Transabdominal and transvaginal ultrasound findings help to guide the clinical management of placenta accreta spectrum cases.

INTRODUCTION: The clinical management of placenta accreta spectrum (PAS) depends on placental topography and vascular involvement. Our aim was to determine whether transabdominal and transvaginal ultrasound signs can predict PAS management. MATERIAL AND METHODS: We conducted a retrospective cohort study of consecutive prenatally suspected PAS cases in a single tertiary-care PAS center between January 2021 and July 2022. When PAS was confirmed during surgery, abdominal and transvaginal ultrasound scans were analyzed in relation to PAS management. The preferred surgical approach of PAS was one-step conservative surgery (OSCS). Massive blood loss and PAS topography in the lower bladder trigone necessitated cesarean hysterectomy. Transvaginal ultrasound-diagnosed intracervical hypervascularity was split into three categories based on their quantity. Anatomically, the internal cervical os is located at the level of the bladder trigone and was used as landmark for upper and lower bladder trigone PAS. RESULTS: Ninety-one women underwent OSCS and 35 women underwent cesarean hysterectomy (total 126 women with PAS). Abdominal and transvaginal ultrasound features differed significantly between women that underwent OSCS and cesarean hysterectomy: decreased myometrial thickness (<1 mm), 82.4% vs. 100%, p = 0.006; placental bulge, 51.6% vs. 94.3%, p < 0.001; bladder wall interruption, 62.6% vs. 97.1%, p < 0.001; abnormal placental lacunae, 75.8% vs. 100%, p < 0.001; hypervascularity (large lacunae feeding vessels, 57.8% vs. 94.6%, p < 0.001; parametrial hypervascularity, 15.4% vs. 60%, p < 0.001; the rail sign, 6.6% vs. 28.6%, p = 0.003; three-dimensional Doppler intra-placental hypervascularity, 81.3% vs. 100%, p < 0.001; intracervical hypervascularity 60.4% vs. 94.3%, p < 0.001); and cervical length 2.5 ± 0.94 vs. 2.2 ± 0.73, p = 0.038. Other ultrasound signs were not significantly different. The results of multivariable logistic regression showed placental bulge (odds ratio [OR] 9.3; 95% CI 1.9-44.3; p = 0.005), parametrial hypervascularity (OR 4.1; 95% CI 1.541-11.085; p = 0.005), and intracervical hypervascularity (OR 9.2; 95% CI 1.905-44.056; p = 0.006) were weak predictors of OSCS. Intracervical hypervascularity Grade 1 (vascularity <50% of cervical tissue) was more present in OSCS than higher gradings two and three (91% vs. 27.6% vs. 14.3%; p < 0.001). CONCLUSIONS: Cesarean hysterectomy is associated with the PAS signs of placental bulge and Grade 2 and 3 intracervical hypervascularity. OSCS is associated with intracervical hypervascularity Grade 1 on transvaginal ultrasound. Prospective validation is required to formulate predictors for PAS management.

Uterine conservative-resective surgery for selected placenta accreta spectrum cases: Surgical-vascular control methods.

INTRODUCTION: The incidence of placenta accreta spectrum (PAS) has increased, but the optimal management and the optimal way to achieve vascular control are still controversial. This study aims to compare maternal outcomes between different methods of vascular control in surgical PAS management. MATERIAL AND METHODS: A retrospective cohort study on consecutive cases diagnosed with PAS between 2013 and 2020 in single tertiary hospital. The final diagnosis of PAS was made following preoperative ultrasound and confirmation during surgery. Management of PAS using cesarean hysterectomy with internal iliac artery ligation (IIAL) was compared with two types of vascular control in uterine conservative-resective surgery (IIAL vs identification-ligation of the upper vesical, upper vaginal, and uterine arteries). RESULTS: Over an 8-year period, 234 pregnant women were diagnosed with PAS meeting the inclusion criteria. Uterine conservative-resective surgery (200 cases) was associated with lower mean blood loss compared with cesarean hysterectomy with IIAL (34 cases) in all PAS cases (1379 ± 769 mL vs 3168 ± 1916 mL; p < 0.001). In sub-analysis of the two uterine conservative-resective surgery subgroups, the group with identification-ligation of the upper vesical, upper vaginal, and uterine arteries had a significantly lower blood loss compared with uterine conservative-resective surgery with IIAL (1307 ± 743 mL vs 1701 ± 813 mL; p = 0.005). Women in the hysterectomy with IIAL group had more massive transfusion (35.3% vs 2.5%; p < 0.001; odds ratio [OR] 21.3, 95% confidence interval [CI] 6.9-66), major blood loss (>1500 mL) (70.6% vs 34%, p < 0.001; OR 4.7; 95% CI 2.1-10.3), catastrophic blood loss (>2500 mL) (64.7% vs 12.5%;p < 0.001; OR 12.8, 95% CI 5.7-29.1), other complications (32% vs 12.4%; p = 0.007; OR 3.4, 95% CI 1.5-7.7), and intensive care unit admission (32.4% vs 1.5%; p < 0.001; OR 31.4, 95% CI 8.2-120.7) compared with the uterine conservative-resective surgery groups. The identification-ligation of the upper vesical, upper vaginal and uterine arteries had a significant lower risk for major blood loss (30.5% vs 50%; p = 0.041; OR 0.44, 95% CI = 0.2-0.9) compared with IIAL for vascular control of uterine conservative-resective surgery. CONCLUSIONS: Cesarean hysterectomy is not the default treatment for PAS, PAS with invasion above the vesical trigone are suitable for uterine conservative-resective surgery with upper vesical, upper vaginal and uterine artery vascular control.

INOVASIA Study: A Multicenter Randomized Clinical Trial of Pravastatin to Prevent Preeclampsia in High-Risk Patients.

OBJECTIVE: Our objective was to determine if treatment with pravastatin prevents preeclampsia in pregnant patients at risk of preeclampsia. MATERIAL AND METHODS: The study was performed in four major tertiary hospitals in Surabaya, Bandung, and Makassar between 2017 and 2021. Pregnant women at high risk of developing preeclampsia were recruited and randomized into an intervention group and control group. The control group received low-dose aspirin (80 mg) and calcium (1 g) daily, while the intervention group received additional pravastatin (20 mg twice daily) starting from 14 to 20 weeks' gestation until delivery. The pregnancy was followed until delivery, and the clinical data were collected. The primary outcome was the occurrence of preeclampsia. RESULT: A total of 173 people participated in this study, including 86 in the control group and 87 in the pravastatin group. The pravastatin group had a significantly lower rate of preterm preeclampsia (13.8 vs. 26.7%; p = 0.034; odds ratio [OR] = 0.034, 95% confidence interval [CI] = 0.202-0.905) and preterm birth (16.1 vs. 36%; p = 0.003; OR = 0.340, 95% CI = 0.165-0.7), mostly indicated preterm birth. Preeclampsia occurred later in the pravastatin group than in the control group (36.39 + 2.32 vs. 34.89 + 3.38 weeks, p = 0.048). Overall, the pravastatin group showed better perinatal outcomes. Neonates with low Apgar scores (<7) at 1 minute (5.7 vs. 25.6%, p = 0.000) and 5 minutes (2.3 vs. 25.6%, p = 0.028) were significantly less common in the pravastatin group. Additionally, the rate of low birthweight babies (<2,500 g) was lower in the pravastatin group (27.6 vs. 40.7%; p = 0.069). CONCLUSION: Pravastatin (20 mg bid) significantly reduces the risk of preterm preeclampsia and preterm birth in women at a high risk of developing preeclampsia. KEY POINTS: · This is an open-label multicenter RCT to evaluate pravastatin effect to prevent preeclampsia.. · Pravastatin significantly reduces the risk of preterm preeclampsia (PE) and preterm birth in high risk PE women.. · Pravastatin had a beneficial effect on perinatal outcomes, including Apgar scores and birth weight..

New three-dimensional/four-dimensional volume rendering imaging software for detecting the abnormally invasive placenta.

OBJECTIVE: This study aimed to determine the role of three-dimensional (3D)/four-dimensional (4D) volume rendering ultrasound (VRU) in the diagnosis of abnormally invasive placenta (AIP). MATERIALS AND METHODS: Twelve consecutive patients strongly suspected of having AIP on the basis of conventional ultrasound (US) and clinical history performed between September 2016 and December 2016 in the main tertiary referral hospital in Surabaya, East Java were included in this prospective observational study. A Samsung WS 80A Elite US scanner with a 3D/4D "crystal vue" and "realistic vue" volume rendering mode was used to establish the diagnosis of AIP and evaluate the site, and depth of placental invasion. The VRU images were compared with the intraoperative findings. RESULTS: Using this novel US technique, all cases of suspected AIP were subsequently confirmed during surgery. Importantly, the new US technique provided a correct diagnosis of the degree of invasion in 11 out of these 12 suspected AIP cases: 5/5 for placenta percreta, 3/3 for placenta increta, and 2/3 for placenta accreta; one patient was misdiagnosed in terms of the degree of placenta accreta, and one patient had normal implantation). CONCLUSION: This new software of 3D/4D VRU represents a promising technique for the preoperative diagnosis and staging of AIP.

Recombinant vascular endothelial growth factor 121 injection for the prevention of fetal growth restriction in a preeclampsia mouse model.

AIM: To discover the potential role of recombinant VEGF121 (rVEGF121) injection for the prevention of fetal growth restriction in a preeclampsia (PE) mouse model (Mus musculus). SUBJECTS AND METHODS: This is an experimental study of 30 pregnant mice that were randomly divided into three groups: normal, PE, and PE with rVEGF121 injection. The PE mouse model was created by injecting anti Qa-2 10 ng iv, which is deleterious to Qa-2 expression (homologous to HLA-G), from the first to the fourth day of gestation. PE was validated by measuring serum levels of soluble fms-like tyrosine kinase-1 (sFlt-1) and placental growth factor(PIGF) and also by kidney histopathology. Recombinant VEGF121 was given on the ninth day until the 11th day of pregnancy; mice were terminated on the 16th day. Fetal weights were acquired with a Denver analytical balance. Serum levels of sFlt-1 and PlGF were measured using enzyme-linked immunosorbent assay (ELISA). The data were statistically analyzed via analysis of variance (ANOVA). RESULTS: On average, fetal birth weight was 0.7150 g in the normal group, 0.4936 g in the PE group, and 0.6768 g in the PE with rVEGF121 injection group. ANOVA showed significant growth restriction in the PE group (P=0.006), confirming the use of anti Qa-2 as a suitable PE model. Kidney histopathology results, sFlt-1 levels, and PlGF levels also demonstrated that anti Qa-2 consistently conferred hallmarks of PE in mice. Vascular endothelial growth factor (VEGF) injection prevented fetal growth restriction; comparable fetal weights were observed between the PE model with VEGF treatment and the normal group (P=0.610) but differed from the untreated PE group (P=0.021). CONCLUSIONS: Injection of rVEGF121 has the potential to prevent fetal growth restriction in a newly proposed PE mouse model.

Connecting the Dots: Exploring the Interplay Between Preeclampsia and Peripartum Cardiomyopathy.

Preeclampsia and peripartum cardiomyopathy (PPCM) are significant obstetric problems that can arise during or after pregnancy. Both are known to be causes of maternal mortality and morbidity. Several recent studies have suggested a link between preeclampsia and the pathophysiology of PPCM. However, the common thread that connects the two has yet to be thoroughly and fully articulated. Here, we investigate the complex dynamics of preeclampsia and PPCM in this review. Our analysis focuses mainly on inflammatory and immunological responses, endothelial dysfunction as a shared pathway, and potential genetic predisposition to both diseases. To begin, we will look at how excessive inflammatory and immunological responses can lead to clinical symptoms of both illnesses, emphasizing the role of proinflammatory cytokines and immune cells in modifying vascular and tissue responses. Second, we consider endothelial dysfunction to be a crucial point at which endothelial damage and activation contribute to pathogenesis through increased vascular permeability, vascular dysfunction, and thrombus formation. Finally, we examine recent information suggesting genetic predispositions to preeclampsia and PPCM, such as genetic variants in genes involved in the management of blood pressure, the inflammatory response, and heart structural integrity. With this synergistic study, we seek to encourage more research and creative therapy solutions by emphasizing the need for an interdisciplinary approach to understanding and managing the connection between preeclampsia and PPCM.

Evidence of Placental Villous Inflammation and Apoptosis in Third-Trimester Symptomatic SARS-CoV-2 Maternal Infection.

PURPOSE: In view of conflicting reports on the ability of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) to infect placental tissue, this study aimed to further evaluate the impact of inflammation and placental damage from symptomatic third-trimester maternal COVID-19 infection. MATERIALS AND METHODS: This case-control study included 32 placenta samples each from symptomatic COVID-19 pregnancy and normal non-COVID-19 pregnancy. The villous placental area's inflammatory expression [angiotensin converting enzyme-2 (ACE-2), transmembrane protease serine-2 (TMPRSS2), interferon-γ (IFN-γ), interleukin-6 (IL-6), and SARS-CoV-2 spike protein] and apoptotic rate were examined using immunohistochemistry and Terminal deoxynucleotidyl transferase dUTP Nick-End Labeling (TUNEL) assay. Comparison and correlation analysis were used based on COVID-19 infection, placental SARS-CoV-2 spike protein evidence, and maternal severity status. RESULTS: Higher expressions of TMPRSS2, IFN-γ, and trophoblast apoptotic rate were observed in the COVID-19 group (p<0.001), whereas ACE-2 and IL-6 expressions were not significantly different from the control group (p>0.05). Additionally, SARS-CoV-2 spike protein was detected in 8 (25%) placental samples of COVID-19 pregnancy. COVID-19 subgroup analysis revealed increased IFN-γ, trophoblast, and stromal apoptosis (p<0.01). Moreover, the results of the current study revealed no correlation between maternal COVID-19 severity and placental inflammation as well as the apoptotic process. CONCLUSION: The presence of SARS-CoV-2 spike protein as well as altered inflammatory and apoptotic processes may indicate the presence of placental disturbance in third-trimester maternal COVID-19 infection. The lack of correlation between placental disruption and maternal severity status suggests the need for more research to understand the infection process and any potential long-term impacts on all offsprings born to COVID-19-infected pregnant women.

Iron metabolism and ferroptosis: A pathway for understanding preeclampsia.

Preeclampsia (PE) is a serious medical condition that poses a significant health risk to women and children worldwide, particularly in the middle- and low-income countries. It is a complex syndrome that occurs as a result of abnormal pregnancy. Hypertension is the most common symptom of PE, with proteinuria and specific organ systems as detrimental targets. PE's pathogenesis is diverse, and its symptoms can overlap with other diseases. In early pregnancy, when the placenta takes over control, oxidative stress may be closely associated with ferroptosis, a type of cell death caused by intracellular iron accumulation. Ferroptosis in the placenta is defined by redox-active iron availability, loss of antioxidant capacity and phospholipids containing polyunsaturated fatty acids (PUFA) oxidation. Recent studies suggest a compelling potential link between ferroptosis and PE. In this article, we comprehensively review the current understanding of PE and discuss one of its emerging underlying mechanisms, the ferroptosis pathway. We also provide perspective and analysis on the implications of this process in the diagnosis, prevention, and treatment of preeclampsia. We aim to bridge the gap between clinicians and basic scientists in understanding this harmful disease and challenge the research community to put more effort into this exciting new area.

The correlation between serum levels and placental tissue expression of PLGF and sFLT-1 and the FIGO grading of the placenta accreta spectrum disorders.

OBJECTIVE: This study aims to further explore the role of angiogenic vs anti-angiogenic factors in placenta accreta spectrum (PAS). METHODS: This cohort study included all patients with placenta previa and placenta accreta spectrum (PAS) disorders undergoing surgery at Dr. Soetomo Hospital (Academic Hospital of Universitas Airlangga, Surabaya, Indonesia) from May to September 2021. Venous blood samples for PLGF and sFlt-1 were drawn immediately prior to surgery. Placental tissue samples were taken during surgery. The FIGO grading was diagnosed intraoperatively by an experienced surgeon and confirmed by the pathologist and followed by immunohistochemistry (IHC) staining. The sFlt-1 and PLGF serum were performed by an independent laboratory technician. RESULTS: Sixty women were included in this study (20 women with placenta previa; 10 women with FIGO PAS grade 1; 8 women with FIGO PAS grade 2; 22 women with FIGO PAS grade 3). The median with 95% Confidence interval of PLGF serum values in placenta previa, FIGO grade I, grade II, and grade III were 233.68 (0.00-2434.00), 124.39 (10.42-663.68), 236.89 (18.83-418.99) and 237.31 (2.26-3101.00) (p = .736); the median values with 95% CI of serum sFlt-1 levels in placenta previa, FIGO grade I, grade II, and grade III were 2816.50 (418.00-12925.00), 2506.00 (227.50-16104.00), 2494.50 (888.52-20812.00), and 1601.00 (662.16-9574.00) (p = .037). Placental PLGF expression in placenta previa, FIGO grade 1, grade II, and grade III showed median values (with 95% CI) of 4.00 (1.00-9.00), 4.00 (2.00-9.00), 4.00 (4.00-9.00), and 6.00 (2.00-9.00) (p = .001); sFlt-1 expression median values (with 95% CI) were 6.00 (2.00-9.00), 6.00 (2.00-9.00), 4.00 (1.00-9.00), and 4.00 (1.00-9.00) (p = .004). Serum PLGF and sFlt-1 levels did not correlate with placental tissue expression (p = .228; p = .586). CONCLUSION: There are differences in PAS's angiogenic processes ​according to the severity of trophoblast cell invasion. But there is no overall correlation between serum levels and PLGF and sFlt-1 expression in the placenta, suggesting the imbalance between angiogenic and anti-angiogenic are local mechanisms in the placental and the uterine wall.

The Risk of Persistent Hypertension and Chronic Kidney Disease in Early- and Late-Onset Preeclampsia: A Report From Developing Country.

BACKGROUND AND OBJECTIVE: Preeclampsia (PE) has been disproportionately prevalent in developing countries and constitutes a leading cause of maternal mortality, and also has long-term impacts, including renal consequences. This study aimed to explore the risk of persistent hypertension and kidney failure in early-onset PE (EOP) and late-onset PE (LOP) in the five years after delivery. METHODS: This retrospective cohort study included women with a prior history of severe PE or normotensive pregnancy admitted to tertiary hospitals in Indonesia. The blood pressure, body mass index (BMI), urea, creatinine serum, and protein urine were analyzed, and the risk of chronic kidney disease (CKD) after five years was performed using the Kidney Disease Improvement Global Outcomes (KDIGO) classification. RESULTS: Twenty-seven EOP, 35 LOP, and 30 normotensive cases were included. Mean blood pressure after five years was recorded as 115.6 ± 14.25 mmHg in the normotensive group, 131.82 ± 19.34 mmHg in the LOP group, and 154.96 ± 23.48 mmHg in the EOP group. According to the KDIGO classification, the normotensive group had an average 10% risk of CKD, but severe PE had a risk of CKD greater than 90%. In the severe PE group, the risk of CKD was 20.94 times higher compared to normotensive women (OR 20.94; 95% CI 2.67-163.72, p = 0.004). The risk of CKD in the EOP group was 6.75 times higher than in the LOP group (OR 6.75; 95% CI 2.19-20.76, p = 0.001), whereas persistent hypertension in the EOP group was 5.78 times higher than in the LOP group (OR 5.78; 95% CI 1.91-17.395, p = 0.002). CONCLUSIONS: PE women have a higher risk of CKD than normotensive women. Women with a history of EOP are more likely to develop persistent hypertension and CKD than women with a prior LOP history.

Traumatic brain injury in pregnancy: A systematic review of epidemiology, management, and outcome.

OBJECTIVE: Traumatic brain injury (TBI) during pregnancy is an extremely rare condition in our neurosurgical emergency practices. Studies on the epidemiology and management of TBI in pregnancy are limited to case reports or serial case reports. There is no specific guidelines of management of TBI in pregnancy yet. METHODS: The authors performed a structured search of all published articles on TBI in pregnancy from 1990 to 2020. We restricted search for papers in English and Bahasa. RESULTS: The literature search yielded 22 articles with total 43 patients. We distinguished C-section based on its timing according to the neurosurgical treatment into primary (simultaneous or prior to neurosurgery) and secondary group (delayed C-section). The mean GOS value in primary C-section is better compared to secondary C-section in severe TBI group (3.57 ± 1.47 vs 3.0 ± 1.27, respectively) consistently in the moderate TBI group (4.33 ± 1.11 vs 3.62 ± 1.47, respectively). The fetal death rate in primary C-section is lower compared to secondary C-section in severe TBI group (14.2 % vs 33.3 %, respectively), contrary, in moderate TBI group (16.7 % vs 12.5 %, respectively). CONCLUSIONS: Care of pregnant patients with TBI often requires multidisciplinary approach to optimize treatment strategy on a case-by-case basis in light of prior experience across different center. We propose management guideline for head injury in pregnancy.

Mesenchymal stem cell secretome ameliorates over-expression of soluble fms-like tyrosine kinase-1 (sFlt-1) and fetal growth restriction (FGR) in animal SLE model.

INTRODUCTION: In the near future, stem cell research may lead to several major therapeutic innovations in medical practice. Secretome, a "by-product" of stem cell line cultures, has many advantages. Its easiness of storage, usage, and fast direct effect are some of those to consider. Fetal growth restriction (FGR) remains one of the significant challenges in maternal-fetal and neonatal medicine. Placentation failure is one of the most profound causal and is often related to increasing sFlt-1 in early pregnancy. This study aimed to investigate hUC-MSC secretome in ameliorating sFlt-1 and how to improve outcomes in preventing FGR in an animal model. MATERIALS AND METHODS: Pristane-induced systemic lupus erythematosus (SLE) in a mouse model was used to represent placentation failure and its consequences. Twenty-one mice were randomized into three groups: (I) normal pregnancy, (II) SLE, and (III) SLE with secretome treatment. Pristane was administered in all Groups four weeks prior mating period. Secretome was derived from human umbilical cord mesenchymal stem cells (hUC-MSC) conditioned medium on the 3rd and 4th passage, around day-21 until day-28 from the start of culturing process. Mesenchymal stem cell was characterized using flow cytometry for CD105+, CD90+, and CD73+ surface antigen markers. Immunohistochemistry anlysis by using Remmele's Immunoreactive Score (IRS) was used to quantify the placental sFlt-1 expression in each group. Birth weight and length were analyzed as the secondary outcome. The number of fetuses obtained was also calculated for pregnancy loss comparison between Groups. RESULTS: The administration of secretome of hUC-MSC was found to lower the expression of the placental sFlt-1 significantly in the pristane SLE animal model (10.30 ± 1.40 vs. 4.98 ± 2.57; p < 0.001) to a level seen in normal mouse pregnancies in Group I (3.88 ± 0.49; p = 0.159). Secretome also had a significant effect on preventing fetal growth restriction in the pristane SLE mouse model (birth weight: 354.29 ± 80.76 mg vs. 550 ± 64.03 mg; p < 0.001 and birth length: 14.43 ± 1.27 mm vs. 19.00 ± 1.41 mm), comparable to the birth weight and length of the normal pregnancy in Group I (540.29 ± 75.47 mg and 18.14 ± 1.34 mm, p = 0.808 and = 0.719). Secretome administration also showed a potential action to prevent high number of pregnancy loss as the number of fetuses obtained could be similar to those of mice in the normal pregnant Group (7.71 ± 1.11 vs. 7.86 ± 1.06; p = 0.794). CONCLUSIONS: Administration of secretome lowers sFlt-1 expression in placenta, improves fetal growth, and prevents pregnancy loss in a mouse SLE model.

Pravastatin suppresses inflammatory cytokines and endothelial activation in patients at risk of developing preeclampsia: INOVASIA study.

INTRODUCTION: The Indonesian INOVASIA study is an ongoing multicentre randomized, open controlled trial of pravastatin for the prevention of preeclampsia in patients deemed to be high risk. Here we evaluate the effects of pravastatin on circulating inflammatory and endothelial markers, i.e. Vascular Endothelial Growth Factor (VEGF), Interleukin-6 (IL-6), Endothelin-1 (ET-1), and Nitric Oxide (NO). METHODS: Pregnant women deemed to be at a high risk of developing preeclampsia women were recruited based on the Fetal Medicine Foundation preeclampsia screening test or a history of preterm preeclampsia, or clinical risk factors in combination with an abnormal uterine artery Doppler flow pattern at 11-20 week's gestation. This is a nested cohort study within the larger trial (INOVASIA); 38 patients were consecutively recruited and assigned to the pravastatin group and the control group. Participants in the pravastatin group received pravastatin (2 × 20 mg p.o) in addition to a standard regimen of aspirin (80 mg p.o) and calcium (1 g p.o), from 14 to 20 weeks until delivery. Blood samples to measure the various biomarkers were obtained in consecutive patients before starting the research medication and just before delivery (pre and post-test examination). RESULT: The number of samples on the 2 time points for the various biomarkers was: VEGF: 38, IL-6: 30, ET-1: 38, and NO: 35. IL-6 levels decreased significantly in the pravastatin group (mean ± SD): (191.87 ± 82.99 vs. 151.85 + 48.46, p = .013), while levels in the control group did not change significantly (median (interquartile range)) (144.17 (53.91) vs. 140.82 (16.18), p = .177). ET-1 levels decreased significantly in the pravastatin group (3.64 ± 0.85 vs. 3.01 ± 0.74, p = .006) while the control group had more or less stable levels (3.57 ± 1.12 vs. 3.78 ± 0.73 p = .594). NO was the only serum marker that showed significant changes in both groups. NO levels increased in pravastatin group (11.30 (17.43) vs. 41.90 (53.18), p = .044) and decreased in control group (38.70 (34.80) vs. 10.03 (26.96), p = .002). VEGF levels appeared to follow opposite trends in the 2 groups (NS) (Pravastatin: 3.22 (0.62) vs. 3.28 (0.75), p = .402. Control: 3.38 (0.83) vs. 3.06 (0.74), p = .287). CONCLUSION: Administration of 40 mg pravastatin resulted in an improvement in NO levels, and a decrease in IL-6 and endothelin (ET-1) levels. The direction of the effect of pravastatin on these biomarkers appears to underpin the potential for a beneficial effect of pravastatin in the prevention of preeclampsia.

The role of magnesium sulfate (MgSO4) in fetal neuroprotection.

Prevention of neurologic disability associated with preterm birth is one of the major challenges in current perinatal medicine. Magnesium sulfate (MgSO4), the focus of this review has been proposed as major step forward for that matter. MgSO4 is easily accessible, cheap, and has been proposed as a mandatory part of the management of inevitable preterm birth. The results of the various RCT's on the use of MgSO4 for neuroprotection has been the subject of many systematic reviews, other studies focused on dosing schedules, side effects and only a few focused on exploring magnesium's mechanism of action. Meanwhile, many guidelines worldwide have plugged MgSO4 as an essential ingredient of daily best practice when managing inevitable preterm birth because it has been shown to reduce the risk of severe neurologic deficit, in particular, cerebral palsy in appropriately selected patients. The more premature, the greater benefit associated with the use of antenatal MgSO4. The dose of 4 g given intravenously 15 min continued by 1 g/h until maximum 24 h and minimum for 4 h is the standard regiment proposed in most guidelines. It should be noted, however, that a recent study found that a total dose of 64 g was associated with the maximum protective effect. Only the protocol used by the largest RCT, the BEAM trial, with a loading dose of 6 g initially followed by a 2-g/h maintenance dose, if continued for 24 h would give a total dose over 50 g. Other studies report on an increased risk of neonatal death with these high doses. Several studies expressed concerns about the risk of serious side effects for both mother and neonate. The results from the systematic review showed that the most commonly used dosage, 4 g bolus continued by 1 g/h maintenance, did not increase neonatal mortality and other suspected neonatal complication such as neonatal asphyxia, spontaneous intestinal perforation, necrotizing enterocolitis, and feeding intolerance. Giving a single bolus injection of 4 g MgSO4 for stimulating BDNF production in highly "suspicious" preterm labor, and 4 g again when preterm birth become inevitable may be best from a safety perspective and also appears to have a stronger rationale.

High Maternal Neonatal Mortality and Morbidity in Pregnancy with Eisenmenger Syndrome.

OBJECTIVES: This study is aimed at evaluating the maternal and perinatal characteristics and pregnancy outcomes of ES. Material and Methods. This is a retrospective cohort study of pregnancy with Eisenmenger syndrome (ES) in Dr. Soetomo Hospital from January 2018 to December 2019. Total sampling size was obtained. We collected all baseline maternal-perinatal characteristic data, cardiac status, and pregnancy outcomes as primary outcomes. The maternal death cases were also evaluated, and we compared characteristics based on defect size (< or >3 cm). RESULTS: During study periods, we collected 18 cases with ES from a total of 152 pregnancies with heart disease. The underlying heart disease type includes atrial septal defect (ASD), ventricle septal defect (VSD), and patent ductus arteriosus (PDA). All cases suffered pulmonary hypertension (PH), 3 cases moderate, and 15 cases as severe. 94% of cases fall into heart failure (DC FC NYHA III-IV) during treatment. The majority of cases are delivered by cesarean section (88.9%). Pregnancy complications found include preterm birth (78%), low birthweight (94%), intrauterine growth restriction (55%), oligohydramnios (16%), severe preeclampsia (33%), and placenta previa (5.5%). Large defect group has an older maternal ages (30.18 ± 4.60 vs. 24.15 ± 2.75; p = 0.002), higher clinical sign (100 vs. 40%, p = 0.003), and higher preterm delivery rate (100% vs. 69%, p = 0.047) compared to small defect groups. The R to L or bidirectional shunt is significantly higher at the large defect group (13 vs. 5 cases, p = 0.006, 95% confidence interval: -1.156 to -0.228). There were seven maternal death cases caused by shock cardiogenic. CONCLUSIONS: Pregnancy with ES is still associated with very high maternal neonatal mortality and morbidity. The larger defect size is correlated with clinical performances and pregnancy outcomes. Effective preconception counseling is the best strategy to reduce the risk of maternal and neonatal death in ES women.

Effects of bone marrow mesenchymal stem cell transplantation on tumor necrosis factor-alpha receptor 1 expression, granulosa cell apoptosis, and folliculogenesis repair in endometriosis mouse models.

BACKGROUND AND AIM: Endometriosis affects the ovaries and causes a decrease in the oocyte quality during endometrial receptivity. During the development of ovarian follicles, paracrine communication occurs between granulosa cells and oocytes. This study was conducted to determine the effects of bone marrow mesenchymal stem cell transplantation on tumor necrosis factor-alpha (TNF-α) receptor 1 (TNFR1) expression, granulosa cell apoptosis, and folliculogenesis in endometriosis mouse models. MATERIALS AND METHODS: This study involved 42 female mice, which were divided into three groups: Healthy mice (T0), endometriosis mice without transplantation (T1), and endometriosis mice with bone marrow mesenchymal stem cell transplantation (T2). The mice were injected intraperitoneally with endometrial fragments (200 µL) to become endometriosis models. On day 15, the endometriosis models received mesenchymal stem cells. Sample collection was performed on day 29. Granulosa cell apoptosis and TNFR1 expression were examined using immunohistochemical staining, and folliculogenesis was assessed using hematoxylin and eosin staining of ovary samples. The data obtained from both examinations were statistically analyzed using Statistical Package for the Social Sciences. RESULTS: The results showed that TNFR1 expression is significantly decreased in T2 (p<0.004). The apoptosis of granulosa cells was lower in T2 (p<0.000). The primary, secondary, and graafian follicle counts in T2 were significantly increased. CONCLUSION: Bone marrow mesenchymal stem cell transplantation in endometriosis mouse models can reduce TNFR1 expression and granulosa cell apoptosis and improve folliculogenesis.

Quantitative HBsAg and Qualitative HBeAg Predicts Intrauterine Placental Infection and Umbilical Blood Cord in Pregnant Women.

Objective: To know the correlation between quantitative Hepatitis B surface Antigen (HbsAg) and maternal Hepatitis B Envelope Antigen (HbeAg) with hepatitis B intrauterine transmission via placental infection. Hepatitis B in pregnancy causes a mother to child transmission (MTCT) via transplacental route started with placental infection. HBV DNA viral load and HBeAg are the independent risk factors for MTCT, but it rarely available in developing country. Materials and methods: A cross-sectional study in 33 pregnant women with HbsAg positive in 4 referral hospital in East Java, Indonesia. Quantitative HBS Ag and HBeAg) status were determined serologically from a peripheral venous blood sample. Placental Hepatitis B infection was detected by immunohistochemistry of HBsAg from placental tissues. The intrauterine transmission was diagnosed by positive HBsAg in cord blood sampling after deliveries. Results: Serum quantitative HBsAg level has a good sensitivity and spesificity to predict placental infection (90% and 83%), with a cut off value of 3.14 Log10 IU/mL (AUC 0.87; 95% CI: 0.74-0.99). Quantitative HBsAg level also has a good sensitivity and spesificity to predict HBV transmission in umbilical blood cord (81.8% and 95.5%) with a cut off value of 3.62 log10 IU/ml (AUC: 0.925, 95% CI: 0.813-1; p = 0.000). Placental infection is significantly related with intrauterine transmission with OR 4.6 (95% CI 2.29-9.4; p = 0.002). Conclusion: The study reveals that maternal serum quantitative HBsAg level can be used as an alternative test to substitute HBeAg or HBV DNA as a marker to predict the placental infection and intrauterine transmission, especially in low-middle income countries.

Magnesium intoxication in women with preeclampsia with severe features treated with magnesium sulfate.

OBJECTIVE: To evaluate the maternal-neonatal outcome in magnesium (Mg)-intoxicated women with preeclampsia with severe features (PESF) treated with magnesium sulfate (MgSO4). METHODS: A total of 19 Mg intoxicated PESF women (cases) were compared with 166 PESF women without signs of intoxication (controls). RESULTS: Mg serum levels of cases was higher compared to control group (12.36 ± 3.54 mg/dl versus 2.69 ± 0.83 mg/dl). 3 women died and 3 had major maternal morbidity in cases group compared with zero in the control group (P = 0.009). Mg intoxication was also significantly associated with perinatal deaths and low Apgar scores at 1 and 5 minutes. CONCLUSION: Mg intoxication is associated with a increased risk of maternal and perinatal mortality and morbidity.

Pulmonary edema in preeclampsia: an Indonesian case-control study.

OBJECTIVE: To analyze risk factors, obstetric outcome and the need for mechanical ventilation in preeclampsia complicated by pulmonary edema. MATERIALS AND METHODS: Case-control study using medical record on preeclampsia complicated by pulmonary edema patients in East Java tertiary referral hospital over 2 years. A simple scoring system was developed to predict the need for mechanical ventilation, using logistic regression. RESULTS: 1106 cases of preeclampsia were admitted, with 62 cases (5.6%) had pulmonary edema. Postpartum (p < .001) and cesarean delivery (p = .001) proportions were higher in the preeclampsia with pulmonary edema group. Of the 62 cases with pulmonary edema, 81% required intensive care admission and 60% needed mechanical ventilation support. Mechanical ventilation used was associated with eclampsia (p = .04), hypertensive crisis (p = .02), lower serum albumin (p = .05) and higher creatinine (p = .01). A simple scoring model developed could predict a 46%-99% probability of need for mechanical ventilation (AUC (ROC): 0.856, 95%CI 0.763-0.95). CONCLUSIONS: Pulmonary edema is a common complication of preeclampsia in Indonesian referral hospitals. This severe complication increased maternal and perinatal morbidity and mortality. The developed scoring model in this study can be used as a triage tool to predict the probability of mechanical ventilation use due to this complication.

Serum heme oxygenase 1 (HO-1), soluble FMS like tyrosine kinase (sFlt-1) level, and neonatal outcome in early onset, late onset preeclampsia, and normal pregnancy.

OBJECTIVE: To compare the level of serum heme oxygenase 1 (HO-1), soluble FMS like tyrosine kinase (sFlt-1), and neonatal outcome in early onset preeclampsia (EO-PE), late onset preeclampsia (LO-PE), and normal pregnancy (NP). METHODS: In this prospective observational case control study, HO-1 and sFlt-1 levels were measured in blood samples within 24 h of hospital admission. Preeclampsia cases were divided into two groups based on gestational age at delivery: EO-PE (<34 weeks) and LO-PE (≥34 weeks). A total of 45 patients were involved in this study. RESULT: Maternal serum level of sFlt-1 was higher in EO-PE than LO-PE and NP groups (mean ± SD; 14.50 ± 17.12 ng/ml vs 5.20 ± 6.69 ng/ml vs 2.72 ± 1.2 ng/ml [p = 0.020]. Maternal serum level of HO-1 was not different between EO-PE, LO-PE, and NP groups (p = 0.681). Birthweights were significantly lower in the EO-PE group compared with the LO-PE and NP groups (1580 ± 536 g vs 2635 ± 578 g vs 3010 ± 371 g [p = 0.000]). The rate of small for gestational age infant (26.7% vs 6.7% vs 0%; p = 0.046) and perinatal death (20% vs 0 vs 0; p = 0.037) was also significantly higher in EO-PE compared to LO-PE and NP. The maternal sFlt-1 level was negatively correlated with birthweight (p = 0.006; CC = -0.445). CONCLUSION: This study did not find a correlation between maternal HO-1 levels and sFlt-1 levels. Maternal serum sFLt-1 levels in preeclampsia were higher in EO-PE and were associated with a worse perinatal outcome.