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.

Achievement of Target Glycemic Goal with Simple Basal Insulin Regimen in Women with Gestational Diabetes: A Prospective Cohort Study.

There is little evidence concerning the need to treat gestational diabetes (GDM) in the same way as pregestational diabetes. We evaluated the efficacy of the simple insulin injection (SII) regimen for achieving the target glucose goal without increasing adverse perinatal outcomes in singleton pregnant women with GDM. All subjects underwent self-monitoring of blood glucose (SMBG), and insulin therapy was indicated according to the SMBG profile. Insulin was initially started with the SII regimen, in which one daily injection of NPH insulin before breakfast was used, and another NPH injection was added at bedtime, if necessary. We used the target glucose as <95 mg/dL at fasting and <120 mg/dL postprandial and accepted <130 mg/dL for the latter. If the target glucose did not reach with the regimen, we switched to the multiple daily injection (MDI) with additional prandial insulin aspart. We compared the SMBG profile before delivery as well as the perinatal outcomes between the SII and MDI groups. Among 361 women (age 33.7 years, nullipara 41%, prepregnancy body mass index 23.2 kg/m2) with GDM, 59%, 18%, and 23% were in the diet-alone, SII, and MDI groups, respectively. Consequently, regarding women requiring insulin therapy, 43% were treated with the SII regimen throughout pregnancy. The severity of baseline hyperglycemia according to the SMBG data at baseline was the MDI>the SII>the diet group. The rate of achieving target glucose levels before delivery in the SII group at fasting, postprandial < 120 mg/dL and <130 mg/dL were 93%, 54% and 87%, respectively, which were similar to that in the MDI group (93%, 57%, and 93%, respectively), with no significant differences in perinatal outcomes. In conclusion, more than 40% of women with GDM requiring insulin therapy achieved the target glucose goal with this simple insulin regimen without any increase in adverse effects.

Tadalafil treatment for fetuses with early-onset growth restriction: a protocol for a multicentre, randomised, placebo-controlled, double-blind phase II trial (TADAFER IIb).

INTRODUCTION: TheTADAlafil treatment for Fetuses with early-onset growth Restriction: multicentrer, randomizsed, phase II trial (TADAFER II) study showed the possibility of prolonging the pregnancy period in cases of early-onset fetal growth restriction; however, it was an open-label study. To establish further evidence for the efficacy of tadalafil in this setting, we planned a multicentre, randomised, placebo-controlled, double-blind trial. METHODS AND ANALYSIS: This trial will be conducted in 180 fetuses with fetal growth restriction enrolled from medical centres in Japan; their mothers will be randomised into three groups: arm A, receiving two times per day placebo; arm B, receiving one time per day 20 mg tadalafil and one time per day placebo and arm C, receiving 20 mg two times per day tadalafil. The primary endpoint is the prolongation of gestational age at birth, defined as days from the first day of the protocol-defined treatment to birth. To minimise bias in terms of fetal baseline conditions and timing of delivery, a fetal indication for delivery as in TADAFER II will be established in this trial. The investigator will evaluate fetal baseline conditions at enrolment and decide the timing of delivery based on this indication. ETHICS AND DISSEMINATION: This study has been approved by Mie University Hospital Clinical Research Review Board on 22 July 2019 (S2018-007). Written informed consent will be obtained from all mothers before recruitment. Our findings will be widely disseminated through peer-reviewed publications. TRIAL REGISTRATION: jRCTs041190065.

Vaginal Ureaplasma urealyticum or Mycoplasma hominis and preterm delivery in women with threatened preterm labor.

BACKGROUND: Amniotic fluid infection with Ureaplasma urealyticum or Mycoplasma hominis can cause chorioamnionitis and preterm birth. The aim of this study was to examine whether vaginal Ureaplasma urealyticum/Mycoplasma hominis colonization is predictive of preterm delivery in patients exhibiting signs of threatened preterm birth or those with asymptomatic short cervix. METHODS: The present retrospective study, which was performed in a perinatal tertiary center, included patients carrying a singleton pregnancy who were referred to the emergency Ob/Gyn unit because of regular preterm uterine contractions and/or short cervical length (<20 mm) at 22-33 weeks of gestation, and in whom a vaginal U. urealyticum/M. hominis examination (Urea-arginine LYO-2, BioMerieux®) was performed. Univariate and multivariate analyses were performed to assess the association between vaginal U. urealyticum or M. hominis and chorioamnionitis or preterm delivery. RESULTS: The median gestational age of the 94 enrolled patients was 29.9 weeks, and 54 (57%) of the patients were vaginal U. urealyticum/M. hominis-positive. The preterm delivery rate in the positive group was higher than in the negative group (53 versus 25%; p = .007). Vaginal U. urealyticum/M. hominis positivity was found to be an independent risk factor for preterm birth at <37 weeks of gestation (adjusted odds ratio = 4.0, 95% confidence interval, 1.1-15.3) in a multivariate analysis adjusted for age, history of preterm delivery and conization, gestational age, cervical length, presence of vaginal bleeding, vaginal fetal fibronectin and serum C-reactive protein at test. U. urealyticum/M. hominis positivity was not associated with delivery at <34 weeks or chorioamnionitis. CONCLUSION: A positive vaginal U. urealyticum/M. hominis culture is an independent predictive factor for preterm birth in patients with symptomatic threatened preterm labor and/or short cervix.

Comparison of the benefits and hemodynamic side effects of oxytocin between intravenous infusion with and without bolus injection during caesarean section.

The aim of this study was to compare the benefits and hemodynamic side effects of oxytocin between intravenous infusion with and without a bolus injection during a caesarean section. Women with singleton pregnancies who underwent caesarean sections under spinal anaesthesia were included. Oxytocin was administered by an iv bolus injection (5 U) followed by an intravenous infusion (10 U of oxytocin in 500 mL normal saline); this was switched to just an intravenous infusion. The amount of blood loss did not differ between the groups. In a multivariate analysis, the adjusted odds ratios for the risk of hypotension (≥20% reduction of systolic BP) and tachycardia (heart rate ≥100 bpm) were 4.5 (95% confidence interval [CI], 1.6-12.5) and 3.7 (95%CI 1.9-7.2) in the iv bolus group, respectively, compared with the just the infusion group. The oxytocin administration by iv bolus injection did not decrease blood loss and increased the rate of hemodynamic side effects.Impact statementWhat is already known on this subject? Oxytocin is used as the first-line uterotonic treatment to prevent a postpartum haemorrhage in women undergoing Caesarean Sections. Oxytocin is known to relax vascular smooth muscle, which can cause hypotension and tachycardia. The protocols for administering oxytocin during CS vary by institution.What do the results of this study add? Combined treatment with oxytocin by iv bolus injection (5 U) followed by iv infusion (10 U of oxytocin in 500 mL normal saline) during CS increased the risk of developing adverse hemodynamic side effects, including hypotension, tachycardia, and the need for vasopressors, without any benefit in the control of intraoperative blood loss in comparison to iv infusion alone.What are the implications of these findings for clinical practice and/or further research? We should abandon the iv bolus injection of oxytocin during CS, especially for women undergoing an elective CS who are not in labour.

Fetal sex and maternal insulin resistance during mid-pregnancy: a retrospective cohort study.

BACKGROUND: Recent studies have suggested that fetal sex influences maternal glucose and insulin metabolism during pregnancy. We examined whether fetal sex is associated with maternal insulin resistance and the ß-cell function during mid-pregnancy. METHODS: This retrospective study included singleton pregnant women who underwent a 75-g oral glucose tolerance test (OGTT) at 24-34 weeks of gestation due to positive diabetic screening. In addition to plasma glucose (PG), we measured plasma insulin during the OGTT to obtain surrogate indices associated with insulin resistance (IR), including homeostasis assessment model (HOMA) -IR and insulin sensitivity index (IsOGTT), and ß-cell function, including insulinogenic index (II), HOMA-ß, and area under the curve of insulin response. We compared these indices between women carrying male fetuses to those carrying female fetuses. RESULTS: The study population included 617 women (mean age, 32.4 ± 4.9 years) with a mean pre-pregnancy body mass index (BMI) of 22.6±4.5. They underwent the 75g-OGTT at 29.0 ± 2.5 weeks. Two hundred fifty-eight (42%) women were diagnosed with gestational diabetes (GDM). There was no significant difference in maternal age, pre-pregnancy BMI, gestational age at OGTT, PG at OGTT, or the prevalence of GDM between women with a male fetus (n=338) (male group) and those with a female fetus (n=279) (female group). Regarding the indices of IR, IR was significantly higher and insulin sensitivity was lower in the female group than in the male group (HOMA-IR: 7.0 [5-9.6] vs. 6.2 [4.6-8.8], p< 0.05; IsOGTT: 5.86 [4.29-7.83] vs. 6.29 [4.59-8.84], p< 0.01) (median [quartile range]). These differences remained significant after adjustment for maternal age, pre-pregnancy BMI, gestational age and fasting PG at OGTT, and the diagnosis of GDM. In contrast, the ß-cell function did not differ between the two groups. CONCLUSION: Maternal IR during mid-pregnancy was significantly higher in women carrying a female fetus than in those with a male fetus. The sex of the fetus may affect maternal insulin sensitivity during mid-pregnancy.

Impact of tocolysis-intent magnesium sulfate and beta-adrenergic agonists on perinatal brain damage in infants born between 28-36 weeks' gestation.

AIMS: Magnesium sulfate has neuroprotective effects in preterm infants. Whether other antepartum treatments interfere with the neuroprotective actions is not well known. This study aims to explore the impacts of antenatal administration of Magnesium sulfate or beta-2 adrenergic agonists as tocolytic agents on the developing brain in premature infants. METHODS: This is a retrospective cohort study in four tertiary perinatal centers in Japan. We collected data of pregnant women and infants born between 28 and 36 weeks for tocolytic agents, gestational age, sex, antenatal corticosteroid, fetal growth restriction, pathological chorioamnionitis, low umbilical arterial pH values (<7.1), multiple pregnancy, mode of delivery and institutions after excluding clinical chorioamnionitis, non-reassuring fetal status or major anomalies. Tocolytic agents were categorized into four groups: no-tocolysis, magnesium sulfate, beta-2 adrenergic agonists and the combination of them. We conducted multiple comparisons with multivariate analyses using generalized linear regression models to compare the prevalence of a poor perinatal outcome defined as infant's death, brain damage, particularly cerebral palsy and developmental delay. RESULTS: Among 1083 infants, 39% were no-tocolysis, 47% were magnesium sulfate, 41% were beta-2 adrenergic agonists and 27% were combination group, including the duplication. The incidence of poor perinatal outcome was decreased by magnesium sulfate (OR 0.27, 95% CI 0.10-0.72), but not changed significantly by beta-2 adrenergic agonists (OR 1.28, 95% CI 0.63-2.59) or the combination group (OR 2.24, 95% CI 0.67-7.54), compared with the no-tocolysis. CONCLUSION: The combination therapy for tocolysis with beta-2 adrenergic agonists diminished the magnesium sulfate neuroprotective action after adjusting for covariables.

Risk factors associated with the development of postpartum diabetes in Japanese women with gestational diabetes.

BACKGROUND: Although the onset of gestational diabetes (GDM) is known to be a significant risk factor for the future development of type 2 diabetes, this risk specifically in women with GDM diagnosed by the International Association of Diabetes and Pregnancy Study Group (IADPSG) criteria has not yet been thoroughly investigated. This study was performed to investigate the risk factors associated with the development of postpartum diabetes in Japanese women with a history of GDM, and the effects of the differences in the previous Japanese criteria and the IADPSG criteria. METHODS: This retrospective cohort study included Japanese women with GDM who underwent at least one postpartum oral glucose tolerance test (OGTT) between 2003 and 2014. Cases with overt diabetes in pregnancy were excluded. We investigated the risk factors including maternal baseline and pregnancy characteristics associated with the development of postpartum diabetes. RESULTS: Among 354 women diagnosed with GDM during the study period, 306 (86%) (116/136 [85.3%] and 190/218 [87.2%] under the previous criteria and the IADPSG criteria, respectively) who underwent at least 1 follow-up OGTT were included in the study. Thirty-two women (10.1%) developed diabetes within a median follow-up period of 57 weeks (range, 6-292 weeks). Eleven (9.5%) and 21 (11.1%) were diagnosed as GDM during pregnancy based on the previous Japanese criteria and the IADPSG criteria, respectively, which did not significantly differ between those criteria. A multivariate logistic regression analysis revealed that HbA1c and 2-h plasma glucose (PG) at the time of the diagnostic OGTT during pregnancy were independent predictors of the development of diabetes after adjusting for confounders. The adjusted relative risk of HbA1c ≥5.6% for the development of diabetes was 4.67 (95% confidence interval, 1.53-16.73), while that of 2-h PG ≥183 mg/dl was 7.02 (2.51-20.72). CONCLUSIONS: A modest elevation of the HbA1c and 2-h PG values at the time of the diagnosis of GDM during pregnancy are independent predictors of the development of diabetes during the postpartum period in Japanese women with a history of GDM. The diagnostic criteria did not affect the incidence of postpartum diabetes.

Factors associated with patients with gestational diabetes in Japan being at increased risk of requiring intensive care.

OBJECTIVE: To investigate factors associated with high-risk gestational diabetes (GDM) among patients with GDM. METHODS: The present retrospective study included women with singleton pregnancies diagnosed with GDM using International Association of Diabetes and Pregnancy Study Group criteria at a single tertiary perinatal care center in Japan between July 1, 2010, and October 31, 2014. High-risk GDM was defined as patients who required at least 20 units of insulin therapy a day, delivering a large-for-gestational age neonate regardless of insulin therapy, or both. Maternal characteristics and diagnostic test results were investigated to identify associations with the high-risk criteria, and odds ratios (ORs) with 95% confidence intervals (CIs) were calculated. RESULTS: Among 217 patients, 95 (43.8%) were categorized as high risk. After adjusting for confounders, a fasting plasma glucose level at diagnosis of at least 4.66 mmol/L (adjusted OR 2.88, 95% CI 1.51-5.58) and pre-pregnancy body mass index (calculated as weight in kilograms divided by the square of height in meters) of at least 24 (adjusted OR 3.27, 95% CI 1.60-6.90) were independently associated with meeting the high-risk criteria. CONCLUSION: Among Japanese patients with GDM, pre-pregnancy body mass index and fasting plasma glucose levels could be used to identify high-risk patients requiring intensive care during pregnancy.

The Routine Use of Prophylactic Oxytocin in the Third Stage of Labor to Reduce Maternal Blood Loss.

OBJECTIVE: To demonstrate whether or not the routine use of prophylactic oxytocin (RUPO) reduces the blood loss and incidence of postpartum hemorrhaging (PPH). METHODS: We used a prospective cohort and a historical control in a tertiary perinatal care center in Japan. In the prospective cohort, we introduced RUPO in April 2012 by infusing 10 units of oxytocin per 500 mL of normal saline into a venous line after anterior shoulder delivery (RUPO group). In the historical control, oxytocin was administered via a case-selective approach (historical control group). We included completed singleton vaginal deliveries and compared the volume of blood loss and the incidence of PPH between the groups. RESULTS: We found a significantly lower volume of blood loss (520 ± 327 versus 641 ± 375 mL, p < 0.001) and a lower incidence of PPH (6.1% versus 14.0%, p < 0.001) in the RUPO group (n = 392) than in the control group (n = 407). Although the oxytocin dose was significantly higher in the RUPO group (12.8 ± 6.7 versus 10.1 ± 8.0 IU, p < 0.001), no adverse outcomes were observed to be associated with RUPO. CONCLUSIONS: The introduction of RUPO significantly reduced blood loss and the incidence of PPH during completed singleton vaginal deliveries without an increase in adverse effects.

Influence of the interval between antenatal corticosteroid therapy and delivery on respiratory distress syndrome.

AIM: In spite of the recommendation for rescue antenatal corticosteroids (ACS), the optimal time interval between primary and rescue courses has not been clearly demonstrated. The aim of this study was to determine the effects of the interval between a single ACS course and delivery on the incidence of respiratory distress syndrome (RDS). METHODS: In this retrospective study, we included singleton pregnant women who received a single course of ACS and delivered beyond 48 h after ACS administration between 24 and 33 weeks' gestation. The risk of RDS was compared between patients who delivered within seven days (Group I), 7-14 days (Group II) and beyond 14 days (Group III) after ACS administration. RESULTS: We included 83, 14 and 20 patients in Groups I, II and III, respectively. After adjusting for confounders, the ACS delivery interval was significantly associated with RDS in Group II (adjusted odds ratio 12.8, 95% confidence interval 1.31-164.7) and Group III (adjusted odds ratio 64.0, 95% confidence interval 1.32-5808.6). CONCLUSION: A longer ACS delivery interval is associated with a higher risk of RDS. Thus, the use of a rescue course could be expected to reduce the incidence of RDS in patients beyond seven days after ACS administration who remain at risk for preterm delivery within seven days, especially in cases of placenta previa and/or women bearing a male fetus.

Risk factors associated with respiratory disorders in late preterm infants.

OBJECTIVE: Late preterm infants are still high risk for respiratory problems. The aim of this study was to identify risk factors associated with respiratory problems in Japanese late preterm infants. METHODS: In this retrospective multicenter study, we included singleton late preterm deliveries at 34+(0/7)-36+(6/7) weeks of gestation. We excluded cases with congenital anomalies. We defined neonatal respiratory disorders (NRD) as the combination of the need for mechanical ventilation or the use of nasal continuous positive airway pressure. We examined the perinatal risk factors associated with NRD. RESULTS: We included 683 late preterm infants. We found that 13.7%, 6.8% and 2.6% of the infants with NRD were born at 34, 35 and 36 weeks of gestation, respectively. In a multivariate logistic regression analysis adjusting for confounders, the gestational age (GA) at birth (adjusted odds ratio 0.40 per week [95% confidence interval, 0.25-0.61]), cesarean birth (4.18 [2.11-8.84]), and a low Apgar score (33.3 [9.93-121.3]) were independent risk factors associated with NRD. CONCLUSIONS: An earlier GA, cesarean delivery, and a low Apgar score are independent risk factors associated with NRD in singleton late preterm infants. Patients with late preterm deliveries exhibiting these risk factors should be managed in the intensive delivery setting.

Risk factors associated with abnormal glucose tolerance in the early postpartum period among Japanese women with gestational diabetes.

OBJECTIVE: To identify the risk factors associated with abnormal glucose tolerance (AGT) on the first postpartum oral glucose tolerance test (OGTT) among Japanese women with gestational diabetes (GDM). METHODS: In a retrospective study, data were analyzed from women with GDM who underwent their first postpartum OGTT 6-8weeks post partum at a center in Omura, Japan, between January 1, 2007, and December 31, 2011. Women with diabetes or impaired glucose tolerance were deemed to have postpartum AGT. The association between postpartum AGT and various risk factors was analyzed. RESULTS: Among 169 women who underwent a postpartum OGTT, 58 (34.3%) had AGT. The significant risk factors associated with postpartum AGT in univariate analysis were pre-pregnancy body mass index (P=0.096), 1-hour plasma glucose (P=0.006), hemoglobin A1c (P<0.001), insulinogenic index (P=0.05), an insulinogenic index of less than 0.4 (P=0.006), and insulin therapy during pregnancy (P<0.001). Independent risk factors identified by multivariate logistic regression models were insulinogenic index (odds ratio [OR] 0.10, 95% confidence interval [CI] 0.01-0.74; P=0.002), an insulinogenic index of less than 0.4 (OR 5.70, 95% CI 1.69-21.66; P=0.005), and insulin therapy during pregnancy (OR 3.43, 95% CI 1.03-12.55; P=0.044). CONCLUSION: Among Japanese women with GDM, a lower insulinogenic index and use of insulin therapy during pregnancy are associated with early postpartum AGT.

The association between maternal insulin resistance in mid-pregnancy and neonatal birthweight in uncomplicated pregnancies.

There have been few studies performed to address the association between the degree of physiological increase in maternal insulin resistance during pregnancy and neonatal birthweight in non-diabetic pregnancy. We attempted to determine whether maternal insulin resistance, as measured by homeostasis model assessment-insulin resistance (HOMA-IR), in mid-pregnancy is associated with neonatal birthweight in normal pregnancies. In this retrospective observational study, we measured HOMA-IR in singleton healthy pregnant women who underwent a 75 g oral glucose tolerance test (OGTT) in mid-pregnancy because of a positive diabetes screen. Using multivariate analyses to adjust for maternal parity, pre-gestational obesity, gestational weight gain, plasma glucose levels, and gestational age at delivery, we tested the association between HOMA-IR and birthweight in their offspring. We also tested the association HOMA-IR and a risk of large-for-gestational-age (LGA) infants. In 655 Japanese women, HOMA-IR was positively associated with birthweight after adjusting for these confounders (p<0.05). A higher HOMA-IR was significantly associated with an increased incidence of LGA infants with an adjusted odds ratio of 1.53 (95% confidence interval, 1.10-2.15) per 1 unit of HOMA-IR. The degree of maternal insulin resistance in mid-pregnancy was associated with birthweight and the risk of giving birth to an LGA infant in normal pregnancies, independent of maternal obesity and glucose levels.

Clinicopathologic study of 53 metaplastic breast carcinomas: their elements and prognostic implications.

Metaplastic carcinoma of the breast is a relatively rare cancer and includes various histologic types. In this cancer, metaplastic elements are heterogeneous and sometimes mixed. We investigated, by histopathologic means, these elements and clinical implications that could indicate the clinical course (including the prognosis). Fifty-three metaplastic breast carcinoma cases and their prognoses were investigated by initially examining the presence or absence of spindle-cell elements, and then the presence or absence of other elements. Spindle cells were classified as high or low grade. The number of spindle-cell-positive cases was 24 (45%) of 53. The 24 spindle-cell (+) cases were subdivided into 12 high-grade (HGsp) (distant metastatic rate per 100 person-years, 13.27) and 12 low-grade (LGsp) (0.00) patients. Spindle-cell (-) cases were subdivided into 22 pure squamous cell carcinomas (5.93) and 7 matrix-producing carcinomas (0.00). There were significant differences among the 4 groups with regard to the disease-free period (P = .0081, log-rank test). The distant metastatic risks in the HGsp and pure squamous cell carcinomas groups were significantly higher than that in the matrix-producing carcinoma + LGsp group (nonmetastatic groups) after controlling for the effects of tumor size and lymph node metastasis (P = .019 and P = .016, respectively, Poisson regression model). The presence of high-grade spindle cells was related to the prognosis, and some histologic subtypes may be important with respect to the prognosis. The presence of high-grade spindle cells in metaplastic breast carcinoma may indicate aggressive behavior.