Survival and unique clinical practices of extremely preterm infants born at 22-23 weeks' gestation in Japan: a national survey.

OBJECTIVES: To investigate prognosis and clinical practices of infants born at 22-23 weeks' gestational age (wkGA) in Japan. DESIGN: A national institutional-level electronic questionnaire surveys performed in September 2021. SETTING: All perinatal centres across Japan. PATIENTS: Infants born at 22-23 wkGA in 2018-2020. MAIN OUTCOME MEASURES: Proportion of active resuscitation and survival at neonatal intensive care unit (NICU) discharge, and various clinical practices. RESULTS: In total, 255 of 295 NICUs (86%) responded. Among them, 145 took care of infants born at 22-23 wkGA and answered the questions regarding their outcomes and care. In most NICUs (129 of 145 (89%)), infants born at 22+0 wkGA can be actively resuscitated. In almost half of the NICUs (79 of 145 (54%)), infants born at ≥22+0 wkGA were always actively resuscitated. Among 341 and 757 infants born alive at 22 and 23 wkGA, respectively, 85% (291 of 341) and 98% (745 of 757) received active resuscitation after birth. Among infants actively resuscitated at birth, 63% (183 of 291) and 80% (594 of 745) of infants born at 22 and 23 wkGA survived, respectively. The survey revealed unique clinical management for these infants in Japan, including delivery with caul in caesarean section, cut-cord milking after clamping cord, immediate intubation at birth, hydrocortisone use for chronic lung disease, analgesia/sedation use for infants on mechanical ventilation, routine echocardiography and brain ultrasound, probiotics administration, routine glycerin enema and skin dressing to prevent pressure ulcers. CONCLUSIONS: Many 22-23 wkGA infants were actively resuscitated in Japan and had a high survival rate. Various unique clinical practices were highlighted.

Use of the Japanese gestational diabetes mellitus diagnostic strategy during the COVID-19 pandemic in Japan: A questionnaire survey.

AIM: Some concerns exist that diagnosis of gestational diabetes mellitus (GDM) may be missed when the simplified diagnostic criteria of the Japanese Society of Diabetes and Pregnancy (JSDP) for GDM (published during the COVID-19 pandemic) are used. Moreover, limited data is available regarding how widespread these diagnostic criteria are used when managing GDM during the COVID-19 pandemic. Therefore, this study aimed to determine how GDM diagnosis has changed during the COVID-19 pandemic in Japan. METHODS: The changes in GDM diagnosis during the COVID-19 pandemic were investigated using an online questionnaire to 2159 obstetric facilities in Japan. The questionnaire collected data on facility type, awareness of Japanese GDM diagnostic strategies, modifications to diagnostic methods for early and late GDM, and opinions on GDM management, with the pandemic divided into seven periods. RESULTS: We received responses from 593 facilities (27%). Approximately 90% of the facilities did not change their diagnostic process for early GDM or late GDM (occurring after 24 weeks gestation). However, during the COVID-19 pandemic, 19 facilities discontinued the use of 75-g oral glucose tolerance tests before 24 weeks of gestation, and 17 facilities discontinued it after 24 weeks of gestation, instead using the aforementioned Japanese GDM diagnostic strategy. CONCLUSIONS: Although a limited number of facilities modified their diagnostic method in response to the COVID-19 pandemic, this study demonstrated that those that adjusted their diagnostic method primarily used the Japanese COVID-19 GDM strategy by the JSDP.

A nationwide study of obstetric management and outcomes in premature rupture of membrane at term: Report from the Perinatology Committee, Japan Society of Obstetrics and Gynecology, 2017-2018.

AIM: This nationwide study aimed to investigate the practical management of term premature rupture of membrane (PROM) and its relationship with maternal and neonatal outcomes. METHODS: We conducted a questionnaire survey of 415 facilities participating in the Japan Perinatal Registry Network of the Japan Society of Obstetrics and Gynecology in 2016. The patients were women expecting vaginal birth after PROM at term without clinical chorioamnionitis. We classified the facilities into three groups based on duration of the expectant management after PROM (within 24, 24, and 48 h). Furthermore, we analyzed the association between perinatal outcomes and management protocol using the Japan Perinatal Registry Network Database 2016. RESULTS: Of 415 facilities, 346 (83.4%) completed and returned the survey. Among 231 facilities with management protocols, an interval of 3 days from PROM to delivery was acceptable in 167 facilities (72.3%). One hundred forty-nine facilities (64.5%) responded that they did not perform mechanical cervical dilation, and 90 (39.0%) used oxytocin as a uterotonic irrespective of cervical maturation. The number of hospitals that had a policy to administer antibiotics to Group B streptococcus-positive patients was 211 (91.3%). Neonatal outcomes at birth and the frequency of cesarean section and postpartum fever did not differ among the three groups. CONCLUSIONS: Most facilities in the Japan Perinatal Registry Network managed women at term to delivery within 3 days after PROM with attention to bacterial infection. Expectant management up to 48 h after PROM did not increase the risk of postpartum fever, compared to labor induction immediately after PROM.

Adenocarcinoma in situ or early-stage cervical cancer is a risk factor for preterm delivery after cervical conization: a multicenter observational study.

OBJECTIVE: Pregnancy after conization is associated with a high risk of preterm delivery. However, because risk factors for preterm delivery after conization remain unknown, we conducted a multicenter observational study to investigate risk factors associated with preterm delivery. METHODS: We selected patients who had previously undergone conization and reviewed medical records from 18 hospitals in cooperation with Keio University School of Medicine between January 2013 and December 2019. Women were classified as nulliparous and primiparous, and a multiple logistic regression analysis was performed to evaluate the relative contributions of the various maternal risk factors for preterm delivery (i.e. delivery before 37 gestational weeks). RESULTS: Among 409 pregnant women after conization, 68 women delivered preterm (17%). The incidence of nulliparity (p = .014) was higher and a history of preterm delivery (p = .0010) was more common in the preterm delivery group than in the term delivery group. Furthermore, the proportion of women diagnosed with adenocarcinoma in situ (AIS) and cervical cancer in the preterm delivery group was higher than that in the term delivery group (p = .0099 and .0004, respectively). In multiple regression models in nulliparous women, cervical cancer or AIS (Odds ratio [OR]: 4.16, 95% CI: 1.26-13.68, p = .019) and a short cervix in the second trimester (OR: 13.41, 95% CI: 3.88-46.42, p < .0001) increased the risk of preterm delivery. Furthermore, a history of preterm delivery (OR: 7.35, 95% CI: 1.55-34.86, p = .012), cervical cancer or AIS (OR: 5.07, 95% CI: 1.24-20.73, p = .024), and a short cervix in the second trimester (OR: 4.29, 95% CI: 1.11-16.62, p = .035) increased the risk of preterm delivery in the multiple regression models in primiparous women. CONCLUSION: Pregnant women who previously underwent conization are at risk for preterm delivery. The histological type of AIS and cervical cancer was evaluated as a risk factor for preterm delivery. KEY MESSAGESPrior preterm delivery, presence of a short cervix, and cervical cancer or AIS were predictors of preterm delivery after conization.The depth of conization in cervical cancer or AIS group was significantly larger than that in the CIN group.

DNA methylation analysis of cord blood samples in neonates born to gestational diabetes mothers diagnosed before 24 gestational weeks.

INTRODUCTION: Genome-wide methylation analyses of gestational diabetes mellitus (GDM) diagnosed after 24 gestational weeks (late GDM (L-GDM)) using cord blood have been reported. However, epigenetic changes in neonates born to mothers with GDM diagnosed before 24 gestational weeks (early GDM (E-GDM)) have not been reported. We investigated DNA methylation in neonates born to mothers with E-GDM using cord blood samples. RESEARCH DESIGN AND METHODS: Genome-wide DNA methylation analysis was performed using an Illumina EPIC array to compare methylation rates of 754 255 autosomal sites in cord blood samples from term neonates born to 162 mothers with GDM (E-GDM: n=84, L-GDM: n=78) and 60 normal glucose tolerance (normal OGTT) pregnancies. GDM was diagnosed based on Japan Society of Obstetrics and Gynecology criteria modified with International Association of Diabetes in Pregnancy Study Group criteria. In this study, all GDM mothers underwent dietary management, while self-monitoring of blood glucose and insulin administration was initiated when dietary modification did not achieve glycemic control. RESULTS: There were no significant differences in genome-wide DNA methylation of cord blood samples between the GDM (E-GDM and L-GDM) groups and normal OGTT group or between the E-GDM and normal OGTT groups, L-GDM and normal OGTT groups, and E-GDM and L-GDM groups. CONCLUSIONS: This is the first report to determine the DNA methylation patterns in neonates born to mothers with E-GDM. Neonates born to mothers with GDM, who were diagnosed based on Japan Society of Obstetrics and Gynecology criteria, may not differ in DNA methylation compared with those born to normal OGTT mothers.

Impaired early phase insulin secretion associated with gestational diabetes mellitus in underweight women.

BACKGROUND: No reports have focused on the clinical and metabolic characteristics of gestational diabetes (GDM) in underweight women. The aim of this study is to investigate the clinical and metabolic features of underweight GDM (pregravid BMI, <18.5 kg/m2: U-GDM). MATERIALS AND METHODS: Women diagnosed with GDM were categorized based on their pre-pregnancy BMI as either underweight (n = 49) or normal weight (pregravid BMI, 18.5-25.0 kg/m2: n = 271: N-GDM). During the study period, GDM was diagnosed using the International Association of Diabetes in Pregnancy Study Group criteria. Women with multi-fetal pregnancies, fetal congenital anomalies, overt diabetes in pregnancy, and pre-gestational diabetes mellitus were excluded. RESULTS: There were no notable differences in maternal age at delivery and the rate of nulliparous between the U-GDM and N-GDM groups. Regarding antepartum oral glucose tolerance test profiles, women with U-GDM exhibited significantly lower fasting plasma glucose (FPG) levels than those with N-GDM (p < .01). The Insulinogenic Index of women with U-GDM was significantly lower than that of women with N-GDM (p < .05). CONCLUSION: Impaired early phase insulin secretion was associated with GDM onset in underweight women.

Effects of prophylactic vaginal progesterone administration on mild cervical shortening (TROPICAL study): a multicenter, double-blind, randomized trial.

Vaginal progesterone reduces the preterm birth frequency among high-risk women with a cervical length ≤25 mm at midtrimester. However, the strategy may promote no substantial reduction in overall preterm birth rates, because such high-risk women are only approximately 2% of all pregnant women, which restrict the number of participants. Our purpose was to determine whether prophylactic vaginal progesterone administration can preserve cervical length and reduce preterm birth rates among women with mild cervical shortening.This multicenter, parallel-arm, double-blind, randomized, placebo-controlled trial involved vaginal progesterone administration (200 mg daily from 16 to 33 weeks of gestation) among asymptomatic women with a singleton pregnancy and a sonographic cervical length of 25 to <30 mm between 16 and 23 weeks of gestation. The primary and secondary endpoints were cervical shortening rates at 34 weeks of gestation and preterm birth rates, respectively. The trial was registered at the University Hospital Medical Information Network (UMIN000013518) in Japan.Between April 2014 and March 2018, 119 women were randomly assigned to the progesterone group (n = 59) and the placebo group (n = 60). No significant differences in the frequency of women with a cervical length ≥20 mm at 34 weeks of gestation were observed between both groups. All preterm births occurred after 34 weeks of gestation, except for one patient in the placebo group. The progesterone group had a lower rate of preterm birth before 37 weeks than the placebo group (3.4% vs. 15.0%, respectively; p < .05).Despite having no effect on preserving cervical length, prophylactic vaginal progesterone administration reduced preterm birth frequency among women with mild cervical shortening. Our results are suggesting that women with mild cervical shortening are at risk for late preterm birth and the need for expanding progesterone treatment indications to include not only high-risk but also low-risk populations.

Epigenetic Changes in Neonates Born to Mothers With Gestational Diabetes Mellitus May Be Associated With Neonatal Hypoglycaemia.

The detection of epigenetic changes associated with neonatal hypoglycaemia may reveal the pathophysiology and predict the onset of future diseases in offspring. We hypothesized that neonatal hypoglycaemia reflects the in utero environment associated with maternal gestational diabetes mellitus. The aim of this study was to identify epigenetic changes associated with neonatal hypoglycaemia. The association between DNA methylation using Infinium HumanMethylation EPIC BeadChip and neonatal plasma glucose (PG) level at 1 h after birth in 128 offspring born at term to mothers with well-controlled gestational diabetes mellitus was investigated by robust linear regression analysis. Cord blood DNA methylation at 12 CpG sites was significantly associated with PG at 1 h after birth after adding infant sex, delivery method, gestational day, and blood cell compositions as covariates to the regression model. DNA methylation at two CpG sites near an alternative transcription start site of ZNF696 was significantly associated with the PG level at 1 h following birth (false discovery rate-adjusted P < 0.05). Methylation levels at these sites increased as neonatal PG levels at 1 h after birth decreased. In conclusion, gestational diabetes mellitus is associated with DNA methylation changes at the alternative transcription start site of ZNF696 in cord blood cells. This is the first report of DNA methylation changes associated with neonatal PG at 1 h after birth.

Risk of preterm birth after the excisional surgery for cervical lesions: a propensity-score matching study in Japan.

INTRODUCTION: There is a paucity of data on the risk of preterm birth subcategorized by gestational age in pregnancies after the pre-pregnancy excisional treatment for cervical lesions. In addition, little is known about the effect of prophylactic cerclage on the risk of preterm birth. The aim of this study was to investigate the risk of preterm birth stratified by gestational period and its reduction by the prophylactic cerclage in women with prior excisional surgery. MATERIALS AND METHODS: We retrospectively analyzed a cohort of singleton pregnancies in the Japan Perinatal Registry Network Database (2013-2014, n = 307,001). Cases included pregnancies after the surgery (i.e. conization and loop electrosurgical excision procedure). Controls comprised the propensity-score matched pregnancies without pre-pregnancy surgery. The main outcome was the occurrence of preterm birth. The effect of prophylactic cervical cerclage on the risk of preterm birth after the excisional surgery was also examined using cases. RESULTS: In the propensity-score matched population (cases, n = 1389; controls, n = 1389), cases exhibited a higher risk of preterm birth and preterm prelabor rupture of membranes (PROM), compared with controls (preterm birth: 25.3 versus 10.6%; preterm PROM: 14.0 versus 3.5%: both p < .0001). Odds ratios (OR; 95% confidence interval [CI]) for preterm birth at 22-27 weeks, 28-31 weeks, 32-33 weeks, and 34-36 weeks were 3.4 [1.8-6.5], 4.6 [2.7-7.7], 2.2 [1.4-3.5], and 2.1 [1.6-2.7], respectively. The association was stronger for preterm PROM at earlier gestational age (22-27 weeks, 28-31 weeks, 32-33 weeks, and 34-36 weeks: 5.2 [2.3-11.8], 7.1 [3.4-15.0], 3.8 [1.7-8.3], and 3.9 [1.8-4.6], respectively). In cases, 171 underwent the prophylactic cervical cerclage. The occurrence of preterm birth and preterm PROM was comparable between those with and without the cerclage (28.7 versus 24.2, and 12.9 versus 13.3%, respectively). CONCLUSIONS: Pre-pregnancy excisional cervical surgery was associated with the increased risk of preterm birth, especially before 32 weeks of gestation. The prophylactic cerclage did not reduce the risk of preterm birth.

Impaired fetal growth in mothers with inadequate gestational weight gain: a retrospective study in Japanese uncomplicated pregnancy.

Introduction: The average birth weight in Japan has gradually decreased and the number of low birth weight infant has increased over the last 30 years. Japanese pregnant women are characterized with lower prevalence of obesity than those in other developed countries, and maternal underweight before pregnancy is independently associated with low birth weight. However, the association between maternal inadequate gestational weight gain (GWG) and the risk of small for gestational age (SGA) in Japanese uncomplicated pregnant women has not been fully understood. This study aimed to examine the effect of maternal inadequate GWG on the risk of SGA in Japanese uncomplicated pregnancies.Methods: We retrospectively analyzed uncomplicated Japanese singleton pregnancies that delivered at term gestation in our institution from 2006 to 2016. The association between GWG and birth weight was analyzed by multiple linear regression. Potential confounding factors included maternal age, parity, prepregnancy BMI, and neonatal sex. The association between inadequate GWG and SGA was also examined by logistic regression.Results: A total of 3837 mother-neonate dyads were analyzed. Maternal GWG was 10.1 ± 3.7 kg (mean ± SD), and 2529 (66%) had inadequate GWG. After adjusting for confounding factors, GWG significantly correlated with birth weight (standardized ß = 0.199, p < .001). Inadequate GWG increased the risk of delivering SGA neonate (adjusted odds ratio (aOR) = 1.97 [1.45-2.68], p < .001). This association was particularly pronounced in underweight (aOR = 2.95 [1.38-6.29], p = .005) and normal weight mothers (aOR = 1.79 [1.27-2.52], p = .001), and not in overweight/obese mothers (p = .115).Conclusion: Maternal GWG is associated with birth weight in Japanese women with uncomplicated singleton pregnancies. Inadequate GWG is an important risk factor of SGA, particularly in non-obese women. The present finding would potentially provide further evidence that promoting adequate gestational weight gain in Japanese underweight and normal weight mothers would reduce SGA, as well as metabolic dysfunction in later life.

In Utero Amniotic Fluid Stem Cell Therapy Protects Against Myelomeningocele via Spinal Cord Coverage and Hepatocyte Growth Factor Secretion.

Despite the poor prognosis associated with myelomeningocele (MMC), the options for prenatal treatments are still limited. Recently, fetal cellular therapy has become a new option for treating birth defects, although the therapeutic effects and mechanisms associated with such treatments remain unclear. The use of human amniotic fluid stem cells (hAFSCs) is ideal with respect to immunoreactivity and cell propagation. The prenatal diagnosis of MMC during early stages of pregnancy could allow for the ex vivo proliferation and modulation of autologous hAFSCs for use in utero stem cell therapy. Therefore, we investigated the therapeutic effects and mechanisms of hAFSCs-based treatment for fetal MMC. hAFSCs were isolated as CD117-positive cells from the amniotic fluid of 15- to 17-week pregnant women who underwent amniocentesis for prenatal diagnosis and consented to this study. Rat dams were exposed to retinoic acid to induce fetal MMC and were subsequently injected with hAFSCs in each amniotic cavity. We measured the exposed area of the spinal cord and hepatocyte growth factor (HGF) levels at the lesion. The exposed spinal area of the hAFSC-treated group was significantly smaller than that of the control group. Immunohistochemical analysis demonstrated a reduction in neuronal damage such as neurodegeneration and astrogliosis in the hAFSC-treated group. Additionally, in lesions of the hAFSC-treated group, HGF expression was upregulated and HGF-positive hAFSCs were identified, suggesting that these cells migrated to the lesion and secreted HGF to suppress neuronal damage and induce neurogenesis. Therefore, in utero hAFSC therapy could become a novel strategy for fetal MMC. Stem Cells Translational Medicine 2019;8:1170-1179.

Changes in bone metabolic profile associated with pregnancy or lactation.

Calcium and nutrients are transferred from mothers to fetuses or infants during pregnancy or lactation, respectively, promoting metabolic changes in the mother, many uncharacterized. To evaluate these changes, we undertook two parallel studies. In one we analyzed fourteen clinical cases of vertebral fragility fractures, at or before three months after partum, in mothers who breastfed their infants. In the other, we enrolled 79 additional pregnant subjects, some who chose to breastfeed and others who did not, and analyzed changes in bone metabolic status starting between 34 and 36 weeks of gestation and ending one month after partum. In the larger group, bone-resorbing and bone-forming parameters such as serum TRACP5b and osteocalcin, respectively, significantly increased after partum. Among parameters that changed after partum, serum PTH and the bone-resorbing markers serum TRACP5b and urine NTX were significantly higher in mothers who only breastfed infants compared to mothers who fed infants formula or a mix of both. However, bone-forming parameters were comparable between breastfeeding and non-breast-feeding groups after partum, suggesting that elevated bone-resorption occurs only in the breastfeeding group. Radiographic analysis after partum demonstrated that no subject among the 79 analyzed showed vertebral fractures, even those who breastfed exclusively. Among fracture cases analyzed, subjects exhibited significantly lower bone mineral density than did non-fracture cases in breastfeeding-only subjects. We conclude that bone metabolic status significantly changes over the period between pregnancy and post-partum lactation, and that low bone mineral density seen in a small subset of breastfeeding-only cases likely causes post-partum vertebral fragility fractures.

Glycemic and metabolic features in gestational diabetes: singleton versus twin pregnancies.

A number of data on gestational diabetes mellitus (GDM) in singleton pregnancy is available, however, little is known about the glycemic characteristics of twin pregnancy with GDM. The aim of this study was to compare the severity of dysglycemia between twin and singleton pregnancies with GDM (T-GDM and S-GDM). We retrospectively analyzed pregnancies with GDM defined by the Japan Diabetes Society criteria (T-GDM, n = 20; S-GDM, n = 451) in our hospital. During the study period, women with GDM underwent self-monitoring of blood glucose measurements as well as dietary management. Insulin treatment was initiated when dietary treatment did not achieve the glycemic goal. The glycemic and metabolic characteristics were compared between T-GDM and S-GDM, as follows: gestational week at the diagnosis of GDM, 75 g oral glucose tolerance test (OGTT) results, HbA1c, insulin secretion (i.e. insulinogenic index [IGI] and Insulin Secretion-Sensitivity Index-2 [ISSI-2]), and insulin requirement before delivery. The rate of one abnormal OGTT value in T-GDM was similar to that in S-GDM (60% vs. 71%). There were no significant differences in gestational week and levels of HbA1c at diagnosis, levels of IGI and ISSI-2 between T-GDM and S-GDM (median, 20 weeks vs. 17 weeks, 5.0% vs. 5.2%, 0.58 vs. 0.71, 1.7 vs. 1.8, respectively). The rate of insulin treatment and a median dosage of insulin needed before delivery was comparable between the two groups (T-GDM vs. S-GDM: 45% vs. 32% and 14 vs. 13 unit/day). Our data suggested that the severity of dysglycemia in T-GDM was similar to that in S-GDM during pregnancy.

The neurorestorative effect of human amniotic fluid stem cells on the chronic phase of neonatal hypoxic-ischemic encephalopathy in mice.

BACKGROUND: Hypoxic-ischemic encephalopathy (HIE) remains a major cause of cerebral palsy. Increasing evidence has suggested that mesenchymal stem cells have a favorable effect on HIE. However, the efficacy of human amniotic fluid stem cells (hAFS) for HIE, especially in the chronic phase, remains unclear. The aim of this study was to determine the neurorestorative effect of hAFS on the chronic phase of HIE. METHODS: hAFS were isolated from AF cells as CD117-positive cells. HI was induced in 9-day-old mice. Animals intranasally received hAFS or phosphate-buffered saline at 10 days post HI and were harvested for histological analysis after functional tests at 21 days post HI. We also implanted PKH26-positive hAFS to assess their migration to the brain. Finally, we determined gene expressions of trophic factors in hAFS co-cultured with HI brain extract. RESULTS: hAFS improved sensorimotor deficits in HIE by gray and white matter restoration and neuroinflammation reduction followed by migration to the lesion. Brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), hepatocyte growth factor (HGF), and stromal cell-derived factor-1 (SDF-1) gene expressions in hAFS were elevated when exposed to HI-induced brain extract. CONCLUSION: hAFS induced functional recovery by exerting neurorestorative effects in HIE mice, suggesting that intranasal administration of hAFS could be a novel treatment for HIE, especially in the chronic phase.

Clinical and genetic characteristics of abnormal glucose tolerance in Japanese women in the first year after gestational diabetes mellitus.

AIMS/INTRODUCTION: Risk factors of type 2 diabetes mellitus in Japanese women with recent gestational diabetes mellitus are unknown. The objective of the present study was to investigate the clinical and genetic characteristics associated with postpartum abnormal glucose tolerance in Japanese women with gestational diabetes mellitus. MATERIALS AND METHODS: A total of 213 Japanese women with recent gestational diabetes mellitus who underwent a postpartum 2-h oral glucose tolerance test were investigated. The association between antepartum clinical characteristics and postpartum abnormal glucose tolerance (diabetes or prediabetes based on the Japan Diabetes Society criteria) was examined. Frequencies of 45 known type 2 diabetes mellitus-associated genetic variants were also compared between women with and without postpartum abnormal glucose tolerance. RESULTS: A total of 59 women showed postpartum abnormal glucose tolerance (prediabetes, n = 51; diabetes, n = 8). Plasma glucose levels at 1 or 2 h, the insulinogenic index and the insulin secretion-sensitivity index-2 of the antepartum oral glucose tolerance test were independent of postpartum abnormal glucose tolerance risk factors (P = 0.006, P = 0.00002, P = 0.01 and P = 0.006, respectively). Four genetic variants (rs266729 [ADIPOQ], rs6017317 [HNF4A], rs5215 [KCNJ11] and rs7177055 [HMG20A]) showed a nominally significant association with postpartum abnormal glucose tolerance (P < 0.05, respectively). Among these, three were related to insulin secretion. Postpartum abnormal glucose tolerance risk significantly increased with increasing risk-allele number (P = 0.0005; odds ratio 1.91). CONCLUSIONS: Clinical features and genetic variants related to impaired insulin secretion are risk factors of postpartum abnormal glucose tolerance in Japanese women with recent gestational diabetes mellitus.

Human amniotic fluid stem cells have a unique potential to accelerate cutaneous wound healing with reduced fibrotic scarring like a fetus.

Adult wound healing can result in fibrotic scarring (FS) characterized by excess expression of myofibroblasts and increased type I/type III collagen expression. In contrast, fetal wound healing results in complete regeneration without FS, and the mechanism remains unclear. Amniotic fluid cells could contribute to scar-free wound healing, but the effects of human amniotic fluid cells are not well characterized. Here, we determined the effect of human amniotic fluid stem cells (hAFS) on FS during wound healing. Human amniotic fluid was obtained by amniocentesis at 15-17 weeks of gestation. CD117-positive cells were isolated and defined as hAFS. hAFS (1 × 106) suspended in PBS or cell-free PBS were injected around wounds created in the dorsal region of BALB/c mice. Wound size was macroscopically measured, and re-epithelialization in the epidermis, granulation tissue area in the dermis and collagen contents in the regenerated wound were histologically analyzed. The ability of hAFS to engraft in the wound was assessed by tracking hAFS labeled with PKH-26. hAFS fulfilled the minimal criteria for mesenchymal stem cells. hAFS injection into the wound accelerated wound closure via enhancement of re-epithelialization with less FS. The process was characterized by lower numbers of myofibroblasts and higher expression of type III collagen. Finally, transplanted hAFS were clearly observed in the dermis until day 7 implying that hAFS worked in a paracrine manner. hAFS can function in a paracrine manner to accelerate cutaneous wound healing, producing less FS, a process resembling fetal wound healing.