Triage of HR-HPV Positive Women with Minor Cytological Abnormalities: A Comparison of mRNA Testing, HPV DNA Testing, and Repeat Cytology Using a 4-Year Follow-Up of a Population-Based Study

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HPV genotyping and potential progression markers in cervical intraepithelial neoplasia : Clinical and diagnostic impact

The aim of this thesis is to identify clinically useful early molecular markers to predict progression to carcinoma in women with preinvasive lesions of the cervix, for the purpose of improving care of these women and enabling more individualized treatment. In order to define the human papillomavirus (HPV) types in minor cytological abnormalities, 343 liquid-based cytology (LBC) samples with atypical squamous cells of uncertain significance (ASCUS) and with low-grade squamous intraepithelial lesions (LSIL) were genotyped using Linear Array. We found high-risk (HR-) HPV in 71% of LSIL and 49% of ASCUS cases (p<0.001). HR-HPV prevalence was similar in LSIL and ASCUS cases among women over 25 years. Younger (50 years) women had higher prevalence of HR-HPV and multiple infections (p=0.01). HPV16 was found in 23% and HPV18 in 10% (p<0.001) of HPV-positive women. To test the utility of HPV genotyping in post-surgical monitoring, we genotyped cones of 90 women and follow-up samples after conization, and evaluated cytological results from two consecutive visits. Margin status and presence of CIN3+ in the cone were poor predictors of treatment outcome (sensitivity <50%). Presence of any probable HR/HR-HPV (18 types) predicted all residual high-grade SIL/ cervical intraepithelial neoplasia (CIN) 2 or worse with 73% specificity. Consideration of only 13 HR-HPV types showed equal sensitivity, but higher specificity (86%, p<0.01). True persistent infection detected high-grade residual disease with 60% sensitivity and 95% specificity, resulting in a positive predictive value (PPV) of 43%. We also assessed the utility of p16INK4a immunocytochemical detection of dysplastic cells in 118 samples from patients referred for further testing because of cytological abnormality. Intensity of p16INK4a staining correlated well with CIN grade, particularly when diagnosis was based on simultaneous routine cytology (p<0.001, Rho 0.70). Immunostaining for p16INK4a was feasible in clinical practice and helped to distinguish premalignant cells from reactive cells. To map local immune responses to HPV, we analyzed expression of several immune markers using real -time RT-PCR in cervical biopsies from 24 female volunteers who had been genotyped for HPV. No difference between the 11 HPV-positive and 13 HPV-negative women was found for mRNA expression of any of the immune markers. Surprisingly, levels of the B cell marker CD19 were elevated among women using hormonal contraception (p<0.05). HPV genotyping revealed age-dependent patterns of HPV infections in LSIL and ASCUS cases. We propose triage HPV testing of LSIL after 30 years of age. Genotyping after conization substantially increased PPV, but with loss in sensitivity. General HR-HPV testing will identify all recurrent or residual high-grade CIN. Demonstration of p16INK4a accumulation in the cell nucleus is a simple way to enhance presence of dysplastic cells and to distinguish these from reactive atypia. HPV infection per se does not evoke local immune response as measured by semi-quantitative RT-PCR. Hormonal contraception may influence B cell activity in the cervix. Further studies are needed to identify potential progression markers

Episiotomy or not? Midwives' experiences of recruiting to a randomized controlled trial during pregnancy and labor : A qualitative study

Objective: The performance of randomized controlled trials (RCTs) is dependent on recruitment. Recruiting women to RCTs regarding interventions during childbirth may be difficult due to time constraints and their vulnerable situation. Midwives play a major role in such recruitment. Few studies have investigated the views and experiences of recruiters. The aim of this study was to describe midwives’ experiences of recruiting pregnant women regarding an RCT of lateral episiotomy or no episiotomy in vacuum-assisted delivery. Methods: In this qualitative study, 19 midwives were interviewed regarding their experiences. The midwives worked at antenatal health care centers or labor wards. The transcribed interviews were analyzed using content analysis. Results: Four categories appeared during the analysis, including “experiences and perceptions of providing trial information” and “the right timing in providing trial information,” which varied among the midwives. Midwives’ perceptions of how the women provided consent or declined participation, and the women’s views and questions about the randomization and intervention, were summarized as “experiences of how the trial information was received by the women.” In the final category, “perceived trial apprehensions and concerns,” some midwives described ethical concerns related to the intervention and financial compensation to the staff involved. Conclusions: Midwives as recruiters would benefit from education and training in incorporating basic and advanced details of trial design and research methods, as well as training and support in recruitment. Awareness and management of the variation among potential recruiters is important when designing and performing an RCT

Delivery mode and severe maternal and neonatal morbidity among singleton term breech births : A population-based cohort study

Objective: The aim of this study was to examine the association between delivery mode and severe maternal and neonatal morbidity in singleton term breech births.&amp; nbsp; Study design: This nationwide population-based cohort study includes 41 319 singleton term and post-term breech births (37 + 0-42 + 6 gestational weeks) in Sweden from 1998 to 2016. Data was retrieved from the Swedish Medical Birth Register. The primary outcomes were two separate composite outcomes, maternal and neonatal severe morbidity. Secondary outcomes were separate severe maternal and neonatal morbidity outcomes. Hospitalization and out-patient visits during childhood were also analyzed in ages 0-5 years. Logistic regression was used to estimate unadjusted and adjusted odds ratios (aOR) with 95% confidence intervals (CI) of severe maternal and neonatal morbidity in women with vaginal breech birth or intrapartum cesarean section. Women with a prelabor breech cesarean section was used as the reference group.&amp; nbsp; Results: No difference between vaginal delivery and prelabor cesarean section was seen regarding maternal morbidity. Intrapartum cesarean section was associated with elevated odds for maternal morbidity (aOR 1.27, 95% CI 1.10-1.47) compared with prelabor cesarean section. A similar result was observed for vaginal delivery and intrapartum cesarean section combined (aOR 1.29, 95% CI 1.11-1.50). Vaginal delivery was associated with higher odds for composite neonatal morbidity (aOR 1.85, CI 1.54-2.21) and most separate outcomes, as well as increased number of hospital nights and out-patient visits during first year of life, compared with prelabor cesarean section.&amp; nbsp; Conclusions: Prelabor cesarean section in breech births improved short-term neonatal health without increasing risks for severe maternal short-term complications

Attitudes and knowledge regarding episiotomy use and technique in vacuum extraction : A web-based survey among doctors in Sweden

Objectives: Correct episiotomy use and technique may prevent obstetric anal sphincter injuries. We aimed to explore the attitudes, use, and technique regarding episiotomy among doctors in Sweden, and their willingness to contribute to a randomized controlled trial of lateral episiotomy or no episiotomy in vacuum extraction in nulliparous women. Study design: A web-based survey was sent to members of the Swedish Society of Obstetrics and Gynecology (n = 2140). The survey included 31 questions addressing personal characteristics, use of episiotomy, a two-dimensional picture on which the respondents drew an episiotomy, and questions regarding attitudes towards episiotomy and participation in a randomized controlled trial. We calculated the proportion of supposedly protective episiotomies (fulfilling criteria of a lateral or mediolateral episiotomy and a length &gt;= 30 mm). We compared the results between obstetricians, gynecologists, and residents using Chi-square and Kruskal-Wallis tests for differences between groups, and logistic regression to estimate the odds ratio (OR) of drawing a protective episiotomy. Results: We received 432 responses. Doctors without a vacuum delivery in the past year were excluded, leaving 384 respondents for further analyses. In all, 222 (57.8%) doctors reported use of episiotomy in&lt;50% of vacuum extractions. We obtained 308 illustrated episiotomies with a median angle of 53 degrees, incision point distance from the midline of 21 mm, and length of 36 mm, corresponding to a lateral episiotomy. Few doctors combined these parameters correctly resulting in 167 (54.2%) incorrectly drawn episiotomies. Residents drew shorter episiotomies than obstetricians and gynecologists. Doctors ranked episiotomy the least important intervention to prevent obstetric anal sphincter injuries in vacuum extraction. Doctors contributing to an ongoing randomized controlled trial of lateral episiotomy or no episiotomy in vacuum extraction were more able to draw a protective episiotomy (OR 3.69, 95% confidence interval 1.94-7.02). Conclusions: Doctors in Sweden reported restrictive use of episiotomy in vacuum extraction and depicted lateral type episiotomies, although the majority were incorrectly drawn. Preventive episiotomy was ranked of low importance. Our results imply a need for education, training, and guidelines to increase uptake of correct episiotomy technique, which could result in improved prevention of obstetric anal sphincter injuries

A step towards better audit : The Robson Ten Group classification system for outcomes other than cesarean section

Introduction The Robson Ten Group Classification System is widely used for the audit of cesarean section (CS) rates. However, CS rate alone is a poor quality indicator and should be balanced with other obstetric endpoints. The aim of this study was to evaluate whether Swedish national data on obstetric outcomes other than CS, stratified by the Robson classification, could be analyzed in a useful way. Material and methods All births in Sweden from 2017 through 2020 recorded in the nationwide Swedish Pregnancy Register were categorized using the Robson classification with subdivision of some groups. Five outcomes were explored: CS, operative vaginal delivery, postpartum hemorrhage, obstetric anal sphincter injury (OASIS) and Apgar score The largest Robson groups were nulliparous and multiparous women with single-term cephalic pregnancies, unscarred uterus and spontaneous labor. Intrapartum CS rates were highest for multiple pregnancies, women with induced labor after previous CS, and nulliparous women with induced labor. Nulliparous women and multiparous women with a previous CS with attempted vaginal birth had the highest operative vaginal delivery and OASIS rates. The postpartum hemorrhage rate was highest for multiple pregnancies and transverse lie, followed by prelabor CS in nulliparous and multiparous women with single-term cephalic pregnancies and unscarred uterus. The highest rates of Apgar score &amp;lt;7 at 5 minute were observed in preterm deliveries, multiple pregnancies, transverse lie and breech presentation. The largest contribution to the total CS rate was made by women with previous CS delivered by prelabor CS, and nulliparous women with induced or spontaneous labor. The largest contribution to all other outcomes was made by nulliparous women with spontaneous or induced labor and, notably, multiparous women with spontaneous labor and unscarred uterus. Conclusions The Robson classification provides a useful framework for analyzing CS rates along with rates of operative vaginal delivery, OASIS, postpartum hemorrhage and low Apgar score. Parallel interpretation of several outcomes allows a systematic and multidimensional audit, helpful for families and healthcare professionals, and can be used for comparisons, assessment of trends and subpopulations

Womens experiences of receiving information about and consenting or declining to participate in a randomized controlled trial involving episiotomy in vacuum-assisted delivery : a qualitative study

Background: Information about and invitation to participate in a clinical trial involving an intervention during childbirth may cause fear or worry in pregnant women. The aim of this study was to describe nulliparous womens experiences of receiving an invitation to participate in a randomized controlled trial (RCT) of lateral episiotomy versus no episiotomy in vacuum-assisted delivery (EVA trial). Methods: This qualitative study was nested in the ongoing EVA trial. Data were collected through semistructured telephone interviews with 23 women regarding their experiences of the information and invitation to participate in the EVA trial. Interviews were audio-recorded and transcribed verbatim. A qualitative content analysis was used to analyse the interview contents. Results: Three main experience categories were identified among the participants. "Timing of trial information and understanding" revealed that women preferred to obtain information about the trial early on during pregnancy. "Reasons to consent to or decline participation in the trial" encompassed a variety of reasons for women to consent, such as goodwill for science or personal benefits, or to decline, such as not wanting to be randomized or fear of increased risk of having a vacuum-assisted delivery. "Thoughts evoked regarding childbirth" were diverse, ranging from not being affected at all to having increased anxiety. Conclusions: The womens experience of receiving an invitation to participate in an RCT of episiotomy in vacuum-assisted delivery varied widely, from immediately giving consent without further worries to increased anxiety or declining participation. Early and personal information with time for reflection was considered most satisfactory.Funding Agencies|Swedish Research CouncilSwedish Research CouncilEuropean Commission [Dnr 2016-00526]; Centre for Clinical Research Dalarna [CKFUU-930828]; Dalarna University</p

Lateral episiotomy versus no episiotomy to reduce obstetric anal sphincter injury in vacuum-assisted delivery in nulliparous women : study protocol on a randomised controlled trial

Obstetric anal sphincter injury (OASIS) occurs in 5%-7% of normal deliveries and increases with vacuum extraction (VE) to 12%-14% in nulliparous women in Sweden. Lateral/mediolateral episiotomy may reduce the prevalence of OASIS at VE in nulliparous women. The current use of episiotomy is restrictive. The protective effect and consequences are uncertain. This trial will investigate if lateral episiotomy can reduce the prevalence of OASIS and assess short-term and long-term effects. Methods and analysis This is a multicentre randomised controlled trial of lateral episiotomy versus no episiotomy in nulliparous women with a singleton, live fetus, after gestational week 34+0 with indication for VE. A lateral episiotomy of 4 cm is cut at crowning, 1-3 cm from the midline, at a 60 degrees angle. The primary outcome is OASIS by clinical diagnosis analysed according to intention to treat. To demonstrate a 50% reduction in OASIS prevalence (from 12.4% to 6.2%), 710 women will be randomised at a 1:1 ratio. Secondary outcomes are pain, blood loss, other perineal injuries, perineal complications, Apgar score, cord pH and neonatal complications. Web-based questionnaires at baseline, 2 months, 1 and 5 years will be used to assess pain, incontinence, prolapse, sexual function, quality of life and childbirth experience. A subset of women will receive follow-up by pelvic floor sonography and pelvic examination. Mode of delivery and recurrence of OASIS/episiotomy in subsequent pregnancies will be assessed at 5 and 10 years using register data. Ethics and dissemination The trial is open for enrolment. The trial has received ethical approval from the Regional Ethical Review Board of Stockholm and full funding from the Swedish Research Council. Women are interested in participation. The predominant restrictive view on episiotomy may limit recruitment. Results are of global interest and will be disseminated in peer-reviewed journals and at international congresses