Publications by authors named "Katharina Weizsäcker"

19 Publications

  • Page 1 of 1

Maternal Serum VEGF Predicts Abnormally Invasive Placenta Better than NT-proBNP: a Multicenter Case-Control Study.

Reprod Sci 2021 02 6;28(2):361-370. Epub 2020 Oct 6.

Department of Obstetrics, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Augustenburger Platz 1, 13353, Berlin, Germany.

The aim of this study was to test if maternal serum vascular endothelial growth factor (VEGF) or N-terminal pro B-type natriuretic peptide (NT-proBNP) predicts abnormally invasive placenta (AIP) better. Secondary objective was to test whether the serum levels of VEGF and NT-proBNP can predict the degree of invasion. In a multicenter case-control study design, gestational age-matched serum samples from pregnant women with AIP (n = 44) and uncomplicated pregnancies (n = 55) who had been enrolled at Charité - Universitätsmedizin Berlin, Germany and Centre Hospitalier Régional de la Citadelle in Liège, Belgium were analyzed. Maternal blood serum VEGF and NT-proBNP levels were immunoassayed from samples taken immediately before delivery (GA median: 35 weeks). Biomarker levels were compared between AIP and control group. The correlation of biomarker levels with the clinical AIP degree was assessed. The predictive biomarker ability was characterized through a multivariate regression model and receiver operating characteristic curves. Women with AIP had significantly lower maternal serum VEGF levels (AIP mean 285 pg/ml, 95% CI 248-322, vs. control: 391 pg/ml, 95% CI 356-426, p < 0.01) and higher NT-proBNP levels (AIP median 329 pg/ml, IQR 287-385, vs. control 295 pg/ml, IQR 273-356, p = 0.03). Maternal serum VEGF levels were able to predict AIP better (AUC = 0.729, 0.622-0.836, p < 0.001; VEGF + number of previous cesarean deliveries: AUC = 0.915, 0.853-0.977, p < 0.001). Maternal serum VEGF levels correlated inversely with the clinical AIP degree (r = - 0.32, p < 0.01). In short, maternal serum VEGF, more than NT-proBNP, can help in predicting AIP and hints at the degree of invasion.
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http://dx.doi.org/10.1007/s43032-020-00319-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7808970PMC
February 2021

The Effect of Pregnancy on the Pharmacokinetics of Total and Unbound Dolutegravir and Its Main Metabolite in Women Living With Human Immunodeficiency Virus.

Clin Infect Dis 2021 01;72(1):121-127

Radboud Institute for Health Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.

Background: Pharmacokinetic and efficacy data on dolutegravir in pregnant women living with human immunodeficiency virus (HIV) are still limited but needed to support its use as one of the preferred antiretroviral agents.

Methods: Within the multicenter Pharmacokinetics of ANtiretroviral agents in HIV-infected pregNAnt women (PANNA) study, pregnant women living with HIV and using dolutegravir once daily (50 mg, with food) underwent 24-hour pharmacokinetic profiling in their third trimester and postpartum. Dolutegravir exposure in the third trimester was considered adequate if geometric mean unbound, pharmacologically active, minimal plasma concentrations (Cmin, unbound) and ≥90% of individual Cmin, unbound levels were >0.85 µg/L, the proposed 90% inhibitory concentration for unbound dolutegravir. Geometric mean ratios (GMRs) with 90% confidence intervals (CIs) for comparison of total and unbound pharmacokinetic parameters in the third trimester and postpartum were calculated, including the metabolic ratio for dolutegravir-glucuronide. Safety and virological data were collected.

Results: Seventeen women (76% black) were enrolled (25 evaluable pharmacokinetic profiles; 15 in the third trimester, 10 in postpartum). In the third trimester, geometric mean (coefficient of variation, %) Cmin, unbound was 2.87 (87) µg/L and 93% of individual Cmin, unbound levels were >0.85 µg/L. The GMR (90% CI) in the third trimester vs postpartum was 0.86 (.68-1.10) for area under the curve (AUC0-24h), and for Cmax, 0.93 (.77-1.13). GMR (90% CI) for the trough concentrations was 0.71 (.49-1.02), based on total dolutegravir concentrations. Four serious adverse events were reported, unlikely related to dolutegravir. The HIV polymerase chain reaction test was negative in 14/17 infants (result unknown for 3 infants).

Conclusions: Pharmacokinetic changes for dolutegravir in late pregnancy are not clinically relevant and support the use of dolutegravir 50 mg once daily with food in pregnancy.

Clinical Trials Registration: NCT00825929.
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http://dx.doi.org/10.1093/cid/ciaa006DOI Listing
January 2021

Safety of tenofovir during pregnancy: early growth outcomes and hematologic side effects in HIV-exposed uninfected infants.

Eur J Pediatr 2020 Jan 29;179(1):99-109. Epub 2019 Oct 29.

Department of Pediatric Pneumology, Immunology and Intensive Care, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.

Intrauterine exposure to zidovudine-based combination antiretroviral therapy (cART) can cause severe anemia within the first weeks of life. Tenofovir disoproxil fumarate (TDF)-based regimens may have less hematologic side effects but may affect growth parameters. This study aimed to assess the safety of TDF for prevention of mother-to-child transmission (PMTCT) in HIV-exposed uninfected infants regarding early growth outcomes and hematologic side effects. Our retrospective observational cohort study included children born (n = 232) to HIV-infected mothers (n = 228) on cART. Blood counts were compared at birth, 4-6 weeks, and 3, 12 and 18 months of age. Growth parameters were measured at birth and 12 and 18 months of age. Data were analyzed according to treatment group (TDF and non-TDF cART regimes). The median hemoglobin (Hgb) was significantly lower in the non-TDF-based group at birth (15.4 g/dl vs. 16.9 g/dl; **p = 0.002) and at 4-6 weeks of age (9.9 g/dl vs. 10.4 g/dl; **p = 0.004). The mean corpuscular volume was higher in the non-TDF-based group (109 fl vs. 105 fl; ***p < 0.001) as well at 4-6 weeks (102 fl vs. 95 fl; ***p < 0.001). In the TDF-based group, a higher proportion of neutropenia (grade 2 and higher) compared to the non-TDF-group (21.4% vs. 11%; *p = 0.015) was observed at three months of age. This effect was transient. There was no difference in growth.Conclusions: TDF appears to have no major side effects in our cohort. Transient anemia was observed more commonly with non-TDF regimens. However, our research suggests a potential delayed effect of TDF on neutrophils at 3 months of age.What is Known:• TDF is suspected to affect the growth of HIV-exposed uninfected infants.• Non-TDF-based cART regimes for prevention of mother-to-child transmission of HIV often result in transient anemia in the infant.What is New:• TDF appears to have no major side effects regarding the growth of HIV-exposed uninfected infants.• Our research suggests a potential delayed effect of TDF on neutrophils at 3 months of age in these infants.
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http://dx.doi.org/10.1007/s00431-019-03481-xDOI Listing
January 2020

Evidence-based guidelines for the management of abnormally invasive placenta: recommendations from the International Society for Abnormally Invasive Placenta.

Am J Obstet Gynecol 2019 06 5;220(6):511-526. Epub 2019 Mar 5.

Departments of Obstetrics and Division of Experimental Obstetrics, Charité Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Campus Virchow-Klinikum and Campus Charité Mitte, Berlin, Germany.

The worldwide incidence of abnormally invasive placenta is rapidly rising, following the trend of increasing cesarean delivery. It is a heterogeneous condition and has a high maternal morbidity and mortality rate, presenting specific intrapartum challenges. Its rarity makes developing individual expertise difficult for the majority of clinicians. The International Society for Abnormally Invasive Placenta aims to improve clinicians' understanding and skills in managing this difficult condition. By pooling knowledge, experience, and expertise gained within a variety of different healthcare systems, the Society seeks to improve the outcomes for women with abnormally invasive placenta globally. The recommendations presented herewith were reached using a modified Delphi technique and are based on the best available evidence. The evidence base for each is presented using a formal grading system. The topics chosen address the most pertinent questions regarding intrapartum management of abnormally invasive placenta with respect to clinically relevant outcomes, including the following: definition of a center of excellence; requirement for antenatal hospitalization; antenatal optimization of hemoglobin; gestational age for delivery; antenatal corticosteroid administration; use of preoperative cystoscopy, ureteric stents, and prophylactic pelvic arterial balloon catheters; maternal position for surgery; type of skin incision; position of the uterine incision; use of interoperative ultrasound; prophylactic administration of oxytocin; optimal method for intraoperative diagnosis; use of expectant management; adjuvant therapies for expectant management; use of local surgical resection; type of hysterectomy; use of delayed hysterectomy; intraoperative measures to treat life-threatening hemorrhage; and fertility after conservative management.
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http://dx.doi.org/10.1016/j.ajog.2019.02.054DOI Listing
June 2019

Application of chitosan-covered gauze in combination with intrauterine balloon tamponade for postpartum hemorrhage treatment - Case report of a novel "uterine sandwich" approach.

Int J Surg Case Rep 2018 26;48:101-103. Epub 2018 May 26.

Department of Obstetrics, Charité - Universitätsmedizin Berlin, Humboldt-Universität zu Berlin, Berlin, Germany.

Introduction: Postpartum or peripartum hemorrhage (PPH) is a major cause of maternal death worldwide. Fertility preserving second stage interventions following uterotonic medications may include compression sutures, uterine balloon tamponade and ligation or embolization of arteries.

Presentation Of Case: We present a case of PPH where a novel "uterine sandwich" approach (combination of chitosan-covered gauze with intrauterine balloon tamponade) was effectively used to stop further blood loss and prevented more invasive second stage interventions. Furthermore, we present the ultrasonographic image of chitosan-covered gauze in the uterine cavity.

Discussion: Chitosan-covered gauze and intrauterine balloon tamponade are complementary in their mechanism of work, the balloon reducing blood flow into the uterus and the chitosan-covered gauze enhancing the coagulation.

Conclusion: This novel "uterine sandwich" approach can be a useful method for fertility preserving management of PPH.
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http://dx.doi.org/10.1016/j.ijscr.2018.05.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6041203PMC
May 2018

Abnormally invasive placenta (AIP): pre-cesarean amnion drainage to facilitate exteriorization of the gravid uterus through a transverse skin incision.

J Perinat Med 2018 Dec;47(1):12-15

Department of Obstetrics and 'Experimental Obstetrics', Charité University Berlin, Campus Virchow, Berlin, Germany.

The number of pregnant women with abnormally invasive placenta (AIP) including clinical relevant placenta increta and percreta has markedly increased with a reported incidence of as high as one in 731, By 2020 in the United States, there will be an estimated 4504 new cases of AIP and 130 AIP-associated maternal deaths annually. The preoperative diagnosis and operative management of AIP is challenging. In a planned cesarean delivery, a vertical lower abdominal skin incision is widely used in order to have enough space to perform a hysterotomy above the cranial edge of the placenta to avoid significant fetal and/or maternal hemorrhage. We have used preoperative drainage of the amniotic fluid after epidural anesthesia and immediately before a planned cesarean delivery through a transverse skin incision in five patients with AIP of the anterior uterine wall. With less uterine volume, exteriorization of the gravid uterus is easily performed through a transverse laparotomy. The combination of amnion drainage, transverse laparotomy and exteriorization of the gravid uterus facilitates identification of the exact site of placental implantation, provides adequate space for performing fundal or high anterior or even posterior uterine wall incisions and to deliver the fetus safely while minimizing the risk of placental separation and subsequent uncontrolled blood loss. Furthermore, this technique provides the chance to leave the untouched placenta in situ or to remove the placenta in toto with a uterine wall segment.
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http://dx.doi.org/10.1515/jpm-2017-0388DOI Listing
December 2018

Functional Implications of LH/hCG Receptors in Pregnancy-Induced Cushing Syndrome.

J Endocr Soc 2017 Jan 12;1(1):57-71. Epub 2017 Jan 12.

Department of Physiology, Institute of Biomedicine, 20520 Turku, Finland.

Context: Elevated human choriogonadotropin (hCG) may stimulate aberrantly expressed luteinizing hormone (LH)/hCG receptor (LHCGR) in adrenal glands, resulting in pregnancy-induced bilateral macronodular adrenal hyperplasia and transient Cushing syndrome (CS).

Objective: To determine the role of LHCGR in transient, pregnancy-induced CS.

Design Setting Patient And Intervention: We investigated the functional implications of LHCGRs in a patient presenting, at a tertiary referral center, with repeated pregnancy-induced CS with bilateral adrenal hyperplasia, resolving after parturition.

Main Outcome Measures And Results: Acute testing for aberrant hormone receptors was negative except for arginine vasopressin (AVP)-increased cortisol secretion. Long-term hCG stimulation induced hypercortisolism, which was unsuppressed by dexamethasone. Postadrenalectomy histopathology demonstrated steroidogenically active adrenocortical hyperplasia and ectopic cortical cell clusters in the medulla. Quantitative polymerase chain reaction showed upregulated expression of , transcription factors , , and proopiomelanocortin (), AVP receptors (AVPRs) and , and downregulated melanocortin 2 receptor () control adrenals. LHCGR was localized in subcapsular, zona glomerulosa, and hyperplastic cells. Single adrenocorticotropic hormone-positive medullary cells were demonstrated in the zona reticularis. The role of adrenal adrenocorticotropic hormone was considered negligible due to downregulated . Coexpression of CYP11B1/CYP11B2 and AVPR1A/AVPR2 was observed in ectopic cortical cells in the medulla. hCG stimulation of the patient's adrenal cell cultures significantly increased cyclic adenosine monophosphate, corticosterone, 11-deoxycortisol, cortisol, and androstenedione production. , , , and gene mutational analyses were negative.

Conclusion: Nongenetic, transient, somatic mutation-independent, pregnancy-induced CS was due to hCG-stimulated transformation of LHCGR-positive undifferentiated subcapsular cells (presumably adrenocortical progenitors) into LHCGR-positive hyperplastic cortical cells. These cells respond to hCG stimulation with cortisol secretion. Without the ligand, they persist with aberrant LHCGR expression and the ability to respond to the same stimulus.
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http://dx.doi.org/10.1210/js.2016-1021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5677213PMC
January 2017

Intrauterine therapy of cytomegalovirus infection with valganciclovir: review of the literature.

Med Microbiol Immunol 2017 Oct 21;206(5):347-354. Epub 2017 Jul 21.

Department of Obstetrics, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin Institute of Health, Berlin, Germany.

Congenital cytomegalovirus (CMV) infection is the leading cause for sensorineural hearing loss and mental retardation in children without genetic diseases worldwide. There is little evidence guiding therapeutic strategies during pregnancy when intrauterine fetal CMV infection is confirmed. We provide a systematic review of the use of ganciclovir (GCV) or VGCV during pregnancy discussing safety of its use for mother and fetus and describe two cases of intrauterine therapy of fetal CMV infection with valganciclovir (VGCV). A PubMed database search was done up to November 16, 2016 without any restrictions of publication date or journal, using the following keywords: "valganciclovir" or "ganciclovir" and "pregnan*". Furthermore, citations were searched and expert references were obtained. Reported cases were considered if therapy was in humans and initiation of treatment of the CMV infection was during pregnancy. In total, seven case reports were retrieved which described GCV or VGCV use during pregnancy for fetal or maternal CMV infection. In the four cases of treatment for maternal CMV infection, no negative effects on the fetus were reported. Three cases of GCV administration to pregnant woman with the intention of fetal treatment after proven fetal infection were found. We additionally present two cases of VGCV treatment in pregnancy from our center of tertiary care. VGCV seems to be a safe treatment for congenital CMV infection for the mother and the fetus. Therapeutic concentrations can be achieved in the fetus by oral intake of the mother and CMV replication can be suppressed. Larger studies are needed to evaluate this therapeutic intervention and the long-term effects.
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http://dx.doi.org/10.1007/s00430-017-0512-3DOI Listing
October 2017

Prevalence of human papillomavirus infection of the anal canal in women: A prospective analysis of high-risk populations.

Oncol Lett 2017 Apr 10;13(4):2495-2501. Epub 2017 Feb 10.

Department of Gynecology and Obstetrics, Ludwig-Maximilian University of Munich, D-80337 Munich, Germany.

Infection with certain types of human papillomavirus (HPV) has been associated with the development of cervical and anal cancer. Worldwide, the incidence of anal cancer has increased markedly. The present study aimed to evaluate the prevalence of HPV infection of the uterine cervix and anal canal in human immunodeficiency virus (HIV)- and non-HIV-infected risk populations. Cervical and anal HPV swabs and cytology samples were collected from 287 patients at the University Hospital of Munich, Germany between 2011 and 2013. Patients were divided into HIV-negative controls (G1) and two risk groups, including HIV-negative patients with cytological abnormalities of the cervix (G2) and HIV-infected patients (G3). Data, including clinical parameters, were analysed. The risk groups had significantly more positive results for HPV in the anus (71.03 and 83.15% for G2 and G3, respectively), as compared with G1. The predominant HPV genotypes found in the anus were high-risk HPV genotypes, which were significantly correlated with concomittant cervical HPV findings. In the risk groups, a significant association between the cytological findings and HPV detection in the cervix was found, while the results of the anus revealed no significance. The results of the present study suggested that the prevalence of HPV infection in the anal canal of risk populations is high. Furthermore, patients with abnormal cervical cytology results and HIV-infected women, irrespective of their individual cervical findings, may have a risk of concomittant anal high-risk HPV infection. Based on the predominant HPV genotypes found in the study, HPV vaccination could reduce the incidence of anal cancer. Nevertheless, high-risk patients should be intensively screened for anal squamous intraepithelial abnormalities to avoid invasive cancer stages.
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http://dx.doi.org/10.3892/ol.2017.5714DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5403543PMC
April 2017

Substantially lowered dolutegravir exposure in a treatment-experienced perinatally HIV-1-infected pregnant woman.

AIDS 2016 07;30(12):1999-2001

aDepartment of Pharmacy bDepartment of Pharmacology and Toxicology, Radboud University Medical Center, Nijmegen, The Netherlands cDepartment of Pediatric Pneumology and Immunology dDepartment of Obstetrics eDepartment of Neonatology, Charité Universitätsmedizin, Berlin, Germany.

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http://dx.doi.org/10.1097/QAD.0000000000001123DOI Listing
July 2016

High seroprevalence of antibodies against Kaposi's sarcoma-associated herpesvirus (KSHV) among HIV-1-infected children and adolescents in a non-endemic population.

Med Microbiol Immunol 2016 Oct 30;205(5):425-34. Epub 2016 May 30.

Institute of Medical Virology, Helmut-Ruska-Haus, Charité University Medicine Berlin, Berlin, Germany.

Human herpesvirus-8 (HHV-8) is the etiological agent of Kaposi's sarcoma (KS), which primarily affects human immunodeficiency virus (HIV)-infected adults with advanced immunodeficiency. Currently, only limited prevalence data for HHV-8 infection in HIV-infected children living in non-endemic areas are available. This multicenter cross-sectional study was conducted in four university hospitals in Germany specializing in pediatric HIV care. Stored serum specimens obtained from 207 vertically HIV-1-infected children and adolescents were tested for antibodies against lytic and latent HHV-8 antigens. Logistic regression was used to assess independent risk factors associated with HHV-8 seropositivity. The overall HHV-8 seroprevalence was 24.6 % (n = 51/207) without significant differences related to sex, age, or ethnicity. In univariate analysis, HHV-8 seropositivity was significantly associated with a child having being born outside Germany, maternal origin from sub-Saharan Africa, a history of breastfeeding, CDC immunologic category 3, and deferred initiation of antiretroviral therapy (>24 months of age). In multivariate analysis, a child's birth outside Germany was the only significant risk factor for HHV-8 seropositivity (odds ratio 3.98; 95 % confidence interval 1.27-12.42). HHV-8-associated malignancies were uncommon; only one patient had a history of KS. Serum specimen of vertically HIV-infected children and adolescents living in Germany showed a high HHV-8 seroprevalence. These findings suggest that primary HHV-8 infection-a risk factor for KS and other HHV-8-associated malignancies-occurs early in life. Thus, management of perinatally HIV-infected children should include testing for HHV-8 coinfection and should consider future risks of HHV-8-associated malignancies.
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http://dx.doi.org/10.1007/s00430-016-0458-xDOI Listing
October 2016

The pharmacokinetics of abacavir 600 mg once daily in HIV-1-positive pregnant women.

AIDS 2016 05;30(8):1239-44

aDepartment of Pharmacy, Radboud Institute of Health Sciences bDepartment of Pharmacology and Toxicology, Radboud Institute of Molecular Life Sciences, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands cInfectious Diseases Department, Saint-Pierre University Hospital, Université Libre de Bruxelles, Brussels, Belgium dDepartment of Obstetrics; Charité Universitätsmedizin, Berlin, Germany eHIV Unit, Hospital Universitari Germans Trias i Pujol, Badalona fHospital Universitario Virgen de las Nieves Granada, Granada, Spain gChelsea & Westminster Hospital hImperial College Healthcare NHS Trust iNorth Middlesex Hospital London, London, UK jErasmus Medical Center, Rotterdam, The Netherlands.

Objective: To describe the pharmacokinetics of abacavir 600 mg once daily (q.d.) in HIV-1-positive women during pregnancy and postpartum.

Design: A nonrandomized, open-label, multicentre, phase-IV study.

Methods: HIV-positive pregnant women receiving abacavir 600 mg q.d. as part of clinical care were included. Intensive 24-h pharmacokinetic sampling was performed during the third trimester and at least 2 weeks after delivery. Pharmacokinetic parameters were calculated by noncompartmental analysis. Paired cord blood and maternal blood samples were taken at delivery when feasible.

Results: A total of 14 women were included in the analysis. Geometric mean ratios (90% confidence intervals) of third trimester versus postpartum were 1.05 (0.92-1.19) for AUC0-24h and 1.00 (0.83-1.21) for Cmax. The median (range) ratio of abacavir cord plasma to maternal plasma was 1.0 (0.7-1.0, n = 3). Viral load at the third trimester visit was less than 50 copies/ml in 13 participants (93%; one unknown). In total, 13 (93%; one unknown) children were tested HIV-negative.

Conclusion: The pharmacokinetics of abacavir 600 mg q.d. during pregnancy are equivalent to postpartum. No dose adjustments are required during pregnancy and similar antiviral activity is expected.
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http://dx.doi.org/10.1097/QAD.0000000000001046DOI Listing
May 2016

Neuraxial anesthesia for pain control after cesarean section: a prospective randomized trial comparing three different neuraxial techniques in clinical practice.

Minerva Anestesiol 2016 05 24;82(5):514-24. Epub 2015 Jul 24.

Department of Anesthesiology and Intensive Care Medicine, Charité, University Medicine, Berlin, Germany -

Background: Cesarean section (CS) is associated with a moderate-high intensity of postoperative pain. We investigate whether continuous local anesthetic/opioid administration using patient controlled epidural anesthesia (PCEA) is superior in controlling pain after CS than epidural (ED) or intrathecal (IT) opioid bolus administration.

Methods: One hundred ninety-nine women undergoing elective CS were randomized into 3 groups: PCEA: Combined spinal-epidural anesthesia (CSE) with a PCEA of ropivacaine 0.1% + sufentanil 0.5 μg/mL for 24 hours after CS. ED: CSE with an ED bolus of 3 mg morphine after CS. IT: spinal anesthesia with an IT bolus of 0.1 mg morphine before CS. Primary objectives were pain (VAS/Visual Analogue Scale 0-100) at 9 h, VAS at 1, 2, 6, 24 and 48 hours, side effects and additional analgesic requirements as secondary endpoints.

Results: VAS (rest/mobilization) 10(0-23)/40(20-56) at 9 hours for IT was lower (P=0.11/P=0.003) than VAS 20(0-30)/50(30-60) for ED and 20(0-40)/50(30-70) for PCEA (P=0.005/P=0.01). VAS 10(0-29)/40(20-60) at 6 hours for IT was significantly lower than VAS 20(4-40)/50(30-70) for ED (P=0.02/P=0.02). During mobilization at 24/48 hours VAS 40(20-58)/30(20-40) between IT and PCEA with VAS 50(40-70)/40(20-63) differed significantly (P=0.04/P=0.001). With exception of pruritus, which was less in the PCEA group at 9 hours, side effects were similar in all groups. Ibuprofen consumption in the first 24 hours was significantly lower for IT and PCEA compared to ED.

Conclusions: PCEA is less effective then IT and ED opioid bolus administration for post cesarean pain relief. IT provides better analgesia than ED or PCEA, as pointed out by lower ibuprofen consumption.
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May 2016

Raltegravir in HIV-1-Infected Pregnant Women: Pharmacokinetics, Safety, and Efficacy.

Clin Infect Dis 2015 Sep 5;61(5):809-16. Epub 2015 May 5.

Radboud University Medical Center, Nijmegen, The Netherlands.

Background: The use of raltegravir in human immunodeficiency virus (HIV)-infected pregnant women is important in the prevention of mother-to-child HIV transmission, especially in circumstances when a rapid decline of HIV RNA load is warranted or when preferred antiretroviral agents cannot be used. Physiological changes during pregnancy can reduce antiretroviral drug exposure. We studied the effect of pregnancy on the pharmacokinetics of raltegravir and its safety and efficacy in HIV-infected pregnant women.

Methods: An open-label, multicenter, phase 4 study in HIV-infected pregnant women receiving raltegravir 400 mg twice daily was performed (Pharmacokinetics of Newly Developed Antiretroviral Agents in HIV-Infected Pregnant Women Network). Steady-state pharmacokinetic profiles were obtained in the third trimester and postpartum along with cord and maternal delivery concentrations. Safety and virologic efficacy were evaluated.

Results: Twenty-two patients were included, of which 68% started raltegravir during pregnancy. Approaching delivery, 86% of the patients had an undetectable viral load (<50 copies/mL). None of the children were HIV-infected. Exposure to raltegravir was highly variable. Overall area under the plasma concentration-time curve (AUC) and plasma concentration at 12 hours after intake (C12h) plasma concentrations in the third trimester were on average 29% and 36% lower, respectively, compared with postpartum: Geometric mean ratios (90% confidence interval) were 0.71 (.53-.96) for AUC0-12h and 0.64 (.34-1.22) for C12h. The median ratio of raltegravir cord to maternal blood was 1.21 (interquartile range, 1.02-2.17; n = 9).

Conclusions: Raltegravir was well tolerated during pregnancy. The pharmacokinetics of raltegravir showed extensive variability. The observed mean decrease in exposure to raltegravir during third trimester compared to postpartum is not considered to be of clinical importance. Raltegravir can be used in standard dosages in HIV-infected pregnant women.

Clinical Trials Registration: NCT00825929.
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http://dx.doi.org/10.1093/cid/civ366DOI Listing
September 2015

Analysis of endoplasmic reticulum stress in placentas of HIV-infected women treated with protease inhibitors.

Reprod Toxicol 2014 Dec 25;50:122-8. Epub 2014 Oct 25.

Department of Obstetrics and Gynecology, Ludwig-Maximilians-University, Munich, Germany.

Combined antiretroviral therapy has proven efficacy in decreasing vertical HIV transmission. However, endoplasmic reticulum stress is a known side effect of HIV protease inhibitors. We investigated endoplasmic reticulum stress in placentas of HIV-infected and uninfected mothers by PCR-based splicing analysis of the specific endoplasmic reticulum stress marker XBP1 in post-delivery placental samples of uninfected mothers and in HIV-infected mothers taking antiretroviral therapy. No elevated XBP1 splicing could be detected in placentas of uninfected mothers and most of the mothers receiving combined anti-retroviral therapy. However, markedly elevated XBP1 splicing was found in the placentas of three individuals on combined antiviral therapy, all receiving lopinavir or atazanavir. In vitro experiments confirmed induction of endoplasmic reticulum stress by lopinavir and atazanavir in trophoblast-derived cell lines. Since endoplasmic reticulum stress occurred in selective patients only, individual differences in susceptibility of HIV-infected mothers to protease inhibitor induced endoplasmic reticulum stress can be postulated.
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http://dx.doi.org/10.1016/j.reprotox.2014.10.012DOI Listing
December 2014

Pharmacokinetics of total and unbound darunavir in HIV-1-infected pregnant women.

J Antimicrob Chemother 2015 Feb 17;70(2):534-42. Epub 2014 Oct 17.

Radboud University Medical Center, Nijmegen, The Netherlands.

Objectives: To describe the pharmacokinetics of darunavir in pregnant HIV-infected women in the third trimester and post-partum.

Patients And Methods: This was a non-randomized, open-label, multicentre, Phase IV study in HIV-infected pregnant women recruited from HIV treatment centres in Europe. HIV-infected pregnant women treated with darunavir (800/100 mg once daily or 600/100 mg twice daily) as part of their combination ART were included. Pharmacokinetic curves were recorded in the third trimester and post-partum. A cord blood sample and maternal sample were collected. The study is registered at ClinicalTrials.gov under number NCT00825929.

Results: Twenty-four women were included in the analysis [darunavir/ritonavir: 600/100 mg twice daily (n=6); 800/100 mg once daily (n=17); and 600/100 mg once daily (n=1)]. Geometric mean ratios of third trimester versus post-partum (90% CI) were 0.78 (0.60-1.00) for total darunavir AUC0-tau after 600/100 mg twice-daily dosing and 0.67 (0.56-0.82) for total darunavir AUC0-tau after 800/100 mg once-daily dosing. The unbound fraction of darunavir was not different during pregnancy (12%) compared with post-partum (10%). The median (range) ratio of darunavir cord blood/maternal blood was 0.13 (0.08-0.35). Viral load close to delivery was <300 copies/mL in all but two patients. All children were tested HIV-negative and no congenital abnormalities were reported.

Conclusions: Darunavir AUC and Cmax were substantially decreased in pregnancy for both darunavir/ritonavir regimens. This decrease in exposure did not result in mother-to-child transmission. For antiretroviral-naive patients, who are adherent, take darunavir with food and are not using concomitant medication reducing darunavir concentrations, 800/100 mg of darunavir/ritonavir once daily is adequate in pregnancy. For all other patients 600/100 mg of darunavir/ritonavir twice daily is recommended during pregnancy.
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http://dx.doi.org/10.1093/jac/dku400DOI Listing
February 2015

Atazanavir exposure is effective during pregnancy regardless of tenofovir use.

Antivir Ther 2015 3;20(1):57-64. Epub 2014 Jul 3.

Radboud University Medical Center, Nijmegen, the Netherlands.

Background: We studied the effect of pregnancy on atazanavir pharmacokinetics in the presence and absence of tenofovir.

Methods: This was a non-randomized, open-label, multicentre Phase IV study in HIV-infected pregnant women recruited from European HIV treatment centres. HIV-infected pregnant women treated with boosted atazanavir (300/100 mg or 400/100 mg atazanavir/ritonavir) as part of their combination antiretroviral therapy (cART) were included in the study. 24 h pharmacokinetic curves were recorded in the third trimester and postpartum. Collection of a cord blood and maternal sample at delivery was optional.

Results: 31 patients were included in the analysis, 21/31 patients used tenofovir as part of cART. Median (range) gestational age at delivery was 39 weeks (36-42). Approaching delivery 81% (25 patients) had an HIV viral load <50 copies/ml, all <1,000 copies/ml. Least squares means ratios (90% CI) of atazanavir pharmacokinetic parameters third trimester/postpartum were: 0.66 (0.57, 0.75) for AUC0-24h, 0.70 (0.61, 0.80) for Cmax and 0.59 (0.48, 0.72) for C24h. No statistical difference in pharmacokinetic parameters was found between patients using tenofovir versus no tenofovir. None of the patients showed atazanavir concentrations <0.15 mg/l (target for treatment-naive patients). One baby had a congenital abnormality, which was not likely to be related to atazanavir/ritonavir use. None of the children were HIV-infected.

Conclusions: Despite 34% lower atazanavir exposure during pregnancy, atazanavir/ritonavir 300/100 mg once daily generates effective concentrations for protease inhibitor (PI)-naive patients, even if co-administered with tenofovir. For treatment-experienced patients (with relevant PI resistance mutations) therapeutic drug monitoring of atazanavir should be considered to adapt the atazanavir/ritonavir dose on an individual basis.
 ClinicalTrials.gov number NCT00825929.
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http://dx.doi.org/10.3851/IMP2820DOI Listing
November 2015

The pharmacokinetics, safety and efficacy of tenofovir and emtricitabine in HIV-1-infected pregnant women.

AIDS 2013 Mar;27(5):739-48

Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.

Objective: To describe the pharmacokinetics of tenofovir and emtricitabine in the third trimester of pregnant HIV-infected women and at postpartum.

Design: A nonrandomized, open-label, multicentre phase IV study in HIV-infected pregnant women recruited from HIV treatment centres in Europe.

Methods: HIV-infected pregnant women treated with the nucleotide/nucleoside analogue reverse transcriptase inhibitors (NRTIs) tenofovir disoproxil fumarate (TDF 300 mg; equivalent to 245 mg tenofovir disoproxil) and/or emtricitabine (FTC 200 mg) were included in the study. Twenty-four-hour pharmacokinetic curves were recorded in the third trimester (preferably week 33) and postpartum (preferably week 4-6). Collection of a cord blood sample and maternal sample at delivery was optional. Pharmacokinetic parameters were calculated using WinNonlin software version 5.3. Statistical analysis was conducted using SPSS version 16.0.

Results: Thirty-four women were included in the analysis. Geometric mean ratios of third trimester vs. postpartum [90% confidence interval (CI)] were 0.77 (0.71-0.83) for TDF area under the curve (AUC0-24 h); 0.81 (0.68-0.96) for TDF Cmax and 0.79 (0.70-0.90) for TDF C24 h and 0.75 (0.68-0.82) for FTC AUC0-24 h; and 0.87 (0.77-0.99) for FTC Cmax and 0.77 (0.52-1.12) for FTC C24 h. The viral load close to delivery was less than 200  copies/ml in all but one patient, the average gestational age at delivery was 38 weeks. All children were tested HIV-negative and no congenital abnormalities were reported.

Conclusion: Although pharmacokinetic exposure of the NRTIs TDF and FTC during pregnancy is approximately 25% lower, this was not associated with virological failure in this study and did not result in mother-to-child transmission.
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http://dx.doi.org/10.1097/QAD.0b013e32835c208bDOI Listing
March 2013

[Emergency caesarean section and interdisciplinary emergency concepts for the delivery room - "What to do if it is urgent?"].

Anasthesiol Intensivmed Notfallmed Schmerzther 2012 Jan 27;47(1):14-21. Epub 2012 Jan 27.

Charité - Universitätsmedizin Berlin.

Resolute and rapid action in obstetric emergencies is essential for the child and/or maternal survival. Therefore emergency caesarean section and the emergency actions for peripartal haemorrhage, shoulder dystocia, fetal bradycardia, hypertension and embolism should be interdisciplinarily coordinated. Interdisciplinary emergency concepts for the major complications could help to optimise their therapy taking structural conditions and legal requirements into account. Emergency concepts should include the alarm- procedure, communication, logistics, the priority steps in therapy as well as the analysis of the passed obstetric emergency. A regular interdisciplinary training of the major obstetric emergencies may help to avoid unnecessary loss of time.
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http://dx.doi.org/10.1055/s-0032-1301375DOI Listing
January 2012