Application of a Physiologically Based Pharmacokinetic Model to Predict Cefazolin and Cefuroxime Disposition in Obese Pregnant Women Undergoing Caesarean Section.

Intravenous (IV) cefuroxime and cefazolin are used prophylactically in caesarean sections (CS). Currently, there are concerns regarding sub-optimal dosing in obese pregnant women compared to lean pregnant women prior to CS. The current study used a physiologically based pharmacokinetic (PBPK) approach to predict cefazolin and cefuroxime pharmacokinetics in obese pregnant women at the time of CS as well as the duration that these drug concentrations remain above a target concentration (2, 4 or 8 µg/mL or µg/g) in plasma or adipose tissue. Cefazolin and cefuroxime PBPK models were first built using clinical data in lean and in obese non-pregnant populations. Models were then used to predict cefazolin and cefuroxime pharmacokinetics data in lean and obese pregnant populations. Both cefazolin and cefuroxime models sufficiently described their total and free levels in the plasma and in the adipose interstitial fluid (ISF) in non-pregnant and pregnant populations. The obese pregnant cefazolin model predicted adipose exposure adequately at different reference time points and indicated that an IV dose of 2000 mg can maintain unbound plasma and adipose ISF concentration above 8 µg/mL for 3.5 h post dose. Predictions indicated that an IV 1500 mg cefuroxime dose can achieve unbound plasma and unbound ISF cefuroxime concentration of ≥8 µg/mL up to 2 h post dose in obese pregnant women. Re-dosing should be considered if CS was not completed within 2 h post cefuroxime administration for both lean or obese pregnant if cefuroxime concentrations of ≥8 µg/mL is required. A clinical study to measure cefuroxime adipose concentration in pregnant and obese pregnant women is warranted.

Pre-conceptual counselling in cardiology patients: still work to do and still missed opportunities. A comparison between 2015 and 2019 in women with cardiac disease attending combined obstetric cardiology clinics. Should the European Guidelines change anything?

Women with underlying cardiac conditions have an increased risk of adverse pregnancy outcomes. Counselling reproductive age women with heart disease is important to assist them in deciding whether to pursue pregnancy, to ensure their best cardiovascular status prior to pregnancy, and that they understand the risks of pregnancy for them and baby. This also provides an opportunity to explore management strategies to reduce risks. For this growing cohort of women, there is a great need for pre-conceptual counselling.This retrospective comparative audit assessed new referrals and pre-conceptual counselling of women attending a joint obstetric-cardiology clinic at a tertiary maternity centre in a 12-month period of 2015-2016 compared with 2018-2019. This reflected the timing of the introduction of a multidisciplinary meeting prior to clinics and assessed the impact on referrals with the introduction of the European Society of Cardiology guidelines.Data were reviewed from 56 and 67 patients in respective audit periods. Patient's risk was stratified using modified World Health Organization classification.Less than 50% of women with pre-existing cardiac conditions had received pre-conceptual counselling, although half of them had risks clearly documented. The majority of patients had a recent electrocardiograph and echocardiogram performed prior to counselling, and there was a modest improvement in the number of appropriate functional tests performed between time points. One-third of patients in both cohorts were taking cardiac medications during pregnancy.There was a significant increase in the number of pregnant women with cardiac disease and in complexity according to modified World Health Organization risk classification. While there have been improvements, it is clear that further work to improve availability and documentation of pre-pregnancy counselling is needed.

Reactivation of IgA vasculitis following COVID-19 vaccination.

A 23-year-old man presented to the acute assessment unit with acute-onset haematuria within 24 hours of receiving his second dose of the Pfizer-BioNTech COVID-19 vaccine. He had been diagnosed with IgA vasculitis 8 months previously. IgA vasculitis is an autoimmune condition characterised by palpable purpura affecting the lower limbs, abdominal pain, arthralgia and renal disease. He was diagnosed with an acute exacerbation of IgA vasculitis and was discharged with oral prednisolone. Reactivation or first presentation of IgA vasculitis is a rare but increasingly recognised complication of COVID-19 vaccination. This is an important new differential in the assessment of patients with haematuria following COVID-19 vaccination.

Impact of Covid-19 on attendances for a 1st episode of reduced fetal movements: A retrospective observational study.

BACKGROUND: Prior studies have demonstrated an increased stillbirth rate. It was suggested that the COVID-19 pandemic may have impacted on attendances for reduced fetal movements. Thus, we sought to ascertain the impact of the pandemic on attendances for reduced fetal movements (RFM) in our unit, ultrasound provision for reduced fetal movements, and the stillbirth rate. METHODS: This was a single site retrospective cohort study involving all women complaining of a 1st episode of reduced fetal movements between 01/03/2020-30/04/2020 (COVID) to 01/03/2019-30/04/2019 (Pre-COVID). Data were retrieved from computerised hospital records and statistical analyses were performed using GraphPad Prism and SPSS. RESULTS: 22% (179/810) of women presented with a 1st episode of reduced fetal movements Pre-COVID compared to 18% (145/803) during COVID (p = 0.047). Primiparous women were significantly over-represented in this population with a 1.4-fold increase in attendances during COVID (67% vs 48%, p = 0.0005). Neither the total stillbirth rate nor the stillbirth rate amongst women who presented with reduced fetal movements changed during COVID. Ultrasound provision was not impacted by COVID with 95% of the scans performed according to local guidelines, compared to Pre-COVID (74%, p = 0.0001). CONCLUSIONS: There is a significant decrease in 1st attendances for reduced fetal movements during COVID-19 pandemic. Primiparous women were 1.4 times more likely to attend with RFM. Women should be reassured that COVID-19 has not resulted in a decreased provision of care for RFM, and has not impacted on the stillbirth rate.

Samba II PCR testing for COVID-19 in pregnant women: a retrospective cohort study and literature review.

BACKGROUND: Asymptomatic carriage of COVID-19 in pregnant women has been reported and could lead to outbreaks in maternity units. We sought to ascertain the impact of rapid isothernal nucleic acid based testing for COVID-19 in an unselected cohort of pregnant women attending our maternity unit. We also assessed the correlation between community prevalence and asymptomatic carriage. METHODS: Data for the retrospective cohort study were collected from a large UK tertiary maternity unit over a 4-week period using computerised hospital records. Literature searches were performed across multiple repositories. COVID-19 prevalence was extracted from online repositories. RESULTS: Nasopharyngeal and oropharyngeal swabs were obtained from 457/465 (98%) women during the study period. The median turnaround time for results was 5.3 h (interquartile range (IQR) 2.6-8.9 h), with 92% of the results returned within 24 h. In our cohort, only one woman tested positive, giving a screen positive rate of 0.22% (1/457; 95% CI: 0.04-1.23%). One woman who tested negative developed a fever postnatally following discharge but was lost to follow-up. From our literature review, we did not find any correlation between asymptomatic carriage in pregnant women and the reported regional prevalence of COVID-19. CONCLUSIONS: Testing using the SAMBA-II machine was acceptable to the vast majority of pregnant women requiring admission and had a low turnaround time. Asymptomatic carriage is low, but not correlated to community prevalence rates. Screening pregnant women on admission will remain an important component in order to minimise nosocomial infection.

Prophylactic perioperative cefuroxime levels in plasma and adipose tissue at the time of caesarean section (C-LACE): a protocol for a pilot experimental, prospective study with non-probability sampling to determine interpatient variability.

BACKGROUND: The aim of the C-LACE study is to measure cefuroxime concentration in plasma and adipose tissue of non-obese and obese pregnant women undergoing caesarean section. METHODS: This study plans to compare maternal cefuroxime concentrations (plasma and adipose tissue), at the time of skin incision and time of skin closure during a caesarean section from non-obese (body mass index BMI < 30 kg/m2) and obese (BMI ≥ 30 kg/m2) pregnant women. The incidence of post-surgical site infection will also be measured. At least 15 participants are required for each arm (non-obese vs obese) with a total of 30 participants. The study participants will be followed up between 30 and 40 days post-caesarean section to record details of any post-caesarean surgical infection to explore correlations between BMI, measured cefuroxime concentrations and post-caesarean infection rates. DISCUSSION: This pilot study will allow the development of a model testing the inter-patient variability in plasma and adipose tissue concentrations of cefuroxime. The results will facilitate the development of a larger study to determine whether differences in cefuroxime plasma and tissue concentration in obese and non-obese women can support the development of a physiologically based pharmacokinetic model. This model can then be used to propose dosing adjustments that can be used in a further trial to optimise cefuroxime dosing for women undergoing caesarean section. TRIAL REGISTRATION: ISRCTN Registry , ISRCTN17527512 . Registered on 26 October 2020.

Mortality in paediatric burns at the Women's and Children's Hospital (WCH), Adelaide, South Australia: 1960-2017.

BACKGROUND: Burn injuries are the third leading cause of preventable death in children worldwide, resulting in over 100 000 annual hospitalisations. In the paediatric population, scalds are the commonest mechanism and burn injuries of greater than 40% total burn surface area (TBSA) are associated with a high mortality and morbidity rate. AIMS: The aim of this study was to review mortality in paediatric burns in a tertiary burns centre over a 60-year period, providing an understanding of local causes of mortality and directing future clinical research. METHODS: We reviewed data collected prospectively from patients treated for burn injuries at the WCH from 1960 to 2017. Data of age, gender, mechanism of injury and TBSA were collected. TBSA of 40% and greater were included in the study. RESULTS: All patients with total burn surface area (TBSA) less than 40% survived. There were a total of 75 patients who sustained burns of or greater than 40% TBSA. Overall mortality was 34% (26 of 75) of which 24 occurred in the 1960s. Of the 21 patients who died of flame burn injuries, 12 of them were described as clothes catching alight from being in close proximity to the source of flame. Average length of stay for patients who did not survive was 7 days (1-26). CONCLUSION: Mortality has since declined and the prognosis for survival good, even in TBSA of greater than 90%. The investigations in fabric flammability led by Dr Thomas Pressley and Mr Murray Clarke prompted the rewriting of Australian standards for production of children's clothing. This, in combination with advances in paediatric resuscitation, surgical techniques as well as wound care has improved survival rates and outcomes in extensive burn injuries. Future studies focus to see not only better survival rates, but also better aesthetic and functional outcomes in burn survivors.

A comparison study of methods for estimation of a burn surface area: Lund and Browder, e-burn and Mersey Burns.

INTRODUCTION: One of the greatest challenges in burn care is the estimation of a total burn surface area (TBSA). It is especially challenging and needs to take into account the growing proportions and the age of a paediatric patient. The aims of this study is to: (1) assess the reliability of the three modalities (LB, MB, and EB) in calculating the extent of burn injuries and fluid resuscitation, and (2) compare the features in terms of usability and efficacy. METHODS: Participants were recruited from Women's and Children's Hospital (WCH), South Australia's surgical and emergency department. Participants were introduced to LB, MB and EB, and then commenced calculation of TBSA on two simulated paediatric (patient A: 12 months, patient B: 4 years) burns. The participants were categorized into three groups; (1) Burns-naïve, (2) Burns-experienced, and (3) Burns-expert. RESULTS: A total of 45 participants took part in this validation study: doctors (49%), nurses (33%), nursing students (11%) and medical students (7%). The burns-naïve group demonstrated higher means in both patients and has greater variance, TBSA mean 28.8%, range 14-40.5% and mean 37.4%, range 20-52.3% in patient A and B respectively. Two-way ANOVA analysis shows a statistically significant interaction between the effects of level of experience and use of applications on estimation of TBSA in larger burns. CONCLUSION: Innovative software and mobile applications demonstrate a high potential as clinical adjuncts in achieving better health outcomes in any health care system. Both Mersey Burns and e-burn reduced the risk of human error particularly from untrained or non-specialised clinicians, however, e-burn proved to be more favourable in our study. Technology-aided models are the future of burns assessment, and further studies are warranted to determine their impact on overall clinical outcome.

Efficacy of perioperative cefuroxime as a prophylactic antibiotic in women requiring caesarean section: A systematic review.

Intravenous (IV) Cefuroxime (CFX) is widely used in Caesarean Section (CS) as a prophylactic antibiotic. The objective of this systematic review to compare CFX concentration in maternal blood and adipose tissue with the incidence of surgical site infection (SSI) following IV CFX in non-obese and obese women undergoing CS. A search in Medline, EMBASE, Cochrane, Web of Science, CINHAL Plus, Scopus and Google Scholar was conducted without language or date restrictions. Published articles or abstracts reporting CFX concentration or rates of SSI following CFX IV administration in adult women requiring CS were included. Studies were screened by title and abstract. Quality of studies was assessed via the ClinPK Statement checklist (Pharmacokinetics studies), or Joanna Briggs Institute Critical Appraisal Tools (SSI studies). The Cochrane Effective Practice and Organisation of Care checklist evaluated the risk of bias (SSI studies). There were no studies evaluating CFX concentrations in obese women undergoing CS. For non-obese women, CFX plasma concentrations ranged from 9.85 to 95.25 mg/L within 30-60 min of administration (1500 mg dose; 4 articles, n = 108 women). Plasma CFX concentrations were above the minimum inhibitory concentration (8 mg/L) for up to 3 h post-dose. No studies reported on CFX concentration in adipose tissue. Reported rates of SSI were 4.7% and 6.8% after administration of a single 1500 mg dose of CFX administrated after cord clamping (n = 144 women). There is limited data on pharmacokinetics of CFX for CS. There were no studies that reported CFX concentrations or SSI in obese women.

Estimated blood loss in pregnant women with cardiac disease compared with low risk women: a restrospective cohort study.

BACKGROUND: Women with cardiac disease are thought to be at increased risk of post-partum haemorrhage. We sought to assess the estimated blood loss (EBL) in our cohort of women with and without cardiac disease (CD) in a quaternary hospital in the UK. Our population consisted of both congenital and acquired CD; and low risk women who delivered in our unit between 01/01/2012-30/09/2016. METHODS: Data were collected using computerised hospital records. CD was classified according to the modified WHO classification (mWHO). The primary outcome measure was estimated blood loss (mL). RESULTS: A total of 5413 women with a singleton fetus in the cephalic presentation delivered during the study period (159 women with CD and 5254 controls). In the CD group, active management of the third stage of labour was consistent with that used in low risk women in 98% (152/155) of cases. Multivariable analyses demonstrated no significant difference in EBL between women with CD vs controls. The adjusted average blood losses were 247.2 ml, 241.8 ml and 295.9 ml in the control group, mWHO 1-2 and 3-4, respectively (p = 0.165). CONCLUSIONS: Women with CD have comparable EBL to low risk women when management of the active third stage of labour is the same.

Prenatal chromosomal microarray testing of fetuses with ultrasound structural anomalies: A prospective cohort study of over 1000 consecutive cases.

OBJECTIVE: Evaluate the diagnostic yield of prenatal submicroscopic chromosome anomalies using prenatal array comparative genomic hybridisation (aCGH). METHOD: Prospective cohort study conducted between March 2013 and June 2017 including fetuses where an elevated nuchal translucency (NT) or structural anomaly was identified on ultrasound and common aneuploidy testing was negative. aCGH was performed using an 8-plex oligonucleotide platform with a genome wide backbone resolution of greater than 200 kb and interpretation in line with American College of Medical Genetics guidance. RESULTS: One thousand one hundred twenty-nine fetuses were included; 371 fetuses with an increased NT (32.9%) and 758 with a structural anomaly (67.1%). The rate of pathogenic copy number variants (CNVs) and variant of uncertain significance (VUS) was 5.9% (n = 22) and 0.5% (n = 2) in the elevated NT group and 7.3% (n = 55) and 0.8% (n = 6) in the mid-trimester anomaly group. No pathogenic CNVs were identified in fetuses with an NT less than 4.0 mm. Multisystem and cardiac anomalies had the greatest yield of pathogenic CNV with a 22q11.2 microdeletion present in 40% (12/30). CONCLUSION: Prenatal aCGH is a useful diagnostic tool in the investigation of fetuses with a significantly elevated NT or structural anomaly. With time and experience, rates of pathogenic CNVs have increased, and VUS have reduced, supporting the prenatal application of increasingly high resolution aCGH platforms.

Age at menarche and the risk of operative delivery.

OBJECTIVES: We sought to evaluate the impact of later menarche on the risk of operative delivery. POPULATION: We studied 38,069 eligible women (first labors at term with a singleton infant in a cephalic presentation) from the Norwegian Mothers and Child Cohort Study. The main exposures were the age at menarche and the duration of the interval between menarche and the first birth. METHODS: Poisson's regression with a robust variance estimator. MAIN OUTCOME MEASURES: Operative delivery, defined as emergency cesarean or assisted vaginal delivery (ventouse extraction or forceps). RESULTS: A 5 year increase in age at menarche was associated with a reduced risk of operative delivery (risk ratio [RR] 0.84, 95%CI 0.78, 0.89; p < .001). Adjustment for the age at first birth slightly strengthened the association (RR 0.79, 95%CI 0.74, 0.84; p < .001). However, the association was lost following adjustment for the menarche to birth interval (RR 0.99, 95%CI 0.93, 1.06; p = .81). A 5 years increase in menarche to birth interval was associated with an increased risk of operative delivery (RR 1.26, 95%CI 1.23, 1.28; p < .001). This was not materially affected by adjustment for an extensive series of maternal characteristics (RR 1.23, 95%CI 1.20, 1.25; p < .001). CONCLUSIONS: Later menarche reduces the risk of an operative first birth through shortening the menarche to birth interval. This observation is consistent with the hypothesis that the pattern and/or duration of prepregnancy exposure of the uterus to estrogen and progesterone contributes to uterine aging.

Pregnancy Outcomes in Women With Transposition of the Great Arteries After an Arterial Switch Operation.

Importance: A growing number of women are approaching childbearing age after arterial switch surgery for transposition of the great arteries. Prepregnancy counseling requires updated knowledge of the additional cardiovascular risks pregnancy poses for this cohort of women and the potential effect on their offspring; however, to our knowledge, this information is currently unknown. Objective: To determine the pregnancy outcomes of women with transposition of the great arteries after an arterial switch operation, as well as the outcomes of their offspring. Design, Setting, and Participants: This cohort study assessed women who had had arterial switch surgery from 1985 to the present and who were 16 years or older as of January 2018. All women with a previous arterial switch surgery for transposition of the great arteries with completed or ongoing pregnancy were included. Data were collected in a level 1 congenital cardiology center and joint obstetrics-cardiology clinic in Birmingham, United Kingdom. Exposures: Patients were assessed before, during, and after pregnancy. Main Outcomes and Measures: Adverse maternal cardiac events (arrhythmia, heart failure, aortic dissection, or acute coronary syndrome) and aortic root dilatation, aortic regurgitation, and left ventricular function before and after pregnancy were the main outcomes. Mode of delivery and fetal outcomes were considered secondary outcomes. Results: A total of 25 pregnancies were identified in 15 women; 8 women had had 1 pregnancy, while 7 were multiparous. There were no adverse maternal cardiac events. Before pregnancy, 8 women (53%) had no aortic regurgitation, 1 (7%) had a trivial degree of regurgitation, 4 (26%) had mild regurgitation, and 2 (14%) had moderate regurgitation. After pregnancies, 1 woman (7%) had minor progression of aortic regurgitation. Five women (36%) had mild neoaortic root dilatation prepregnancy, but none developed progressive dilatation in the first year post-partum. A total of 24 pregnancies were completed by the end of the study, with all infants born alive and well. Nineteen modes of delivery were known; there were 7 cesarean deliveries (37%), of which 2 (11%) were recommended for aortic dilatation and 5 (26%) for obstetric indications or maternal choice. Conclusions and Relevance: Pregnancy is well tolerated after arterial switch operation; no adverse maternal cardiac events or early progression of neoaortic root dilatation or aortic regurgitation were observed in this study. These results provide evidence to allow reassurance of women with previous arterial switch surgery who are planning pregnancies.

Otoplasty techniques in children: a comparative study of outcomes.

BACKGROUND: Numerous otoplasty techniques have been described in the literature to correct prominent ears; however, few have focused on the complication rates. We reviewed our experience aiming to assess peri-operative care requirements and complication rates. METHOD: We conducted a retrospective review of 207 otoplasty procedures performed in 119 patients over a 5-year period (2009-2014) at the Women's and Children's Hospital, Adelaide. Information pertaining to demographic details, length of stay, otoplasty technique and complications (early and late) were obtained. RESULTS: In the study period, 97% of the 119 patients had an overnight stay. There was an early complication of 2.2% (return to theatre for bleeding) in the modified Chongchet technique and 0.9% (wound infection) in the Mustarde technique. Late complications included suture extrusion (1.9%) with the Mustarde technique and hypertrophic scarring (2.2%) in the modified Chongchet technique. The recurrence rate requiring revision following modified Chongchet technique was 10% and Mustarde technique was 2.9%. The Mustarde otoplasty technique was associated with a slightly lower antiemetic requirement than the Chongchet technique (3.2 versus 14.3%, P = 0.032). Both techniques had comparable opioid analgesic requirement of 30-35% post-operatively (P = 0.248). CONCLUSION: Our results are comparable to the huge variation in available literature. We note the higher revision rate following modified Chongchet technique. Both techniques had a low and acceptable rate of post-operative analgesia and antiemetic requirement. We are considering either otoplasty technique as a day surgery procedure within our unit with the provision of adequate patient support as a safe and economical advance.

Age-related changes in murine myometrial transcript profile are mediated by exposure to the female sex hormones.

In humans, the risk of operative first delivery increases linearly with maternal age. We previously hypothesized that prolonged, cyclical, prepregnancy exposure to estrogen and progesterone contributes to uterine aging. Here, we test this hypothesis. Myometrium was obtained from four groups of virgin mice: (i) 10- to 12-week- and 28- to 30-week-old mice; (ii) 10- to 12-week- and 38- to 40-week-old mice; (iii) 38-week-old mice that had an ovariectomy or sham operation early in life; (iv) 38-week-old mice that had been treated with progesterone or vehicle containing implants from 8 to 36 weeks. Transcript profiling was carried out using Affymetrix Gene ST 1.1 arrays, and data were normalized. We identified 60 differentially regulated transcripts associated with advancing age (group 1). We validated these changes in group 2 (P for overlap = 5.8 × 10(-46) ). Early ovariectomy prevented the age-related changes in myometrial transcript profile. Similarly, progesterone-mediated long-term ovarian suppression prevented the age-related changes in myometrial transcript profile. Interferon regulatory factor 7 (Irf7) mRNA was regulated by age and hormonal exposure, and was identified as a predicted regulator of the other differentially expressed transcripts by both promoter sequence and canonical pathway activation analysis (P = 8.47 × 10(-5) and P < 10(-10) , respectively). Immunohistochemistry demonstrated IRF7 in both mouse and human myometrium. We conclude the following: (i) Myometrial aging in mice is associated with reproducible changes in transcript profile; (ii) these changes can be prevented by interventions which inhibit cyclical changes in the female sex hormones; and (iii) IRF7 may be an important regulator of myometrial function and aging.

Twiddler's syndrome in spinal cord stimulation.

BACKGROUND: The aims are to present a case series of Twiddler's syndrome in spinal cord stimulators with analysis of the possible mechanism of this syndrome and discuss how this phenomenon can be prevented. METHOD: Data were collected retrospectively between 2007 and 2013 for all patients presenting with failure of spinal cord stimulators. The diagnostic criterion for Twiddler's syndrome is radiological evidence of twisting of wires in the presence of failure of spinal cord stimulation. RESULTS: Our unit implants on average 110 spinal cord stimulators a year. Over the 5-year study period, all consecutive cases of spinal cord stimulation failure were studied. Three patients with Twiddler's syndrome were identified. Presentation ranged from 4 to 228 weeks after implantation. Imaging revealed repeated rotations and twisting of the wires of the spinal cord stimulators leading to hardware failure. CONCLUSIONS: To the best of our knowledge this is the first reported series of Twiddler's syndrome with implantable pulse generators (IPGs) for spinal cord stimulation. Hardware failure is not uncommon in spinal cord stimulation. Awareness and identification of Twiddler's syndrome may help prevent its occurrence and further revisions. This may be achieved by implanting the IPG in the lumbar region subcutaneously above the belt line. Psychological intervention may have a preventative role for those who are deemed at high risk of Twiddler's syndrome from initial psychological screening.