Therapeutic effect of dose-dense paclitaxel plus carboplatin with or without bevacizumab for Japanese patients with epithelial ovarian cancer.

BACKGROUND: Evidence regarding chemosensitivity to different therapeutic regimens in epithelial ovarian cancer (EOC) remains limited. This study aimed to investigate EOC implementation in daily clinical practice and reveal favorable regimens for EOC among Japanese patients. METHODS: We retrospectively collected clinical data of patients newly diagnosed with EOC from 2012 to 2021 at our affiliated institutions. We evaluated overall survival (OS) and progression-free survival (PFS) of conventional paclitaxel plus carboplatin (TC) vs. dose-dense TC (ddTC) according to the eligibility of GOG262 and JGOG3016 and those with bevacizumab (BEV) vs. without BEV based on GOG218. Further, we evaluated OS and PFS of ddTC and ddTC + BEV to TC + BEV among patients with stage III/IV. RESULTS: The ddTC group (n = 402) demonstrated longer PFS and OS than the TC group (n = 165) (adjusted hazard ratios [aHRs] [95% confidential intervals (CIs)]: 0.69 [0.55-0.88] and 0.67 [0.50-0.90], respectively). The group with BEV (n = 158) demonstrated a longer PFS than those without BEV (n = 296) (0.74 [0.57-0.95]), but not for OS (0.84 [0.60-1.17]). The ddTC and ddTC + BEV groups (n = 259 and 117) demonstrated no statistically significant differences in PFS and OS than the TC + BEV group (n = 75) (1.09 [0.79-1.50] and 0.74 [0.52-1.08] for PFS and 0.89 [0.59-1.34] and 0.73 [0.50-1.05] for OS, respectively). CONCLUSION: Our study may indicate ddTC, BEV, and their combination regimen as the promising first-line chemotherapy option among Japanese patients with advanced EOC.

Annual numbers of diagnoses and medical expenses for obstetric diseases in Japan: A report from the National Database of Health Insurance Claims.

AIM: The present study aimed to estimate the total numbers of obstetric diseases diagnosed, total amounts of medical expenses claimed for obstetric diseases, their averages per livebirth, and yearly trends in Japan. METHODS: This is a secondary analysis of the National Database of Health Insurance Claims and Specific Health Checkups of Japan (NDB) (data from 2015 to 2019). The target population was women of reproductive age (15-49 years old) with diseases in pregnancy, childbirth, and the puerperium, defined by having O codes according to the International Classification of Diseases 10th Revision. We calculated the numbers of obstetric diseases diagnosed, amounts of medical expenses claimed for obstetric diseases marked with the "main injury/disease decision flag," and the totals divided by the annual numbers of livebirths, by year and women's age group. RESULTS: From 2015 to 2019, both the numbers of obstetric diseases diagnosed and amounts of medical expenses claimed for obstetric diseases per livebirth were on an upward trend, whereas the total numbers of obstetric diseases diagnosed were decreased. Women in advanced age groups had a higher number of diagnoses and a higher amount of medical expenses for obstetric diseases per livebirth. "Preterm labour without delivery" had the highest amounts of medical expenses claimed for and the second highest numbers of diagnoses throughout the study period. CONCLUSIONS: This study suggests that pregnant women in Japan would have an increasing number of obstetric complications and necessary medical expenses year by year. Further study is warranted to elucidate these trends and identify possible mitigation measures.

Association Between Birth Weight and Risk of Pregnancy-Induced Hypertension and Gestational Diabetes in Japanese Women: JPHC-NEXT Study.

BACKGROUND: Although prevalence of low birth weight has increased in the last 3 decades in Japan, no studies in Japanese women have investigated whether birth weight is associated with the risk of pregnancy complications, such as pregnancy-induced hypertension (PIH) and gestational diabetes mellitus (GDM). METHODS: We used data from the Japan Public Health Center-based Prospective Study for the Next Generation (JPHC-NEXT), a population-based cohort study in Japan that launched in 2011. In the main analysis, we included 46,365 women who had been pregnant at least once, for whom information on birth weight and events during their pregnancy was obtained using a self-administered questionnaire. Women were divided into five categories according to their birth weight, and the relationship between birth weight and risk of PIH and GDM was examined using multilevel logistic regression analyses with place of residence as a random effect. RESULTS: Compared to women born with birth weight of 3,000-3,999 grams, the risk of PIH was significantly higher among women born <1,500 grams (adjusted odd ratio [aOR] 1.60; 95% confidence interval [CI], 1.17-2.21), 1,500-2,499 grams (aOR 1.16; 95% CI, 1.03-1.30), and 2,500-2,999 grams (aOR 1.13; 95% CI, 1.04-1.22). The risk of GDM was significantly higher among women born 1,500-2,499 grams (aOR 1.20; 95% CI, 1.02-1.42), albeit non-significant association among women in other birthweight categories. CONCLUSIONS: We observed an increased risk of PIH among women born with lower birth weight albeit non-significant increased risk of GDM among Japanese women.

Antenatal screening timeline and cutoff scores of the Edinburgh Postnatal Depression Scale for predicting postpartum depressive symptoms in healthy women: a prospective cohort study.

BACKGROUND: It is worthwhile to identify women at risk of developing postpartum depression during pregnancy. This study aimed to determine the optimal time and cutoff score for antenatal screening for prediction of postpartum depressive symptoms (PDS) using the Edinburgh Postnatal Depression Scale (EPDS) and to identify risk factors for PDS. METHODS: The target population was healthy pregnant women receiving antenatal care at a university hospital in Tokyo, Japan. During the first, second, and third trimesters, 3-4 days postpartum, and one month postpartum, they were asked to take the Japanese version of the EPDS questionnaire. The primary outcome of the study was PDS, defined as an EPDS score ≥ 9 at one month postpartum. The area under the receiver operating characteristics curve (AUC), sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of EPDS scores at each antenatal screening time were calculated. RESULTS: From 139 pregnant women, 129 were successfully followed up throughout the study. The number of women with an EPDS score ≥ 9 during the first, second, and third trimesters, 3-4 days postpartum, and one month postpartum were 6/126 (4.8%), 9/124 (7.3%), 5/117 (4.3%), 17/123 (13.8%), and 15/123 (12.2%), respectively. Screening during the second trimester had the highest AUC to predict PDS (0.89) among antenatal screenings. The optimal EPDS cutoff score during the second trimester was 4/5 (sensitivity: 85.7%; specificity: 77.1%; PPV: 33.3%; NPV: 97.6%). An EPDS score ≥ 5 during the second trimester (adjusted odds ratio [aOR]: 15.9; 95% confidence interval [95%CI]: 3.2-78.1) and a family history of mental illness (aOR: 4.5; 95%CI: 1.2-17.5) were significantly associated with PDS. CONCLUSIONS: Our study suggests that the EPDS score at the second trimester with the cutoff value of 4/5 may be adequate for initial screening for prediction of PDS. Women with an EPDS score ≥ 5 at the second trimester require more elaborate follow-up.

Lack of catch-up in weight gain may intermediate between pregnancies with hyperemesis gravidarum and reduced fetal growth: the Japan Environment and Children's Study.

BACKGROUND: Women with nausea and vomiting of pregnancy (NVP) have higher birth weight infants, while those with hyperemesis gravidarum, a severe manifestation of NVP, have lower birth weight infants. We aimed to investigate the associations between maternal weight loss (a consequence of hyperemesis gravidarum), NVP, and infant birth weight. METHODS: This study was a secondary analysis of a nationwide birth cohort in Japan. Singleton pregnancies delivered at 28-41 weeks of gestation were included in the analysis. Women were categorized based on their weight change in the 1st trimester (as a proportion to their pre-pregnancy weight: > + 3%, > 0 to + 3%, > -3 to 0%, > -5 to -3%, ≤ -5%) and severity of NVP (no nausea, only nausea, vomiting but able to eat, vomiting and unable to eat). The effects of weight change and severity of NVP on infant birth weight and small for gestational age (SGA) were assessed using regression models. We further examined how these effects could be modified by maternal weight gain up to the 2nd trimester. RESULTS: Among 91,313 women, 5,196 (5.7%) lost ≥ 5% of their pre-pregnancy weight and 9,983 (10.9%) experienced vomiting and were unable to eat in the 1st trimester. Women with weight loss ≥ 5% in the 1st trimester had infants 66 (95% CI: 53, 78) g lighter and higher odds of SGA (aOR: 1.29; 95% CI: 1.14, 1.47) than women who gained > 3% during the same period. However, when adjusting for weight gain up to the 2nd trimester, women with weight loss ≥ 5% in the 1st trimester had infants 150 (95% CI: 135, 165) g heavier and lower odds of SGA (aOR: 0.39; 95% CI: 0.33, 0.46) than those who gained > 3% during the same period. In contrast, women with more severe NVP tended to have infants with larger birth weight and lower odds of SGA compared to women without NVP. These trends were strengthened when adjusting for weight gain up to the 2nd trimester. CONCLUSIONS: Our study suggests the possibility that reduced fetal growth in pregnancies with hyperemesis gravidarum may be caused by the lack of catch-up in gestational weight gain up to the 2nd trimester.

External validation of prognostic models predicting pre-eclampsia: individual participant data meta-analysis.

BACKGROUND: Pre-eclampsia is a leading cause of maternal and perinatal mortality and morbidity. Early identification of women at risk during pregnancy is required to plan management. Although there are many published prediction models for pre-eclampsia, few have been validated in external data. Our objective was to externally validate published prediction models for pre-eclampsia using individual participant data (IPD) from UK studies, to evaluate whether any of the models can accurately predict the condition when used within the UK healthcare setting. METHODS: IPD from 11 UK cohort studies (217,415 pregnant women) within the International Prediction of Pregnancy Complications (IPPIC) pre-eclampsia network contributed to external validation of published prediction models, identified by systematic review. Cohorts that measured all predictor variables in at least one of the identified models and reported pre-eclampsia as an outcome were included for validation. We reported the model predictive performance as discrimination (C-statistic), calibration (calibration plots, calibration slope, calibration-in-the-large), and net benefit. Performance measures were estimated separately in each available study and then, where possible, combined across studies in a random-effects meta-analysis. RESULTS: Of 131 published models, 67 provided the full model equation and 24 could be validated in 11 UK cohorts. Most of the models showed modest discrimination with summary C-statistics between 0.6 and 0.7. The calibration of the predicted compared to observed risk was generally poor for most models with observed calibration slopes less than 1, indicating that predictions were generally too extreme, although confidence intervals were wide. There was large between-study heterogeneity in each model's calibration-in-the-large, suggesting poor calibration of the predicted overall risk across populations. In a subset of models, the net benefit of using the models to inform clinical decisions appeared small and limited to probability thresholds between 5 and 7%. CONCLUSIONS: The evaluated models had modest predictive performance, with key limitations such as poor calibration (likely due to overfitting in the original development datasets), substantial heterogeneity, and small net benefit across settings. The evidence to support the use of these prediction models for pre-eclampsia in clinical decision-making is limited. Any models that we could not validate should be examined in terms of their predictive performance, net benefit, and heterogeneity across multiple UK settings before consideration for use in practice. TRIAL REGISTRATION: PROSPERO ID: CRD42015029349 .

Delivery mode and maternal and neonatal outcomes of combined spinal-epidural analgesia compared with no analgesia in spontaneous labor: A single-center observational study in Japan.

AIM: We aimed to assess the outcomes of combined spinal-epidural (CSE) analgesia compared with no analgesia in spontaneous labor. METHODS: We performed a retrospective cohort study of deliveries between 2008 and 2014 comparing two groups based on the use of CSE analgesia in both nulliparous and multiparous women. Adjusted odds ratios (aOR) were calculated using logistic regression analysis. RESULTS: Among 5247 (3334 nulliparous, 1913 multiparous) singleton deliveries, 3041 (2045, 996, respectively) patients received CSE analgesia and 2206 (1289, 917, respectively) had no analgesia. CSE analgesia was associated with increased risk of oxytocin augmentation (P < 0.01), prolonged duration of labor (P < 0.01), instrumental delivery (aOR, 3.35; 95% confidence interval (CI), 2.69-4.19 for nulliparous and aOR, 2.13; 95% CI, 1.32-3.53 for multiparous women), blood loss volume during vaginal delivery (P < 0.01), meconium-stained amniotic fluid (aOR, 1.23; 95% CI, 1.02-1.51 and aOR, 1.39; 95% CI, 1.01-1.93) and Apgar score less than 7 at 1 min (aOR, 1.85; 95% CI, 1.28-2.74 and aOR, 2.65; 95% CI, 1.35-5.61) in both nulliparous and multiparous women, respectively, and umbilical arterial blood gas pH less than 7.15 (aOR, 2.69; 95% CI, 1.35-5.75) and umbilical arterial blood gas pH less than 7.10 (aOR, 3.69; 95% CI, 1.11-16.69) in multiparous women. There was no significant difference in incidence of cesarean delivery or Apgar score less than 7 at 5 min. CONCLUSION: We observed several increased risks in obstetric and neonatal outcomes among pregnant women who received CSE analgesia during labor. Preparations for these risks are needed when administering CSE analgesia during labor.

Positive airway pressure therapy for the treatment of central sleep apnoea associated with heart failure.

BACKGROUND: Ischaemic heart disease including heart failure is the most common cause of death in the world, and the incidence of the condition is rapidly increasing. Heart failure is characterised by symptoms such as fatigue and breathlessness during light activity, as well as disordered breathing during sleep. In particular, sleep disordered breathing (SDB), including central sleep apnoea (CSA) and obstructive sleep apnoea (OSA), is highly prevalent in people with chronic heart failure. A previous meta-analysis demonstrated that positive airway pressure (PAP) therapy dramatically increased the survival rate of people with heart failure who had CSA, and thus could contribute to improving the prognosis of these individuals. However, recent trials found that adaptive servo-ventilation (ASV) including PAP therapy had a higher risk of all-cause mortality and cardiovascular mortality. A meta-analysis that included recent trials was therefore needed. OBJECTIVES: To assess the effects of positive airway pressure therapy for people with heart failure who experience central sleep apnoea. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) in the Cochrane Library, MEDLINE, Embase, and Web of Science Core Collection on 7 February 2019 with no limitations on date, language, or publication status. We also searched two clinical trials registers in July 2019 and checked the reference lists of primary studies. SELECTION CRITERIA: We excluded cross-over trials and included individually randomised controlled trials, reported as full-texts, those published as abstract only, and unpublished data. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted outcome data from the included studies. We double-checked that data had been entered correctly by comparing the data presented in the systematic review with study reports. We analysed dichotomous data as risk ratios (RRs) with 95% confidence intervals (CIs) and continuous data as mean difference (MD) or standardised mean difference (SMD) with 95% CIs. Furthermore, we performed subgroup analysis in the ASV group or continuous PAP group separately. We used GRADEpro GDT software to assess the quality of evidence as it relates to those studies that contribute data to the meta-analyses for the prespecified outcomes. MAIN RESULTS: We included 16 randomised controlled trials involving a total of 2125 participants. The trials evaluated PAP therapy consisting of ASV or continuous PAP therapy for 1 to 31 months. Many trials included participants with heart failure with reduced ejection fraction. Only one trial included participants with heart failure with preserved ejection fraction. We are uncertain about the effects of PAP therapy on all-cause mortality (RR 0.81, 95% CI 0.54 to 1.21; participants = 1804; studies = 6; I2 = 47%; very low-quality evidence). We found moderate-quality evidence of no difference between PAP therapy and usual care on cardiac-related mortality (RR 0.97, 95% CI 0.77 to 1.24; participants = 1775; studies = 5; I2 = 11%). We found low-quality evidence of no difference between PAP therapy and usual care on all-cause rehospitalisation (RR 0.95, 95% CI 0.70 to 1.30; participants = 1533; studies = 5; I2 = 40%) and cardiac-related rehospitalisation (RR 0.97, 95% CI 0.70 to 1.35; participants = 1533; studies = 5; I2 = 40%). In contrast, PAP therapy showed some indication of an improvement in quality of life scores assessed by all measurements (SMD -0.32, 95% CI -0.67 to 0.04; participants = 1617; studies = 6; I2 = 76%; low-quality evidence) and by the Minnesota Living with Heart Failure Questionnaire (MD -0.51, 95% CI -0.78 to -0.24; participants = 1458; studies = 4; I2 = 0%; low-quality evidence) compared with usual care. Death due to pneumonia (N = 1, 3% of PAP group); cardiac arrest (N = 18, 3% of PAP group); heart transplantation (N = 8, 1% of PAP group); cardiac worsening (N = 3, 9% of PAP group); deep vein thrombosis/pulmonary embolism (N = 1, 3% of PAP group); and foot ulcer (N = 1, 3% of PAP group) occurred in the PAP therapy group, whereas cardiac arrest (N = 16, 2% of usual care group); heart transplantation (N = 12, 2% of usual care group); cardiac worsening (N = 5, 14% of usual care group); and duodenal ulcer (N = 1, 3% of usual care group) occurred in the usual care group across three trials. AUTHORS' CONCLUSIONS: The effect of PAP therapy on all-cause mortality was uncertain. In addition, although we found evidence that PAP therapy did not reduce the risk of cardiac-related mortality and rehospitalisation, there was some indication of an improvement in quality of life for heart failure patients with CSA. Furthermore, the evidence was insufficient to determine whether adverse events were more common with PAP than with usual care. These findings were limited by low- or very low-quality evidence. PAP therapy may be worth considering for individuals with heart failure to improve quality of life.

Complications and adverse outcomes in pregnancy and childbirth among women who conceived by assisted reproductive technologies: a nationwide birth cohort study of Japan environment and children's study.

BACKGROUND: Although pregnancies conceived by assisted reproductive technology (ART) have a higher risk of maternal/perinatal complications, the overall risk of adverse outcomes necessitating advanced obstetric care has not been closely examined. The present study aimed to assess and compare the risk of maternal/perinatal complications and adverse outcomes in pregnancy and childbirth conceived by ART with those conceived naturally. METHODS: This study was conducted as a part of the Japan environment and children's study (JECS), an ongoing nationwide birth cohort study in Japan. The risk of maternal/perinatal complications and adverse outcomes was assessed by mode of conception (natural conception, ovulation induction [OI] without ART, conventional in vitro fertilization and embryo transfer [IVF-ET], or intracytoplasmic sperm injection [ICSI]) using logistic regression and generalized estimating equations controlling for potential confounders. RESULTS: The final dataset included women who conceived naturally (N = 90,506), by OI without ART (N = 3939), by conventional IVF-ET (N = 1476), and by ICSI (N = 1671). Compared with women who conceived naturally, those who conceived by conventional IVF-ET were at higher risk of placenta previa (adjusted OR 2.90 [95% CI 1.94, 4.34]), morbidly adherent placenta (6.85 [3.88, 12.13]), and pregnancy-induced hypertension (1.40 [1.10, 1.78]) whereas those who conceived by ICSI had a higher risk of placental abruption (2.16 [1.20, 3.88]) as well as placenta previa (2.01 [1.29, 3.13]) and morbidly adherent placenta (7.81 [4.56, 13.38]). Women who conceived by ART had a higher risk of blood transfusion (conventional IVF-ET: 3.85 [2.52, 5.88]; ICSI: 3.76 [2.49, 5.66]) and ICU admission (conventional IVF-ET: 2.58 [1.11, 6.01]; ICSI: 3.45 [1.68, 7.06]) even after controlling for potential confounders. Neonates conceived by ART had a higher risk of preterm birth (conventional IVF-ET: 1.42 [1.13, 1.78]; ICSI: 1.31 [1.05, 1.64]). CONCLUSIONS: Women who conceived by ART had a higher risk of maternal/perinatal complications necessitating advanced obstetric care. Obstetricians should be aware of the increased risk of adverse outcomes among this population.

Optimal protein intake during pregnancy for reducing the risk of fetal growth restriction: the Japan Environment and Children's Study.

Clinical trials show that protein supplement increases infant size in malnourished populations; however, epidemiological studies in high-income countries have reported mixed results. Although these findings suggest a non-linear relationship between maternal macronutrient intake and fetal growth, this relationship has not been closely examined. We assessed the association between maternal protein intake and fetal growth among 91 637 Japanese women with singletons in a nation-wide cohort study using validated FFQ. The respondents answered the FFQ twice, once during early pregnancy (FFQ1; 16·3 (sd 6·0) weeks), and second during mid-pregnancy (FFQ2, 28·1 (sd 4·1) weeks). Daily energy intake and percentage energy from protein, fats and carbohydrates were 7477 (sd 2577) kJ and 13·5 (sd 2·0), 29·5 (sd 6·5) and 55·3 (sd 7·8) %, respectively, for FFQ1, and 7184 (sd 2506) kJ and 13·6 (sd 2·1), 29·8 (sd 6·6) and 55·3 (sd 7·9) %, respectively, for FFQ2. The average birth weight was 3028 (sd 406) g, and 6350 infants (6·9 %) were small for gestational age (SGA). In both phases of the survey, birth weight was highest and the risk of SGA was lowest when the percentage energy from protein was 12 %, regardless of whether isoenergetic replacement was with fat or carbohydrates. Furthermore, when protein density in the maternal diet was held constant, birth weight was highest when 25 % of energy intake came from fat and 61 % came from carbohydrates during early pregnancy. We found maternal protein intake to have an inverse U-curve relationship with fetal growth. Our results strongly suggest that the effect of protein on birth weight is non-linear, and that a balanced diet fulfilling the minimum requirement for all macronutrients was ideal for avoiding fetal growth restriction.

Risk factors of long hospital stay for immunoglobulin A vasculitis: Single-center study.

BACKGROUND: Immunoglobulin A (IgA) vasculitis is a common, systemic childhood disease that occasionally interferes with oral intake of food and necessitates hospitalization. In Japan, there are no reports on the length of hospitalization or factors related to long-term hospitalization in children with IgA vasculitis. In this study, we investigated the factors related to long-term hospitalization. METHODS: We reviewed the medical records of children aged ≤15 years with IgA vasculitis who were admitted to the National Center for Child Health and Development (Tokyo, Japan) between March 2008 and April 2017. We reviewed their gender, age, previous episodes, digestive symptoms, fever, laboratory data, urine analysis, ultrasound, and use of glucocorticoid on admission day. We compared the long-stay (≥10 days) group (L) and the short-stay (≤9 days) group (S) on logistic regression analysis. RESULTS: Of the 68 children included in the analysis, 34 were male, and the average age was 71.9 ± 26.4 months. The median period of hospitalization was 10.5 days (range, 0.5-75 days), and 36 children were allocated to group L. In the logistic regression model including age, gender, gastrointestinal (GI) bleeding, and use of glucocorticoid, male sex (OR: 4.2; 95%CI: 1.3-13.5) and GI bleeding (OR: 7.6; 95%CI: 1.4-41.5) were significantly associated with hospitalization ≥10 days. CONCLUSIONS: In children with IgA vasculitis, male patients and those with GI bleeding were more likely to have a hospital stay ≥10 days.

Prognostic impact of interleukin-6 expression in stage I ovarian clear cell carcinoma.

OBJECTIVE: Ovarian clear cell carcinoma (OCCC) frequently presents at an early stage. In stage I OCCC, the prognosis differs according to substage. In particular, predictive biomarkers and new treatment strategies are needed for stage IC2/IC3 disease. We investigated tumor biology and prognostic factors for stage I OCCC from a clinicopathological perspective, including the expression of ARID1A and IL-6, which are considered critical for OCCC carcinogenesis. METHODS: A retrospective cohort study of 192 patients with stage I OCCC treated at a single institution was performed. We calculated overall survival (OS) with respect to 12 clinicopathological parameters that included the unique and diverse histological features of OCCC. RESULTS: The estimated 5-year OS rate in patients with all stage I OCCC was 88.9% during a median of 91months of follow-up. The multivariate analysis indicated that substage classification and IL-6 expression status were associated with poor OS (p=0.010 and p=0.027, respectively). Loss of ARID1A expression had no impact on survival; however, it was associated with substage (p=0.001), capsule rupture status (p=0.011), and ascites cytology (p=0.016). No clear association was found between ARID1A and IL-6 expressions. Histological findings, including the presence of endometriosis, adenofibroma, architectural pattern, and tumor cell type, showed no prognostic effects. CONCLUSIONS: Both substage classification and IL-6 expression status may be independent prognostic factors in stage I OCCC. Therefore, IL-6 molecular stratification may be crucial in optimizing therapeutic strategies for early stage OCCC to improve survival.

Cost-effectiveness analysis of different types of human papillomavirus vaccination combined with a cervical cancer screening program in mainland China.

BACKGROUND: China has a high prevalence of human papillomavirus (HPV) and a consequently high burden of disease with respect to cervical cancer. The HPV vaccine has proved to be effective in preventing cervical cancer and is now a part of routine immunization programs worldwide. It has also proved to be cost effective. This study aimed to assess the cost-effectiveness of 2-, 4-, and 9-valent HPV vaccines (hereafter, HPV2, 4 or 9) combined with current screening strategies in China. METHODS: A Markov model was developed for a cohort of 100,000 HPV-free girls to simulate the natural history to HPV infection. Three recommended screening methods (1. liquid-based cytology test + HPV DNA test; 2. pap smear cytology test + HPV DNA test; 3. visual inspection with acetic acid) and three types of HPV vaccination program (HPV2/4/9) were incorporated into 15 intervention options, and the incremental cost-effectiveness ratio (ICER) was calculated to determine the dominant strategies. Costs, transition probabilities and utilities were obtained from a review of the literature and national databases. One-way sensitivity analyses and threshold analyses were performed for key variables in different vaccination scenarios. RESULTS: HPV9 combined with screening showed the highest health impact in terms of reducing HPV-related diseases and increasing the number of quality-adjusted life years (QALYs). Under the current thresholds of willingness to pay (WTP, 3 times the per capita GDP or USD$ 23,880), HPV4/9 proved highly cost effective, while HPV2 combined with screening cost more and was less cost effective. Only when screening coverage increased to 60% ~ 70% did the HPV2 and screening combination strategy become economically feasible. CONCLUSIONS: The combination of the HPV4/9 vaccine with current screening strategies for adolescent girls was highly cost-effective and had a significant impact on reducing the HPV infection-related disease burden in Mainland China.

Adjuvant therapy after radical surgery for stage IB-IIB cervical adenocarcinoma with risk factors.

OBJECTIVE: Patients with adeno/adenosquamous carcinoma may have a poorer prognosis than patients with squamous cell carcinoma. Radiotherapy and concurrent chemoradiotherapy are used as adjuvant therapies for cervical cancer, regardless of the histological subtype. The aim of this study was to investigate the prognostic outcome of adjuvant therapy for patients with adeno/adenosquamous carcinoma with pathological risk factors. METHODS: The medical records of 135 patients with stage IB-IIB cervical cancer with squamous cell carcinoma or adeno/adenosquamous carcinoma who underwent primary surgery followed by adjuvant therapy were retrospectively reviewed. Patients with a pathologically confirmed bulky tumor (≥4 cm), nodal metastasis and/or parametrium invasion were included in the study. RESULTS: The median follow-up period was 48 (1-132) months. Of the 135 patients, 90 with squamous cell carcinoma and 23 with adeno/adenosquamous carcinoma were treated with adjuvant radiotherapy and concurrent chemoradiotherapy (SCC-RT/CCRT and AC-RT/CCRT groups), and 22 with adeno/adenosquamous carcinoma were treated with adjuvant systemic chemotherapy (AC-CT group). There were no significant differences in clinicopathological factors between the SCC-RT/CCRT and AC-RT/CCRT groups and between the AC-RT/CCRT and AC-CT groups. Progression-free survival was significantly shorter in the AC-RT/CCRT group compared to the SCC-RT/CCRT group (P = 0.002). Adeno/adenosquamous carcinoma histology and multiple lymph node metastasis were independent prognostic factors for shorter progression-free survival in patients treated with adjuvant radiotherapy and concurrent chemoradiotherapy. Progression-free survival was also significantly shorter in the AC-RT/CCRT group compared to the AC-CT group (P = 0.026). CONCLUSIONS: Adjuvant radiotherapy and concurrent chemoradiotherapy may be less effective for patients with adeno/adenosquamous carcinoma than for those with squamous cell carcinoma. Adjuvant systemic chemotherapy may be beneficial for adeno/adenosquamous carcinoma and further studies are warranted.

Pre-pregnancy BMI-specific optimal gestational weight gain for women in Japan.

BACKGROUND: The Institute of Medicine (IOM) guidelines are the most widely used guidelines on gestational weight gain; however, accumulation of evidence that body composition in Asians differs from other races has brought concern regarding whether their direct application is appropriate. We aimed to study to what extent optimal gestational weight gain among women in Japan differs by pre-pregnancy body mass index (BMI) and to compare estimated optimal gestational weight gain to current Japanese and Institute of Medicine (IOM) recommendations. METHODS: We retrospectively studied 104,070 singleton pregnancies among nulliparous women in 2005-2011 using the Japanese national perinatal network database. In five pre-pregnancy BMI sub-groups (17.0-18.4, 18.5-19.9, 20-22.9, 23-24.9, and 25-27.4 kg/m2), we estimated the association of the rate of gestational weight gain with pregnancy outcomes (fetal growth, preterm delivery, and delivery complications) using multivariate regression. RESULTS: Weight gain rate associated with the lowest risk of adverse outcomes decreased with increasing BMI (12.2 kg, 10.9 kg, 9.9 kg, 7.7 kg, and 4.3 kg/40 weeks) for the five BMI categories as described above, respectively. Current Japanese guidelines were lower than optimal gains, with the lowest risk of adverse outcomes for women with BMI below 18.5 kg/m2, and current IOM recommendations were higher than optimal gains for women with BMI over 23 kg/m2. CONCLUSION: Optimal weight gain during pregnancy varies largely by pre-pregnancy BMI, and defining those with BMI over 23 kg/m2 as overweight, as proposed by the World Health Organization, may be useful when applying current IOM recommendations to Japanese guidelines.

Assessment and support during early labour for improving birth outcomes.

BACKGROUND: The progress of labour in the early or latent phase is usually slow and may include painful uterine contractions. Women may feel distressed and lose their confidence during this phase. Support and assessment interventions have been assessed in two previous Cochrane Reviews. This review updates and replaces these two reviews, which have become out of date. OBJECTIVES: To investigate the effectiveness of assessment and support interventions for women during early labour.In order to measure the effectiveness of the interventions, we compared the duration of labour, the rate of obstetrical interventions, and the rate of other maternal or neonatal outcomes. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register, ClinicalTrials.gov, the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (31 October 2016) and reference lists of retrieved studies. SELECTION CRITERIA: Randomised controlled trials of any assessment or support intervention in the latent phase of labour. We planned to include cluster-randomised trials if they were eligible. We did not include quasi-randomised trials. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trials for inclusion and risk of bias, extracted data and checked them for accuracy. We resolved any disagreement by discussion or by involving a third assessor. The quality of the evidence was assessed using the GRADE approach. MAIN RESULTS: We included five trials with a total of 10,421 pregnant women in this review update. The trials were conducted in the UK, Canada and America. The trials compared interventions in early labour versus usual care. We examined three comparisons: early labour assessment versus immediate admission to hospital; home visits by midwives versus usual care (telephone triage); and one-to-one structured midwifery care versus usual care. These trials were at moderate- risk of bias mainly because blinding women and staff to these interventions is not generally feasible. For important outcomes we assessed evidence using GRADE; we downgraded evidence for study design limitations, imprecision, and where we carried out meta-analysis, for inconsistency.One trial with 209 women compared early labour assessment with direct admission to hospital. Duration of labour from the point of hospital admission was reduced for women in the assessment group (mean difference (MD) -5.20 hours, 95% confidence interval (CI) -7.06 to -3.34; 209 women, low-quality evidence). There were no clear differences between groups for the number of women undergoing caesarean section or instrumental vaginal birth (risk ratio (RR) 0.72, 95% CI 0.30 to 1.72, very low quality evidence; and, RR 0.86, 95% CI 0.58 to 1.26, very low quality evidence, respectively). Serious maternal morbidity was not reported. Women in the early assessment group were slightly less likely to have epidural anaesthesia (RR 0.87, 95% CI 0.78 to 0.98, low-quality evidence), and considerably less likely to have oxytocin for labour augmentation (RR 0.57, 95% CI 0.37 to 0.86) and this group also had increased satisfaction with their care compared with women in the immediate admission group (MD 16.00, 95% CI 7.53 to 24.47). No babies were born before admission to hospital and only one infant had a low Apgar score at five minutes after the birth (very low quality evidence). Admission to neonatal special care was not reported.Three studies examined home assessment and midwifery support versus telephone triage. One trial reported the duration of labour; home visits did not appear to have any clear impact compared with usual care (MD 0.29 hours, 95% CI -0.14 to 0.72; 1 trial, 3474 women, low-quality evidence). There was no clear difference for the rate of caesarean section (RR 1.05, 95% CI 0.95 to 1.17; 3 trials, 5170 women; I² = 0%; moderate-quality evidence) or the rate of instrumental vaginal birth (average RR 0.95, 95% CI 0.79 to 1.15; 2 trials, 4933 women; I² = 69%; low-quality evidence). One trial reported birth before arrival at hospital or unplanned home birth; there was no clear difference between the groups (RR 1.33, 95% CI 0.30 to 5.95; 1 trial, 3474 women). No clear differences were identified for serious maternal morbidity (RR 0.93, 95% CI 0.61 to 1.42; 1 trial, 3474 women; low-quality evidence), or use of epidural (average RR 0.95, 95% CI 0.87 to 1.05; 3 trials, 5168 women; I² = 60%; low-quality evidence). There were no clear differences for neonatal admission to special care (average RR 0.84, 95% CI 0.50 to 1.42; 3 trials, 5170 infants; I² = 71%; very low quality evidence), or for Apgar score less than seven at five minutes after birth (RR 1.19, 95% CI 0.71 to 1.99; 3 trials, 5170 infants; I² = 0%; low-quality evidence).One study, with 5002 women, examined one-to-one structured care in early labour versus usual care. Length of labour was not reported. There were no clear differences between groups for the rate of caesarean section (RR 0.93, 95% CI 0.84 to 1.02; 4996 women, high-quality evidence), or for instrumental vaginal birth (RR 0.94, 95% CI 0.82 to 1.08; 4996 women, high-quality evidence). No clear differences between groups were reported for serious maternal morbidity (RR 1.13, 95% CI 0.84 to 1.52; 4996 women, moderate-quality evidence). Use of epidural was similar in the two groups (RR 1.00, 95% CI 0.99 to 1.01; 4996 women, high-quality evidence). For infant outcomes, there were no clear differences between groups (admission to neonatal intensive care unit: RR 0.98, 95% CI 0.80 to 1.21; 4989 infants, high-quality evidence; Apgar score less than seven at five minutes: RR 1.07, 95% CI 0.64 to 1.79; 4989 infants, moderate-quality evidence). AUTHORS' CONCLUSIONS: Assessment and support in early labour does not have a clear impact on rate of caesarean section or instrumental vaginal birth, or whether the baby was born before arrival at hospital or in an unplanned home birth. However, evidence suggested that interventions may have an impact on reducing the use of epidural anaesthesia, labour augmentation and on increasing maternal satisfaction with giving birth. Evidence about the effectiveness of early labour assessment versus immediate admission was very limited and more research is needed in this area.

Zika virus infection in pregnancy: a systematic review of disease course and complications.

OBJECTIVES: To characterize maternal Zika virus (ZIKV) infection and complement the evidence base for the WHO interim guidance on pregnancy management in the context of ZIKV infection. METHODS: We searched the relevant database from inception until March 2016. Two review authors independently screened and assessed full texts of eligible reports and extracted data from relevant studies. The quality of studies was assessed using the Newcastle-Ottawa Scale (NOS) and the National Institute of Health (NIH) tool for observational studies and case series/reports, respectively. RESULTS: Among 142 eligible full-text articles, 18 met the inclusion criteria (13 case series/reports and five cohort studies). Common symptoms among pregnant women with suspected/confirmed ZIKV infection were fever, rash, and arthralgia. One case of Guillain-Barré syndrome was reported among ZIKV-infected mothers, no other case of severe maternal morbidity or mortality reported. Complications reported in association with maternal ZIKV infection included a broad range of fetal and newborn neurological and ocular abnormalities; fetal growth restriction, stillbirth, and perinatal death. Microcephaly was the primary neurological complication reported in eight studies, with an incidence of about 1% among newborns of ZIKV infected women in one study. CONCLUSION: Given the extensive and variable fetal and newborn presentations/complications associated with prenatal ZIKV infection, and the dearth of information provided, knowledge gaps are evident. Further research and comprehensive reporting may provide a better understanding of ZIKV infection in pregnancy and attendant maternal/fetal complications. This knowledge could inform the creation of effective and evidence-based strategies, guidelines and recommendations aimed at the management of maternal ZIKV infection. Adherence to current best practice guidelines for prenatal care among health providers is encouraged, in the context of maternal ZIKV infection.

Inter-prefecture disparity in under-5 mortality: 115 year trend in Japan.

BACKGROUND: Child poverty is a growing, serious issue in Japan, where various social disparities are increasing. Numerous reports have focused on the relationship between social inequity and health, but few studies have assessed how the overall magnitude of disparities in child health has changed in the course of drastic social and economic transitions from 1899 to more recent times. In this study, we assessed the trend of the under-5 mortality rate (U5MR) and its inter-prefecture disparity in Japan. METHODS: This is a secondary analysis of Japan's vital statistics data from 1899 to 2014 (115 years), which covers a core period of modern Japan. We calculated the U5MR of each prefecture and its Theil index by year to assess the trend of inter-prefecture disparity in child health from 1899 to 2014. RESULTS: The U5MR monotonically decreased from 238 per 1,000 births in 1899 to 3 in 2014. The Theil index of the U5MR increased in the post-war period, peaked in 1962 (0.027) and gradually reduced to <0.01 in the 1970s. In the 2000s, however, even though U5MR continued to decrease, the Theil index started to increase, and in 2014 (0.013) it exceeded that in 1970 and was more similar to that before World War II. CONCLUSIONS: The disparities in child health appear to be widening, and may serve as a warning to today's society that increasing socioeconomic gradients may lead to rising health inequity among children. Further investigations into the causes, mechanisms, and possible interventions are needed.

Antitumor effects of interleukin-6 (IL-6)/interleukin-6 receptor (IL-6R) signaling pathway inhibition in clear cell carcinoma of the ovary.

Among epithelial ovarian cancers, clear cell carcinoma of the ovary (CCC) has unique clinical and molecular characteristics that include chemoresistance resulting in poor prognosis. It was shown that CCC recently was characterized by specific upregulation of the IL-6/IL-6R-signal transducer and activator of transcription 3 (Stat3) signaling pathway. In this study, we aim to clarify whether IL-6/IL-6R mediated signaling pathway could have clinical relations with CCC and to evaluate inhibitory effects of the pathway on CCC carcinogenesis. A total of 84 CCC cases collected from primary surgical specimens were evaluated by the immunohistochemical analysis for IL-6R and phosphorylated Stat3 (pStat3), and we found that high IL-6R expression correlated with poor patient survival both by the univariate and multivariate analyses, suggesting that IL-6/IL-6R signaling pathway could be implicated in the progression of CCC. We further investigated the effects of IL-6/IL-6R mediated signaling pathway inhibition either by IL-6R small interfering RNA (siRNA) approach or humanized anti-human IL-6R antibody (tocilizumab) in CCC. Inhibition of endogenous IL-6R including tocilizumab in CCC cells did reduce cell invasion ability and restored their response to cytotoxic reagent. These data suggest that IL-6/IL-6R signaling pathway could act on CCC cells to enhance invasion and chemoresistance and, therefore, targeting IL-6/IL-6R mediated signaling pathway could be a promising therapeutic strategy for CCC.

Vitamin C supplementation in pregnancy.

BACKGROUND: Vitamin C supplementation may help reduce the risk of pregnancy complications such as pre-eclampsia, intrauterine growth restriction and maternal anaemia. There is a need to evaluate the efficacy and safety of vitamin C supplementation in pregnancy. OBJECTIVES: To evaluate the effects of vitamin C supplementation, alone or in combination with other separate supplements on pregnancy outcomes, adverse events, side effects and use of health resources. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (31 March 2015) and reference lists of retrieved studies. SELECTION CRITERIA: All randomised or quasi-randomised controlled trials evaluating vitamin C supplementation in pregnant women. Interventions using a multivitamin supplement containing vitamin C or where the primary supplement was iron were excluded. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trials for inclusion and risk of bias, extracted data and checked them for accuracy. MAIN RESULTS: Twenty-nine trials involving 24,300 women are included in this review. Overall, 11 trials were judged to be of low risk of bias, eight were high risk of bias and for 10 trials it was unclear. No clear differences were seen between women supplemented with vitamin C alone or in combination with other supplements compared with placebo or no control for the risk of stillbirth (risk ratio (RR) 1.15, 95% confidence intervals (CI) 0.89 to 1.49; 20,038 participants; 11 studies; I² = 0%; moderate quality evidence), neonatal death (RR 0.79, 95% CI 0.58 to 1.08; 19,575 participants; 11 studies; I² = 0%), perinatal death (average RR 1.07, 95% CI 0.77 to 1.49; 17,105 participants; seven studies; I² = 35%), birthweight (mean difference (MD) 26.88 g, 95% CI -18.81 to 72.58; 17,326 participants; 13 studies; I² = 69%), intrauterine growth restriction (RR 0.98, 95% CI 0.91 to 1.06; 20,361 participants; 12 studies; I² = 15%; high quality evidence), preterm birth (average RR 0.99, 95% CI 0.90 to 1.10; 22,250 participants; 16 studies; I² = 49%; high quality evidence), preterm PROM (prelabour rupture of membranes) (average RR 0.98, 95% CI 0.70 to 1.36; 16,825 participants; 10 studies; I² = 70%; low quality evidence), term PROM (average RR 1.26, 95% CI 0.62 to 2.56; 2674 participants; three studies; I² = 87%), and clinical pre-eclampsia (average RR 0.92, 95% CI 0.80 to 1.05; 21,956 participants; 16 studies; I² = 41%; high quality evidence).Women supplemented with vitamin C alone or in combination with other supplements compared with placebo or no control were at decreased risk of having a placental abruption (RR 0.64, 95% CI 0.44 to 0.92; 15,755 participants; eight studies; I² = 0%; high quality evidence) and had a small increase in gestational age at birth (MD 0.31, 95% CI 0.01 to 0.61; 14,062 participants; nine studies; I² = 65%), however they were also more likely to self-report abdominal pain (RR 1.66, 95% CI 1.16 to 2.37; 1877 participants; one study). In the subgroup analyses based on the type of supplement, vitamin C supplementation alone was associated with a reduced risk of preterm PROM (average RR 0.66, 95% CI 0.48 to 0.91; 1282 participants; five studies; I² = 0%) and term PROM (average RR 0.55, 95% CI 0.32 to 0.94; 170 participants; one study). Conversely, the risk of term PROM was increased when supplementation included vitamin C and vitamin E (average RR 1.73, 95% CI 1.34 to 2.23; 3060 participants; two studies; I² = 0%). There were no differences in the effects of vitamin C on other outcomes in the subgroup analyses examining the type of supplement. There were no differing patterns in other subgroups of women based on underlying risk of pregnancy complications, timing of commencement of supplementation or dietary intake of vitamin C prior to trial entry. The GRADE quality of the evidence was high for intrauterine growth restriction, preterm birth, and placental abruption, moderate for stillbirth and clinical pre-eclampsia, low for preterm PROM. AUTHORS' CONCLUSIONS: The data do not support routine vitamin C supplementation alone or in combination with other supplements for the prevention of fetal or neonatal death, poor fetal growth, preterm birth or pre-eclampsia. Further research is required to elucidate the possible role of vitamin C in the prevention of placental abruption and prelabour rupture of membranes. There was no convincing evidence that vitamin C supplementation alone or in combination with other supplements results in other important benefits or harms.