Browsing by Author "Gebhardt, Stefan"

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    Characterization of the genetic variation present in CYP3A4 in three South African populations
    (Frontiers, 2013-02) Drogemoller, Britt; Plummer, Marieth; Korkie, Lundi; Agenbag, Gloudi; Dunaiski, Anke; Niehaus, Dana; Koen, Liezl; Gebhardt, Stefan; Schneider, Nicol; Olckers, Antonel; Wright, Galen; Warnich, Louise
    The CYP3A4 enzyme is the most abundant human cytochrome P450 (CYP) and is regarded as the most important enzyme involved in drug metabolism. Inter-individual and inter-population variability in gene expression and enzyme activity are thought to be influenced, in part, by genetic variation. Although Southern African individuals have been shown to exhibit the highest levels of genetic diversity, they have been under-represented in pharmacogenetic research to date. Therefore, the aim of this study was to identify genetic variation within CYP3A4 in three South African population groups comprising of 29 Khoisan, 65 Xhosa and 65 Mixed Ancestry (MA) individuals. To identify known and novel CYP3A4 variants,15 individuals were randomly selected from each of the population groups for bi-directional Sanger sequencing of∼600 bp of the 5'-upstream region and all thirteen exons including flanking intronic regions. Genetic variants detected were genotyped in the rest of the cohort. In total, 24 SNPs were detected, including CYP3A4∗12, CYP3A4∗15, and the reportedly functional CYP3A4∗1B promoter polymorphism, as well as two novel non-synonymous variants. These putatively functional variants, p.R162W and p.Q200H, were present in two of the three populations and all three populations, respectively, and in silico analysis predicted that the former would damage the protein product. Furthermore, the three populations were shown to exhibit distinct genetic profiles. These results confirm that South African populations show unique patterns of variation in the genes encoding xenobiotic metabolizing enzymes. This research suggests that population-specific genetic profiles for CYP3A4 and other drug metabolizing genes would be essential to make full use of pharmacogenetics in Southern Africa. Further investigation is needed to determine if the identified genetic variants influence CYP3A4 metabolism phenotype in these populations.
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    Elective delivery at term after a previous unexplained intra-uterine fetal death : audit of delivery outcome at Tygerberg Hospital, South Africa
    (Public Library of Science, 2015) Gebhardt, Stefan; Oberholzer, Leana
    Objectives: To assess the delivery outcome in a pregnancy with a previous unexplained intra-uterine death by elective induction of labour at term. Methods: An audit of the pregnancy outcome of all women within the catchment area with a current singleton pregnancy; and a previous unexplained or unexplored singleton fetal demise ≥24 weeks (or 500 grams birth weight if gestation unknown) after planned routine induction of labour at full term (39-40 weeks). Results: During the audit period, 306 patients with a previous intra-uterine fetal death were referred for further management. Of these, 161 had a clear indication for earlier intervention and were excluded from the protocol. Of the remaining 145 patients, 9 met further exclusion criteria and there were 2 patients who defaulted. Forty-two of the remaining study patients (with no known previous medical problems) developed complications during their antenatal course that necessitated a change in clinical management and earlier (<39 weeks) delivery. Of the remaining 92 patients in the audit, 47 (51%) went into spontaneous labour before their induction date; all 92 women delivered without major complications. There were no intra-uterine deaths prior to induction. Conclusions: Careful follow up at a high risk clinic identifies new or concealed maternal or fetal complications in 29% of patients with a previous intra-uterine death and no obvious maternal or fetal disease in the index pregnancy. When all risks are excluded and the pregnancy allowed to progress to full term (39-40 weeks) before an induction is offered, 50% will go into spontaneous labour.
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    Introducing a mobile-connected umbilical doppler device (UmbiFlow™) into a primary care maternity setting : does this reduce unnecessary referrals to specialised care? results of a pilot study in Kraaifontein, South Africa
    (Public Library of Science, 2015-11) Mufenda, Josef; Gebhardt, Stefan; Van Rooyen, Rita; Theron, Gerhard
    Objectives: UmbiFlow™ is a mobile-connected Doppler device that utilises a continuous waveform to measure resistance in the umbilical artery. The main aim of this pilot study was to determine whether the use of UmbiFlow™ for umbilical artery Doppler in patients with a suspected decreased symphysis fundal (SF) growth could safely lead to a decreased number of patients requiring referral to a more specialised level of care. A secondary aim of the study was to evaluate the effectiveness of UmbiFlow™ Doppler as a screening tool for concealed placental insufficiency in late bookers by using a single screening cut-off value that will be abnormal for any gestation >28 weeks. Methods: The cohort comprised two groups of patients: The first group included all follow-up patients with suspected intra-uterine growth restriction (a decreased symphysis-fundus measurement based on serial assessment) who underwent on-site UmbiFlow™Doppler testing performed by the midwife directly after the clinical examination. The second group included late bookers, where gestation was uncertain; but estimated >28 weeks based on clinical grounds. This group was comprised of unselected patients who report to antenatal care late for the first time and received an UmbiFlow™Doppler test for concealed placental insufficiency. Results: UmbiFlow™Doppler could reduce the number of false referrals to hospital by 55%. A single UmbiFlow™Doppler test in late bookers appeared to identify a group of women at moderate risk of lower birth weight babies.
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    Major obstetric haemorrhage in Metro East, Cape Town, South Africa : a population-based cohort study using the maternal near-miss approach
    (BMC (part of Springer Nature), 2020-01-06) Heitkamp, Anke; Aronson, Simcha Lot; Van Den Akker, Thomas; Vollmer, Linda; Gebhardt, Stefan; Van Roosmalen, Jos; De Vries, Johanna I.; Theron, Gerhard
    Background: Major obstetric haemorrhage is a leading cause of maternal mortality and accounts for one-third of maternal deaths in of Africa. This study aimed to assess the population-based incidence, causes, management and outcomes of major obstetric haemorrhage and risk factors associated with poor maternal outcome. Methods: Women with major obstetric haemorrhage who met the WHO maternal near-miss criteria or died in the Metro East region, Cape Town, South Africa, were evaluated from November 2014–November 2015. Major obstetric haemorrhage was defined as haemorrhage in pregnancies of at least 20 weeks’ gestation or occurring up to 42 days after birth, and leading to hysterectomy, hypovolaemic shock or blood transfusion of ≥5 units of Packed Red Blood Cells. A logistic regression model was used to analyse associations with poor outcome, defined as major obstetric haemorrhage leading to massive transfusion of ≥8 units of packed red blood cells, hysterectomy or death. Results: The incidence of major obstetric haemorrhage was 3/1000 births, and the incidence of massive transfusion was 4/10.000 births in the Metro East region (32.862 births occurred during the studied time period). Leading causes of haemorrhage were placental abruption 45/119 (37.8%), complications of caesarean section 29/119 (24.4%) and uterine atony 13/119 (10.9%). Therapeutic oxytocin was administered in 98/119 (82.4%) women and hysterectomy performed in 33/119 (27.7%). The median numbers of packed red blood cells and units of Fresh Frozen Plasma transfused were 6 (interquartile range 4–7) and 3 (interquartile range 2–4), ratio 1.7:1. Caesarean section was independently associated with poor maternal outcome: adjusted OR 4.01 [95% CI 1.58, 10.14]. Conclusions: Assessment of major obstetric haemorrhage using the Maternal Near Miss approach revealed that placental abruption and complications of caesarean section were the major causes of major obstetric haemorrhage. Caesarean section was associated with poor outcome.
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    Standardized outcome measures for pregnancy and childbirth, an ICHOM proposal
    (BMC (part of Springer Nature), 2018-12-11) Nijagal, Malini A.; Wissig, Stephanie; Stowell, Caleb; Olson, Elizabeth; Amer-Wahlin, Isis; Bonsel, Gouke; Brooks, Allyson; Coleman, Matthew; Karalasingam, Shamala Devi; Duffy, James M. N.; Flanagan, Tracy; Gebhardt, Stefan; Greene, Meridith E.; Groenendaal, Floris; Jeganathan, J. Ravichandran R.; Kowaliw, Tessa; Lamain-de-Ruiter, Marije; Main, Elliott; Owens, Michelle; Petersen, Rod; Reiss, Irwin; Sakala, Carol; Speciale, Anna Maria; Thompson, Rachel; Okunade, Oluwakemi; Franx, Arie
    Background: Value-based health care aims to optimize the balance of patient outcomes and health care costs. To improve value in perinatal care using this strategy, standard outcomes must first be defined. The objective of this work was to define a minimum, internationally appropriate set of outcome measures for evaluating and improving perinatal care with a focus on outcomes that matter to women and their families. Methods: An interdisciplinary and international Working Group was assembled. Existing literature and current measurement initiatives were reviewed. Serial guided discussions and validation surveys provided consumer input. A series of nine teleconferences, incorporating a modified Delphi process, were held to reach consensus on the proposed Standard Set. Results: The Working Group selected 24 outcome measures to evaluate care during pregnancy and up to 6 months postpartum. These include clinical outcomes such as maternal and neonatal mortality and morbidity, stillbirth, preterm birth, birth injury and patient-reported outcome measures (PROMs) that assess health-related quality of life (HRQoL), mental health, mother-infant bonding, confidence and success with breastfeeding, incontinence, and satisfaction with care and birth experience. To support analysis of these outcome measures, pertinent baseline characteristics and risk factor metrics were also defined. Conclusions: We propose a set of outcome measures for evaluating the care that women and infants receive during pregnancy and the postpartum period. While validation and refinement via pilot implementation projects are needed, we view this as an important initial step towards value-based improvements in care.