Antenatal diagnosis and management of fetal inguinoscrotal hernia: A case report with literature review.

Primary inguinal hernia is a common pediatric surgical condition with an incidence of 1%-4%, which is higher in male or premature newborns. It is characterized by the protrusion of abdominal contents through inguinal canal in newborns. However, prenatal fetal inguinal hernia is a rare condition because the pressure of amniotic fluid is similar to intra-abdominal pressure. Only 19 English publications were found with 21 reported cases until now. We report belatedly discovered inguinoscrotal hernia at 38+0 weeks' gestation. Usually, the fetal testicular descent begins from 24 to 25 weeks' gestation, and it is found after 32 weeks of gestational age in 97% of the fetuses. Therefore, it is necessary to get into the habit of checking fetal testicles during routine US after at least 32 weeks of gestational age.

Hydroxychloroquine in obstetrics: potential implications of the prophylactic use of hydroxychloroquine for placental insufficiency during pregnancy.

Proper placentation during early pregnancy is a key factor for maintaining a healthy pregnancy. Placental insufficiency leads to critical complications such as preeclampsia, fetal growth restriction, and fetal demise. These complications are often associated with pathological findings of restricted remodeling and obstructive lesions of the myometrial spiral arteries, which have high recurrence rates during subsequent pregnancies. Currently, there are no pharmacological interventions other than aspirin for the prevention of preeclampsia. Hydroxychloroquine (HCQ), a well-known antimalarial drug, reduces inflammatory and thrombotic changes in vessels. For decades, the use of HCQ for autoimmune diseases has resulted in the successful prevention of both arterial and venous thrombotic events and has been extended to the treatment of lupus and antiphospholipid antibody syndrome during pregnancy. HCQ reduces the risk of preeclampsia with lupus by up to 90%. Several recent studies have investigated whether HCQ improves pregnancy outcomes in women with a history of poor outcomes. In addition, in vitro and animal studies have demonstrated the beneficial effects of HCQ in improving endothelial dysfunction and alleviating hypertension and proteinuria. Therefore, we hypothesized that HCQ has the potential to attenuate the vascular inflammatory and thrombogenic pathways associated with placental insufficiency and conducted a multicenter clinical trial on the efficacy of combining aspirin with HCQ for pregnancies at high risk for preeclampsia in Korea. This study summarizes the potential effects of HCQ on pregnancies with placental insufficiency and the implications of HCQ treatment in the field of obstetrics.

Improving Prenatal Diagnosis Precision for Congenital Clubfoot by Using Three-Dimensional Ultrasonography.

Prenatal diagnosis of clubfoot traditionally relied on two-dimensional ultrasonography. To enhance diagnosis and predict postnatal outcomes, we examined the parameters that differentiate pathological clubfoot using three-dimensional ultrasonography. In our retrospective study, we examined the findings of prenatal ultrasound and the postnatal outcomes of pregnancies with suspected congenital clubfoot between 2018 and 2021. Based on the three-dimensional perspective, we measured the angles of varus, equinus, calcaneopedal block, and forefoot adduction and compared the sonographic variables between the postnatal treated and non-treated groups. We evaluated 31 pregnancies (47 feet) with suspected clubfoot using three-dimensional ultrasonography. After delivery, a total of 37 feet (78.7%) underwent treatment involving serial casting only or additional Achilles tenotomy. The treated group showed significantly greater hindfoot varus deviation (60.5° vs. 46.6°, p = 0.026) and calcaneopedal block deviation (65.6° vs. 26.6°, p < 0.05) compared to the non-treated group. The calcaneopedal block had an area under the curve of 0.98 with a diagnostic threshold of 46.2 degrees (sensitivity of 97%, specificity of 90%, positive predictive value of 97%, and negative predictive value of 90%). During prenatal evaluation of clubfoot using three-dimensional ultrasonography, the calcaneopedal block deviation has the potential to predict postnatal treatment.

Combination of local radiotherapy and anti-glucocorticoid-induced tumor necrosis factor receptor (GITR) therapy augments PD-L1 blockade-mediated anti-tumor effects in murine breast cancer model.

PURPOSE: In this study, we investigated whether local radiotherapy (RT) and an anti-glucocorticoid-induced tumor necrosis factor receptor (GITR) agonist could increase the efficacy of PD-L1 blockade. METHODS AND MATERIALS: We analyzed a breast cancer dataset from the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) to determine the role of GITR in breast cancer. We used the 4T1 murine TNBC model (primary and secondary tumors) to investigate the efficacy of PD-L1 blockade, local RT, anti-GITR agonist, and their combinations. We assessed tumor growth by tumor volume measurements, in vivo bioluminescence imaging, and metastatic lung nodule counts to evaluate the effects of these treatments. Flow cytometry and immunohistochemistry determined the proportions and phenotypes of CD8+ T-cells and regulatory T-cells (Tregs) in the tumors and spleen. Plasma cytokine levels were measured by enzyme-linked immunosorbent assay. RESULTS: In the METABRIC cohort, patients with high expression of TNFRSF18, which encodes GITR, had significantly better survival than those with low expression. Adding local RT or anti-GITR agonist to PD-L1 blockade did not significantly augment efficacy compared to PD-L1 blockade alone; however, adding both to PD-L1 blockade significantly reduced tumor growth and lung metastasis. The benefits of the triple combination were accompanied by increased CD8+ T-cells and decreased Tregs in the tumor microenvironment and spleen. CONCLUSIONS: The combination of local RT and an anti-GITR agonist significantly enhanced the anti-tumor immune responses induced by PD-L1 blockade. These results provide the preclinical rationale for the combination of therapy.

Association between Neck Circumference and Chronic Kidney Disease in Korean Adults in the 2019-2021 Korea National Health and Nutrition Examination Survey.

Chronic kidney disease (CKD) is a major public health problem and a leading cause of cardiovascular disease and death. Early recognition and management of CKD risk factors are necessary to prevent its onset and progression. Neck circumference (NC) is a non-invasive and easily accessible anthropometric measure associated with central obesity and subcutaneous fat accumulation in the upper body. Our study aimed to explore the relationship between NC and the prevalence of CKD using data from the nationally representative Korea National Health and Nutrition Examination Survey (2019-2021). We analyzed data from 10,219 subjects (age > 19 years, no missing values). CKD was defined as an estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2. Logistic regression analysis was performed, which revealed a significant association between NC and CKD prevalence even after adjusting for confounding factors, both when NC was considered a continuous variable (OR [95% CI], 1.11 [1.03-1.19]) and in quartiles (Q1 as reference; Q2 OR [95% CI], 1.23 [0.91-1.67]; Q3 OR [95% CI], 1.59 [1.16-2.18]; Q4 OR [95% CI], 1.70 [1.16-2.50]). Our findings suggest that NC could be a simple and effective anthropometric measurement for identifying individuals at risk for CKD.

The Multifaceted Clinical Characteristics of Congenital Cytomegalovirus Infection: From Pregnancy to Long-Term Outcomes.

BACKGROUND: The aim of this study was to capture multifaceted clinical characteristics of congenital cytomegalovirus (CMV) infection from diagnosis to treatment using a multidisciplinary approach including obstetrics, pediatrics, pathology, and otorhinolaryngology-head and neck surgery. METHODS: This is a retrospective study including 30 consecutive cases of congenital CMV infection that were diagnosed at a single tertiary hospital located in Seoul, Korea from January 2009 to December 2020. Congenital CMV infection was defined as a positive result by polymerase chain reaction from urine, saliva or cerebrospinal fluid or positive CMV IgM from neonatal blood sampled within 3 weeks after birth. All cases were analyzed with respect to whole clinical characteristics from diagnosis to treatment of congenital CMV by a multidisciplinary approach including prenatal sonographic findings, maternal immune status regarding CMV infection, detailed placental pathology, neonatal clinical manifestation, auditory brainstem response test, and antiviral treatment (ganciclovir or valganciclovir). Long-term outcomes including developmental delay and hearing loss were also investigated. RESULTS: The total number of births during the study period in our institution was 19,385, with the prevalence of congenital infection estimated to be 0.15%. Among 30 cases of congenital CMV, the median gestational age at delivery was 32.2 weeks [range, 22.6-40.0] and 66.7% of these infants were delivered preterm at less than 37 weeks. Suspected fetal growth restriction was the most common prenatal ultrasound finding (50%) followed by ventriculomegaly (17.9%) and abnormal placenta (17.9%), defined as thick placenta with calcification. No abnormal findings on ultrasound examination were observed in one-third of births. Maternal CMV serology tests were conducted in only 8 cases, and one case each of positive and equivocal IgM were found. The most common placental pathologic findings were chronic villitis (66.7%) and calcification (63.0%), whereas viral inclusions were identified in only 22.2%. The most common neonatal manifestations were jaundice (58.6%) followed by elevation of aspartate aminotransferase (55.2%) and thrombocytopenia (51.7%). After excluding cases for which long-term outcomes were unavailable due to death (n = 4) or subsequent follow up loss (n = 3), developmental delay was confirmed in 43.5% of infants (10/23), and hearing loss was confirmed in 42.9% (9/21) during the follow-up period. In our cohort, 56.7% (17/30) of neonates were treated for congenital CMV with ganciclovir or valganciclovir. CONCLUSION: Our data show that prenatal findings including maternal serologic tests and ultrasound have limited ability to detect congenital CMV in Korea. Given that CMV is associated with high rates of developmental delay and hearing loss in infants, there is an urgent need to develop specific strategies for the definite diagnosis of congenital CMV infection during the perinatal period by a multidisciplinary approach to decrease the risks of neurologic impairment and hearing loss through early antiviral treatment.

Obstructive Sleep Apnea Is Associated With Late-Onset Preeclampsia in Overweight Pregnant Women in Korea.

BACKGROUND: Obstructive sleep apnea (OSA) is closely related to maternal obesity in pregnant women, and the association increases with later pregnancy. Obesity and OSA are risk factors of pregnancy-related complications, including gestational hypertension, gestational diabetes mellitus (GDM), and fetal morbidities. We aimed to determine the prevalence of OSA and to assess the impact of OSA on pregnancy-related disorders in overweight pregnant women. METHODS: Eligible participants who were overweight [body mass index (BMI) ≥ 23 kg/m²] in gestational age 30 weeks or more, assessed OSA using a portable polysomnography at home. Clinical data were collected from pregnant women and their babies. RESULTS: The average age of 51 participants was 34.5 years (27-44 years). The number of primipara was 25 (49%) and that of multipara was 26 (51%). Eight cases of GDM (15.7%) and five cases of preeclampsia (9.8%) were reported, and six patients (11.8%) experienced preterm delivery. In results of polysomnography, 14 patients (27.5%) were diagnosed as OSA. Apnea-hypopnea index moderately correlated with BMI (r = 0.515, P < 0.001). The BMI (P < 0.005) and preeclampsia rate (P < 0.017) were higher in the OSA group compared to the control group. Odds ratios (ORs) adjusting age, BMI, parity, and abortion history were calculated. The presence of OSA increased OR of preeclampsia (OR, 13.1; 95% confidence interval, 1.1-171.3). The majority of preeclampsia patients (4/5, 80%) underwent preterm delivery. CONCLUSION: OSA is an important risk factor for preeclampsia, resulting in preterm delivery. For overweight pregnant women, an OSA evaluation should be mandatory.

Obstetric and neonatal outcomes of gestational diabetes mellitus in twin pregnancies according to changes in its diagnostic criteria from National Diabetes Data Group criteria to Carpenter and Coustan criteria: a retrospective cohort study.

BACKGROUND: To compare obstetric and neonatal outcomes in twin pregnancies with or without gestational diabetes mellitus (GDM) before and after changes in GDM diagnostic criteria. METHODS: This was a retrospective cohort study of 1,764 twin pregnancies including 130 women with GDM (GDM group) and 1,634 women without GDM (non-GDM group). Patients with pregestational diabetes, unknown GDM status, and fetal death at < 24 gestational weeks were excluded. Obstetric and neonatal outcomes were compared between the two groups by two periods: period 1 (1995-2005) and period 2 (2005-2018) when National Diabetes Data Group criteria and Carpenter and Coustan criteria were used for diagnosis of GDM, respectively. RESULTS: The incidence of GDM in twin pregnancies increased from 4.0% in period 1 to 9.3% in period 2. Composite obstetric complications rate was significantly higher in the GDM group than that in the non-GDM group during period 1 (72.0% vs. 45.5%, P = 0.009). However, it became comparable during period 2 (60.0% vs. 57.4%, P = 0.601). Interaction between GDM and period indicated a significant differential effect of GDM by period on the rate of composite obstetric complications. The rate of composite neonatal complications was similar between the two groups during both periods. The interaction between GDM and period was not significant. CONCLUSION: After changes of GDM diagnostic criteria, the incidence of GDM increased more than twice, and the rate of composite obstetric complications decreased, but the rate of composite neonatal complications did not change significantly.

Constitutive Oxidative Stress by SEPHS1 Deficiency Induces Endothelial Cell Dysfunction.

The primary function of selenophosphate synthetase (SEPHS) is to catalyze the synthesis of selenophosphate that serves as a selenium donor during selenocysteine synthesis. In eukaryotes, there are two isoforms of SEPHS (SEPHS1 and SEPHS2). Between these two isoforms, only SEPHS2 is known to contain selenophosphate synthesis activity. To examine the function of SEPHS1 in endothelial cells, we introduced targeted null mutations to the gene for SEPHS1, Sephs1, in cultured mouse 2H11 endothelial cells. SEPHS1 deficiency in 2H11 cells resulted in the accumulation of superoxide and lipid peroxide, and reduction in nitric oxide. Superoxide accumulation in Sephs1-knockout 2H11 cells is due to the induction of xanthine oxidase and NADPH oxidase activity, and due to the decrease in superoxide dismutase 1 (SOD1) and 3 (SOD3). Superoxide accumulation in 2H11 cells also led to the inhibition of cell proliferation and angiogenic tube formation. Sephs1-knockout cells were arrested at G2/M phase and showed increased gamma H2AX foci. Angiogenic dysfunction in Sephs1-knockout cells is mediated by a reduction in nitric oxide and an increase in ROS. This study shows for the first time that superoxide was accumulated by SEPHS1 deficiency, leading to cell dysfunction through DNA damage and inhibition of cell proliferation.

Association of adherence to guidelines for cervical cerclage with perinatal outcomes and placental inflammation in women with cervical length ≥2.0 cm.

OBJECTIVES: Cerclage operation is one of the most common obstetric controversies. The aim of this study was to compare the perinatal outcomes and placental inflammation of cerclage performed adherent and non-adherent to international guidelines. MATERIAL AND METHODS: This study included all consecutive women with singleton deliveries who underwent cerclage. According to the current American College of Obstetricians and Gynecologists (ACOG) guideline, we designated our study population into two groups: the adherent-to-guideline and non-adherent groups. Each group was categorized into two groups according to cervical length (CL) at the time of cerclage (<2.0 cm vs. ≥2.0 cm). We evaluated the reasons for cerclage, maternal characteristics, perioperative variables, pregnancy and neonatal outcomes, and placental inflammatory pathology according to the criteria proposed by the Society of Pediatric Pathology. RESULTS: Among 310 women with cerclage, we excluded patients (n = 21) with indicated preterm delivery (PTD), major fetal anomaly, fetal death in-utero, and missing information for reason of cerclage. We also excluded patients who underwent physical examination-indicated cerclage (n = 53) and with missing information of CL at the time of cerclage (n = 52). A total of 184 women were eventually analyzed. In women with CL < 2.0 cm, the non-adherent group showed similar PTD (<28 weeks, <34 weeks) and neonatal composite morbidity rates compared to the adherent-to-guideline group. However, in women with CL ≥ 2.0 cm, the non-adherent group manifested significantly higher PTD (<28 weeks; 16.7% vs. 4.4%, p = 0.04, <34 weeks; 23.8% vs. 5.8%, p = 0.006) and neonatal composite morbidity (20.5% vs. 5.9%, p = 0.028) rates than the adherent-to-guideline group despite similar perioperative variables and lower PTD history rates. The non-adherent group with CL ≥ 2 cm at the time of cerclage was also associated with severe histologic chorioamnionitis (p = 0.033). CONCLUSION: Cerclage performed beyond the current guidelines in pregnant women with CL ≥ 2.0 cm may confer an additional risk of perinatal complications in association with severe placental inflammation.

Perioperative, short-, and long-term outcomes of gastric cancer surgery: Propensity score-matched analysis of patients with or without prior solid organ transplantation.

BACKGROUND: Details of perioperative outcomes and survival after gastric cancer surgery in prior transplant recipients have received minimal research attention. METHODS: We performed an observational cohort study using the database of 20,147 gastric cancer patients who underwent gastrectomy at a single gastric cancer center in Korea. Forty-one solid organ recipients [kidney (n = 35), liver (n = 5), or heart (n = 1)] were matched with 205 controls using propensity score matching. RESULTS: Operation time, blood loss, and postoperative pain were similar between groups. Short-term complication rates were similar between transplantation and control groups (22.0% vs. 20.1%, P = 0.777). Transplantation group patients with stage 1 gastric cancer experienced no recurrence, while those with stage 2/3 cancer had significantly higher recurrence risk compared to the controls (P = 0.049). For patients with stage 1 cancer, the transplantation group had a significantly higher rate of non-gastric cancer-related deaths compared to the controls (19.2% vs. 1.4%, P = 0.001). For those with stage 2/3 cancer, significantly lower proportion of the transplantation group received adjuvant chemotherapy compared to the control group (26.7% vs. 80.3%, P < 0.001). The transplantation group had a higher (albeit not statistically significant) rate of gastric cancer-related deaths compared to the controls (40.0% vs. 18.0%, P = 0.087). CONCLUSION: Transplant recipients and non-transplant recipients exhibited similar perioperative and short-term outcomes after gastric cancer surgery. From long-term outcome analyses, we suggest active surveillance for non-gastric cancer-related deaths in patients with early gastric cancer, as well as strict oncologic care in patients with advanced cancer, as effective strategies for transplant recipients.

Prognostic Value of Postoperative Neutrophil and Albumin: Reassessment One Month After Gastric Cancer Surgery.

OBJECTIVE: The prognostic value of postoperative parameters reflecting the inflammatory and nutritional status of patients undergoing cancer surgery has been rarely studied. This study investigated the prognostic value of inflammatory and nutritional parameters measured preoperatively and 1 month after curative gastrectomy for gastric cancer. METHODS: Data from a prospectively maintained database of 1,194 patients with gastric cancer who underwent curative surgery in 2009-2018 were retrospectively reviewed. Demographics, clinicopathologic characteristics, operative data, survival data, and laboratory parameters were extracted. Neutrophil counts, lymphocyte counts, and albumin levels before surgery and 1 month postoperatively were analyzed. RESULTS: In multivariable analysis adjusted for age, sex, and pathologic stage, high neutrophil count (hazard ratio [HR] 1.09, 95% confidence interval [CI] 1.01-1.17, p = 0.022) and low albumin (HR 0.45, 95% CI 0.27-0.74, p = 0.002) 1 month postoperatively were independent prognostic factors for overall survival. High neutrophil count (HR 1.09, 95% CI 1.02-1.16, p = 0.015) 1 month postoperatively was also an independent prognostic factor for recurrence-free survival after adjusting for age, sex, body mass index, extent of gastrectomy, and pathologic stage. Patients were classified into risk groups based on thresholds of 4.2 × 103 cells/mm3 and 4.1 g/dl for 1-month neutrophil count and albumin. High-risk groups had a significantly worse prognosis than low-risk groups for overall survival (HR 5.87, 95% CI 3.28-10.51, p <0.001) and recurrence-free survival (HR 1.52, 95% CI 1.07-2.16, p = 0.021). CONCLUSIONS: Neutrophil count and albumin level 1 month after curative surgery reflect long-term prognosis better than preoperative values. These parameters can be used to stratify patients with the same stage into different prognostic groups.

Prevalence of associated extracardiac anomalies in prenatally diagnosed congenital heart diseases.

OBJECTIVE: To investigate the prevalence of extracardiac anomalies (ECA) in prenatally diagnosed congenital heart diseases (CHD), and to provide more information for counseling of women with prenatally diagnosed fetal CHD. METHODS: This was a retrospective cohort study of 791 cases of fetal CHD diagnosed by prenatal ultrasound from January 2005 to April 2018. Associated ECAs included extracardiac structural malformation (ECM), chromosomal anomaly, and 22q11.2 microdeletion. CHD was classified into 10 groups according to a modified anatomic and clinical classification of congenital heart defects. RESULTS: The overall prevalence of ECA in our CHD cohort was 28.6% (226/791): ECM, 25.3%; chromosomal anomaly, 11.7%; and 22q11.2 microdeletion, 5.5%. For those with ECM, ventricular septal defect (VSD) had the highest prevalence (34.5%), followed by anomalies of atrioventricular junctions and valves (28.8%) and heterotaxy (26.9%). For those with chromosomal anomaly, anomalies of atrioventricular junctions and valves had the highest prevalence (37.5%), followed by anomalies of atria and interatrial communications (25.0%) and VSD (22.9%). 22q11.2 microdeletion was detected only in those with anomalies of extrapericardial arterial trunks (14.3%) or ventricular outflow tracts (6.4%). CONCLUSION: ECM, chromosomal anomaly, and 22q11.2 microdeletion have different prevalence according to the type of CHD.

The effects of maternal body mass index and plurality on maternal and umbilical cord serum magnesium levels in preterm birth at less than 32 weeks of gestation.

OBJECTIVE: To evaluate the effects of maternal body mass index (BMI) and plurality on maternal and umbilical cord serum magnesium levels after antenatal magnesium sulfate treatment. METHODS: This was a retrospective cohort analysis of 135 women treated with antenatal magnesium sulfate at less than 32 weeks of gestation between January 2012 and June 2018. Subjects were stratified into groups according to maternal BMI (group I [18.5-22.9 kg/m²], group II [23.0-24.9 kg/m²], and group III [≥25.0 kg/m²]) and plurality (singleton and twin). Univariable and multivariable analyses were performed to compare the umbilical cord serum magnesium levels between the groups. RESULTS: Maternal serum magnesium levels were not significantly different between the maternal BMI groups and singleton and twin pregnancies. Umbilical cord serum magnesium levels were significantly different among the maternal BMI groups (3.3±1.2 mg/dL in group I, 3.3±1.2 mg/dL in group II, and 4.0±1.4 mg/dL in group III, P=0.003). The trend of increase in magnesium levels was statistically significant (P=0.001, Jonckheere-Terpstra test). Umbilical cord serum magnesium levels were not significantly different according to plurality. However, in the multivariable analysis, maternal BMI and plurality were not significantly associated with umbilical cord serum magnesium levels after adjusting for indication and total dose of magnesium sulfate treatment, gestational age at delivery, mode of delivery, neonatal sex, and birth weight. CONCLUSION: Maternal BMI and plurality were not significantly associated with maternal or umbilical cord serum magnesium levels after exposure to antenatal magnesium sulfate treatment.

Author Correction: Antenatal magnesium sulfate treatment and risk of necrotizing enterocolitis in preterm infants born at less than 32 weeks of gestation.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Antenatal magnesium sulfate treatment and risk of necrotizing enterocolitis in preterm infants born at less than 32 weeks of gestation.

Antenatal magnesium sulfate (MgSO4) treatment is widely used for fetal neuroprotection in women at risk of preterm delivery. However, some studies have recently suggested that in utero MgSO4 exposure is associated with an increased risk of necrotizing enterocolitis (NEC). This study aimed to investigate the association between antenatal MgSO4 treatment and risk of NEC. This retrospective cohort study included 756 infants born at 24‒31 weeks' gestation. Subjects were classified into three groups: period 1, when MgSO4 treatment protocol for fetal neuroprotection was not adopted (n = 267); period 2, when the protocol was adopted (n = 261); and period 3, when the protocol was withdrawn because of concern of risk of NEC (n = 228). Rates of NEC (≥ stage 2b) were analyzed according to time period and exposure to antenatal MgSO4. Significant difference in the rate of NEC was not found across the three time periods (2.6% vs. 6.5% vs. 4.8% in periods 1, 2 and 3, respectively, p = 0.103). The rate of NEC was comparable between the infants exposed and unexposed to antenatal MgSO4 (5.1% vs. 3.6%, p = 0.369). These results showed that antenatal MgSO4 treatment was not associated with risk of NEC in our study population.

Autophagy regulates trophoblast invasion by targeting NF-κB activity.

Preeclampsia is one of the most serious complications of pregnancy, affecting 5-10% of parturients worldwide. Recent studies have suggested that autophagy is involved in trophoblast invasion and may be associated with defective placentation underlying preeclampsia. We thus aimed to understand the mechanistic link between autophagy and trophoblast invasion. Using the two most commonly used trophoblast cell lines, JEG-3 and HTR-8/SVneo, we inhibited autophagy by ATG5 and beclin-1 shRNA. Conversion of LC3-II was evaluated in ATG5 and beclin-1 knock-down cells in the presence of the lysosomal protease inhibitors E-64d and pepstatin A, to detect the efficiency of autophagy inhibition. Upon autophagy inhibition, we measured cell invasion, activity of NF-κB and related signaling pathways, MMP-2, MMP-9, sFlt-1, and TNF-α levels. Autophagy inhibition increased the invasiveness of these trophoblastic cell lines and increased Akt and NF-κB activity as well as p65 expression. Of note, an NF-κB inhibitor significantly attenuated the trophoblast invasion induced by autophagy inhibition. Autophagy inhibition was also associated with increased MMP-2 and MMP-9 levels and decreased the production of sFlt-1 and TNF-α. Collectively, our results indicate that autophagy regulates trophoblast invasiveness in which the NF-κB pathway and MMP-2, MMP-9, sFlt-1 and TNF-α levels are affected.

Changes in the perinatal outcomes of twin pregnancies delivered at a tertiary referral center in Korea during a 24-year period from 1995 to 2018.

OBJECTIVE: To analyze the changes in the clinical characteristics and perinatal outcomes of twin pregnancies delivered at a tertiary referral center in Korea during a 24-year period. METHODS: This was a retrospective cohort study of twin pregnancies delivered at 24-40 weeks of gestation, from 1995 to 2018. The subjects were divided into 4 groups according to the year of delivery: 1995-2000, 2001-2006, 2007-2012, and 2013-2018. The trends in the changes in the twin birth rate, maternal age, assisted reproductive technology (ART) pregnancy rate, chorionicity, obstetric complications, delivery outcomes, and neonatal outcomes over the periods were analyzed. RESULTS: A total of 2,133 twin pregnancies were included in the study. The twin birth rate increased from 16.7/1,000 in 1995-2000 to 42.2/1,000 in 2001-2006, 49.5/1,000 in 2007-2012, and 61.8/1,000 in 2013-2018. The maternal age and ART pregnancy and dichorionic twin rates increased, while the monochorionic twin rate decreased over the periods. The incidence of fetal congenital anomalies, cervical incompetence, gestational diabetes mellitus, preeclampsia, and placental abruption increased over the periods. The preterm birth (PTB) rate significantly decreased owing to the decreasing elective late-PTB rate; however, the early-PTB rate significantly increased. CONCLUSION: This study found that twin pregnancies increased steadily over the last 24 years and that the increase was related to increased maternal age and ART pregnancy rate. The incidence of obstetric complications increased over the periods; however, the neonatal intensive care unit admission rate decreased, along with decreases in the elective late-PTB rate.

The effects of birth order on neonatal outcomes in early-preterm, late-preterm and term twin infants.

Objectives: Birth order is one of the main factors that influences the neonatal outcome of twins. However, there is little prior data regarding the effect of birth order under different clinical circumstances. This study investigates the effect of birth order on the neonatal outcomes of twins delivered during early-preterm, late-preterm and term gestations according to chorionicity, delivery mode and indication for delivery.Methods: This is a retrospective cohort study of women with twin pregnancies delivered at 24-40 weeks of gestation between 1995 and 2014. We excluded twin pregnancies with the following complications: twin-to-twin transfusion syndrome, monoamnionic twins, delayed interval delivery and fetal death, chromosomal anomalies or major congenital malformation in one or more of the twins. The neonatal outcomes, including death, admission to neonatal intensive care unit (NICU), mechanical ventilator support, and respiratory distress syndrome (RDS) was compared between the first and second twin born at early-preterm (24-33 weeks of gestation), late-preterm (34-36 weeks of gestation) and term (≥37 weeks of gestation) gestations. These outcomes were further analyzed according to chorionicity, mode of delivery and indication for delivery by multivariable analysis (after adjusting for sex, presentation, and birth weight).Results: Among a total of 1,614 women with twin pregnancies who met the selection criteria, 423, 674 and 517 women delivered at early-preterm, late-preterm and term gestation, respectively. Overall, the second-born twins were lighter and had higher rates of NICU admission, mechanical ventilator support, and RDS than did first-born twins. Second twins born at early-preterm gestation had higher rates of RDS and mechanical ventilator support than did first twins. Second twins born at late-preterm gestation had higher rates of NICU admission and mechanical ventilator support than did first twins. Second twins born at term gestation also had a higher NICU admission rate than did first twins. However, in the multivariable analysis of the subgroups, the rates of NICU admission, mechanical ventilator support and RDS were not significantly different between most twin pairs. However, there were several significant differences. There was a higher risk of RDS in the second twins in the early-preterm premature rupture of membranes (PROM) subgroup, and a higher risk of mechanical ventilator support in the late-preterm PROM subgroup. Low birth weight was the only significant factor independently associated with a higher risk of adverse neonatal outcome in the second twins compared with the first twins in all subgroups.Conclusions: Second twins born at early-preterm, late-preterm and term were at higher risk of adverse neonatal outcome than were their respective first twins. However, this finding was mainly represented lower birth weight of the second twin. Still, second twins delivered due to early-preterm and late-preterm PROM had a higher risk of RDS and mechanical ventilator support, respectively, than did the first twin after adjusting for birth weight.