Neonatal and maternal adverse outcomes and exposure to nonsteroidal anti-inflammatory drugs during early pregnancy in South Korea: A nationwide cohort study.

BACKGROUND: Existing data on the use of nonsteroidal anti-inflammatory drugs (NSAIDs) during late pregnancy is well established, providing assurance. However, the use of NSAIDs during early pregnancy remains inconclusive owing to conflicting findings on adverse neonatal outcomes as well as the limited data on adverse maternal outcomes. Therefore, we sought to investigate whether early prenatal exposure to NSAIDs was associated with neonatal and maternal adverse outcomes. METHODS AND FINDINGS: We conducted a nationwide, population-based cohort study using Korea's National Health Insurance Service (NHIS) database with a mother-offspring cohort constructed and validated by the NHIS to include all live births in women aged 18 to 44 years between 2010 and 2018. We defined exposure to NSAIDs as at least two records of NSAID prescriptions during early pregnancy (first 90 days of pregnancy for congenital malformations and first 19 weeks for nonmalformation outcomes) and compared against three distinct referent groups of (1) unexposed, no NSAID prescription during the 3 months before pregnancy start to end of early pregnancy; (2) acetaminophen-exposed, at least two acetaminophen prescriptions during early pregnancy (i.e., active comparator); and (3) past users, at least two NSAID prescriptions before the start of pregnancy but no relevant prescriptions during pregnancy. Outcomes of interest were adverse birth outcomes of major congenital malformations and low birth weight and adverse maternal outcomes of antepartum hemorrhage and oligohydramnios. We estimated relative risks (RRs) with 95% CIs using generalized linear models within a propensity score (PS) fine stratification weighted cohort that accounted for various potential confounders of maternal sociodemographic characteristics, comorbidities, co-medication use, and general markers of burden of illness. Of 1.8 million pregnancies in the PS weighted analyses, exposure to NSAIDs during early pregnancy was associated with slightly increased risks for neonatal outcomes of major congenital malformations (PS-adjusted RR, 1.14 [CI, 1.10 to 1.18]) and low birth weight (1.29 [1.25 to 1.33]), and for maternal outcome of oligohydramnios (1.09 [1.01 to 1.19]) but not antepartum hemorrhage (1.05 [0.99 to 1.12]). The risks of overall congenital malformations, low birth weight, and oligohydramnios remained significantly elevated despite comparing NSAIDs against acetaminophen or past users. Risks of adverse neonatal and maternal outcomes were higher with cyclooxygenase-2 selective inhibitors or use of NSAIDs for more than 10 days, whereas generally similar effects were observed across the three most frequently used individual NSAIDs. Point estimates were largely consistent across all sensitivity analyses, including the sibling-matched analysis. Main limitations of this study are residual confounding by indication and from unmeasured factors. CONCLUSIONS: This large-scale, nationwide cohort study found that exposure to NSAIDs during early pregnancy was associated with slightly higher risks of neonatal and maternal adverse outcomes. Clinicians should therefore carefully weigh the benefits of prescribing NSAIDs in early pregnancy against its modest, but possible, risk of neonatal and maternal outcomes, where if possible, consider prescribing nonselective NSAIDs for <10 days, along with continued careful monitoring for any safety signals.

Growing threat of extended-spectrum ß-lactamase-producing Enterobacteriaceae colonisation in high-risk pregnancies: A cross-sectional study.

OBJECTIVE: To investigate the epidemiological changes in extended-spectrum ß-lactamase-producing Enterobacteriaceae (ESBL-E) vaginal colonisation in pregnant women deemed at high risk, and to identify independent risk factors. Further, the differences in perinatal outcomes according to maternal ESBL-E vaginal colonisation were analysed. DESIGN: Cross-sectional study. SETTING: Republic of Korea. POPULATION: A cohort of 1460 women admitted to our high-risk pregnancy unit between 14+0 and 36+6  weeks of gestation. METHODS: The trend of changes in the association of ESBL-E vaginal colonisation from January 2010 to December 2020 was analysed. The main outcomes were analysed over the study period and ESBL-E vaginal colonisation. MAIN OUTCOME MEASURES: Rate of ESBL-E vaginal colonisation, risk factors for ESBL-E vaginal colonisation and perinatal outcomes. RESULTS: The ESBL-E vaginal colonisation rate has tended to increase over the past 11 years, which was attributed to a significantly higher proportion of ESBL-producing Escherichia coli. Cerclage (RR 3.7, 95% CI 2.19-6.40) and prior antibiotic treatment (RR 4.0, 95% CI 2.44-6.54) were found as independent risk factors for ESBL-E vaginal colonisation. Earlier gestational age at delivery and higher proven early-onset neonatal sepsis (EONS) rate were observed in the ESBL-E-positive group. CONCLUSIONS: The ESBL-E vaginal colonisation rate in pregnant patients at high risk has increased over the past decade, and the independent risk factors for colonisation are cerclage and prior antibiotic treatment. Additionally, maternal ESBL-E vaginal colonisation is associated with higher rates of proven EONS.

Obesity Is Associated With Higher Risk of Adverse Maternal and Neonatal Outcomes Than Supervised Gestational Diabetes.

BACKGROUND: Unlike gestational diabetic mellitus (GDM), which is strictly managed by most patients and physicians, obesity does not have proper management guidelines, and the importance of its management during pregnancy is often ignored. The aim of this study was to compare maternal and neonatal outcomes according to obesity and GDM, alone or in combination. METHODS: This was a retrospective cohort study of 3,078 consecutive pregnant women who experienced prenatal care and delivery of a live singleton neonate between January 2016 and December 2020 at our institution. Study participants were categorized into 4 mutually exclusive groups, as follows: group 1, no GDM without obesity; group 2, GDM without obesity; group 3, no GDM with obesity; and group 4, GDM with obesity. RESULTS: Compared to group 2, group 3 had higher rates of pre-eclampsia, cesarean section including emergent cesarean section rate. Also, neonates in group 3 were heavier and had lower glucose levels compared to those in group 2. Of note, there was no significant difference in maternal or neonatal outcomes except the rate of large-for-gestational-age (LGA) between group 1 and group 2. Among the GDM groups, group 4 had higher risks for pre-eclampsia, cesarean section, and LGA infant status than group 2. CONCLUSION: Our data showed that obese women without GDM face higher risk of adverse pregnancy outcomes than women with supervised GDM and non-obese women. We also confirmed that adverse pregnancy outcomes associated with GDM were mainly attributable to obesity among women receiving GDM education.

Antenatal Magnesium Sulfate Is Not Associated With Improved Long-Term Neurodevelopment and Growth in Very Low Birth Weight Infants.

BACKGROUND: Though antenatal magnesium sulfate (MgSO4) is widely used for fetal neuroprotection, suspicions about the long-term neuroprotection of antenatal MgSO4 have been raised. METHODS: We investigated short- and long-term outcomes of antenatal MgSO4 use for 468 infants weighing < 1,500 g with a gestational age of 24-31 weeks. RESULTS: Short-term morbidities and the risk of developmental delay, hearing loss, and cerebral palsy at a corrected age of 18-24 months and 3 years of age did not decrease in the MgSO4 group (infants who were exposed to MgSO4 for any purpose) or neuroprotection group (infants who were exposed to MgSO4 for fetal neuroprotection) compared with the control group (infants who were not exposed to MgSO4). The z-scores of weight, height, and head circumference did not increase in the MgSO4 group or neuroprotection group compared with the control group. CONCLUSION: Antenatal MgSO4 including MgSO4 for neuroprotection did not have beneficial effects on long-term neurodevelopmental and growth outcomes.

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.

Clinical-Scale Mesenchymal Stem Cell-Derived Extracellular Vesicle Therapy for Wound Healing.

We developed an extracellular vesicle (EV) bioprocessing platform for the scalable production of human Wharton's jelly mesenchymal stem cell (MSC)-derived EVs. The effects of clinical-scale MSC-EV products on wound healing were tested in two different wound models: subcutaneous injection of EVs in a conventional full-thickness rat model and topical application of EVs using a sterile re-absorbable gelatin sponge in the chamber mouse model that was developed to prevent the contraction of wound areas. In vivo efficacy tests showed that treatment with MSC-EVs improved the recovery following wound injury, regardless of the type of wound model or mode of treatment. In vitro mechanistic studies using multiple cell lines involved in wound healing showed that EV therapy contributed to all stages of wound healing, such as anti-inflammation and proliferation/migration of keratinocytes, fibroblasts, and endothelial cells, to enhance wound re-epithelialization, extracellular matrix remodeling, and angiogenesis.

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.

Mitochondrial energy metabolic transcriptome profiles during cardiac differentiation from mouse and human pluripotent stem cells.

Simultaneous myofibril and mitochondrial development is crucial for the cardiac differentiation of pluripotent stem cells (PSCs). Specifically, mitochondrial energy metabolism (MEM) development in cardiomyocytes is essential for the beating function. Although previous studies have reported that MEM is correlated with cardiac differentiation, the process and timing of MEM regulation for cardiac differentiation remain poorly understood. Here, we performed transcriptome analysis of cells at specific stages of cardiac differentiation from mouse embryonic stem cells (mESCs) and human induced PSCs (hiPSCs). We selected MEM genes strongly upregulated at cardiac lineage commitment and in a time-dependent manner during cardiac maturation and identified the protein-protein interaction networks. Notably, MEM proteins were found to interact closely with cardiac maturation-related proteins rather than with cardiac lineage commitment-related proteins. Furthermore, MEM proteins were found to primarily interact with cardiac muscle contractile proteins rather than with cardiac transcription factors. We identified several candidate MEM regulatory genes involved in cardiac lineage commitment (Cck, Bdnf, Fabp4, Cebpα, and Cdkn2a in mESC-derived cells, and CCK and NOS3 in hiPSC-derived cells) and cardiac maturation (Ppargc1α, Pgam2, Cox6a2, and Fabp3 in mESC-derived cells, and PGAM2 and SLC25A4 in hiPSC-derived cells). Therefore, our findings show the importance of MEM in cardiac maturation.

Predictive value of quad serum markers for adverse pregnancy outcome in antiphospholipid antibody syndrome.

PURPOSE: We investigated the validity of quad serum markers for the prediction of adverse pregnancy outcome (APO) in women with antiphospholipid antibody syndrome (APS). METHODS: We included 75 women with APS delivered at our institution. APO was defined as stillbirth, small for gestational age (SGA), severe preeclampsia, or preterm delivery. First, we compared clinical characteristics between patients with or without composite APO. Second, we compared the rate of APO according to abnormal level of quad serum markers. Lastly, receiver operating characteristic (ROC) curve analysis was performed. RESULTS: APS mothers with APO showed higher median α-fetoprotein (AFP) and inhibin A compared with those without APO. They were also associated with higher rates of positive risk of Down syndrome and neural tube defect. Elevated AFP, human chorionic gonadotropin (hCG), and inhibin A level was associated with higher rates of stillbirth, SGA, preterm delivery, and composite APO. ROC curve for prediction of stillbirth revealed an area under the curve of 0.835 for AFP, 0.781 for hCG, and 0.932 for inhibin A. For composite APO, the area under the ROC curve was 0.692 for AFP and 0.810 for inhibin A. CONCLUSION: Elevated AFP, hCG, and inhibin A in women with APS demonstrated a high predictive value for APO, especially stillbirth.

Validation of a Strict Obesity Definition Proposed for Asians to Predict Adverse Pregnancy Outcomes in Korean Pregnant Women.

BACKGROUND: People are generally considered overweight and obese if their body mass index (BMI) is above 25 kg/m² and 30.0 kg/m², respectively. The World Health Organization proposed stricter criteria for Asians (≥ 23 kg/m²: overweight, ≥ 25 kg/m²: obese). We aimed to verify whether this criteria could predict adverse pregnancy outcomes in Korean women. METHODS: We included 7,547 Korean women from 12 institutions enrolled between June 2016 and October 2018. Women with no pre-pregnancy BMI data, not Korean, or lost to follow-up were excluded, leaving 6,331. The subjects were categorized into underweight, normal, overweight, class I obesity, and class II/III obesity based on a pre-pregnancy BMI of < 18.5, 18.5-22.9, 23.0-24.9, 25.0-29.9, and ≥ 30.0 kg/m², respectively. RESULTS: Overall, 13.4%, 63.0%, 11.8%, 9.1%, and 2.6% of women were underweight, normal, and overweight and had class I obesity and class II/III obesity, respectively. In the multivariable analysis adjusted for maternal age, a higher BMI significantly increased the risk of preeclampsia, gestational diabetes, preterm delivery caused by maternal-fetal indications, cesarean section, large for gestational age, and neonatal intensive care unit admission. CONCLUSION: Adverse pregnancy outcomes started to increase in those with a pre-pregnancy BMI ≥ 23.0 kg/m² after adjusting for maternal age. The modified obesity criteria could help predict adverse pregnancy outcomes in Koreans.

Leak-proof technique in laparoscopic surgery for large ovarian cysts.

The aim of this study was to compare the spillage rate and surgical outcomes between the leak-proof technique and the conventional technique in laparoscopy for large ovarian cysts (more than 15 cm in diameter) presumed to be benign tumours and free from adhesion. Thirty-five consecutive patients who underwent laparoscopy with the leak-proof technique between 2017 and 2019 (the practice change cohort) were compared retrospectively with 35 case-matched consecutive patients who underwent the conventional purse-string method between 2014 and 2016 (the historical cohort). In the practice change cohort, through the wound retractor in the umbilicus, large ovarian cysts were first covered with a sterilised vinyl membrane applied with a skin adhesive, then punctured, and the contents directly aspirated. The primary outcome was tumour spillage. The two cohorts had similar baseline characteristics. The spillage rate in the practice change cohort was significantly lower than in the historical cohort (0% vs 28.6%; p = .001). Other surgical outcomes, including operative time, operative blood loss, hospital stay, and operative complications were similar between the cohorts. In conclusion, laparoscopy with the leak-proof technique is reliable, safe, and easily implemented in the management of selected patients with large ovarian tumours and low probability of malignancy.IMPACT STATEMENTWhat is already known on this subject: Large ovarian cysts preclude the laparoscopic surgery because the size of the cyst interferes with adequate visualisation of the pelvic anatomy and confines the mobilisation of laparoscopic devices.What do the results of this study add: Laparoscopy with the leak-proof technique is reliable, safe, and easily implemented in the management of selected patients with large ovarian tumours and low probability of malignancy.What are the implications of these findings for clinical practice and/or further research: This technique is easily implemented and useful for most gynaecologic surgeons in treating extremely large ovarian cysts.

MERS-CoV Infection in a Pregnant Woman in Korea.

Middle East respiratory syndrome (MERS) is a lethal respiratory disease - caused by MERS-coronavirus (MERS-CoV) which was first identified in 2012. Especially, pregnant women can be expected as highly vulnerable candidates for this viral infection. In May 2015, this virus was spread in Korea and a pregnant woman was confirmed with positive result of MERS-CoV polymerase chain reaction (PCR). Her condition was improved only with conservative treatment. After a full recovery of MERS, the patient manifested abrupt vaginal bleeding with rupture of membrane. Under an impression of placenta abruption, an emergent cesarean section was performed. Our team performed many laboratory tests related to MERS-CoV and all results were negative. We report the first case of MERS-CoV infection during pregnancy occurred outside of the Middle East. Also, this case showed relatively benign maternal course which resulted in full recovery with subsequent healthy full-term delivery without MERS-CoV transmission.

Neonatal outcomes of twin pregnancies delivered at late-preterm versus term gestation based on chorionicity and indication for delivery.

OBJECTIVE: To investigate the neonatal outcomes of twin pregnancies delivered at late-preterm versus term gestation based on chorionicity and indication for delivery. STUDY DESIGN: This is a retrospective cohort study of women with twin pregnancies delivered at ≥34 weeks of gestation from 1995 to 2014. Subjects were categorized into two groups according to gestational age at delivery: late-preterm group (34-36 weeks) and term group (≥37 weeks). Neonatal outcome measures including neonatal intensive care unit (NICU) admission, mechanical ventilator support, and respiratory distress syndrome (RDS) were compared between the late-preterm and term group based on chorionicity (monochorionic or dichorionic) and delivery indication (elective or non-elective). RESULTS: A total of 1198 twin pregnancies were included in the study: 679 in the late-preterm group and 519 in the term group. Late-preterm twin infants had higher rates of NICU admission, mechanical ventilator support, and RDS than did term twin infants, regardless of the chorionicity and indication for delivery. In the multivariable analysis, late-preterm birth, monochorionicity, and non-elective delivery were independently associated with a significantly higher risk of NICU admission and mechanical ventilator support. CONCLUSION: The late-preterm birth was associated with a higher risk of adverse neonatal outcome regardless of chorionicity and indication for delivery, and showed significantly increased risk by monochorionicity and non-elective delivery.

Evaluation of coronary artery disease and cardiac morphology and function in patients with hypertrophic cardiomyopathy, using cardiac computed tomography.

Coronary artery disease and cardiac morphology and function were evaluated in 51 patients with hypertrophic cardiomyopathy (HCM), without typical chest pain, using cardiac computed tomography (CT). This study investigated the prevalence of coronary artery disease, the indicators of obstructive coronary stenosis, and the magnitude of left ventricular (LV) hypertrophy. The patients' mean coronary artery calcium score was 198.8 ± 312.0 and was positively correlated with the number of coronary risk factors (r = 0.32; P < 0.05). Of the 51 patients with HCM, 42 (82.4 %) had some degree of stenosis and 8 (15.7 %) had obstructive stenosis. Noncalcified and mixed plaques were detected in 14 (27.5 %) and 11 (21.6 %) patients, respectively. Multivariate logistic regression revealed that diabetes was an independent indicator of the presence of obstructive stenosis in HCM patients. Multivariate linear regression revealed that low estimated glomerular filtration rates and high triglyceride concentrations were independent indicators of higher LV mass indexes. In conclusion, cardiac CT revealed that coronary artery disease was common among patients with HCM. The presence of obstructive coronary stenosis and the magnitude of LV hypertrophy were related to the presence of diabetes, triglyceride levels, and estimated glomerular filtration rate.

Prognostic factors influencing decisions about surgical treatment of villoglandular adenocarcinoma of the uterine cervix.

OBJECTIVE: The objectives of this study were to analyze the clinicopathologic features of villoglandular adenocarcinoma (VGA) of the uterine cervix, a variant of cervical adenocarcinoma with good prognosis, and to discuss the association of human papillomavirus (HPV) infection with VGA. METHODS: A retrospective review of medical records was performed to identify the patients with VGA between 1999 and 2007 at the Samsung Medical Center. RESULTS: Fifteen patients were identified among 171 women diagnosed with adenocarcinoma of the cervix. The median age was 40 years (range, 32-72 years). Four patients were treated by cone biopsy and 10 patients by hysterectomy with or without pelvic lymphadenectomy. Five patients had invasion of more than half of the depth of tumor in the cervix. Lymphovascular space invasion was present in 2 patients, one of whom also had lymph node metastases. Three recurrences were identified during the median follow-up of 64 months (range, 9-149 months). An HPV test was positive in 6 of 7 patients. Of the 6 patients with HPV infection, 2 were positive for HPV type 18, one for HPV type 6, and the remaining 3 were positive for 1 or more types of high-risk HPV. CONCLUSIONS: Although VGA has been reported to have a favorable prognosis, we observed recurrences in those patients with close margins by the tumor, lymph node metastasis, or advanced stage. Human papillomavirus DNA, mostly HPV types 16 and 18, was associated with VGA. Further studies are warranted on prognostic factors and the pathogenetic role of HPV infections.

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.

Association between uterine artery embolization for postpartum hemorrhage and second delivery on maternal and offspring outcomes: a nationwide cohort study.

STUDY QUESTION: What are the maternal and neonatal outcomes of second delivery in women who underwent uterine artery embolization (UAE) during their first delivery? SUMMARY ANSWER: Women who underwent UAE during their first delivery exhibited higher risks of placental problems, preterm births, and postpartum hemorrhage (PPH) in second delivery and the second offspring also showed increased risk of major congenital malformations, admission to the neonatal intensive care units (NICU), necrotizing enterocolitis, intraventricular hemorrhage, and bronchopulmonary dysplasia. WHAT IS KNOWN ALREADY: UAE is a minimally invasive procedure used as an alternative to hysterectomy for managing severe PPH. However, recent studies have raised concerns about potential obstetric complications, including recurrent PPH, placenta accreta spectrum (PAS), and fetal growth restriction in subsequent delivery following UAE. STUDY DESIGN SIZE DURATION: This was a nationwide retrospective cohort study using the Korean National Health Insurance Service (K-NHIS) database, covering 50 million individuals from 2004 to 2020. The cohort included 3 616 923 women with live births between 1 January 2005 and 31 December 2019 with follow-up data extending to 31 December 2020. PARTICIPANTS/MATERIALS SETTING METHODS: The study included women who had their first live birth between 2005 and 2019, excluding those who underwent hysterectomy (without UAE = 3 612 389, UAE = 4534). Among them, we selected women who had single gestation secondary delivery (without UAE = 1 694 600, UAE = 1146). Propensity score matching was used to control for confounding factors, resulting in 11 184 women without UAE and 1119 women with UAE for subsequent analysis. MAIN RESULTS AND THE ROLE OF CHANCE: Women in the UAE group had significantly higher risks of PAS (odds ratio (OR) = 38.91, 95% CI = 18.61-81.34), placenta previa (OR = 6.98, 95% CI = 5.57-8.75), and preterm birth (OR = 2.23, 95% CI = 1.71-2.90) during their second delivery. The risk of recurrent PPH was also significantly higher (OR = 8.94, 95% CI = 7.19-11.12). Their second offspring were more likely to have major congenital malformations (OR = 1.62, 95% CI = 1.25-2.11) and adverse neonatal outcomes, including NICU admissions (OR = 1.83, 95% CI = 1.48-2.25). Long-term outcomes showed a higher risk of attention-deficit/hyperactivity disorder (hazard ratio = 1.64, 95% CI = 1.03-2.63) but were otherwise comparable to those in the without UAE group. LIMITATIONS REASONS FOR CAUTION: Retrospective nature of the study may have introduced exposure and outcome misclassifications, despite the reliability of the K-NHIS database. Unmeasured confounders and selection bias due to only including live births could also have influenced the results. WIDER IMPLICATIONS OF THE FINDINGS: Women with a history of UAE require meticulous prenatal care and close monitoring during subsequent deliveries due to increased risks of complications. Counseling and referral to high-risk medical centers may improve outcomes. Further research is needed to understand the mechanisms of complications in both mothers and offspring at sequential delivery, as well as to refine UAE procedures. STUDY FUNDING/COMPETING INTERESTS: This study supported by Patient-Centered Clinical Research Coordinating Center (PACEN) funded by the Ministry of Health & Welfare, Republic of Korea (HC21C0123). This study was funded by S.-Y.O. The authors of this manuscript declare no relationships with any companies whose products or services may be related to the subject matter of the article. TRIAL REGISTRATION NUMBER: N/A.

The influence of advanced maternal age on congenital malformations, short- and long-term outcomes in offspring of nulligravida: a Korean National Cohort Study over 15 years.

OBJECTIVE: To assess the influence of advanced maternal age on congenital malformations, short- and long-term outcomes in offspring of nulligravida. METHODS: A retrospective study was conducted using the Korean National Health Insurance Service database spanning from January 2005 to December 2019. All live-born offspring of nulligravida (n=3,685,817) were included. The maternal age was subdivided into the following subgroups: <25 years (n=153,818), 25-29 years (n=845,355), 30-34 years (n=1,738,299), 35-39 years (n=787,530), 40-44 years (n=151,519), and >44 years (n=9,296). Outcomes were assessed based on International Classification of Diseases-10 codes. Adjusted odds ratios (aOR) were calculated with the group of 25-29 years as a reference. RESULT: Most congenital malformations showed an age dependent increase, but cleft lip and abdominal wall defect exhibited a U-shape curve, indicating an increase even in those <25 years old. Similarly, various disorders included in the neonatal composite outcomes from short-term outcomes showed aged dependent escalation. However, the preterm birth from the short-term outcome and most of the long-term developmental outcomes, except for motor developmental delay and Tics, showed a U-shaped pattern. The aOR of autism and cerebral palsy, showing the most obvious U-shaped curved in the long-term outcomes, was 1.50 (95% confidence interval [CI], 1.24-1.82) and 1.54 (95% CI, 1.17-2.03), respectively in the group >44 years old and 1.18 (95% CI, 1.11-1.25) and 1.19 (95% CI, 1.09-1.30) in <25 years old group. CONCLUSION: Overall, an advanced maternal age has an age-dependent correlation with most congenital malformations and shortand long-term outcomes of neonates.

Comparison of analgesic effects between programmed intermittent epidural boluses and continuous epidural infusion after cesarean section: a randomized controlled study.

BACKGROUND: This study aimed to compare the analgesic effects of programmed intermittent epidural boluses (PIEB) and continuous epidural infusion (CEI) for postoperative analgesia after elective cesarean section (CS). METHODS: Seventy-four women who underwent elective CS were randomized to receive either PIEB or CEI. The PIEB group received 4 ml-intermittent boluses of 0.11% ropivacaine every hour at a rate of 120 ml/h. The CEI group received a constant rate of 4 ml/h of 0.11% ropivacaine. The primary outcome was the pain score at rest at 36 h after CS. Secondary outcomes included the pain scores during mobilization, time-weighted pain scores, the incidence of motor blockade, and complications-related epidural analgesia during 36 h after CS. RESULTS: The pain score at rest at 36 h after CS was significantly lower in the PIEB group compared with that in the CEI group (3.0 vs. 0.0; median difference: 2, 95% CI [1, 2], P < 0.001). The mean time-weighted pain scores at rest and during mobilizations were also significantly lower in the PIEB group than in the CEI group (pain at rest; mean difference [MD]: 37.5, 95% CI [24.6, 50.4], P < 0.001/pain during mobilization; MD: 56.6, 95% CI [39.8, 73.5], P < 0.001). The incidence of motor blockade was significantly reduced in the PIEB group compared with that in the CEI group (P < 0.001). CONCLUSIONS: PIEB provides superior analgesia with less motor blockade than CEI in postpartum women after CS, without any apparent adverse events.

Pregnancy outcomes of cerclage in twin gestations: a multicenter retrospective cohort study.

OBJECTIVES: To determine the effects of cerclage on twin pregnancies. METHODS: A multicenter, retrospective, cohort study was conducted at 10 tertiary centers using a web-based data collection platform. The study population included twin pregnancies delivered after 20 weeks of gestation. Patients with one or two fetal deaths before 20 weeks of gestation were excluded. Maternal characteristics, including prenatal cervical length (CL) and obstetric outcomes, were retrieved from the electronic medical records. RESULTS: A total of 1,473 patients had available data regarding the CL measured before 24 weeks of gestation. Seven patients without CL data obtained prior to cerclage were excluded from the analysis. The study population was divided into two groups according to the CL measured during the mid-trimester: the CL ≤2.5 cm group (n = 127) and the CL >2.5 cm group (n = 1,339). A total of 127 patients (8.7%) were included in the CL ≤2.5 cm group, including 41.7% (53/127) who received cerclage. Patients in the CL >2.5 cm group who received cerclage had significantly lower gestational age at delivery than the control group (hazard ratio (HR): 1.8; 95% confidence interval (CI): 1.11-2.87; p = .016). Patients in the CL ≤2.5 cm group who received cerclage had a significantly higher gestational age at delivery than the control group (HR: 0.5; 95% CI: 0.30-0.82; p value = .006). CONCLUSIONS: In twin pregnancies with a CL ≤2.5 cm, cerclage significantly prolongs gestation. However, unnecessary cerclage in women with a CL >2.5 cm may result in a higher risk of preterm labor and histologic chorioamnionitis although this study has a limitation originated from retrospective design.