Recurrent embolic stroke associated with adenomyosis: A single case report and literature review.

INTRODUCTION: Uterine adenomyosis is a benign disorder in which endometrial glands and stroma are present within the myometrium. There have been several case reports of cerebral infarction associated with adenomyosis, but their clinical characteristics, optimal treatment, and prognosis have not been systematically reviewed. METHODS: A case of cerebral infarction with adenomyosis is reported, and a comprehensive systematic literature search using the PubMed database was conducted. RESULTS: A 42-year-old woman, previously diagnosed with adenomyosis, developed multiple cerebral infarctions during menstruation. Her CA125 level was 293 U/mL, and treatment with edoxaban 30 mg was started. Seven days after hospital discharge, she had her subsequent menstrual period and then developed a recurrent stroke. Her CA125 level was 743 U/mL on readmission. A hysterectomy was performed, and the patient has had no further stroke recurrence. A systematic review identified 19 cases with cerebral infarction associated with adenomyosis, including the present case. The patients' clinical characteristics included young age (44.7 ± 6.2 years), stroke development during menstruation (85%), multiple infarctions affecting ≥ 3 vessel territories (39%), and high levels of CA125 and D-dimer (810.6 ± 888.4 U/mL, and 10.3 ± 18.6 µg/mL, respectively). Antithrombotic therapy was given to 14 patients, but recurrent stroke occurred in 5 (36%) patients. Hysterectomy was conducted in 5 and 4 patients with initial and recurrent stokes, respectively, and there were no further recurrences thereafter. CONCLUSION: Cerebral infarction associated with adenomyosis has specific clinical characteristics. Antithrombotic therapy was insufficient, and hysterectomy should particularly be considered in cases of recurrent stroke.

Prognostication of Ovarian Function after Ovarian Torsion Using Intraoperative Indocyanine Green Angiography.

STUDY OBJECTIVE: To quantitatively evaluate the blood flow in ovaries (ischemic ovaries) that underwent torsion using indocyanine green angiography (ICGA) and assess the use of ICGA as an indicator for functional preservation of the ovaries. DESIGN: In vivo animal study. SETTING: The University of Yamanashi Animal Experimentation Center. SUBJECTS: Eighteen female Wistar albino rats. INTERVENTIONS: As an alternative to ovarian torsion, we occluded an ovary in each rat for 24 hours, after which we performed ICGA before and after releasing ischemia and extracted the following 8 parameters: Fmax (maximum F value before releasing ischemia); Tmax (time taken from the onset of an increase in F to reaching Fmax); T½max (time taken from the onset of an increase in F to reaching half of Fmax); slope (Fmax/Tmax); time ratio (T½max/Tmax); F'max (maximum F value after releasing ischemia); reperfusion rate (F'max/Fmax); and reperfusion gap (F'max - Fmax). Four weeks later, we counted the total number of primordial and primary follicles and classified the rats into functional and nonfunctional groups. MEASUREMENTS AND MAIN RESULTS: On the basis of the total number of primordial and primary follicles, 13 rats had "functional" ovaries on the clamped side, and 5 rats had "nonfunctional" ovaries. The area under the curve values for each parameter were as follows: Fmax, 0.908; Tmax, 0.569; T½max, 0.546; time ratio, 0.746; slope, 0.877; F'max, 0.723; reperfusion rate, 0.938; and reperfusion gap, 0.862. CONCLUSION: ICGA can be used to quantitatively evaluate ovaries that have been subjected to ischemia, and the magnitude of fluorescence intensity can be an excellent predictor of ovarian necrosis. Quantifying the degree of reperfusion immediately after the release of ischemia can be an equally excellent predictor of necrosis.

Influence of laparoscopic surgery for endometriosis and its recurrence on perinatal outcomes.

Purpose: It is unknown whether surgery for endometriosis or recurrence of endometriosis affects obstetric outcomes. Methods: A total of 208 pregnant women with a history of endometriosis were analyzed. Patients who had endometriomas >3 cm and no history of laparoscopic surgery for endometriosis were defined as non-surgery group (n = 60), while those who had a history of surgery for endometriosis (n = 148) were defined as surgery group. We investigated the obstetric outcomes in 208 patients according to with or without postoperative recurrence of endometriosis and the time from surgery to pregnancy. Results: Among 177 cases of on-going pregnancy, in surgery group, there were lower prevalence of placenta previa compared with non-surgery group (8.5% vs. 23.4%; p = 0.020). Subgroup analysis revealed a decreased prevalence of placenta previa in postoperative non-recurrence group (6.0%: p = 0.007) compared with non-surgery (23.4%) and postoperative recurrence group (28.6%). Placenta previa was more prevalent in the patients who got pregnant more than 2 years after surgery (20.0%) than the patients who got pregnant within 2 years (2.4%: p = 0.002). Multivariate analysis revealed that the surgery was associated with a reduction in placenta previa (OR: 0.32, 95% CI [0.11-0.90]; p = 0.032). Conclusions: Pregnancy within two years after laparoscopic surgery for endometriosis may reduce placenta previa.

Gestational body weight gain and risk of low birth weight or macrosomia in women of Japan: a nationwide cohort study.

OBJECTIVE: Both maternal prepregnancy body mass index (BMI) and gestational weight gain (GWG) influence maternal and pediatric outcomes. We sought to clarify the impact of prepregnancy BMI-specific GWG and its patterns on the risk of low birth weight (LBW) or macrosomia using data from a large nationwide study in Japan. METHODS: This cohort study (n = 98,052) used data from the Japan Environment and Children's Study (JECS). The outcome variables in this study were LBW and macrosomia. We stratified the subjects into groups according to prepregnancy BMI. RESULTS: GWG from pre-pregnancy to the first trimester had a small effect on the risk of LBW and macrosomia. From the first to second trimesters, insufficient GWG was associated with the risk of LBW, and from the second trimester to delivery, a GWG of less than 2 kg was associated with the risk of LBW. These associations were commonly observed in all prepregnancy BMI categories. Irrespective of the GWG from pre-pregnancy to the first trimester, GWG from the first to second trimesters affects LBW and/or macrosomia. Irrespective of the GWG from the first to second trimesters, GWG from the second trimester to delivery affects LBW and/or macrosomia. LBW or macrosomia was associated with the prevalence of a sustained low or high BMI percentile until three years of age, respectively. CONCLUSIONS: The present large national cohort study indicates that the risk of LBW or macrosomia is associated with GWG in women in Japan; the significance of this risk depends on the GWG patterns.

High-grade uterine sarcoma with osteosarcomatous differentiation arising from a MED12-mutated leiomyoma, a case report.

Uterine osteosarcoma has been reported, but it is an extremely rare tumor with highly aggressive behavior and poor prognosis. The pathogenesis of uterine osteosarcoma is not fully understood. Herein, we report on a high-grade uterine sarcoma with focal osteosarcomatous differentiation that developed from a long-standing MED12-mutated leiomyoma. A 47-year-old nulligravida woman, with known uterine leiomyoma presented with abdominal pain and distention. Imaging analyses revealed a tumor with a large cystic area in the uterine corpus and multiple metastases in intrapelvic and paraaortic lymph nodes, left ovary and left lung. With a clinical diagnosis of uterine sarcoma the patient underwent abdominal total hysterectomy, bilateral salpingo-oophorectomy, partial omentectomy and removal of the left obturator lymph node. Despite postoperative chemotherapy and radiation therapy, the tumor progressed rapidly. She died 18 weeks after the surgery. Histopathologic examination identified a high-grade pleomorphic sarcoma in which focal osteoid production was observed. This high-grade sarcoma with focal osteosarcomatous differentiation was located within the uterine leiomyoma, and Sanger sequencing showed the identical MED12 L36R mutation in both the osteosarcomatous and leiomyomatous components supporting the shared origin of these two components. We, therefore, concluded that the high-grade sarcoma with osteosarcomatous differentiation arose from the transformation of the precedent leiomyoma.

A case of ovarian stimulation for fertility preservation in a patient with Philadelphia chromosome-positive acute lymphoblastic leukemia after treatment with dasatinib.

Tyrosine kinase inhibitors (TKIs) are effective for treating Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL). However, the use of TKIs may decrease the number of collected oocytes during fertility preservation procedures. We report the case of a 19-year-old patient with Ph+ALL for whom 21 oocytes were frozen after controlled ovarian stimulation was initiated 2 days after the completion of 28 days of remission induction therapy with dasatinib. After collecting the oocytes, consolidation therapy was initiated immediately, and a hematopoietic stem cell transplant from her younger brother was scheduled. It is believed that a 2-day withdrawal period is sufficient for fertility preservation or that the effect of dasatinib on the number of oocytes obtained is minimal.

Leptomeningeal metastasis from cervical cancer: Report of two cases and a review of the literature.

Leptomeningeal metastases from cervical cancer are extremely rare, with only 24 cases reported in the English-language literature. Leptomeningeal metastasis (LM) is usually a late event, but it can develop at any stage. A 44-year-old woman presented with vertigo, tinnitus, diminution of hearing, and a cervical tumor at the initial visit. She underwent whole brain radiotherapy and systemic chemotherapy. Five months after the initial visit, her condition deteriorated rapidly and she died. A 49-year-old woman underwent surgery and pelvic radiotherapy for cervical cancer. She underwent resection of lung metastases 2 years later and received systemic chemotherapy for lymph node metastases 4 years later. Five years after the initial visit, the patient suddenly presented with diplopia, headache, and vomiting; her clinical course was fulminant and she died. Most patients with LM present with diverse clinical manifestations and deteriorate rapidly despite multiple treatment modalities. Gynecologic oncologists should be aware of this rare complication.

Effect of transdermal estrogen dose regimen for endometrial preparation of frozen-thawed embryo transfer on reproductive and obstetric outcomes.

PURPOSE: Previous studies have reported different methods of estrogen administration during endometrial preparation for frozen-thawed embryo transfer (FET). This study aimed to investigate a beneficial regimen of transdermal estrogen administration for FET. METHODS: We investigated the reproductive and obstetric outcomes of FET by comparing the increasing dose (ID) group that mimics changes in serum estradiol during the menstrual cycle and the constant dose (CD) group. Transdermal patches were used for estrogen administration in both groups. In our hospital, we targeted 315 cycles of the ID group in which FET was performed in 2017 and 324 cycles of the CD group in which FET was performed in 2018. In all cases, single embryo transfer was performed. RESULTS: All were singleton pregnancies. There was no difference in clinical pregnancy rate (28.9% vs 28.2%, P =.837) and live birth rate (17.3% vs 21.4%, P =.201) between the ID and CD groups. Spontaneous abortion rate was significantly lower in the CD group than in the ID group (37.2% vs 23.0%, P =.041). There was no difference in obstetrical outcomes. CONCLUSIONS: It was considered that the simple CD regimen may be more beneficial than the complicated ID regimen.

Lesion-targeted cytology to improve cytological sampling for atypical polypoid adenomyomas of the uterus: A case series and review of the literature.

OBJECTIVE: Atypical polypoid adenomyomas (APAs) are uncommon tumours consisting of atypical endometrioid glands and fibromyomatous stroma. Identifying the biphasic nature of atypical glandular components and spindle mesenchymal components without atypia is crucial for the cytological diagnosis of APA. We investigated the utility of lesion-targeted cytology (LTC) to directly collect firm spindle components. METHODS: We recruited seven consecutive surgical patients who underwent cytological examinations before surgery and were diagnosed with APA on postoperative histological examinations. Cytological smears were obtained by routine sampling in five cases and by targeted sampling using transvaginal ultrasonography, that is, LTC, in two cases. We retrospectively analysed the cytological findings from our cases and compared them to those of APA cases previously reported in the English literature. RESULTS: Among 5/7 cases that involved routine cytological sampling, normal cytological findings were found in 2 and atypical glandular cells were found in 3, but spindle cells from mesenchymal components were not detected. In contrast, among 2/7 cases in which sampling involved LTC, spindle cells without atypia, in addition to atypical glandular cells were found. CONCLUSIONS: Lesion-targeted cytology is useful to assess mesenchymal components of APAs and may improve the cytological diagnosis of APA.

Adenomyosis as a Potential Risk Factor for Adverse Pregnancy Outcomes: A Multicenter Case-Control Study.

As the number of women who postpone their first pregnancy until their late 30s or early 40s is increasing, adenomyosis is more frequently encountered by obstetricians. Some studies have reported on the relationship between adenomyosis and pregnancy complications. We aimed to investigate the effect of adenomyosis on pregnancy complications and outcomes and associations between adenomyosis type and pregnancy outcomes. This multicenter retrospective 1:4 case-control study included 61 women with singleton pregnancies diagnosed with adenomyosis. The control group included women with singleton pregnancies without adenomyosis; these women were matched to those with adenomyosis using propensity scores. The incidence of obstetric complications, delivery, and neonatal outcomes were compared. The adenomyosis group (n = 61) had significantly higher incidence of preterm delivery (21.3% vs. 9.4%), hypertensive disorders of pregnancy (13.1% vs. 5.3%), cesarean delivery (46.0% vs. 20.9%), and postpartum hemorrhage (57.3% vs. 36.8%) than the control group (n = 244). Subgroup analysis by the adenomyosis type revealed that the diffuse adenomyosis group (n = 41) was significantly more likely to experience preterm labor (29.3% vs. 7.3%), hypertensive disorders of pregnancy (17.0% vs. 5.5%), severe hypertensive disorders of pregnancy (12.2% vs. 1.8%), preterm premature rupture of membranes (12.2% vs. 2.4%), cesarean delivery (61.3% vs. 18.9%), and postpartum hemorrhage (70.7% vs. 44.5%) than the control group (n = 164). The focal adenomyosis (n = 20) group was not statistically different from the control group (n = 80) with respect to obstetric complications. Women with diffuse adenomyosis require more careful perinatal management than previously thought.

Improvement of early developmental competence of postovulatory-aged oocytes using metaphase II spindle injection in mice.

PURPOSE: Assisted reproductive technology (ART) is a widely applied fertility treatment. However, the developmental competence of aged oocytes from women of a late reproductive age is seriously reduced and the aged oocytes often fail in fertilization even when ART is used. To resolve this problem, we examined usefulness of a new method "the metaphase II spindle transfer (MESI)" as ART using mouse oocytes. METHODS: This work was composed of two experiments. First, 24 hours after collection, embryos from oocytes (1-day-old oocytes, called postovulatory-aged oocytes), were observed, after intracytoplasmic sperm injection (ICSI), and it was found that they were not able to reach the blastocyst stage. Next, the metaphase II chromosome-spindle complexes from 1-day-old oocytes were injected into cytoplasts from oocytes just collected, using piezo pulses to generate reconstructed oocytes. This procedure was named metaphase II spindle injection (MESI). RESULTS: After ICSI, embryos from the reconstructed oocytes (32/105), which contained the genes of 1-day-old oocytes, were able to develop into the blastocyst stage. The fragmentation rate after ICSI was 28.6%. Thus, the developmental competence of 1-day-old oocytes was improved by MESI. CONCLUSIONS: The MESI method has the potential to improve the success rate of infertility treatments for women of a late reproductive age.

Association between birth weight and massive haemorrhage in pregnancy with a low-lying placenta: a 9-year single-centre retrospective cohort study in Japan.

A low-lying placenta is a well-known cause of a massive intrapartum haemorrhage. We aimed to evaluate whether neonatal birth weight deviation from the nationwide average could predict a massive haemorrhage during a delivery in the women with a low-lying placenta. This study included 40 women. The main outcomes were a massive haemorrhage and a neonatal birth weight deviation. We used a receiver operating characteristic curve analysis to determine the optimal birth weight deviation cut-off for predicting a massive haemorrhage. A multiple logistic regression model was used to identify the variables significantly associated with a massive haemorrhage. The best cut-off for predicting a massive haemorrhage was a birth weight deviation of +0.51 standard deviations (SDs) from the nationwide average. A birth weight deviation of ≥ +0.51 SDs was significantly associated with an increased massive haemorrhage risk. Impact statement What is already known on this subject? A low-lying placenta is a well-known cause of a massive intrapartum haemorrhage. Therefore, when managing pregnancies with a low-lying placenta, the possibility of severe perinatal bleeding should be considered, and it is desirable to determine reliable predictors of a haemorrhage. However, few studies have reported the predictive factors of a massive haemorrhage in patients with a low-lying placenta. What do the results of this study add? We demonstrated that a birth weight deviation from the nationwide average was significantly associated with a massive intrapartum haemorrhage in patients with a low-lying placenta. To our knowledge, this is the first study to clarify the association between a neonatal birth weight and a massive intrapartum haemorrhage incidence and to determine the optimal birth weight deviation cut-off for predicting a massive haemorrhage in patients with a low-lying placenta. What are the implications of these findings for clinical practice and/or further research? An accurate risk stratification using the foetal weight as a marker for a predicting massive intrapartum haemorrhage may help in the management of patients with a low-lying placenta. Studies with a larger sample size are required to confirm our findings.

Dysregulation of CDK inhibitors and p53 in HPV-negative endocervical adenocarcinoma.

Human papillomavirus (HPV)-negative adenocarcinoma (AC) is a minor subset of endocervical cancer, but its pathogenesis has yet to be elucidated. This study investigated the clinicopathologic features of HPV-negative endocervical AC (n=14) in comparison with HPV-positive endocervical AC (n=30), and further studied aberrations of cell-cycle regulators. Expression patterns of cyclin-dependent kinase inhibitors (p16, p14, p27, and p21) and p53 were evaluated immunohistochemically, and nuclear high-risk HPV DNA signals were detected by in situ hybridization and polymerase chain reaction. Immunoexpression of p16, p14, p27, p21, and p53 were observed in 90%, 67%, 77%, 40%, and 20% of HPV-positive ACs, and in 0%, 0%, 29%, 14%, and 57% of HPV-negative ACs, respectively. A higher frequency of lymph node metastasis and worse prognosis were significantly associated with HPV-negative AC. Our findings suggest that alteration of cyclin-dependent kinase inhibitors and p53 status may contribute to carcinogenesis and the clinical behavior of HPV-negative AC of the uterine cervix.

Relation between low 50-g glucose challenge test results and small-for-gestational-age infants.

AIM: There is no consensus opinion regarding a possible relation between low 50-g glucose challenge test (GCT) results and small-for-gestational-age infants (SGA). This study aimed to clarify the relation between low 50-g GCT results and SGA, after adjusting for potential confounding factors, using a large clinical dataset. MATERIAL AND METHODS: Our retrospective cohort study evaluated the obstetric records of women who delivered at Kofu Municipal Hospital (Japan) between January 2011 and December 2013. The exclusion criteria were gestational diabetes mellitus, diabetes in pregnancy, and GCT results of ≥140 mg/dL. Based on these criteria, we included 1603 women who had undergone a GCT between 24 and 28 weeks of gestation, and divided the subjects into a low-GCT group (≤90 mg/dL) and a non-low-GCT group (91-139 mg/dL). The χ(2) -test and multivariate logistic regression analysis were used to investigate the association between low GCT results and SGA. RESULTS: The mean subject age was 30.4 ± 5.4 years, with 45.1% nulliparity (n = 723) and 1538 (96.0%) term deliveries. The incidence of SGA was 10.7% (172/1603), and 17.9% (287/1603) of the women had low GCT results. Low GCT results were significantly associated with an increased risk of SGA (odds ratio, 1.66; 95% confidence interval, 1.14-2.42), after controlling for maternal age, pre-pregnancy maternal weight, maternal weight gain during pregnancy, and pregnancy-induced hypertension. CONCLUSION: It appears that there is a significant association between low GCT results and SGA. However, further studies are needed to explore the detailed mechanisms of this association.

Effectiveness of Laparoscopic Adenomyomectomy on Perinatal Outcomes.

Objectives: The objective of this study was to observe the influence of laparoscopic adenomyomectomy on perinatal outcomes. Materials and Methods: The retrospective cohort study included 43 pregnant cases with adenomyosis who did not undergo laparoscopic surgery before pregnancy (nonsurgery group; 26 cases) and did (surgery group; 17 cases). To evaluate the impact of surgery on perinatal outcomes, nine obstetric complications including preterm delivery, hypertensive disorder of pregnancy, placental malposition, oligohydramnios, gestational diabetes mellitus, uterine rupture, abruptio placentae, and postpartum hemorrhage were selected. One obstetric complication was counted as one point (Maximum 9 points for one person). The obstetrical morbidity was compared by adding up the number of relevant events (0-9) between the two groups. Apgar score, umbilical artery pH (UApH), neonatal intensive care unit (NICU) admission, and neonatal death were also examined. Results: The surgery group had a significantly lower prevalence of fetal growth restriction compared to the nonsurgery group (nonsurgery vs. surgery; 26.9%, 7/26 vs. 0%, 0/17: P = 0.031). No differences were found in the morbidity of the nine obstetric complications (19.2%, 45/234 vs. 13.7%, 21/153), gestational weeks (mean ± standard deviation, 37.2 ± 2.4 vs. 36.4 ± 3.2), birth weight (2573.6 ± 557.9 vs. 2555.4 ± 680.8 g), Apgar score (1, 5 min; 8.0 ± 0.7 vs. 7.7 ± 1.2, 8.9 ± 0.6 vs. 8.5 ± 1.8), UApH (7.28 ± 0.08 vs. 7.28 ± 0.06), NICU admission (26.9%, 7/26 vs. 41.2%, 7/17), and neonatal death (0%, 0%) between both groups. Conclusion: Laparoscopic adenomyomectomy may not increase obstetric complications, although attention must be paid to uterine rupture during pregnancy.

Cytoplasmic streaming induced by intracytoplasmic spindle translocation contributes to developmental competence through mitochondrial distribution in mouse oocytes.

OBJECTIVE: To evaluate the developmental competency of mouse metaphase II oocytes and the pattern of mitochondrial positioning through cytoplasmic streaming in mouse metaphase II oocytes. DESIGN: We observed cytoplasmic streaming as movement indicated by fluorescently stained mitochondria using a newly developed method in which the spindle is translocated to the opposite site of the oocyte. This method is termed as intracytoplasmic spindle translocation (ICST). SETTING: University research laboratory. ANIMALS: Female B6D2F1 mice. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Fresh oocytes, postovulatory-aged oocytes, and oocytes treated with cytochalasin B were classified based on the presence of cytoplasmic streaming induced by ICST. The pattern of redistributed mitochondria and developmental competence caused by parthenogenetic activation were evaluated in oocytes with or without cytoplasmic streaming. RESULT(S): Induced cytoplasmic streaming occurred in 84% of the fresh oocytes but not in the postovulatory-aged oocytes and the oocytes treated with cytochalasin B. Abnormal mitochondrial aggregation was observed in oocytes in which cytoplasmic streaming was not induced. Furthermore, the developmental competence was significantly lower in oocytes without cytoplasmic streaming. CONCLUSION(S): Cytoplasmic streaming induced by ICST contributes to developmental competence through the redistribution of mitochondria and may be a valuable criterion for predicting early developmental competence in mouse oocytes.

Predictive factors for secondary postpartum hemorrhage: a case-control study in Japan.

BACKGROUND: Secondary postpartum hemorrhage (PPH) is defined as excessive vaginal blood loss occurring between 24 h and 6-12 weeks after birth. The incidence of secondary PPH varies from 0.2% to 3.0%, and the peak incidence ranges from 1 to 2 weeks postpartum. There is no clinical evidence regarding the cause of secondary PPH. Therefore, this study aimed to determine the predictive factors for secondary PPH in an Asian population. METHODS: A case-control study was performed. The clinical data of 25 secondary PPH patients who had been admitted to our hospital between June 2012 and January 2019 were obtained for this study. Control patients (n = 100) were selected from pregnant women who delivered at the hospital during the same period; they were matched to secondary PPH patients using propensity score matching to adjust for maternal age at delivery, parity, and the use of assisted reproductive technology (ART). A multiple logistic regression analysis was used to determine the predictive factors for secondary PPH. RESULTS: The median maternal age was 34 years (range, 24-42 years); 85 (68.0%) women were nulliparous, 31 (24.8%) used ART, and 116 (92.8%) had term deliveries. Immediate PPH (adjusted odds ratio [OR], 2.84; 95% confidence interval [CI], 1.04-7.75) and manual removal of the placenta (adjusted OR, 6.14; 95% CI, 1.21-31.1) were associated with secondary PPH. CONCLUSION: Increasing the awareness of the predictive factors for secondary PPH could play an important role in the recognition and treatment of postpartum morbidity.

Association of glycated hemoglobin at an early stage of pregnancy with the risk of gestational diabetes mellitus among non-diabetic women in Japan: The Japan Environment and Children's Study.

AIMS/INTRODUCTION: Gestational diabetes mellitus (GDM) is one of the most common complications of pregnancy and is associated with adverse pregnancy outcomes. This study aimed to explore the associations between glycated hemoglobin (HbA1c) levels at the early stage of pregnancy and the GDM risk among non-diabetic women in a nationwide study in Japan. In addition, the relationship between GDM and adverse pregnancy outcomes was also analyzed. MATERIALS AND METHODS: This cohort study (n = 89,799) used data from the Japan Environment and Children's Study. We stratified the participants into four groups according to HbA1c levels at an early stage of pregnancy. We investigated the association of HbA1c at an early stage of pregnancy with the risk of GDM, and of GDM with the risk of some representative adverse pregnancy outcomes, using the multiple logistic regression model with adjustment for potential confounders. RESULTS: The adjusted odds ratio for GDM per 0.1 percentage point increase in HbA1c (%) was 1.20. The adjusted odds ratio for developing GDM was significantly increased in women from the HbA1c 5.0-5.4% category. GDM significantly increased the adjusted odds ratio for adverse pregnancy outcomes, such as hypertensive disorders of pregnancy, polyhydramnios and premature birth. CONCLUSIONS: High-normal HbA1c levels at the early stage of pregnancy are significantly associated with GDM risk in women in Japan. GDM was significantly associated with adverse pregnancy outcomes.