K Hecher

University Medical Center Hamburg - Eppendorf, Hamburg, Hamburg, Germany

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Publications (255)964.29 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Intrauterine growth restriction (IUGR) affects up to 10% of pregnancies in Western societies. IUGR is a strong predictor of reduced short-term neonatal survival and impairs long-term health in children. Placental insufficiency is often associated with IUGR; however, the molecular mechanisms involved in the pathogenesis of placental insufficiency and IUGR are largely unknown. Here, we developed a mouse model of fetal-growth restriction and placental insufficiency that is induced by a midgestational stress challenge. Compared with control animals, pregnant dams subjected to gestational stress exhibited reduced progesterone levels and placental heme oxygenase 1 (Hmox1) expression and increased methylation at distinct regions of the placental Hmox1 promoter. These stress-triggered changes were accompanied by an altered CD8+ T cell response, as evidenced by a reduction of tolerogenic CD8+CD122+ T cells and an increase of cytotoxic CD8+ T cells. Using progesterone receptor- or Hmox1-deficient mice, we identified progesterone as an upstream modulator of placental Hmox1 expression. Supplementation of progesterone or depletion of CD8+ T cells revealed that progesterone suppresses CD8+ T cell cytotoxicity, whereas the generation of CD8+CD122+ T cells is supported by Hmox1 and ameliorates fetal-growth restriction in Hmox1 deficiency. These observations in mice could promote the identification of pregnancies at risk for IUGR and the generation of clinical interventional strategies.
    Journal of Clinical Investigation 03/2015; 125(4). DOI:10.1172/JCI68140 · 13.77 Impact Factor
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    ABSTRACT: BACKGROUND: No consensus exists for the best way to monitor and when to trigger delivery in mothers of babies with fetal growth restriction. We aimed to assess whether changes in the fetal ductus venosus Doppler waveform (DV) could be used as indications for delivery instead of cardiotocography short-term variation (STV). METHODS: In this prospective, European multicentre, unblinded, randomised study, we included women with singleton fetuses at 26-32 weeks of gestation who had very preterm fetal growth restriction (ie, low abdominal circumference [<10th percentile] and a high umbilical artery Doppler pulsatility index [>95th percentile]). We randomly allocated women 1:1:1, with randomly sized blocks and stratified by participating centre and gestational age (<29 weeks vs ≥29 weeks), to three timing of delivery plans, which differed according to antenatal monitoring strategies: reduced cardiotocograph fetal heart rate STV (CTG STV), early DV changes (pulsatility index >95th percentile; DV p95), or late DV changes (A wave [the deflection within the venous waveform signifying atrial contraction] at or below baseline; DV no A). The primary outcome was survival without cerebral palsy or neurosensory impairment, or a Bayley III developmental score of less than 85, at 2 years of age. We assessed outcomes in surviving infants with known outcomes at 2 years. We did an intention to treat study for all participants for whom we had data. Safety outcomes were deaths in utero and neonatal deaths and were assessed in all randomly allocated women. This study is registered with ISRCTN, number 56204499. FINDINGS: Between Jan 1, 2005 and Oct 1, 2010, 503 of 542 eligible women were randomly allocated to monitoring groups (166 to CTG STV, 167 to DV p95, and 170 to DV no A). The median gestational age at delivery was 30·7 weeks (IQR 29·1-32·1) and mean birthweight was 1019 g (SD 322). The proportion of infants surviving without neuroimpairment did not differ between the CTG STV (111 [77%] of 144 infants with known outcome), DV p95 (119 [84%] of 142), and DV no A (133 [85%] of 157) groups (ptrend=0·09). 12 fetuses (2%) died in utero and 27 (6%) neonatal deaths occurred. Of survivors, more infants where women were randomly assigned to delivery according to late ductus changes (133 [95%] of 140, 95%, 95% CI 90-98) were free of neuroimpairment when compared with those randomly assigned to CTG (111 [85%] of 131, 95% CI 78-90; p=0.005), but this was accompanied by a non-significant increase in perinatal and infant mortality. INTERPRETATION: Although the difference in the proportion of infants surviving without neuroimpairment was non-significant at the primary endpoint, timing of delivery based on the study protocol using late changes in the DV waveform might produce an improvement in developmental outcomes at 2 years of age.
    The Lancet 03/2015; DOI:10.1016/S0140-6736(14)62049-3.[Epub · 45.22 Impact Factor
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    ABSTRACT: No consensus exists for the best way to monitor and when to trigger delivery in mothers of babies with fetal growth restriction. We aimed to assess whether changes in the fetal ductus venosus Doppler waveform (DV) could be used as indications for delivery instead of cardiotocography short-term variation (STV). In this prospective, European multicentre, unblinded, randomised study, we included women with singleton fetuses at 26-32 weeks of gestation who had very preterm fetal growth restriction (ie, low abdominal circumference [<10th percentile] and a high umbilical artery Doppler pulsatility index [>95th percentile]). We randomly allocated women 1:1:1, with randomly sized blocks and stratified by participating centre and gestational age (<29 weeks vs ≥29 weeks), to three timing of delivery plans, which differed according to antenatal monitoring strategies: reduced cardiotocograph fetal heart rate STV (CTG STV), early DV changes (pulsatility index >95th percentile; DV p95), or late DV changes (A wave [the deflection within the venous waveform signifying atrial contraction] at or below baseline; DV no A). The primary outcome was survival without cerebral palsy or neurosensory impairment, or a Bayley III developmental score of less than 85, at 2 years of age. We assessed outcomes in surviving infants with known outcomes at 2 years. We did an intention to treat study for all participants for whom we had data. Safety outcomes were deaths in utero and neonatal deaths and were assessed in all randomly allocated women. This study is registered with ISRCTN, number 56204499. Between Jan 1, 2005 and Oct 1, 2010, 503 of 542 eligible women were randomly allocated to monitoring groups (166 to CTG STV, 167 to DV p95, and 170 to DV no A). The median gestational age at delivery was 30·7 weeks (IQR 26·1-40·6) and mean birthweight was 1019 g (SD 322). The proportion of infants surviving without neuroimpairment did not differ between the CTG STV (111 [77%] of 144 infants with known outcome), DV p95 (119 [84%] of 142), and DV no A (133 [85%] of 157) groups (ptrend=0·09). 12 fetuses (2%) died in utero and 27 (6%) neonatal deaths occurred. Of survivors, more infants where women were randomly assigned to delivery according to late ductus changes (133 [95%] of 144, 95%, 95% CI 90-98) were free of neuroimpairment when compared with those randomly assigned to CTG (111 [85%] of 131, 95% CI 78-90; p=0.005), but this was accompanied by a non-significant increase in perinatal and infant mortality. Although the difference in the proportion of infants surviving without neuroimpairment was non-significant at the primary endpoint, timing of delivery based on the study protocol using late changes in the DV waveform might produce an improvement in developmental outcomes at 2 years of age. ZonMw, The Netherlands and Dr Hans Ludwig Geisenhofer Foundation, Germany. Copyright © 2015 Elsevier Ltd. All rights reserved.
    The Lancet 03/2015; DOI:10.1016/S0140-6736(14)62049-3 · 45.22 Impact Factor
  • Zeitschrift für Geburtshilfe und Neonatologie 02/2015; 219(1):12-9. DOI:10.1055/s-0034-1395575 · 0.46 Impact Factor
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    ABSTRACT: Population-based pregnancy cohorts recruiting women before or at the moment of childbirth allow a longitudinal follow-up on children's health later in life. Important findings arising from pregnancy cohorts are discussed in the present review. These insights have led to revised guidelines on how to minimize disease risks in children, e.g., in the context of chronic immune diseases including allergies and asthma. Moreover, insights from pregnancy cohorts also unveiled a collateral effect of pregnancy on maternal immunity, mirrored by an ameliorated course of certain autoimmune diseases, but also an increased risk of infection with influenza A virus. Future pregnancy cohort studies are still required to close gaps in knowledge on how parameters involved in the developmental origin of health or poor immunity observed in children later in life are operational. We discuss here features that should be covered by future pregnancy cohort studies. Expected insights from such studies will then lay the foundation for biomarker discovery and offer opportunities for interventions to ameliorate adverse immune responses in humans. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.
    Journal of Reproductive Immunology 01/2015; 108. DOI:10.1016/j.jri.2015.01.001 · 2.37 Impact Factor
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    ABSTRACT: The aim of this study was to develop an automatic differentiation of two perfusion compartments within the mouse placenta based on times of maximal contrast enhancement for a detailed and reproducible perfusion assessment. Placentas (n = 17) from pregnant BALB/c mice (n = 10) were examined in vivo at 7T on gestation day 16.5. Coronal dual-echo 3D T1-weighted gradient-echo sequences were acquired after application of contrast agent for dynamic MRI. An adapted gamma variate function was fitted to the discrete concentration time curves to evaluate the effect of noise on perfusion and segmentation results. Time-to-peak maps based on fitted and discrete curves of each placenta were used to classify each voxel into the high- or low-blood flow compartment using k-means clustering. Perfusion analysis was performed using the steepest slope model and also applied to fitted and discrete curves. Results were compared to manually defined compartments from two independent observers using the Dice coefficient D. Manually defined placental areas of high-flow and low-flow were similar to the automatic segmentation for discrete (D = 0.76/0.75; D = 0.76/0.79) and fitted (D = 0.80/0.80; D = 0.81/0.82) concentration time curves. Mean perfusion values of discrete and fitted curves ranged in the high-flow compartment from 134 to 142 ml/min/100 ml (discrete) vs. 138-143 ml/min/100 ml (fitted) and in the low-flow compartment from 91 to 94 ml/min/100 ml (discrete) vs. 74-82 ml/min/100 ml (fitted). Our novel approach allows the automatic differentiation of perfusion compartments of the mouse placenta. The approach may overcome limitations of placental perfusion analyses caused by tissue heterogeneity and a potentially biased selection of regions of interest. Copyright © 2014 Elsevier Ltd. All rights reserved.
    Placenta 12/2014; 36(3). DOI:10.1016/j.placenta.2014.12.010 · 3.29 Impact Factor
  • Biology of Reproduction 11/2014; 92(1). DOI:10.1095/biolreprod.114.126110 · 3.45 Impact Factor
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    ABSTRACT: Objective To investigate time intervals of the ductus venosus (DV) flow velocity waveform (FVW) and those of cardiac cycle which correspond with each DV-FVW component in fetuses complicated with intrauterine growth restriction (IUGR) due to placental insufficiency.Methods Time intervals for systolic (S) and diastolic (D) components were measured in DV-FVW as following: SDV, from the nadir of the a-wave during atrial contraction to the nadir between S-wave and D-wave; DDV, from the nadir between S-wave and D-wave to the nadir of a-wave. Regarding the cardiac cycles, the following variables were measured in ventricular inflow through tricuspid valve (TV) and mitral valve (MV): STV and SMV, from the second peak of ventricular inflow caused by atrial contraction (A-wave) to the opening of the atrio-ventricular valve; DTV and DMV, from the opening of the atrio-ventricular valve to the peak of A-wave. All variables were statistically analyzed using z-score.ResultsThe data were obtained from 249 normal fetuses and 26 IUGR fetuses. Compared to normal fetuses, SDV showed a significant decrease (P < 0.001), while DDV increased significantly (P < 0.001) in the IUGR group. Regarding the cardiac cycles, STV and SMV decreased significantly (P = 0.014 and P < 0.001, respectively), and DTV and DMV showed significant increases (P = 0.008 and P = 0.002, respectively) in IUGR fetuses.Conclusion Time interval alterations of DV-FVW in growth restricted fetuses reflect the hemodynamic events caused by placental insufficiency.
    Ultrasound in Obstetrics and Gynecology 11/2014; DOI:10.1002/uog.14717 · 3.14 Impact Factor
  • Geburtshilfe und Frauenheilkunde 09/2014; 74(S 01). DOI:10.1055/s-0034-1388224 · 0.96 Impact Factor
  • Geburtshilfe und Frauenheilkunde 09/2014; 74(S 01). DOI:10.1055/s-0034-1388140 · 0.96 Impact Factor
  • Geburtshilfe und Frauenheilkunde 09/2014; 74(S 01). DOI:10.1055/s-0034-1388167 · 0.96 Impact Factor
  • P C Arck, K Hecher
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    ABSTRACT: An increasing incidence of chronic immune diseases such as allergies, multiple sclerosis, and type 2 diabetes, as well as obesity and cardiovascular and psychiatric disorders has been reported over the last five decades. Since the human genome has not altered significantly over this period of time, gene-environment interactions are suspected to be responsible for these increased disease incidences. In this context, the prenatal period is believed to significantly contribute to altered disease susceptibilities, which could be associated with environmental factors to which pregnant women were exposed to. This observation has led to a concept entitled 'developmental origin of health and disease', a topic that is enjoying much attention in clinical and basic science research. The aim of these research endeavors is to postulate guidelines for primary disease prevention. Whilst the emerging insights from this field of research provide significant pieces of the puzzle, one area is still largely neglected: the clear identification of a sex-specific programming effect. Thus it is essential that such an approach becomes fully integrated in future research goals.
    Bundesgesundheitsblatt - Gesundheitsforschung - Gesundheitsschutz 08/2014; 57(9). DOI:10.1007/s00103-014-2015-3 · 1.01 Impact Factor
  • Ultraschall in der Medizin 07/2014; 35(6). DOI:10.1055/s-0034-1366518 · 4.65 Impact Factor
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    ABSTRACT: Background In twin-to-twin transfusion syndrome (TTTS), genetically identical twins are exposed to different haemodynamic conditions during fetal life, which are considered to be the cause of prenatal and postnatal cardiovascular differences between the donor and the recipient. Objective To assess intertwin differences on childhood cardiac outcome after intrauterine laser coagulation therapy (LC) of severe TTTS. Design and patients Prospective, detailed, echocardiographic follow-up of 31 twin pairs aged 9.95 +/- 0.8 years (mean +/- SD) with severe TTTS treated by LC, and the comparison with reference values. Results Cardiac function was normal and did not show intertwin differences in twins without structural heart disease. Discordant birth weight or birth weight <3rd centile for gestational age had no influence on blood pressure and cardiac indices. Pulmonary stenosis was more common (5/62; 8.1%) than in the general population (prevalence 0.066%, relative risk 134.4, 95% CI 42.1 to 428.8, p<0.0001) and affected both donor and recipient. Intertwin differences in late diastolic right ventricular filling (peak velocities: recipient 0.51 +/- 0.11 m/s vs donor 0.45 +/- 0.10 m/s, mean difference 0.74 m/s, 95% CI 0.23 to 1.24, p=0.009) and early septal relaxation (mean myocardial velocities: recipient -8.2 +/- 1.5 cm/s vs donor -8.9 +/- 1.2 cm/s, mean difference 0.7 cm/s, 95% CI 0.02 to 1.38, p=0.044) were found only when twins with right heart disease were included. Conclusions Despite severe prenatal cardiac involvement, childhood cardiac function is normal in the majority of surviving donors and recipients after successful LC of severe TTTS. This underlines the favourable impact of intrauterine LC on postnatal cardiovascular performance.
    Archives of Disease in Childhood - Fetal and Neonatal Edition 06/2014; 99(5). DOI:10.1136/archdischild-2013-305034 · 3.86 Impact Factor
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    ABSTRACT: Compare cardiac function at ten years in three groups of monochorionic twin pairs (MCDA): uncomplicated MCDA (n = 6), Twin-Twin Transfusion Syndrome (TTTS) managed by amnioreduction (TTTS-amnio, n = 9) or laser photocoagulation (TTTS-laser, n = 10).and dichorionic (DCDA, n = 6) controls. Echocardiograms optimising apical 4-chamber and short axis left ventricular views were stored for off-line speckle-tracking analysis, blinded to twin type. Myocardial long axis shortening (S') and lengthening (E' and A') velocities were measured using pulsed Doppler at the cardiac base. M-mode measurements of fractional shortening (short axis) and maximal displacement of the atrioventricular annulus (4-chamber) were recorded. Syngo Vector Velocity Imaging software tracked left ventricular myocardial motion off-line to produce free wall Strain, Strain Rate and Rotation. Inter-twin pair and group differences were investigated using ANOVA. Cardiac measurements lay within normal ranges for 10 year olds. No significant within twin-pair and inter-group differences were found in current size, heart rates, Strain or Strain Rate. Compared to DCDA controls, TTTS showed lower cardiac rotation (TTTS-laser, p < 0.001 and TTTS-amnio, p = 0.054) with significant inter-twin pair reduction in ex-Recipient, TTTS-amnio (p = 0.006) and larger MCDA twins (p = 0.027) compared to their co-twins. A similar pattern was seen in left ventricular early relaxation velocities (MVE') in all monochorionic groups only achieving significance in TTTS-amnio (p = 0.037). Intra-pair differences in rotation and MVE' were significantly different following treatment at Quintero stages 3 or 4. Within twin-pair patterns of left ventricular rotation and diastolic function differ at 10 years in ex-Recipients of TTTS-amnio compared with TTTS-laser and controls.
    Ultrasound in Obstetrics and Gynecology 06/2014; 43(6). DOI:10.1002/uog.13279 · 3.14 Impact Factor
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    ABSTRACT: Objectives To investigate time-related variables of ductus venosus (DV) flow velocity waveforms (FVW) in twin to twin transfusion syndrome (TTTS), comparing the results with reference ranges from normal singleton fetuses, and to evaluate the impact of laser surgery and prognostic factors.Methods In 107 TTTS cases DV-FVWs of both, recipients and donors, were recorded 1 day before and 2 days after laser therapy. Time intervals for systolic (S) and early diastolic (D) peaks were retrospectively analyzed regarding acceleration time (acc-S for S, acc-D for D) and deceleration time (dec-S for S, dec-D for D), respectively. For each variable, z-scores were calculated.ResultsCompared to reference ranges, all z-scores except dec-S of donors showed significant differences and the most striking differences were observed in longer dec-S of recipients (P < 0.001) and dec-D of donors (P < 0.001). Laser therapy showed significant impacts on dec-S and acc-D in recipients and on all variables in donors. Regarding the short term prognosis, acc-S and dec-S showed significant differences for the prediction of intrauterine fetal demise in donors (P = 0.009 and P = 0.011, respectively).Conclusions This study demonstrates that time-related variables of DV-FVWs may differentiate the characteristic hemodynamic changes caused by unbalanced blood volume between recipients and donors.
    Ultrasound in Obstetrics and Gynecology 06/2014; 45(5). DOI:10.1002/uog.13449 · 3.14 Impact Factor
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    ABSTRACT: In 2006 WHO presented the infant and child growth charts suggested for universal application. However, major determinants for perinatal outcomes and postnatal growth are laid down during antenatal development. Accordingly, monitoring fetal growth in utero by ultrasonography is important both for clinical and scientific reasons. The currently used fetal growth references are derived mainly from North American and European population and may be inappropriate for international use, given possible variances in the growth rates of fetuses from different ethnic population groups. WHO has, therefore, made it a high priority to establish charts of optimal fetal growth that can be recommended worldwide.
    BMC Pregnancy and Childbirth 05/2014; 14(1):157. DOI:10.1186/1471-2393-14-157 · 2.15 Impact Factor
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    ABSTRACT: Background and study design: Prenatal growth restriction and low birth weight have been linked to long-term alterations of health, presumably via adaptive modifications of the epigenome. Recent studies indicate a plasticity of the 11p15 epigenotype in response to environmental changes during early stages of human development. We analyzed methylation levels at different 11p15 loci in 20 growth-discordant monozygotic twin pairs. Intrauterine development was discordant due to severe twin-to-twin transfusion syndrome (TTTS), which was treated by fetoscopic laser coagulation of communicating vessels before 25 weeks of gestation. Methylation levels at age 4 were determined in blood and buccal cell-derived DNA by the single nucleotide primer extension reaction ion pair reverse-phase high performance liquid chromatography (SNuPE IP RP HPLC) assay. Methylation at LINE-1 repeats was analyzed as an estimate of global methylation.In general, variance of locus-specific methylation levels appeared to be higher in buccal cell- as compared to blood cell-derived DNA samples. Paired analyses within the twin pairs revealed significant differences at only one CpG site (IGF2 dmr0 SN3 (blood), +1.9% in donors; P = 0.013). When plotting the twin pair-discordance in birth weight against the degree of discordance in site-specific methylation at age 4, only a few CpGs were found to interact (one CpG site each at IGF2dmr0 in blood/saliva DNA, one CpG at LINE-1 repeats in saliva DNA), with 26 to 36% of the intra-twin pair divergence at these sites explained by prenatal growth discordance. However, across the entire cohort of 40 children, site-specific methylation did not correlate with SD-scores for weight or length at birth. Insulin-like growth factor-II serum concentrations showed significant within-twin pair correlations at birth (R = 0.57) and at age 4 (R = 0.79), but did not differ between donors and recipients. They also did not correlate with the analyzed 11p15 methylation parameters. In a cohort of 20 growth-discordant monozygotic twin pairs, severe alteration in placental blood supply due to TTTS appears to leave only weak, if any, epigenetic marks at the analyzed CpG sites at 11p15.
    Clinical Epigenetics 03/2014; 6(1):6. DOI:10.1186/1868-7083-6-6 · 6.22 Impact Factor
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    ABSTRACT: The pathogenesis of intestinal dysmotility in gastroschisis is not completely understood. Peel formation and disorganization of interstitial Cajal cells (ICC) have been proposed in humans. The aim of this study was to evaluate the impact of prenatal coverage of gastroschisis on gut inflammation and expression of ICC in a fetal lamb model. Twenty-one German blackhead sheep with an abdominal wall defect that was created fetoscopically on day 77 of 145 days gestation were used in this study. Intrauterine surgery with the aim to cover the defect was performed 3 weeks later; two fetuses were covered completely, 5 partially and 11 remained uncovered. Three fetuses without gastroschisis were used as controls. All fetuses were retrieved by cesarean section at day 135. Samples of the small intestine were stained with hematoxylin and eosin for histologic analysis of peel formation and serosal and muscular thickness. For ICC detection, immunohistochemistry using anti-CD117 (c-Kit) antibody was used. In all samples with exposure to amniotic fluid, peel formation and significantly decreased ICC were found. Complete coverage reduced peel formation and disorganization of ICC compared to uncovered animals almost to the level of controls. Peel formation and ICC derangement were significantly reduced by prenatal coverage of gastroschisis. Moreover, this animal model mimics the histopathological bowel changes as seen in human gastroschisis and may, therefore, be used for further research on the pathophysiology and fetal therapy of this malformation.
    Surgical Endoscopy 03/2014; 28(8). DOI:10.1007/s00464-014-3494-x · 3.31 Impact Factor
  • Zeitschrift für Geburtshilfe und Neonatologie 12/2013; 217(06):225-226. DOI:10.1055/s-0033-1363903 · 0.46 Impact Factor

Publication Stats

5k Citations
964.29 Total Impact Points

Institutions

  • 2003–2014
    • University Medical Center Hamburg - Eppendorf
      • Department of Obstetrics and Fetal Medicine
      Hamburg, Hamburg, Germany
    • Imperial College London
      Londinium, England, United Kingdom
  • 2000–2011
    • Universität Hamburg
      • Department of Obstetrics and Fetal Medicine
      Hamburg, Hamburg, Germany
    • St. Mary's Hospital (WI, USA)
      Madison, Wisconsin, United States
    • Allgemeines Krankenhaus Hagen
      Hagen, North Rhine-Westphalia, Germany
  • 2007–2010
    • Universitair Ziekenhuis Leuven
      • Department of Gynaecology and obstetrics
      Louvain, Flanders, Belgium
  • 2008
    • William Beaumont Army Medical Center
      El Paso, Texas, United States
    • University of Bonn
      Bonn, North Rhine-Westphalia, Germany
  • 2003–2008
    • University of Bonn - Medical Center
      Bonn, North Rhine-Westphalia, Germany
  • 2005
    • University of Maryland, Baltimore
      Baltimore, Maryland, United States
    • University of Münster
      • Department of Obstetrics and Gynaecology
      Münster, North Rhine-Westphalia, Germany
  • 1999
    • Academisch Medisch Centrum Universiteit van Amsterdam
      • Department of Obstetrics & Gynecology
      Amsterdamo, North Holland, Netherlands
  • 1994–1995
    • King's College London
      • Division of Asthma, Allergy and Lung Biology
      Londinium, England, United Kingdom
    • The Fetal Medicine Foundation
      Londinium, England, United Kingdom
    • King's College Hospital NHS Foundation Trust
      • Department of Obstetrics and Gynaecology
      Londinium, England, United Kingdom
  • 1992–1994
    • The Peninsula College of Medicine and Dentistry
      Plymouth, England, United Kingdom