Low Birth Weight and Prematurity Are Associated with Hypertensive Disorder of Pregnancy in Later Life: A Cross-Sectional Study in Japan.

OBJECTIVE: We previously reported that hypertensive disorder of pregnancy (HDP) was a risk factor for hypertension and hypercholesterolemia in later life. Additionally, the age-adjusted odds ratio (OR) of HDP was 2.72 for Japanese women whose mothers had a history of HDP versus those whose mothers did not. This study aimed to clarify the association of HDP with birth weight and gestational age. STUDY DESIGN: A self-administered baseline survey of the Japanese Nurses' Health Study (JNHS) cohort was conducted from 2001 to 2007. Data on 17,278 parous female nurses who knew their own birth weights were extracted from the JNHS baseline survey (n = 49,927) and subjected to cross-sectional, retrospective analysis. Data on weeks of gestation, birth weight, and history of HDP were collected. RESULTS: The age-adjusted ORs for HDP were 1.62 (95% confidence interval [CI]: 1.20-2.19) for birth weight <2,000 g, 1.24 (CI: 1.04-1.48) for 2,000 to 2,499 g, 1.11 (CI: 1.00-1.23) for 2,500 to 2,999 g, and 1.08 (CI: 0.94-1.24) for ≥3,500 g compared with 3,000 to 3,499 g. The age-adjusted ORs for HDP were 1.27 (95% CI: 1.04-1.54) for a gestational age < 37 weeks and 0.93 (0.70-1.23) for ≥42 weeks compared with 37-41 weeks. The age-adjusted OR of the birth weight score for HDP in later life was 0.98 (CI: 0.94-1.03; Cochran-Armitage trend test: z = 0.401, p = 0.688). CONCLUSION: Among women in Japan, a history of low birth weight and prematurity are risk factors for HDP in later life. The risk of HDP among women born with low birth weight and/or premature deserves attention.

Effects of MTHFR C677T polymorphism on vitamin D, homocysteine and natural killer cell cytotoxicity in women with recurrent pregnancy losses.

STUDY QUESTION: Is there any relationship between vitamin D [25 (OH) vitamin D], total plasma homocysteine and methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism in women with recurrent pregnancy losses (RPL)? SUMMARY ANSWER: Women with MTHFR 677TT (homozygous mutation, TT) genotype have significantly lower vitamin D levels, higher homocysteine and natural killer (NK) cell cytotoxicities than those of women with MTHFR 677CC (wild type, CC) and 677CT (heterozygous mutation, CT) genotypes. WHAT IS KNOWN ALREADY: Vitamin D insufficiency, MTHFR C677T polymorphism and hyperhomocysteinemia have been reported as risk factors for RPL. However, the relationship between these risk factors is not known in this population. STUDY DESIGN, SIZE, DURATION: This is a retrospective cross-sectional study, including 837 women with RPL, who were enrolled in Reproductive Medicine and Immunology, Chicago Medical School, between 2012 and 2017. PARTICIPANTS/MATERIALS, SETTING, METHODS: Women with two or more RPL prior to 20 weeks of gestation were included. To investigate whether the MTHFR C677T polymorphism affects the levels of homocysteine and vitamin D as well as immune parameters in women with RPL, biochemical data, such as plasma total homocysteine and serum vitamin D levels, and immune parameters, including NK cell cytotoxicity, were analyzed by MTHFR C677T genotype (CC, CT and TT). MAIN RESULTS AND THE ROLE OF CHANCE: The serum level of vitamin D in TT was significantly lower when compared with those of CT (P = 0.001) and CC (P = 0.003), while the level of homocysteine in TT was significantly higher than those in CT (P = 0.01) and CC (P = 0.01). NK cytotoxicity in TT was significantly higher than that of CC (P = 0.04) but not CT (P = 0.09). There was a significant negative correlation between the levels of vitamin D and homocysteine in TT (r = -0.357, P < 0.01). In multivariate analysis, vitamin D insufficiency (<30 ng/ml) was an independent risk factor for hyperhomocysteinemia (adjusted odds ratio 1.89, 95% CI 1.41-2.52). LIMITATIONS, REASONS FOR CAUTION: The study was retrospective and included only women with RPL but not healthy fertile controls. In addition, folic acid, vitamin B6 and B12 intake, which could modify the level of homocysteine and vitamin D, were not investigated. Thus, a considerable part of women might have folic acid and vitamin D supplementation and prenatal vitamin pills, and there are probable confounders in this study associated with unrestricted vitamin supplementation. Therefore, the findings should be carefully interpreted and applied to RPL women with MTHFR gene polymorphism. WIDER IMPLICATIONS OF THE FINDINGS: The findings attained in this analysis regarding the MTHFR polymorphism and its relationship with vitamin D, homocysteine and NK cytotoxicity may aid in uncovering the underlying etiology and mechanism for RPL. The study highlights an interplay between nutrition and immune responses in RPL. STUDY FUNDING/COMPETING INTEREST(S): No external funding was received for this study. None of the authors have any conflict of interest to declare. TRIAL REGISTRATION NUMBER: N/A.

Successful monozygotic triplet pregnancy after a single blastocyst transfer following in vitro maturation of oocytes from a woman with polycystic ovary syndrome: a case report.

BACKGROUND: Although women with polycystic ovarian syndrome (PCOS)-related sub-fertility are high responders to controlled ovarian stimulation, it is difficult to obtain mature oocytes in these women. Therefore, in vitro maturation (IVM), which is the technique of letting the contents of the ovarian follicles and the oocytes inside mature in vitro, has often been proposed in such women. We describe the first successful delivery of monozygotic triplets resulting from transfer of a single blastocyst following IVM of oocytes. CASE PRESENTATION: A 32-year-old nulligravida female with PCOS underwent IVM. She underwent vitrified-warmed single blastocyst transfer following IVM, and a dichorionic triamniotic triplet pregnancy was confirmed at 8 weeks. Healthy triplets were delivered by cesarean section at 33 weeks' gestation. This is the first case of monozygotic triplets derived from IVM oocytes that were successfully delivered. The determination of chorionicity and amnionicity is generally supposed until 3 days after fertilization, and no division or splitting of her embryo was observed on transfer. Interestingly, her embryo might have split after the transfer, resulting in a dichorionic triamniotic triplet pregnancy. CONCLUSIONS: Patients should be informed of a possible increased risk of monozygotic multiple pregnancies after single embryo transfer following IVM.

Spontaneous unscarred uterine rupture and surgical repair at 11 weeks of gestation in a twin pregnancy.

A uterine rupture may result in a massive hemoperitoneum, which can be fatal to both the fetus and mother. Most uterine ruptures during pregnancy occur within a scarred uterus, rarely occurring in an unscarred uterus. Here, we report a very rare case of spontaneous rupture in an unscarred uterus at 11 weeks of gestation of a twin pregnancy and its surgical repair. A 37-year-old nulliparous infertile woman became pregnant with twins after artificial insemination and gonadotropin therapy. She underwent emergency surgery at 11 weeks of gestation due to an acute abdomen caused by massive hemoperitoneum. Upon laparotomy, one fetus with placenta was extruded into the abdominal cavity through a 3-cm myometrium rupture on the left posterior wall of the uterus. After surgical repair of the rupture site, the remaining fetus was alive and was successfully delivered by cesarean section at 34 weeks of gestation.

Ulipristal acetate for Japanese women with symptomatic uterine fibroids: A double-blind, randomized, phase II dose-finding study.

PURPOSE: A multicenter, randomized, double-blind, placebo-controlled trial was conducted to evaluate the efficacy, safety, and appropriate dose of ulipristal acetate (UPA) in Japanese women with symptomatic uterine fibroids (UFs). METHODS: A total of 121 premenopausal women with UFs were enrolled to receive either placebo, UPA-2.5 mg, UPA-5 mg, UPA-10 mg, or leuprorelin acetate (LEU), a reference drug, for 12 weeks. The primary end point was the rate of patients having achieved amenorrhea for 35 days at Week 12. RESULTS: The rates for amenorrhea were 4.5%, 60.0%, 72.7%, 88.0%, and 76.2% in the placebo, UPA-2.5 mg, UPA-5 mg, UPA-10 mg, and LEU groups, respectively. The median times to amenorrhea were 20.0, 5.0, 5.0, and 23.0 days for treatment with UPA-2.5 mg, UPA-5 mg, UPA-10 mg, and LEU, respectively. A significant dose-response of UPA for the rate of amenorrhea was observed. The overall incidence rates of adverse events were 45.8% in the placebo group, 56.5%-80.0% in the UPA groups, and 100.0% in the LEU group. There were no notable safety issues with UPA. CONCLUSIONS: Ulipristal acetate was effective and well tolerated in Japanese women with UFs. The recommended dose of UPA is considered to be 10 mg.

Premenopausal cardiovascular disease and age at natural menopause: a pooled analysis of over 170,000 women.

Early menopause is associated with an increased risk of subsequent cardiovascular disease (CVD). Few studies have investigated the converse. We examined whether premenopausal CVD events are associated with early age at menopause. We pooled the individual data of 177,131 women from nine studies. We used multinomial logistic regression models to estimate multivariable relative risk ratios (RRR) and 95% confidence intervals (CI) for the associations between age at onset of premenopausal CVD events-including coronary heart disease (CHD) and stroke-and age at natural menopause. Altogether 1561 (0.9%) premenopausal participants reported CVD events (including 1130 CHD and 469 stroke) at a mean age of 41.3 years. Compared with women without any premenopausal CVD events, women who experienced a first CVD event before age 35 years had a twofold risk of menopause before age 45 years (early menopause); adjusted RRR (95% CI) of 1.92 (1.17, 3.14) for any CVD, 1.86 (1.01, 3.43) for CHD and 2.17 (1.43, 3.30) for stroke. Women who experienced a first premenopausal CVD event after age 40 years underwent a natural menopause at the expected age (around 51 years). These associations were robust to adjustment for smoking status, BMI, educational level, race/ethnicity, age at menarche, parity, hypertension and family history of CVD. For premenopausal women, a first CVD event before age 35 years is associated with a doubling of the risk of an early menopause, while a first CVD event occurred after 35 years indicates a normal menopause at around 51 years. Shared genetic and environmental factors (such as smoking), as well as compromised vasculature following CVD events, may contribute to this outcome.

Establishing a Treatment Algorithm for Puerperal Genital Hematoma Based on the Clinical Findings.

Postpartum hemorrhage within 24 hours after delivery remains the leading cause of maternal mortality worldwide. Puerperal genital hematoma (PGHA) is a rare complication of postpartum hemorrhage, and PGHA can be life-threatening if hemostasis is not properly achieved. However, a reliable management algorithm for PGHA based on the clinical findings has not been developed. The objectives were to evaluate the management strategies for PGHA and identify the clinical findings that help select the treatment for PGHA. The medical records of women who were treated for PGHA in our department were reviewed, and data regarding the clinical findings and the treatment strategy for PGHA were analyzed. Thirty-four women who underwent treatment for PGHA were identified and divided into three groups according to the final procedure that achieved hemostasis: conservative management (CM) (n = 9), surgical management (SURG) (n = 15), and arterial embolization management (AEM) (n = 10). Regarding the clinical findings on initial evaluation, the shock index was significantly higher in the AEM group than in the CM or SURG group; and initial platelet count and fibrinogen level were significantly lower in the AEM group than in the CM group. There was no significant difference in any computed tomography (CT) finding among the three groups. In conclusion, this study clearly shows the difference in clinical findings among treatment strategies for PGHA. We suggest that the clinical findings of shock index, platelet count, and fibrinogen level together with CT findings are helpful and valuable for selecting the treatment strategy for PGHA.

[Calcium Metabolism and Skeletal Changes during Pregnancy and Lactation.]

Calcium metabolism changes dramatically during pregnancy and lactation because offspring needs a supply of calcium. Approximately 30g of calcium, which passes through the placenta, is accumulated in a fetus during pregnancy mostly in the third trimester, and 220-340mg/day of calcium is supplied via breast milk during lactation. However, there are elaborate mechanisms to maintain maternal calcium homeostasis, which differs during pregnancy and lactation. Extra required calcium supply to the offspring in neither pregnancy nor breastfeeding normally do not cause any adverse consequences to the maternal skeleton even if any oral intake of calcium or vitamin D are increased. This article reviews the adaptation in calcium kinetics during pregnancy and lactation. Vitamin D, calciotropic hormones, and bone metabolism are also reviewed.

Relationships between intensity, duration, cumulative dose, and timing of smoking with age at menopause: A pooled analysis of individual data from 17 observational studies.

BACKGROUND: Cigarette smoking is associated with earlier menopause, but the impact of being a former smoker and any dose-response relationships on the degree of smoking and age at menopause have been less clear. If the toxic impact of cigarette smoking on ovarian function is irreversible, we hypothesized that even former smokers might experience earlier menopause, and variations in intensity, duration, cumulative dose, and age at start/quit of smoking might have varying impacts on the risk of experiencing earlier menopause. METHODS AND FINDINGS: A total of 207,231 and 27,580 postmenopausal women were included in the cross-sectional and prospective analyses, respectively. They were from 17 studies in 7 countries (Australia, Denmark, France, Japan, Sweden, United Kingdom, United States) that contributed data to the International collaboration for a Life course Approach to reproductive health and Chronic disease Events (InterLACE). Information on smoking status, cigarettes smoked per day (intensity), smoking duration, pack-years (cumulative dose), age started, and years since quitting smoking was collected at baseline. We used multinomial logistic regression models to estimate multivariable relative risk ratios (RRRs) and 95% confidence intervals (CIs) for the associations between each smoking measure and categorised age at menopause (<40 (premature), 40-44 (early), 45-49, 50-51 (reference), and ≥52 years). The association with current and former smokers was analysed separately. Sensitivity analyses and two-step meta-analyses were also conducted to test the results. The Bayesian information criterion (BIC) was used to compare the fit of the models of smoking measures. Overall, 1.9% and 7.3% of women experienced premature and early menopause, respectively. Compared with never smokers, current smokers had around twice the risk of experiencing premature (RRR 2.05; 95% CI 1.73-2.44) (p < 0.001) and early menopause (1.80; 1.66-1.95) (p < 0.001). The corresponding RRRs in former smokers were attenuated to 1.13 (1.04-1.23; p = 0.006) and 1.15 (1.05-1.27; p = 0.005). In both current and former smokers, dose-response relationships were observed, i.e., higher intensity, longer duration, higher cumulative dose, earlier age at start smoking, and shorter time since quitting smoking were significantly associated with higher risk of premature and early menopause, as well as earlier menopause at 45-49 years. Duration of smoking was a strong predictor of age at natural menopause. Among current smokers with duration of 15-20 years, the risk was markedly higher for premature (15.58; 11.29-19.86; p < 0.001) and early (6.55; 5.04-8.52; p < 0.001) menopause. Also, current smokers with 11-15 pack-years had over 4-fold (4.35; 2.78-5.92; p < 0.001) and 3-fold (3.01; 2.15-4.21; p < 0.001) risk of premature and early menopause, respectively. Smokers who had quit smoking for more than 10 years had similar risk as never smokers (1.04; 0.98-1.10; p = 0.176). A limitation of the study is the measurement errors that may have arisen due to recall bias. CONCLUSIONS: The probability of earlier menopause is positively associated with intensity, duration, cumulative dose, and earlier initiation of smoking. Smoking duration is a much stronger predictor of premature and early menopause than others. Our findings highlight the clear benefits for women of early smoking cessation to lower their excess risk of earlier menopause.

Monthly oral ibandronate 100 mg is as effective as monthly intravenous ibandronate 1 mg in patients with various pathologies in the MOVEST study.

The non-inferiority of oral ibandronate 100 mg to intravenous (i.v.) ibandronate 1 mg in increasing lumbar spine (LS) bone mineral density (BMD) after 12 months of treatment was demonstrated in the randomized, phase III MOVEST study. We conducted subgroup analyses in the per-protocol set of the study (n = 183 oral ibandronate; n = 189 i.v. ibandronate). In patients with LS BMD T score ≥ -3.0 or < -3.0 at screening, LS BMD gains from baseline were 4.42 and 5.79%, respectively, with oral ibandronate, and 4.60 and 5.83%, respectively, with i.v. ibandronate. LS BMD gains in patients with or without prevalent vertebral fractures were 5.21 and 5.23%, respectively, with oral ibandronate, and 5.01 and 5.49%, respectively, with i.v. ibandronate. In patients aged <75 or ≥75 years, LS BMD gains were 5.46 and 4.51%, respectively, with oral ibandronate, and 5.25 and 5.77%, respectively, with i.v. ibandronate. LS BMD gains in patients with baseline 25-hydroxyvitamin D levels ≥20 or <20 ng/mL were 5.35 and 4.76%, respectively, with oral ibandronate, and 5.05 and 6.57%, respectively, with i.v. ibandronate. Similar results were obtained in patients with or without prior bisphosphonate (BP) treatment, and in those receiving osteoporosis drug treatment other than BPs. In conclusion, oral ibandronate 100 mg demonstrated comparable BMD gains with monthly i.v. ibandronate, and thus shows high utility in the lifestyle and disease conditions associated with osteoporosis in Japanese patients.

Pregnancy complicated with PFAPA (periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis) syndrome: a case report.

BACKGROUND: Periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis (PFAPA) syndrome has been considered as a childhood syndrome. The underlying etiology of PFAPA syndrome is unclear however, currently considered as auto-immune inflammatory disease. Recently, a few cases of adult-onset of PFAPA syndrome have been reported. However, there is no report about the successful management of pregnancy complicated with PFAPA syndrome. CASE PRESENTATION: The patient was a 31-year-old woman who developed recurrent episodes of high fever associated with cervical adenitis, pharyngitis and vomiting started 9 months after a delivery. She was diagnosed with PFAPA syndrome and cimetidine 800 mg/day was initiated. Since then, these symptoms got better. Cimetidine treatment was discontinued since she became pregnant (6 weeks of pregnancy). Except one febrile episode at 8 weeks gestation, she did not develop a febrile episode during pregnancy. Peripheral blood Th1/Th2 ratio was decreased from the first trimester to the second trimester of pregnancy. Then again, the ratio was steadily elevated during the third trimester. At 38 weeks, she delivered a live born infant without any complication. Two months after delivery, she developed PFAPA syndrome again and cimetidine treatment was re-initiated. However, febrile episodes were not controlled well, and Th1/Th2 ratio was further elevated compared to pregnancy status. Colchicine 0.5 mg once a day was initiated. Symptoms were diminished and Th1/Th2 ratio was gradually decreased. CONCLUSION: There was no case report of pregnancy complicated with PFAPA syndrome, though there were several reports of adult-onset PFAPA cases without pregnancy. The current case may be the first case report of a successful pregnancy complicated with PFAPA. In this case, PFAPA symptoms were ameliorated during pregnancy, but reappeared after delivery. We speculate that PFAPA syndrome, a Th1 type immune disorder, might be improved due to the Th1 to Th2 shifting, which was induced by pregnancy. It is necessary to investigate further about PFAPA syndrome with pregnancy and Th1/Th2 immune responses in the future.

Combination of microwave endometrial ablation and postoperative dienogest administration is effective for treating symptomatic adenomyosis.

AIM: Menorrhagia and dysmenorrhea are common symptoms. Uterine adenomyosis is one of the causes of menorrhagia and dysmenorrhea. These symptoms often decrease the quality of life in women. Microwave endometrial ablation (MEA) is a recently developed procedure that enables endometrial ablation. Dienogest has long been used to suppress endometrium development and reduce adenomyosis-related dysmenorrhea. However, some cases could be resistant to dienogest. In this study, we evaluated the efficacy of a combination of MEA and postoperative dienogest in reducing adenomyosis-related dysmenorrhea and menorrhagia. METHODS: Ten patients with hormone treatment-resistant symptomatic adenomyosis underwent MEA and were administered oral dienogest after the procedure. The primary endpoints were reduction in pain recurrence and anemia. The secondary endpoint was a change in the adenomyosis lesion and its symptomatic recurrence. RESULTS: Statistically significant improvements were seen in the visual analog scale score and hemoglobin levels in women post-treatment. The difference in myometrial thickness pre- and post-MEA was statistically significant. There were no cases of symptomatic recurrence. CONCLUSION: The combination of MEA and postoperative dienogest is useful for treating uterine adenomyosis with menorrhagia and dysmenorrhea.

Japan Society of Obstetrics and Gynecology and Japan Society for Menopause and Women's Health 2017 guidelines for hormone replacement therapy.

Hormone replacement therapy (HRT) plays a large part in maintaining and improving the quality of life (QOL) of postmenopausal women. Despite this obvious role, the use of HRT has stagnated in Japan as well as the United States, since the interim report of the HRT trial of Women's Health Initiative study was published in 2002. The Japan Society of Obstetrics and Gynecology and Japan Society for Menopause and Women's Health formulated the Guidelines for Hormone Replacement Therapy in 2009, which was subsequently revised in 2012, with the aim of organizing perceptions about HRT and allowing people to provide or receive HRT with a sense of security. Later on, in light of changes in indications for HRT and attitudes toward its impact on cancer risks, amendments were made again in 2017. With the establishment of the 2017 guidelines, practitioners in Japan are able to address various issues related to HRT with more appropriate judgment. Moreover, the practice of reliable, safe and effective HRT is expected to promote further efforts toward improvement or maintenance of QOL in patients.

Uterine leiomyomata: a retrospective study of correlations with hypertension and diabetes mellitus from the Japan Nurses' Health Study.

We performed a scrutiny survey of self-reported uterine leiomyomata (UL) to investigate the associations of parental history with hypertension and personal history of hypertension in the UL cases in Japanese women. Questionnaires that included items on the sites of UL determined by imaging techniques and surgical procedure were mailed to 2015 women with a self-reported UL at a baseline survey of the Japan Nurses' Health Study (n = 15,019). We found that women with a past history and a maternal history of hypertension had an increase in their risk of UL. A maternal history of hypertension was significantly associated with an increase in the risk of UL in women without a past history of hypertension but not in the women with a past history of hypertension. A past history and a parental history of diabetes mellitus were not associated with an increase in the risk of UL. Women of reproductive age with a maternal history of hypertension may be at a higher risk for hypertension and UL. Impact Statement What is already known on this subject? A positive association of uterine leiomyomata (UL) with a past history of hypertension has been found but the association of a parental history of hypertension with UL has not yet been clarified. What do the results of this study add? Maternal hypertension, as well as a personal history of hypertension, was associated with an increased risk of UL and a past history and a parental history of diabetes mellitus were not associated with an increase in the risk of UL. What are the implications of these findings for clinical practice and/or further research? Women of a reproductive age with a maternal history of hypertension may be at a higher risk for hypertension and UL.

Early menarche, nulliparity and the risk for premature and early natural menopause.

STUDY QUESTION: Are parity and the timing of menarche associated with premature and early natural menopause? SUMMARY ANSWER: Early menarche (≤11 years) is a risk factor for both premature menopause (final menstrual period, FMP <40 years) and early menopause (FMP 40-44 years), a risk that is amplified for nulliparous women. WHAT IS KNOWN ALREADY: Women with either premature or early menopause face an increased risk of chronic conditions in later life and of early death. Findings from some studies suggest that early menarche and nulliparity are associated with early menopause, however overall the evidence is mixed. Much of the evidence for a direct relationship is hampered by a lack of comparability across studies, failure to adjust for confounding factors and inadequate statistical power. STUDY DESIGN, SIZE, DURATION: This pooled study comprises 51 450 postmenopausal women from nine observational studies in the UK, Scandinavia, Australia and Japan that contribute to the International collaboration for a Life course Approach to reproductive health and Chronic disease Events (InterLACE). PARTICIPANTS/MATERIALS, SETTING, METHODS: Age at menarche (categorized as ≤11, 12, 13, 14 and 15 or more years) and parity (categorized as no children, one child and two or more children) were exposures of interest. Age at FMP was confirmed by at least 12 months of cessation of menses where this was not the result of an intervention (such as surgical menopause due to bilateral oophorectomy or hysterectomy) and categorized as premature menopause (FMP before age 40), early menopause (FMP 40-44 years), 45-49 years, 50-51 years, 52-53 years and 54 or more years. We used multivariate multinomial logistic regression models to estimate relative risk ratio (RRR) and 95% CI for associations between menarche, parity and age at FMP adjusting for within-study correlation. MAIN RESULTS AND THE ROLE OF CHANCE: The median age at FMP was 50 years (interquartile range 48-53 years), with 2% of the women experiencing premature menopause and 7.6% early menopause. Women with early menarche (≤11 years, compared with 12-13 years) were at higher risk of premature menopause (RRR 1.80, 95% CI 1.53-2.12) and early menopause (1.31, 1.19-1.44). Nulliparity was associated with increased risk of premature menopause (2.26, 1.84-2.77) and early menopause (1.32, 1.09-1.59). Women having early menarche and nulliparity were at over 5-fold increased risk of premature menopause (5.64, 4.04-7.87) and 2-fold increased risk of early menopause (2.16, 1.48-3.15) compared with women who had menarche at ≥12 years and two or more children. LIMITATIONS, REASONS FOR CAUTION: Most of the studies (except the birth cohorts) relied on retrospectively reported age at menarche, which may have led to some degree of recall bias. WIDER IMPLICATIONS OF THE FINDINGS: Our findings support early monitoring of women with early menarche, especially those who have no children, for preventive health interventions aimed at mitigating the risk of adverse health outcomes associated with early menopause. STUDY FUNDING/COMPETING INTEREST(S): InterLACE project is funded by the Australian National Health and Medical Research Council project grant (APP1027196). G.D.M. is supported by Australian Research Council Future Fellowship (FT120100812). There are no competing interests.

Impact of birth weight on adult-onset diabetes mellitus in relation to current body mass index: The Japan Nurses' Health Study.

BACKGROUND: Although birth weight is considered as a fetal determinant of the development of adult-onset diabetes mellitus (DM), its public health importance relative to adult body mass index (BMI) remains unclear. We aimed to examine the association between adult-onset DM and birth weight in relation to adult BMI. METHODS: We conducted a self-administered questionnaire as a baseline survey of the Japanese Nurses' Health Study cohort between 2001 and 2007. Exclusion criteria were applied to the volunteer sample of 49,927 female nurses (age <30 years or unknown, current pregnancy, development of DM before the age of 30 years, unknown core variables), and data from 26,949 female nurses aged 30 years or older were used. The association between history of DM diagnosis and birth weight was analyzed using logistic regression. RESULTS: A linear inverse association was observed between birth weight and DM, after adjustment for age, BMI, and parental history of DM. The odds ratio for developing DM per 100 g increase in birth weight was 0.93 (95% confidence interval [CI], 0.90-0.96). The association was unchanged when birth weight was converted to percentile for gestational age. In the BMI-stratified analysis, the odds ratio for DM in the <2500 g birth weight group reached 4.75 (95% CI, 1.22-18.44, compared to the reference 3000-3499 g group) among women with normal low BMI (18.5-20.9). CONCLUSIONS: Birth weight and its percentile for gestational age were associated with adult-onset DM. Attention should be paid to the risk of DM among women born with low weight, even when their current BMI is normal.

Hypertensive disorders of pregnancy increase the risk for chronic kidney disease: A population-based retrospective study.

Hypertensive disorders of pregnancy (HDP) and chronic kidney disease (CKD) are well-known risk factors for cardiovascular disease (CVD) in later life. However, few studies have investigated the association of HDP with CKD. Moreover, these studies utilized either registry- or clinical-based data and did not include subclinical CKD patients. To address this gap in the literature, we investigated whether HDP is related to CKD, diagnosed based on the estimated glomerular filtration rate (eGFR), in later life. We designed a population-based, retrospective study, and reviewed the results of blood and physiological examinations as well as the results of pregnancy data available in patients' Maternity Health Record Books for 312 women. We identified 15 women with a diagnosis of CKD based on the eGFR, and 14 women with HDP. We found that women who experienced HDP had a high risk of CKD in later life compared with women without HDP (odds ratio (OR): 4.854; 95% confidence interval (CI): 1.042-22.621). Compared with normotensive women, those who were hypertensive at the time of the examination were significantly associated with CKD (OR: 3.109; 95% CI: 1.213-11.510). Awareness regarding the risk for CKD and CVD in a relatively young age can enable women to prevent diseases effectively.

Clinical efficacy of nedaplatin-based concurrent chemoradiotherapy for uterine cervical cancer: a Tohoku Gynecologic Cancer Unit Study.

OBJECTIVE: The aim of this study was to compare the efficacy of nedaplatin-based concurrent chemoradiotherapy (CCRT) with that of cisplatin-based CCRT in patients with cervical cancer. METHODS: The medical records of patients with cervical cancer who had undergone CCRT between 2003 and 2007 were retrospectively reviewed. Of these, 129 patients were treated postoperatively with CCRT (n = 52) or primary CCRT (n = 77). A total of 29 patients were treated with nedaplatin-based postoperative CCRT and 23 patients were treated with cisplatin-based postoperative CCRT. A total of 28 patients were treated with nedaplatin-based postoperative CCRT, and 49 patients were treated with cisplatin-based postoperative CCRT. Progression-free survival (PFS) and overall survival (OS) were compared between the treatment groups. RESULTS: With postoperative CCRT, there were no significant differences in recurrence rate (P = 1.0000), PFS (log-rank: P = 0.8503), and OS (log-rank: P = 0.8926) between the two treatment groups. With primary CCRT, there were no significant differences in PFS (log-rank: P = 0.7845) and OS (log-rank: P = 0.3659). The frequency of acute toxicity was not significantly different between the cisplatin-based postoperative CCRT group and the nedaplatin-based postoperative CCRT group. CONCLUSIONS: Nedaplatin-based postoperative CCRT is an effective and well-tolerated regimen for both early-stage and advanced-stage cervical cancer patients.

Expression of retinoid-related orphan receptor (ROR)γt on NK22 cells in the peripheral blood and uterine endometrium of women with unexplained recurrent pregnancy loss and unexplained infertility.

AIM: Recently, NK22 cells, a subset of interleukin (IL)-22-producing natural killer (NK) cells, were identified. We have previously reported the higher percentage of NK22 cells in women suffering recurrent pregnancy loss (RPL). Moreover, we have also reported lower expression of NKp46, a kind of natural cytotoxicity receptor (NCR), on NK cells and the changes of NK cell producing cytokines in women who experience RPL. NK22 cells express NCRs, such as NKp44 or NKp46. Retinoid-related orphan receptor γt (RORγt) is known as a regulator of NK22 cells; however, in NK22 cells of peripheral blood (PB) and the uterine endometrium (UE), the relationship between NCRs and RORγt is unclear. We investigate RORγt expression NK22 cells in the PB and UE of women with unexplained infertility (uI) or unexplained RPL (uRPL). METHODS: Lymphocytes were extracted from PB and UE, derived from women with uI or uRPL. Expression of RORγt and NCRs in NK cells and NK cell-produced cytokines were analyzed by flow cytometry. RESULTS: CD56+ /NKp46+ /RORγt+ cells were positively correlated with CD56+ /IL-22+ cells in both PB and UE. CD56bright /NKp46bright /RORγt+ cells were significantly higher in uRPL than in uI, and endometrial CD56bright /NKp46bright /RORγt+ cells were positively correlated with PB. In UE, CD56bright /RORγt+ cells were negatively correlated with CD56bright /interferon-γ+ and CD56bright /tumor necrosis factor-α+ cells of uRPL. CONCLUSION: RORγt may be associated with NK22 cells in reproduction. Particularly, higher expression of RORγt may be associated with elevated NK22 cells in uRPL.

Bridging analysis of the efficacy and safety of bazedoxifene in Japanese and global populations of postmenopausal women with osteoporosis.

This study examined whether the global clinical data for bazedoxifene could be extrapolated to a Japanese population by evaluating the results of a phase 2 study in postmenopausal Japanese women with osteoporosis as compared to those of a pivotal, phase 3 study. The efficacy of bazedoxifene 20 and 40 mg versus placebo on lumbar spine bone mineral density (BMD), bone turnover markers, lipid profile, incidence of fractures, and safety parameters was compared between the Japanese phase 2 study (N = 429) and the global phase 3 study (N = 7,492) during a 2-year period. In the primary population for assessment of bridging, differences in the mean percent change from baseline in lumbar spine BMD at 2 years relative to placebo were greater for women treated with bazedoxifene 20 and 40 mg in the phase 2 study than in the phase 3 study. BMD changes in the bazedoxifene groups were confirmed to be similar between the phase 2 study population and a subset of the phase 3 study population with similar baseline characteristics. The effects of bazedoxifene on incidence of fractures, bone turnover markers, and lipid metabolism were similar between studies. There were no major differences in safety parameters between studies. The greater improvement in lumbar spine BMD and similar results in bone turnover markers, fracture incidence, and safety profile observed with bazedoxifene in the phase 2 study compared with the phase 3 study confirmed the feasibility of extrapolating the global clinical data to a Japanese population.