as an independent variable in cardiovascular risk prediction models for women.
PMCID: PMC3680191  PMID: 23734952
Cardiovascular risk; Cardiovascular risk prediction; Follow-up study; Gestational hypertension; Preeclampsia
4.  The influence of pregnancy termination on the outcome of subsequent pregnancies: a retrospective cohort study 
BMJ Open  2013;3(5):e002803.
To compare the incidences of preterm delivery, cervical incompetence treated by cerclage, placental implantation or retention problems (ie, placenta praevia, placental abruption and retained placenta) and postpartum haemorrhage between women with and without a history of pregnancy termination.
 A retrospective cohort study using aggregated data from a national perinatal registry.
All midwifery practices and hospitals in the Netherlands.
All pregnant women with a singleton pregnancy without congenital malformations and a gestational age of ≥20 weeks who delivered between January 2000 and December 2007.
Main outcome measures
Preterm delivery, cervical incompetence treated by cerclage, placenta praevia, placental abruption, retained placenta and postpartum haemorrhage.
A previous pregnancy termination was reported in 16 000 (1.2%) deliveries. The vast majority of these (90–95%) were performed by surgical methods. The incidence of all outcome measures was significantly higher in women with a history of pregnancy termination. Adjusted ORs (95% CI) for cervical incompetence treated by cerclage, preterm delivery, placental implantation or retention problems and postpartum haemorrhage were 4.6 (2.9 to 7.2), 1.11 (1.02 to 1.20), 1.42 (1.29 to 1.55) and 1.16 (1.08 to 1.25), respectively. Associated numbers needed to harm were 1000, 167, 111 and 111, respectively. For any listed adverse outcome, the number needed to harm was 63.
In this large nationwide cohort study, we found a positive association between surgical termination of pregnancy and subsequent preterm delivery, cervical incompetence treated by cerclage, placental implantation or retention problems and postpartum haemorrhage in a subsequent pregnancy. Absolute risks for these outcomes, however, remain small. Medicinal termination might be considered first whenever there is a choice between both methods.
PMCID: PMC3669713  PMID: 23793655
termination of pregnancy; preterm delivery; cervical incompetence; placenta praevia; placental abruption; retained placenta
5.  Maternal Characteristics, Mean Arterial Pressure and Serum Markers in Early Prediction of Preeclampsia 
PLoS ONE  2013;8(5):e63546.
In a previous study, we have described the predictive value of first-trimester Pregnancy-Associated Plasma Protein-A (PAPP-A), free β-subunit of human Chorionic Gonadotropin (fβ-hCG), Placental Growth Factor (PlGF) and A Disintegrin And Metalloprotease 12 (ADAM12) for early onset preeclampsia (EO-PE; delivery <34 weeks). The objective of the current study was to obtain the predictive value of these serum makers combined with maternal characteristics and first-trimester maternal mean arterial blood pressure (MAP) in a large series of patients, for both EO-PE and late onset PE (LO-PE; delivery ≥ 34 weeks).
This was a nested case-control study, using stored first-trimester maternal serum from women who developed EO-PE (n = 68) or LO-PE (n = 99), and 500 uncomplicated singleton pregnancies. Maternal characteristics, MAP, and pregnancy outcome were collected for each individual woman and used to calculate prior risks for PE in a multiple logistic regression model. Models containing prior PE risks, serum markers, and MAP were developed for the prediction of EO-PE and LO-PE. The model-predicted detection rates (DR) for fixed 10% false-positive rates were calculated for EO-PE and LO-PE with or without the presence of a small-for-gestational age infant (SGA, birth weight <10th centile).
The best prediction model included maternal characteristics, MAP, PAPP-A, ADAM12, and PlGF, with DR of 72% for EO-PE and 49% for LO-PE. Prediction for PE with concomitant SGA was better than for PE alone (92% for EO-PE and 57% for LO-PE).
First-trimester MAP, PAPP-A, ADAM12, and PlGF combined with maternal characteristics and MAP are promising markers in the risk assessment of PE, especially for EO-PE complicated by SGA.
PMCID: PMC3661579  PMID: 23717445
6.  Effectiveness of continuous glucose monitoring during diabetic pregnancy (GlucoMOMS trial); a randomised controlled trial 
Hyperglycemia in pregnancy is associated with poor perinatal outcome. Even if pregnant women with diabetes are monitored according to current guidelines, they do much worse than their normoglycaemic counterparts, marked by increased risks of pre-eclampsia, macrosomia, and caesarean section amongst others. Continuous Glucose Monitoring (CGM) is a new method providing detailed information on daily fluctuations, used to optimize glucose control. Whether this tool improves pregnancy outcome remains unclear. In the present protocol, we aim to assess the effect of CGM use in diabetic pregnancies on pregnancy outcome.
The GlucoMOMS trial is a multicenter open label randomized clinical trial with a decision and cost-effectiveness study alongside. Pregnant women aged 18 and over with either diabetes mellitus type 1 or 2 on insulin therapy or with gestational diabetes requiring insulin therapy before 30 weeks of gestation will be asked to participate. Consenting women will be randomly allocated to either usual care or complementary CGM. All women will determine their glycaemic control by self-monitoring of blood glucose levels and HbA1c. In addition, women allocated to CGM will use it for 5–7 days every six weeks. Based on their CGM profiles they receive dietary advice and insulin therapy adjustments if necessary. The primary outcome measure is rate of macrosomia, defined as a birth weight above the 90th centile. Secondary outcome measures will be birth weight, composite neonatal morbidity, maternal outcome and costs. The analyses will be according to the intention to treat principle.
With this trial we aim at clarifying whether the CGM improves pregnancy outcome when used during diabetic pregnancies.
Trial registration
Nederlands Trial Register: NTR2996
PMCID: PMC3582540  PMID: 23270328
Diabetes; Pregnancy; Continuous glucose monitor; Macrosomia; Effectiveness
7.  Study protocol: Cost effectiveness of two strategies to implement the NVOG guidelines on hypertension in pregnancy: An innovative strategy including a computerised decision support system compared to a common strategy of professional audit and feedback, a randomized controlled trial 
Hypertensive disease in pregnancy remains the leading cause of maternal mortality in the Netherlands. Seventeen percent of the clinical pregnancies are complicated by hypertension and 2% by preeclampsia. The Dutch Society of Obstetrics and Gynaecology (NVOG) has developed evidence-based guidelines on the management of hypertension in pregnancy and chronic hypertension. Previous studies showed a low adherence rate to other NVOG guidelines and a large variation in usual care in the different hospitals. An explanation is that the NVOG has no general strategy of practical implementation and evaluation of its guidelines. The development of an effective and cost effective implementation strategy to improve adherence to the guidelines on hypertension in pregnancy is needed.
The objective of this study is to assess the cost effectiveness of an innovative implementation strategy of the NVOG guidelines on hypertension including a computerised decision support system (BOS) compared to a common strategy of professional audit and feedback. A cluster randomised controlled trial with an economic evaluation alongside will be performed. Both pregnant women who develop severe hypertension or pre-eclampsia and professionals involved in the care for these women will participate. The main outcome measures are a combined rate of major maternal complications and process indicators extracted from the guidelines. A total of 472 patients will be included in both groups. For analysis, descriptive as well as regression techniques will be used. A cost effectiveness and cost utility analysis will be performed according to the intention-to-treat principle and from a societal perspective. Cost effectiveness ratios will be calculated using bootstrapping techniques.
PMCID: PMC2940931  PMID: 20819222
8.  10-Year cardiovascular event risks for women who experienced hypertensive disorders in late pregnancy: the HyRAS study 
Cardiovascular disease is the cause of death in 32% of women in the Netherlands. Prediction of an individual's risk for cardiovascular disease is difficult, in particular in younger women due to low sensitive and specific tests for these women. 10% to 15% of all pregnancies are complicated by hypertensive disorders, the vast majority of which develop only after 36 weeks of gestation. Preeclampsia and cardiovascular disease in later life show both features of "the metabolic syndrome" and atherosclerosis. Hypertensive disorders in pregnancy and cardiovascular disease may develop by common pathophysiologic pathways initiated by similar vascular risk factors. Vascular damage occurring during preeclampsia or gestational hypertension may contribute to the development of future cardiovascular disease, or is already present before pregnancy. At present clinicians do not systematically aim at the possible cardiovascular consequences in later life after a hypertensive pregnancy disorder at term. However, screening for risk factors after preeclampsia or gestational hypertension at term may give insight into an individual's cardiovascular risk profile.
Women with a history of preeclampsia or gestational hypertension will be invited to participate in a cohort study 2 1/2 years after delivery. Participants will be screened for established modifiable cardiovascular risk indicators. The primary outcome is the 10-year cardiovascular event risk. Secondary outcomes include differences in cardiovascular parameters, SNP's in glucose metabolism, and neonatal outcome.
This study will provide evidence on the potential health gains of a modifiable cardiovascular risk factor screening program for women whose pregnancy was complicated by hypertension or preeclampsia. The calculation of individual 10-year cardiovascular event risks will allow identification of those women who will benefit from primary prevention by tailored interventions, at a relatively young age.
Trial registration
The HYPITAT trial is registered in the clinical trial register as ISRCTN08132825.
PMCID: PMC2889848  PMID: 20515501
9.  Cardiovascular risk factor assessment after pre-eclampsia in primary care 
BMC Family Practice  2009;10:77.
Pre-eclampsia is associated with an increased risk of development of cardiovascular disease later in life. It is not known how general practitioners in the Netherlands care for these women after delivery with respect to cardiovascular risk factor management.
Review of medical records of 1196 women in four primary health care centres, who were registered from January 2000 until July 2007 with an International Classification of Primary Care (ICPC) code indicating pregnancy. Records were searched for indicators of pre-eclampsia. Of those who experienced pre-eclampsia and of a random sample of 150 women who did not, the following information on cardiovascular risk factor management after pregnancy was extracted from the records: frequency and timing of blood pressure, cholesterol and glucose measurements - and vascular diagnoses. Additionally the sensitivity and specificity of ICPC coding for pre-eclampsia were determined.
35 women experienced pre-eclampsia. Blood pressure was more often checked after pregnancy in these women than in controls (57.1% vs. 12.0%, p < 0.001). In 50% of the cases blood pressure was measured within 3 months after delivery with no further follow-up visit. A check for glucose and cholesterol levels was rare, and equally frequent in PE and control women. 20% of the previously normotensive women in the PE group had hypertension at one or more occasions after three months post partum versus none in the control group. The ICPC coding for pre-eclampsia showed a sensitivity of 51.4% and a specificity of 100.0%.
Despite the evidence of increased risk of future cardiovascular disease in women with a history of pre-eclampsia, follow-up of these women is insufficient and undeveloped in primary care in the Netherlands.
PMCID: PMC2796641  PMID: 19995418
10.  Accuracy of mean arterial pressure and blood pressure measurements in predicting pre-eclampsia: systematic review and meta-analysis 
BMJ : British Medical Journal  2008;336(7653):1117-1120.
Objective To determine the accuracy of using systolic and diastolic blood pressure, mean arterial pressure, and increase of blood pressure to predict pre-eclampsia.
Design Systematic review with meta-analysis of data on test accuracy.
Data sources Medline, Embase, Cochrane Library, Medion, checking reference lists of included articles and reviews, contact with authors.
Review methods Without language restrictions, two reviewers independently selected the articles in which the accuracy of blood pressure measurement during pregnancy was evaluated to predict pre-eclampsia. Data were extracted on study characteristics, quality, and results to construct 2×2 tables. Summary receiver operating characteristic curves and likelihood ratios were generated for the various levels and their thresholds.
Results 34 studies, testing 60 599 women (3341 cases of pre-eclampsia), were included. In women at low risk for pre-eclampsia, the areas under the summary receiver operating characteristic curves for blood pressure measurement in the second trimester were 0.68 (95% confidence interval 0.64 to 0.72) for systolic blood pressure, 0.66 (0.59 to 0.72) for diastolic blood pressure, and 0.76 (0.70 to 0.82) for mean arterial pressure. Findings for the first trimester showed a similar pattern. Second trimester mean arterial pressure of 90 mm Hg or more showed a positive likelihood ratio of 3.5 (95% confidence interval 2.0 to 5.0) and a negative likelihood ratio of 0.46 (0.16 to 0.75). In women deemed to be at high risk, a diastolic blood pressure of 75 mm Hg or more at 13 to 20 weeks’ gestation best predicted pre-eclampsia: positive likelihood ratio 2.8 (1.8 to 3.6), negative likelihood ratio 0.39 (0.18 to 0.71). Additional subgroup analyses did not show improved predictive accuracy.
Conclusion When blood pressure is measured in the first or second trimester of pregnancy, the mean arterial pressure is a better predictor for pre-eclampsia than systolic blood pressure, diastolic blood pressure, or an increase of blood pressure.
PMCID: PMC2386627  PMID: 18480117
11.  Maternal TLR4 and NOD2 Gene Variants, Pro-Inflammatory Phenotype and Susceptibility to Early-Onset Preeclampsia and HELLP Syndrome 
PLoS ONE  2008;3(4):e1865.
Altered maternal inflammatory responses play a role in the development of preeclampsia and the hemolysis, elevated liver enzymes and low platelets (HELLP) syndrome. We examined whether allelic variants of the innate immune receptors Toll-like receptor 4 (TLR4) and nucleotide-binding oligomerization domain 2 (NOD2), that impair the inflammatory response to endotoxin, are related to preeclampsia and HELLP syndrome.
Methods and Findings
We determined five common mutations in TLR4 (D299G and T399I) and NOD2 (R702W, G908R and L1007fs) in 340 primiparous women with a history of early-onset preeclampsia, of whom 177 women developed HELLP syndrome and in 113 women with a history of only uneventful pregnancies as controls. In addition, we assessed plasma levels of pro-inflammatory biomarkers C-reactive protein, interleukin-6, soluble intercellular adhesion molecule-1, fibrinogen and von Willebrand factor in a subset of 214 women included at least six months after delivery. After adjustment for maternal age and chronic hypertension, attenuating allelic variants of TLR4 were more common in women with a history of early-onset preeclampsia than in controls (OR 2.9 [95% CI 1.2–6.7]). Highest frequencies for TLR4 variants were observed in women who developed HELLP syndrome (adjusted OR 4.1 [95% CI 1.7–9.8]). In addition, high levels of interleukin-6 and fibrinogen were associated with a history of early-onset preeclampsia. Combined positivity for any of the TLR4 and NOD2 allelic variants and high levels of interleukin-6 was 6.9-fold more common in women with a history of early-onset preeclampsia (95% CI 2.1–23.2) compared to controls.
We observed an association of common TLR4 and NOD2 gene variants, and pro-inflammatory phenotype with a history of early-onset preeclampsia and HELLP syndrome. These findings suggest involvement of the maternal innate immune system in severe hypertensive disorders of pregnancy.
PMCID: PMC2270909  PMID: 18382655
12.  Induction of labour versus expectant monitoring in women with pregnancy induced hypertension or mild preeclampsia at term: the HYPITAT trial 
Hypertensive disorders, i.e. pregnancy induced hypertension and preeclampsia, complicate 10 to15% 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.
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%.
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.
PMCID: PMC1950708  PMID: 17662114

Results 1-12 (12)