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Background: The assessment of fetal blood flow using Doppler waveform can be used to identify placental insufficiency, and hence is a tool to identify fetuses at risk of stillbirth due to fetal growth restriction (FGR). In South Africa the largest category of perinatal deaths is ‘unexplained intrauterine death’. The majority of the mothers are clinically healthy women. This study was performed to determine the prevalence of abnormal umbilical resistance indices (abnormal RI) to see if screening a low-risk pregnant population is worthwhile. Methods: A descriptive study across 9 sites in 8 provinces of South Africa was performed to determine the prevalence of abnormal RI of the umbilical artery in women classified as having a low-risk pregnancy. The study was conducted from 1st September 2017- February 2020.The pregnant women classified were screened using a continuous wave Doppler ultrasound apparatus (Umbiflow™) between 28 and 34 weeks’ gestation. Women with fetuses with an abnormal RI were referred to a high-risk clinic and were managed according to standard protocol. The outcomes of all the deliveries were recorded. Findings: Umbiflow™ screening of the umbilical artery was performed in 7088 women across nine sites; 919 (13·0%) fetuses had an abnormal RI. Absent end diastolic flow (AEDF) was found in 87 (1·2%) fetuses. The prevalence of small for gestational ages (SGA) babies was 23·1% in the normal RI group and was significantly higher in the abnormal RI group 32·1% (p<0·0001). There was a statistical difference in the perinatal mortality rate between the normal RI (9.8/1000) and abnormal RI group (21.4/1000) [RR 0·046; 95% CI -0·06–0·98]. Interpretation: The prevalence of abnormal RI and AEDF in this screened low-risk population was about ten times higher than that previously recorded in high income countries. Continuous wave Doppler ultrasound screening detected previously undiagnosed growth restricted babies. The prevalence of AEDF warrants continuous wave Doppler ultrasound screening of the low-risk pregnant population in South Africa. Funding: This study was funded by the South African Medical Research Council (SAMRC) and the Council for Scientific and Industrial Research (CSIR)
A descriptive study investigated the prevalence of abnormal RI and AEDF of the umbilical artery detected by screening in women classified as having low-risk pregnancies attending primary health antenatal care at their local clinics. The population of low-risk women, were defined as pregnant woman attending non-specialist antenatal care clinics and classified as “low-risk” according to local clinical guidelines at the time of recruitment [12], based on their obstetric and clinical assessment, as guided by the SA basic antenatal care plus program following the WHO recommendations for a positive pregnancy experience [12,22]. The risk classification is updated and revised after each antenatal contact based on the pregnancy progress and assessment [12,22]. Basic antenatal care plus, pregnant women have a minimum of eight antenatal contacts, including the booking contact prior to 12 weeks, and 20 weeks dating ultrasound (This is recommended, but not available and or accessible at all facilities in the country. Routine ultrasounds are not done in primary health care clinics and ultrasound is performed on indication [e.g. symphysis fundal height greater than dates, multiple pregnancy, or fetal heart activity not heard]. The woman needs to be referred to hospital to have an ultrasound). A pragmatic approach incorporating information such as the last menstrual period, symphysis fundal height and early ultrasound if it available is used. Women are then seen four weekly till 32; followed by 2 weekly contacts until 38 weeks, then weekly contact till delivery [12,15,22,23]. At the booking contact women are fully assessed, medical and previous obstetric history considered, appropriate physical examinations done and side room investigations are done for; haemoglobin, rhesus blood group, rapid plasma reagin and human immunodeficiency virus (HIV) testing after informed consent has been obtained. HIV reactive women are only classified as high risk if they develop complications associated with HIV infection or have other secondary pregnancy or medical complications. Pregnant women are issued with patient-held maternity case record [22]. They are referred to the higher level of care if they develop pregnancy related complications or have pre-existing medical conditions [2]. The recruitment sites consisted of primary care clinics in the catchment areas of nine regional hospitals across South Africa; namely Pholosong Hospital, Mafikeng Hospital, Dr Harry Surtie Hospital, Tshilidzini Hospital, Themba Hospital, Bongani Hospital, Stanger Hospital, Klerksdorp Hospital and Dora Nginza Hospital. The sites were purposively selected, and had a study health care worker screening eligible women on specific days of the week. Each site had an established referral route to refer women with abnormal RI findings for further assessment and management by a hospital team at the appropriate level of care. The next level of care had a maternal and neonatal unit, with access to theatre, blood products and ability to care for neonates of 1000 g or more. Facilities had access to emergency medical services for ease of patient transportation when necessary and were familiar with the Perinatal Problem Identification Program [13] (PPIP) data system. The study started with recruitment and screening in September 2017, the different sites started at different times to allow for adequate training and quality control at all of the nine sites across SA. Ethics approval was obtained from the University of Pretoria faculty of Health Sciences (473/2014), and the study was registered with the South African National Research database. Written, informed consent was obtained from all women prior to conducting the Umbiflow™ screening. A sub-set of women classified as having low-risk pregnancies, between 28 and 34 week's gestations or a symphysis fundal height of more than 26 cm if gestational age was unknown were recruited by health care workers for an Umbiflow™ screening examination. Gestational age staging was determined by the best available clinical obstetric assessment using the last normal menstrual period, early dating ultrasound, or both and or antenatal symphysis fundal height measurement if gestational age was unknown. Dating ultrasound services are not available at all facilities offering antenatal care [23] and only 25·5% of the Umbiflow screened women had a dating sonar before 22 weeks gestation [not shown]. Women screened had a printout of the Umbiflow™ examination for transparency and quality of the Doppler waveform of the umbilical artery could be assessed. Women with multiple pregnancies (multiple pregnancies are considered as high-risk, and were not eligible) and those women with a gestational age below 28 weeks or symphysis fundal height below 26 cm, or aged below 18 years were excluded. Screening was done at or after 28 weeks’ gestation, so most fetuses would have weighed more than 1000 g at enrolment into the study. Fig. 1 illustrates the flow diagram of women recruited in the study. . Flow diagram of participants in the Umbiflow study Flow diagram of participants screened with Umbiflow. RI=Resistance index. Umbiflow device is a low-cost continuous wave Doppler device, it has been developed by the Council for Scientific and Industrial Research (CSIR) and SAMRC in SA [24]. Umbiflow™ is a mobile-connected Doppler device that uses a continuous-wave waveform to detect blood flow within the fetal umbilical cord [24,25]. It consists of a handheld proprietary Doppler probe (transducer) with a universal serial bus (USB) cable that connects to any windows-based notebook on which the necessary software is installed [24,25]. Umbiflow™ measures the RI in the umbilical cord and plots it against the estimated gestational age to identify the fetus at risk for growth restriction [24], [25], [26]. The accuracy of the Umbiflow system in measuring the RI in the fetal umbilical artery has already been proven to be comparable to the commercial standard unit “gold standard” [24,25]. The Umbiflow™ of the umbilical artery screening was classified as either normal or abnormal RI depending on the RI value in relation to gestational age, which was plotted on a graphic representation using the 75th centile as a cut off [26,27]. Screened women with a RI findings below the 75th centile for their gestational age were considered normal RI, and continued their routine antenatal care at their local primary health care clinics. Those with RI findings above the 75th centile for gestational age were considered as having an abnormal RI and were referred to a high-risk clinic at their local regional hospitals for further assessment and management. At the high-risk clinic a detailed ultrasound examination and pulsed wave Doppler were performed. Women identified as having abnormal RIs were managed according to a standard protocol. Women with AEDF at the high risk visit were admitted, given corticosteroids (unless gestational age was more than 34 weeks) and the fetus was monitored using a cardiotocograph. Women with an abnormal RI were followed-up biweekly at the clinic and received a Doppler ultrasound at each visit and a growth scan every two weeks. Delivery was performed if the pregnancy reached 34 weeks’ gestation and had AEDF or 38 weeks’ gestation based on risk; or if cardiotocograph became pathological; no fetal growth or if the maternal condition deteriorated. We estimated that 1000 women were needed per site to detect a prevalence of 1.5% of AEDF in women screened with the Umbiflow™ device, based on the findings from Nkosi et al [21]. Participant information including sociodemographic, behavioural factors, medical and obstetric history was obtained at enrolment through an interview and medical record review. The Umbiflow™ findings were documented. The details of all the women delivering at the antenatal clinics and the referral hospitals was recorded in the electronic birth registers. The outcome of all Umbiflow™ screened was recorded, and the normal RI and abnormal RI groups compared, with focus on demographics and delivery outcomes. Outcome data was obtained from the electronic birth register at the various delivery sites. An outcome was regarded as missing if there was no record of delivery at the relevant hospitals or clinics and after three attempts were made to contact the participants telephonically at different times of the day using the contact details recorded at the start of the study. Analysis of the prevalence of abnormal Doppler's was limited to all screened women, analysis of delivery outcomes was limited to woman-infant dyad that had available delivery outcomes; including the mode of delivery, neonates’ sex, and birth weight. Maternal clinical information was collected at the time of enrolment in the study. Variables reported in this manuscript include maternal age in years, parity, HIV status, birth weight in grams (g), low birth weight (defined by birth weight below 2500 g), neonatal admission to neonatal unit post-delivery, mode of delivery, and stillbirths (defined as an infant with no signs of life at 1 min and 5 min [APGAR of zero]) and neonatal deaths (defined as death of neonate in the first 28 days of life). Neonatal clinical outcomes were abstracted from the maternity case records, this included birth weight, sex, APGAR at one and five minutes, neonatal admission and neonatal complications. The maternal demographics are reported as frequency and the prevalence of normal RI and abnormal RI are reported in percentage. Categorical characteristics were investigated using chi square tests to express differences between the normal RI and abnormal RI groups and the two-proportion z tests for cases where only certain categories were compared. The WHO multinational fetal growth charts were used for categorizing birth weight according to percentiles, and corrected for gestational age at delivery and neonatal sex [27]. All tests were performed at a 5% level of significance. The relative risk was calculated using the incidence proportions of total stillbirth rate, fresh and macerated stillbirth rate and the overall perinatal mortality rate between the normal RI and abnormal RI groups. All statistical analyses were done with R Core Team (2020) https://www.R-project.org/. The funding source played no role in the study design, screening, data collection and analyses, preparation of manuscript or approval of the manuscript. The funder was provided the opportunity to hear the preliminary findings of this study, but the authors were solely responsible for the final content and interpretation of the manuscript. The authors had access to all the data in the study and had final responsibility for the decision to submit for publication.
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