Recurrent implantation failure and inflammatory markers in serum and follicle fluid of women undergoing assisted reproduction.

It has been shown previously that the immune system plays a role in implantation and embryo development. The objective was therefore to evaluate cytokine levels and Th1/Th2 ratio in women with recurrent implantation failure in this nested case-control study. Women with no implantation after ≥ 3 embryo transfers were included in the recurrent implantation failure group (n = 29) and were compared with women with successful pregnancy after the first embryo transfer, with an indication of male factor (n = 26). Cytokines analyzed with the Meso scale discovery (MSD) technology Proinflammatory Human Kit 1 and calculated Th1/Th2 ratios were the main outcome measures. In serum there was a difference between the recurrent implantation failure group and the control group in ratios for IFN-γ/IL-10 (p = 0.01), IL-1ß/IL-10 (p = 0.04), IL-2/IL-10 (p = 0.00), TNF-α/IL-10 (p = 0.02), IFN-γ/IL-13 (p = 0.01), IL-12/IL-13 (p = 0.02), IL-2/IL-13 (p = 0.00), and TNF-α/IL-13 (p = 0.00), where the control group had higher ratios, i.e. a shift towards a Th1 pro-inflammatory profile before treatment start. In follicular fluid there were differences in ratios between IL-2/IL-10 (p = 0.02), IL-8/IL-10 (p = 0.02), TNF-α/IL-10 (p = 0.02), IFN-γ/IL-13 (p = 0.01), and TNF-α/IL-13 (p = 0.03). The recurrent implantation failure group had higher ratios except for IFN-γ/IL-13, indicating a shift towards a Th1 pro-inflammatory profile in their follicular fluid. Pro-inflammatory activity in both serum and follicle fluid differs in recurrent implantation failure patients and patients with successful assisted reproduction treatment. Women at risk of immune-related recurrent implantation failure could be identified proactively. Because it is taken at a timepoint closer to implantation, ratios in follicular fluid are specifically interesting as risk markers.

Prevalence of adenomyosis features in women scheduled for assisted reproductive treatment, using the Morphological Uterus Sonographic Assessment group definitions.

INTRODUCTION: Studies that use standardized ultrasonographic criteria to diagnose adenomyosis in subfertile women are needed. These would improve the understanding of the disease burden and enable further studies on its impact on fertility and assisted reproductive treatment (ART) outcome. The aim of this study was to determine the prevalence of different features of adenomyosis in women scheduled for their first ART, diagnosed at two (2D) and three-dimensional (3D) transvaginal ultrasonography (TVUS) using the revised Morphological Uterus Sonographic Assessment (MUSA) group definitions. MATERIAL AND METHODS: This was a prospective, observational cross-sectional study of subfertile women aged 25 to ≤39 years, that were referred to a university hospital for their first ART between December 2018 and May 2021. Of 1224 eligible women, 1160 women fulfilled the inclusion criteria and consented to participate in the study. All women underwent a systematic 2D and 3D TVUS examination. The primary outcome was the presence of direct and indirect features of adenomyosis, as proposed by the MUSA group. Secondary outcomes were to describe the ultrasonographic characteristics of the different features, as well as any difference in the diagnostics at 2D or 3D TVUS and any association with clinical characteristics such as endometriosis. RESULTS: At least one direct or indirect feature of adenomyosis was observed in 272 (23.4%, 95% confidence interval [CI] 21.0-25.9) women. Direct features that are pathognomonic for the disease were observed in 111 (9.6%, 95% CI, 7.9-11.3) women. Direct features were visible only at 3D TVUS in 56 (4.8%, 95% CI 3.6-6.1) women, that is, 56/111 (50.5%) of women with at least one direct adenomyosis feature. Direct features were more common in women with endometriosis (OR 2.8, 95% CI 1.8-4.3). CONCLUSIONS: We found than one in 10 women scheduled for ART had direct features of adenomyosis at ultrasound examination. The present study suggests that the use of 3D TVUS is an important complement to 2D in the diagnostics of adenomyosis. Our results may further improve the counseling of women scheduled for ART and enables future studies on the impact of different features of adenomyosis on subfertility, ART results and obstetric outcomes.

Endometriosis diagnosed by ultrasound is associated with lower live birth rates in women undergoing their first in vitro fertilization/intracytoplasmic sperm injection treatment.

OBJECTIVE: To study the cumulative live birth rate (CLBR) after the first in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) treatment in women with or without deep-infiltrating endometriosis (DIE) and/or endometrioma diagnosed by transvaginal ultrasonography (TVUS), using the International Deep Endometriosis Analysis (IDEA) group definitions. DESIGN: Prospective observational cohort study at a university hospital. PATIENTS(S): In total, 1,040 women with subfertility aged 25 to ≤39 years were undergoing their first IVF/ICSI treatment between January 2019 and October 2022. Of these, 234 (22.5%; 95% confidence interval [CI], 20.0-25.0) women were diagnosed with DIE and/or endometrioma at systematic TVUS before starting their treatment. INTERVENTION(S): All women underwent their first IVF or ICSI treatment. Fresh and/or frozen embryos from the first cycle were used until pregnancy was achieved or no embryos remained. MAIN OUTCOME MEASURE(S): Cumulative live birth rate after the first IVF/ICSI cycle in women with or without DIE and/or endometrioma. RESULT(S): The CLBR after the first IVF/ICSI treatment in the total cohort of women was 426/1,040 (41.0%; 95% CI, 38.0-44.0). Women with DIE and/or endometrioma had a lower CLBR (78/234, 33.3%; 95% CI, 27.3-39.4) than women without the disease (348/806, 43.2%; 95% CI, 39.8-46.6). The crude relative risk (RR) for cumulative live birth for women with DIE and/or endometrioma was 0.77; 95% CI, 0.63-0.94, and after adjustments were made for age, body mass index, s-antimüllerian hormone, stimulation protocol, and day for embryo transfer, the adjusted RR was 0.63; 95% CI, 0.48-0.82. There was no difference in the number of retrieved mature oocytes, fertilization rate, or good quality embryos between the 2 groups. CONCLUSION: The presence of DIE and/or endometrioma diagnosed by TVUS lowers the chance of live birth in women undergoing their first IVF/ICSI treatment.

Prevalence of endometrioma and deep infiltrating endometriosis at transvaginal ultrasound examination of subfertile women undergoing assisted reproductive treatment.

OBJECTIVE: To estimate the prevalence of endometrioma and deep infiltrating endometriosis (DIE), assessed by systematic transvaginal ultrasound examination, in women with subfertility accepted for their first assisted reproductive treatment and to describe the prevalence of endometriotic lesions in different anatomical locations of the pelvis. DESIGN: Cross-sectional study. SETTING: Reproductive Medicine Center, Department of Obstetrics and Gynecology, University hospital. PATIENT(S): A total of 1,191 women with subfertility aged 25-39 years accepted for their first assisted reproductive treatment between December 2018 and May 2021. INTERVENTION(S): All women underwent a systematic transvaginal ultrasound examination. The endometriotic lesions visible on ultrasound examination were described according to the International Deep Endometriosis Analysis group consensus opinion for systematic approach to assess endometriotic lesions. MAIN OUTCOME MEASURE(S): Prevalence of endometrioma and DIE in women with subfertility and prevalence of endometriotic lesions in various anatomical locations of the pelvis. RESULT(S): Endometriosis prevalence was 21.8%, with endometriotic lesions found in 260 of the 1,191 women. Overall, 125 (10.5%) women had endometrioma and 205 (17.2%) women had DIE. Of these 260 women, 197 (75.8% of women with endometriosis) did not have any previous knowledge about having endometriosis. The most common location for endometriotic lesions was the uterosacral ligaments, with lesions found in 151 (12.7%) of all women. The second most common location was the ovaries containing endometrioma, found in 125 (10.5%) women. Most women had 1 (n = 121, 10.2%) or 2 (n = 82, 6.9%) endometriotic lesions. CONCLUSION(S): The prevalence of endometrioma and DIE in women with subfertility, diagnosed by systematic transvaginal ultrasound examination, was 21.8%. Of these, three-fourth of women had no knowledge about the presence of disease.

RUBIC (ReproUnion Biobank and Infertility Cohort): A binational clinical foundation to study risk factors, life course, and treatment of infertility and infertility-related morbidity.

BACKGROUND: Infertility affects 15%-25% of all couples during their reproductive life span. It is a significant societal and public health problem with potential psychological, social, and economic consequences. Furthermore, infertility has been linked to adverse long-term health outcomes. Despite the advanced diagnostic and therapeutic techniques available, approximately 30% of infertile couples do not obtain a live birth after fertility treatment. For these couples, there are no further options to increase their chances of a successful pregnancy and live birth. OBJECTIVES: Three overall questions will be studied: (1) What are the risk factors and natural life courses of infertility, early embryonic loss, and adverse pregnancy outcomes? (2) Can we develop new diagnostic and prognostic biomarkers for fecundity and treatment success? And (3) what are the health characteristics of women and men in infertile couples at the time of fertility treatment and during long-term follow-up? MATERIAL AND METHODS: ReproUnion Biobank and Infertility Cohort (RUBIC) is established as an add-on to the routine fertility management at Copenhagen University Hospital Departments in the Capital Region of Denmark and Reproductive Medicine Centre at Skåne University Hospital in Sweden. The aim is to include a total of 5000 couples equally distributed between Denmark and Sweden. The first patients were enrolled in June 2020. All eligible infertile couples are prospectively asked to participate in the project. Participants complete an extensive questionnaire and undergo a physical examination and collection of biospecimens (blood, urine, hair, saliva, rectal swabs, feces, semen, endometrial biopsies, and vaginal swabs). After the cohort is established, the couples will be linked to the Danish and Swedish national registers to obtain information on parental, perinatal, childhood, and adult life histories, including disease and medication history. This will enable us to understand the causes of infertility and identify novel therapeutic options for this important societal problem.

Premature ovarian failure after childhood cancer and risk of metabolic syndrome: a cross-sectional analysis.

OBJECTIVE: Female childhood cancer survivors (CCS) are at risk of several late effects, such as metabolic syndrome (MetS) and premature ovarian insufficiency (POI). The objective is to study if POI is associated with risk of MetS and increased cardiovascular risk in CSS. DESIGN: A cross-sectional study with a median time since the cancer diagnosis of 25 (12-41) years. Patients and controls were recruited from the South Medical Region of Sweden. METHODS: The study included 167 female CCS, median age 34 (19-57) years, diagnosed with childhood cancer at median age 8.4 (0.1-17.9) years together with 164 controls, matched for age, sex, ethnicity, residence, and smoking habits. All subjects were examined with fasting glucose, insulin, HbA1c, and lipid profile. Fat mass was calculated with dual-energy X-ray absorptiometry (DXA), and questionnaires for medication were obtained. Detailed information of cancer treatment was available. RESULTS: POI was present in 13% (22/167) among CCS (hypothalamic/pituitary cause excluded) and in none among controls. MetS was present in 14% (24/167) among all CCS (P = 0.001), in 23% (5/22) of those with POI (P < 0.001), compared with 4% (6/164) among controls. OR for MetS in all CCS compared with controls was 4.4 (95% CI: 1.8, 11.1) (P = 0.002) and among CCS with POI the OR was 7.7 (CI: 2.1, 28.1) (P = 0.002). CONCLUSION: The prevalence of MetS was higher in females treated for childhood cancer compared with controls, and the presence of POI significantly increased the risk of developing MetS.

Interaction between serum levels of Anti-Mullerian Hormone and the degree of sperm DNA fragmentation measured by sperm chromatin structure assay can be a predictor for the outcome of standard in vitro fertilization.

Serum levels of Anti-Mullerian Hormone (AMH) have been shown to be biomarker for prediction of the quantitative aspects of ovarian reserve. On the male side, sperm chromatin structure assay (SCSA) DNA fragmentation index (DFI) has been demonstrated to be an important predictor of outcomes in standard IVF procedures but to less degree in intracytoplasmic sperm injection procedures (ICSI). The purpose of this study was to investigate whether the combination of female AMH serum levels and sperm DFI adds to prediction of the outcome of assisted reproduction. A total of 352 couples was included (ICSI-148: IVF-204) A venous blood sample was drawn for AMH analysis before IVF/ICSI treatment. DFI was measured in the ejaculate used for assisted reproduction. Regression models for the following odds ratio calculations were constructed: for obtaining at least one Good Quality Embryo; for live birth in all procedures; for pregnancy in procedures where embryo transfer was performed; for miscarriage. For DFI increase by 10 percentage points (not increased DFI as reference) odds ratio for Good Quality Embryo was statistically significantly lower when AMH was at lower quartile (AMH <12 pmol/L; OR = 0.29, 95% CI: 0.14-0.59,) but not when AMH was at upper quartile (AMH ≥ 36 pmol/L; OR = 0.95, 95% CI: 0.43-2.13,). The marginal effect of an increase in DFI by 10 percentage points was statistically significant only when AMH < 25.2 pmol/L. Similar results were obtained as considers live birth following standard IVF. No interactions were seen for standard IVF in relation to the risk of miscarriage and for any of the outcomes when ICSI was used as method of treatment. We conclude that the impact of high DFI on the outcome of standard IVF is most pronounced if the female partner has relatively low AMH levels. This finding may help in defining the role of sperm DNA integrity testing in management of infertile couples. It may also explain some of the heterogeneity in results of studies focusing on predictive value of DFI measurements in assisted reproduction.

The N680S variant in the follicle-stimulating hormone receptor gene identifies hyperresponders to controlled ovarian stimulation.

OBJECTIVE: To study if the follicle-stimulating hormone receptor (FSHR) variant asparagine/serine in amino acid 680 (N680S) can predict hypersensitivity to gonadotropins in women undergoing assisted reproduction. PATIENTS AND METHODS: In this retrospective study, 586 women undergoing their first in-vitro fertilisation treatment were enroled, and their FSHR N680S genetic variant was analysed. The main outcome measures were number of retrieved oocytes and any grade of ovarian hyperstimulation syndrome (OHSS). Experimental studies were performed on FSHR variants transfected into eukaryotic cells treated with 1-90 IU recombinant follicle-stimulating hormone. The receptors' ability to induce a second messenger 3',5'-cyclic AMP was measured. RESULTS: The proportion of women who developed OHSS was 6% (n=36). None of the women who developed this condition had the homozygous serine variant. The N680S polymorphism in the FSHR was associated with the condition, Ptrend (genotype)=0.004 and Pallelic (alleles)=0.04. Mean oocyte number was 11±6 in women without OHSS and 16±8 in women who developed OHSS (P=0.001), despite exposure to lower total hormonal dose in the latter group. The odds ratio for developing OHSS in carriers of the asparagine allele was 1.7 (95% confidence interval: 1.025-2.839, P=0.04). A higher receptor activity in cells expressing asparagine compared with the serine was also evident at all concentrations of recombinant follicle-stimulating hormone used (P<0.05 for all). CONCLUSION: This study confirms previous findings regarding higher hormonal sensitivity in carriers of asparagine in the N680S position. These women are at higher risk for OHSS during in-vitro fertilisation. Genetic testing could identify those at highest risk to develop this adverse effect.

Anti-müllerian hormone compared with other ovarian markers after childhood cancer treatment.

BACKGROUND: Gonadal dysfunction is one of the major late complications after cancer diagnosis and treatment. The best markers of ovarian reserve in clinical practice are antral follicle count (AFC) and ovarian volume. We aimed to study the prevalence of premature ovarian insufficiency (POI) and evaluate anti-Müllerian hormone (AMH) and other serum markers for ovarian function in adult women who were childhood cancer survivors (CCS) in comparison with a control group. MATERIAL AND METHODS: Altogether, 167 female CCS were compared to 164 matched controls. Prevalence of POI was documented and serum levels of AMH, inhibin B, follicle stimulating hormone (FSH), and estradiol (E2) were compared with AFC and ovarian volume. RESULTS: POI was reported in 22 (13%) of the CCS and in none of the controls. Serum levels of AMH, inhibin B, and FSH, but not E2, correlated significantly with AFC and ovarian volume; AMH showed the highest correlation. There was no difference between CCS and controls regarding the different serum markers as measured by linear regression analysis. ROC curve AUC for primary POI showed the highest values for AMH (0.930) and AFC (0.944). For AFC <10, ROC curve AUC showed highest value for AMH for CCS (0.866) and controls (0.878). In a subgroup of female CCS <40 years (n = 120), the results were similar. CONCLUSION: We found POI in 13% among CCS, slightly more than in other studies. Serum levels of AMH, inhibin B, and FSH correlated significantly with AFC and ovarian volume, and no difference was noted between CCS and controls. AMH was the most reliable serum marker for ovarian function in terms of POI and low AFC.

Anti-müllerian hormone levels are associated with live birth rates in ART, but the predictive ability of anti-müllerian hormone is modest.

OBJECTIVES: The aim was to evaluate the association between serum Anti-Müllerian Hormone (AMH) level and cumulative live birth rates (LBR) in patients undergoing their first in vitro fertilization (IVF) treatment cycle, and to compare serum AMH levels with Antral Follicle Count (AFC) and Ovarian Sensitivity Index (OSI) as predictors of live birth. STUDY DESIGN: A prospective cohort study of 454 patients under the age of 40 and with a regular menstrual cycle of 21-35 days, undergoing their first IVF treatment cycles between September 2010 and June 2015. Participants were divided into three groups based on their AMH level, (AMH ≤10, AMH 10-<30 and AMH ≥30 pmol/l). Any difference in AMH-distribution between patients with or without live birth was analyzed using a Mann-Whitney-test, and live birth rates were compared between groups by a chi-squared test for linear trend. The ability of AMH, OSI and AFC as predictors of live birth was assessed by a receiver operating characteristics-analysis and the area under the curve (AUC) was calculated. RESULTS: Patients with live birth had a higher AMH, median (range) 26 [0-137] pmol/l, compared with patients without live birth, AMH 22 [0-154] pmol/l, p = 0.035. Mean live birth rate (SD) was 0.36 (0.48) in the total cohort, 0.26 (0.44) in AMH-group <10, 0.34 (0.48) in AMH-group 10-<30, and 0.41(0.49) in AMH-group ≥30. Thus live birth rates increased with 8% per AMH-group (95% CI: 0.02 -0.14, p = 0.015). The AUC for AFC was 0.56, for AMH 0.57 and for OSI 0.63, respectively. CONCLUSION: AMH concentration in serum is associated with live birth rates after IVF. Our results suggest that both AMH, AFC and OSI have an equal but modest predictive ability in relation to live birth rate.

Treatment efficacy for idiopathic recurrent pregnancy loss - a systematic review and meta-analyses.

INTRODUCTION: Medical treatment of women with idiopathic recurrent pregnancy loss is controversial. The objective was to assess the effects of different treatments on live birth rates and complications in women with unexplained recurrent pregnancy loss. MATERIAL AND METHODS: We searched MEDLINE, Embase and the Cochrane Library, and identified 1415 publications. This systematic review included 21 randomized controlled trials regarding acetylsalicylic acid, low-molecular-weight heparin, progesterone, intravenous immunoglobulin or leukocyte immune therapy in women with three or more consecutive miscarriages of unknown cause. The study quality was assessed and data was extracted independently by at least two authors. RESULTS: No significant difference in live birth rate was found when acetylsalicylic acid was compared with low-molecular-weight heparin or with placebo. Meta-analyses of low-molecular-weight heparin vs. control found no significant differences in live birth rate [risk ratio (RR) 1.47, 95% CI 0.83-2.61]. Treatment with progesterone starting in the luteal phase seemed effective in increasing live birth rate (RR 1.18, 95% CI 1.09-1.27) but not when started after conception. Intravenous immunoglobulin showed no effect on live birth rate compared with placebo (RR 1.07, 95% CI 0.91-1.26). Paternal immunization compared with autologous immunization showed a significant difference in outcome (RR 1.8, 95% CI 1.34-2.41), although the studies were small and at high risk of bias. CONCLUSION: The literature does not allow advice on any specific treatment for idiopathic recurrent pregnancy loss, with the exception of progesterone starting from ovulation. We suggest that any treatment for recurrent pregnancy loss should be used within the context of a randomized controlled trial.

Prematurity and neonatal outcome including congenital malformations after maternal malignancy within six months prior to or during pregnancy.

INTRODUCTION: The proportion of women who postpone childbearing is increasing. As malignancy risk increases with age, pregnancy in connection with malignancy will become more common. MATERIAL AND METHODS: We compared infants born 1994-2011 to women with a malignancy within six months prior to the last menstrual period or during pregnancy with offspring of women without a previous malignancy. Five national registers were used. RESULTS: A total of 790 women with a malignancy diagnosis from six months prior to the last menstrual period up to delivery were identified. Their 802 infants were compared with 1 742 757 infants of women without a malignancy. A high rate of prematurity was found, especially when the malignancy was diagnosed during the second or third trimesters (33%). Most of these premature births were the result of induced delivery before 35 weeks (91%). The most remarkable finding is the observation that these premature infants had a significantly higher risk for neonatal morbidity than premature infants in the control group with an adjusted odds ratio of 2.67 (95% confidence interval; 1.86-3.84). We found a significantly increased risk of mainly relatively mild malformations among infants of women with a malignancy diagnosis within six months prior to the last menstrual period or during the first trimester with a risk ratio of 1.81 (95% confidence interval; 1.20-2.61). CONCLUSIONS: A high incidence of prematurity, mostly due to induced delivery, was found, including an increased risk for neonatal morbidity among these infants. An increased risk for relatively mild malformations was also found.

Congenital malformations in offspring of women with a history of malignancy.

BACKGROUND: Survival after malignancy has increased and the question of risks, including risk for congenital malformations for the offspring of these women has become important. Data on congenital malformations in such offspring are limited. METHODS: We compared congenital malformation in offspring, born 1994 to 2011 of women with a history of malignancy (at least 1 year before delivery) with all other offspring. Adjustment for confounders was mainly made by Mantel-Haenszel methodology. Data were obtained by linkage between Swedish national health registers. RESULTS: We identified 71,954 (4.1%) infants with congenital malformation, of which 47,081 (2.7%) were relatively severe (roughly corresponding to major malformation). Among 7284 infants to women with a history of malignancy 204 relatively severe malformations were found (2.8%; odds ratio [OR] = 1.04; 95% confidence interval [CI], 0.91-1.20). After in vitro fertilization, the risk of a relatively severe malformation was significantly increased in women without a history of malignancy (OR = 1.31; 95% CI, 1.24-1.38) and still more in women with such a history (risk ratio = 1.85; 95% CI, 1.08-2.97). However, there were no significant differences neither, for any malformations (OR = 1.04; 95% CI, 0.92-1.16) nor for relatively severe malformations (OR = 1.04; 95% CI, 0.91-1.20), when comparing offspring only after maternal history of malignancy. CONCLUSION: No general increase in malformation rate was found in infants born to women with a history of malignancy. A previously known increased risk after in vitro fertilization was verified and it is possible that this risk is further augmented among infants born of women with a history of malignancy. Birth Defects Research 109:224-233, 2017. © 2016 Wiley Periodicals, Inc.

Characteristics of the Offspring of Women with a History of Malignancy, Excluding Congenital Malformations.

OBJECTIVE: To study the characteristics (except congenital malformations) of offspring born to women with a history of malignancy. METHODS: Data were obtained by linkage between four different Swedish national health registers. We compared the offspring born between 1994 and 2011 of women with a history of malignancy with all other infants. Survival of the infants was followed up through 2013. Adjusting for confounders was performed using Mantel-Haenszel methodology. We identified 7315 infants born to women with a history of a malignancy diagnosed at least 1 year before delivery. The total number of deliveries in Sweden in these years was 1 746 870, with 1 780 112 infants being born. We assessed rates of intrauterine death, preterm birth, low birth weight, and the nature of intrauterine growth. We also examined neonatal diagnoses (asphyxia, chronic respiratory condition, intracranial hemorrhage, jaundice, hypoglycemia, CNS symptoms) and infant death. RESULTS: In women with a history of malignancy, we found no significantly increased risk for stillbirth or infant death. There were elevated rates of preterm birth (OR 1.50, 95% CI 1.37 to 1.64), very preterm birth (OR 1.89, 95% CI 1.54 to 2.32), and low birth weight (OR 1.50, 95% CI 1.34 to 1.68). There was a significantly increased risk of birth asphyxia, jaundice, hypoglycemia, and low Apgar score among infants born to women with a history of malignancy (OR 1.24, 95% CI 1.15 to 1.33), and this risk was maintained after excluding infants born after IVF. CONCLUSION: We found an increased risk of preterm birth and low birth weight among infants of women with a history of malignancy, and as a result, found an increased risk of neonatal morbidity. No significant increase in risk of intrauterine or postnatal death was noted.

Follow up with HPV test and cytology as test of cure, 6 months after conization, is reliable.

INTRODUCTION: Human papillomavirus (HPV) infection is an objective marker with a high sensitivity for finding cervical dysplasia. The objective of the current study is to investigate whether HPV testing, combined with liquid-based cytology, is reliable as a test of cure after the loop electrical excision procedure (LEEP). MATERIAL AND METHODS: The LEEP was performed in 330 women for excision of cervical dysplasia. Follow up consisted of HPV testing and liquid-based cytology at six, 12, and 36 months after treatment. Patients with negative co-testing after 6 months were re-examined after 3 years. Patients who tested positive for high-risk HPV and/or dysplasia were followed up 12 months postoperatively. RESULTS: At 6 months, the co-testing was double negative in 169 of 260 tested cases (65%). A positive high-risk HPV test (n = 40) was associated with cytological abnormalities (p < 0.001). After 3 years, 227 of 275 examined cases (83%) co-tested negative, including 154 patients who had already tested negative at 6 months and 37 cases with viral clearance at 12 months. Of 26 patients with high-risk HPV at the 3-year follow up, six had LSIL findings on liquid-based cytology, but neither HSIL lesions nor glandular atypia or cervical cancer was found. A negative high-risk HPV test showed a negative predictive value for HSIL of 100% (95% CI 99.8-100%). CONCLUSIONS: Negative co-testing 6 months after LEEP can be considered a reliable test of cure as 3-year follow-up results are consistent with neither HSIL or cancer.

Deliveries After Malignant Disease Before Pregnancy: Maternal Characteristics, Pregnancy, and Delivery Complications.

PURPOSE: Survival after cancer has increased, and the question of risks in later pregnancies has become important. A previous malignancy may affect pregnancy outcome. METHODS: Comparison of women with malignant disease before pregnancy with all other women giving birth during 1994-2011. Data were obtained by linkage between Swedish national health registers. Subfertility, evaluated as time to pregnancy, and in vitro fertilization (IVF) before the relevant delivery were studied. The following delivery diagnoses were studied: gestational diabetes, preeclampsia, placenta previa, placenta abruption, placenta retention, bleeding around delivery, and premature rupture of membranes. The rates of cesarean section and vacuum extraction or forceps delivery were also studied. RESULTS: We identified 3931 women with 7176 deliveries and with a malignancy diagnosed at least 1 year before the delivery. The total number of deliveries in Sweden in these years was 1,746,870. Overall, an increased risk of subfertility (odds ratio [OR] 1.17, 95% confidence interval [CI] 1.07-1.28), use of IVF (OR = 1.36, CI 1.21-1.53), delivery complications (OR = 1.17, 95% CI 1.10-1.24), and rate of caesarean sections (OR = 1.27, 95% CI 1.20-1.34) was observed among women with a history of malignancy compared with other women. CONCLUSION: We found an increased risk of subfertility, pregnancy, and delivery complications in women with a history of malignant disease. Further studies are needed to evaluate the risks of specific treatments and to provide these women with reliable information that could affect their family planning.

A Biomarker Panel Increases the Diagnostic Performance for Epithelial Ovarian Cancer Type I and II in Young Women.

BACKGROUND/AIM: To assess preoperative blood levels of a biomarker panel in relation to the new classification system of epithelial ovarian cancer (EOC) type I and II. PATIENTS AND METHODS: Preoperative plasma levels of B7-family protein homolog 4 (B7-H4), intact and cleaved soluble urokinase plasminogen activator receptor (suPAR), human epididymis protein 4 (HE4) and cancer antigen 125 (CA125) were analyzed in 350 patients with adnexal lesions. RESULTS: The levels of suPAR(II-III), HE4, CA125 were all higher in EOC II than in EOC I, borderline and benign ovarian tumors. B7-H4 was increased in EOC II compared with benign ovarian tumors. The combination of suPAR(II-III), HE4, CA125 and age in premenopausal women discriminates EOC and borderline tumors from benign tumors to higher accuracy compared to the Risk of Ovarian Malignancy Algorithm (p=0.007). CONCLUSION: The biomarker panel suPAR(II-III), HE4, CA125 and age in premenopausal women improved discrimination of malignant and benign ovarian tumors. The plasma levels of B7-H4 were increased in patients with EOC II compared to those with benign ovarian tumors.

Age influences the clinical significance of atypical glandular cells on cytology.

AIM: To evaluate women with atypical glandular cells (AGC) or adenocarcinoma in situ (AIS) on cytology. PATIENTS AND METHODS: Population-based data of cervical smears taken between 2008-2012 were analyzed. RESULTS: Cancer was diagnosed in 107 out of 199 patients (54%) with AGC or AIS; 30 with cervical adenocarcinoma and 77 with endometrial cancer. All women with endometrial cancer were 50 years or older. In women younger than 50 years, cervical pre-cancerous lesions were found in 44 (47%) and cervical adenocarcinoma in 24 out of 92 cases (26%). High-risk HPV infection was found in 62 out of 103 women (60%). The detection rate of high-risk HPV at finding histopathological AGC, AIS, low-grade squamous intraepithelial lesions, high-grade squamous intraepithelial lesions or cervical cancer was 98% (95% confidence interval=0.903-1.000) (54/55). CONCLUSION: AGC or AIS indicates endometrial neoplasia in women 50 years or older and pre-cancerous or invasive glandular cervical lesions in younger women. HPV testing seems to identify underlying cervical adenocarcinoma and high grade squamous intraepithelial lesions.

Comparison of use of vaginal HPV self-sampling and offering flexible appointments as strategies to reach long-term non-attending women in organized cervical screening.

BACKGROUND: Many cervical cancers occur among women who have not attended cervical screening. Strategies to reach non-attending women may improve the effectiveness of cervical screening programmes. OBJECTIVE: To compare the responses among long-term non-attending women to either (i) HPV-testing of a self-collected vaginal sample, or (ii) cytological screening with a flexible no-fee appointment for sampling at an outpatient clinic. STUDY DESIGN: Among the 242,000 women aged 32-65 years in Southern Sweden, we identified 28,635 women who had not had any cervical smears taken for >9 years. We randomized 1000 women to invitation to HPV self-sampling, and 500 women to flexible outpatient clinic appointments. Responding women received a questionnaire about their reasons for previous non-attendance. RESULTS: The response rate to HPV self-sampling was three times higher than the flexible outpatient clinic invitations (147/1000 women (14.7%) compared to 21/500 (4.2%) p<0.0001). High-risk (hr)-HPV was found in 10/147 self-sampled women (6.9%). 7/10 hr-HPV-positive women attended colposcopy, but no HSIL was found. Among the clinic-sampled women, 2/21 had hr-HPV and 1/21 had HSIL. Reasons for not attending were "uncomfortable with vaginal examination", "feel healthy", "lack of time" and "experience of unfriendly health workers". CONCLUSIONS: Although the response rate was low for both interventions, the invitation to vaginal HPV self-sampling was more effective for increasing the coverage of the screening programme. The fact that "uncomfortable with vaginal examination" was the most common reason for non-attending suggests that self-sampling could be further explored as a strategy to increase the coverage of cervical screening programmes.

Vaginal self-sampling without preservative for human papillomavirus testing shows good sensitivity.

BACKGROUND: Several strategies have been used to reach non-attending women in organized cervical-cancer-screening programs, with varying success. Self-sampling (SS) for HPV is effective for increasing coverage in screening programs, but requires expensive commercial sampling kits. OBJECTIVE: We aimed to evaluate if vaginal SS, without commercial preservatives was adequate for HPV testing. STUDY DESIGN: Women with abnormal cervical smears as determined from the organized screening program were invited to a colposcopy clinic. The 121 women were asked to insert a cotton swab into the vagina and rotate it, put the cotton swab into a sterile cryotube, break the upper part of the stick and put the cap on. Thereafter, the gynaecologist collected a liquid based cytology (LBC) sample. The presence of HPV-types in SS and LBC samples was analysed with PCR and luminex-based typing. RESULTS: High-risk-HPV (hr-HPV) DNA was found in 65 of the tested 108 SS (60%; 95% CI 0.50-0.69), whereas LBC found hr-HPV in 64/108 samples (59%; 95% CI 0.49-0.69). The agreement between sampling with SS and LBC was good, kappa value 0.67 (95% CI; 0.53-0.81). The sensitivity for SS with hr-HPV to find HSIL was 77% (95% CI; 62-91%), specificity 47% (95% CI; 35-59%) [corrected] and the sensitivity for LBC with hr-HPV to find HSIL was 79% (95% CI 66-93%), specificity 50% (95% CI; 38-62%). [corrected] CONCLUSIONS: This new vaginal self-sampling method detects hr-HPV-infections with similar sensitivity as a cervical smear taken by a gynaecologist. This self-sampling method is cost-effective and well tolerated, and the kit is suitable for regular mail transport.