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.

A retrospective cohort study of hypertension, cardiovascular disease, and metabolic syndrome risk in women with history of preterm and term preeclampsia five years after delivery.

OBJECTIVES: To evaluate maternal hypertension, risk of cardiovascular disease (CVD), and metabolic syndrome five years after delivery in preterm preeclampsia (P-PE), term preeclampsia (T-PE), and normal pregnancy. STUDY DESIGN: This was a retrospective cohort study of women who delivered at Dr. Soetomo Academic Hospital (Indonesia) in 2013 with a diagnosis of PE and were compared with women with normal pregnancies. MAIN OUTCOMES MEASURES: Blood pressure, National Cholesterol Education Program Adult Treatment Panel III criteria for metabolic syndrome (NCE-ATP III), and Framingham Risk Score (FRS). RESULTS: In this study, 92 women participated. They were divided into the P-PE (27), T-PE (35), and control groups (30). Women with a history of PE, P-PE, or T-PE had higher blood pressure five years after delivery than those in the control group (p < 0.05). Systolic blood pressure (SBP) >140 mmHg was seen in 66.7% of P-PE and 25.7% of T-PE, while 55.6% of P-PE and 34.3% of T-PE had diastolic blood pressure (DBP) >90 mmHg (p < 0.05). Women with P-PE had the highest risk of developing hypertension (Relative risk (RR): 20; 95% Confidence interval [CI]: 2.85-139.92). Women with history of P-PE (RR: 1.85; 95% CI: 0.77-4.41), T-PE (RR: 1.28; 95% CI: 0.51-3.19), and total PE (RR: 1.53; 95% CI: 0.68-3.43) had an increased risk of positive NECP-ATP III five years after delivery. Women with history of P-PE (RR: 5.17; 95% CI: 0.26-103.22; p = 0.282) and T-PE (RR: 6.03; 95% CI: 0.32-112.22; p = 0.228) are at a greater risk of having an FRS >10% compared to the control group (p = 0.04). CONCLUSIONS: History of PE, P-PE, and T-PE increased the risk of hypertension and CVD five years after delivery. The results also showed a tendency toward an increased risk of metabolic syndrome in women with a previous history of PE and P-PE.

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.

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..

Cesarean scar pregnancy with devastating profuse vaginal bleeding.

A cesarean scar pregnancy (CSP) is a rare type of ectopic pregnancy that does not have any obvious signs or symptoms. However, the gestational sac in CSP is often embedded in the myometrial scar from the previous cesarean section. We report two cases of CSP in women with a history of cesarean sections who experienced profuse vaginal bleeding. The patients underwent hysterectomy at their own request due to devastating bleeding. CSP is one of the complications of cesarean sections. The patient may present with devastating bleeding, and immediate management is necessary. In a woman who is early into her pregnancy and has a history of cesarean section with profuse vaginal bleeding, CSP is one of the possible diagnoses.

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.

Clinical manifestations and pregnancy outcomes of COVID-19 in indonesian referral hospital in central pandemic area.

OBJECTIVE: s Data on the clinical manifestations and pregnancy outcomes of pregnant women with COVID-19 are limited, particularly in developing countries. The aim of this study was to analyze the clinical manifestations and pregnancy outcomes in COVID-19 maternal cases in a large referral hospital in Indonesia. METHODS: This study used a prospective cohort design and included all pregnant women with suspected COVID-19. Subjects were divided into COVID-19 and non-COVID-19 groups based on the results of real-time polymerase chain reaction (RT-PCR) for severe acute respiratory syndrome coronavirus 2. Clinical characteristics, laboratory results, and pregnancy outcomes were compared between the two groups. RESULTS: Of the 141 suspected maternal cases, 62 cases were COVID-19-confirmed (43.9%), while 79 suspected cases were negative (56.1%). The clinical manifestations and laboratory findings between the two groups were not significantly different (P>0.05). However, the maternal mortality directly caused by COVID-19 was significantly higher than that in the non-COVID-19 group (8.3% vs. 1.3%; P=0.044; odd ratio, 6.91; 95% confidence interval, 0.79-60.81). CONCLUSION: The clinical manifestations and laboratory results of suspected pregnant women with positive and negative RT-PCR COVID-19 results were similar. However, within the Indonesian setting, COVID-19 significantly increases the risk of maternal death through both direct and indirect factors.

INOVASIA Study: A Randomized Open Controlled Trial to Evaluate Pravastatin to Prevent Preeclampsia and Its Effects on sFlt1/PlGF Levels.

OBJECTIVES: This study aimed to evaluate the effect of pravastatin to prevent preeclampsia (PE) in pregnant women at a high risk of developing PE and the maternal and perinatal outcomes and the soluble fms-like tyrosine kinase 1/placental growth factor (sFlt1/PlGF) ratio. STUDY DESIGN: This is an open-labeled randomized controlled trial (RCT), a part of INOVASIA (Indonesia Pravastatin to Prevent Preeclampsia study) trial. Pregnant women at a high risk of developing PE were recruited and randomized into an intervention group (40) and a control group (40). The inclusion criteria consisted of pregnant women with positive clinical risk factor and abnormal uterine artery Doppler examination at 10 to 20 weeks' gestational age. The control group received low dose aspirin (80 mg/day) and calcium (1 g/day), while the intervention group received additional pravastatin (20-mg twice daily) starting from 14 to 20 weeks' gestation until delivery. Research blood samples were collected before the first dose of pravastatin and before delivery. The main outcome was the rate of maternal PE, maternal-perinatal outcomes, and sFlt-1, PlGF, sFlt-1/PlGF ratio, and soluble endoglin (sEng) levels. RESULTS: The rate of PE was (nonsignificantly) lower in the pravastatin group compared with the control group (17.5 vs. 35%). The pravastatin group also had a (nonsignificant) lower rate of severe PE, HELLP (hemolysis, elevated liver enzymes and low platelets) syndrome, acute kidney injury, and severe hypertension. The rate of (iatrogenic) preterm delivery was significantly (p = 0.048) lower in the pravastatin group (n = 4) compared with the controls (n = 12). Neonates in the pravastatin group had significantly higher birth weights (2,931 ± 537 vs. 2,625 ± 872 g; p = 0.006), lower Apgar's scores < 7 (2.5 vs. 27.5%, p = 0.002), composite neonatal morbidity (0 vs. 20%, p = 0.005), and NICU admission rates (0 vs. 15%, p = 0.026). All biomarkers show a significant deterioration in the control group compared with nonsignificant changes in the pravastatin group. CONCLUSION: Pravastatin holds promise in the secondary prevention of PE and placenta-mediated adverse perinatal outcomes by improving the angiogenic imbalance. KEY POINTS: · Prophylactic pravastatin was associated with a significantly lower rate of adverse perinatal outcome.. · The sFlt1/PlGF ratio stabilized in the pravastatin group compared with a deterioration in the control group.. · Pravastatin holds promise in the secondary prevention of PE and placenta-mediated adverse perinatal outcomes..

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.

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.

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.

Maternal and perinatal outcome related to severity of chronic hypertension in pregnancy.

OBJECTIVES: Chronic hypertension in pregnancy is an important cause of maternal and neonatal morbidity and mortality. The aim of this study was to determine the effect of severity of chronic hypertension in pregnancy on maternal and perinatal outcome in an Indonesian population. STUDY DESIGN: This study was performed in Dr Soetomo General Hospital, a tertiary center in East - Java, Indonesia over the period of 2013-2017. Chronic hypertension (CH) was divided using JNC VII criteria, as stage 1 (Blood pressure ≥140/90 mmHg) and Stage 2 (BP > 160/110 mmHg) hypertension. MAIN OUTCOME MEASURES: The primary outcomes were maternal and perinatal outcome. Data was statistically analyzed using Chi-square, Fischer exact test, and Mann-Whitney test (program: SPSS ®23). RESULTS: Over these 5 years, 352 patients were diagnosed with CH. The stage 2 of CH was associated with worse maternal outcome: maternal death (5.6% vs 0.8%; p = 0.016), laboratory values of urinary protein +3 (67% vs 21,5%, p = 0.001) and +4 (12.3% vs 0.4%, p = 0.001), LDH > 600 IU/L (11.3% vs 5.3%, p = 0.04), ALT > 70 IU/L (11.3% vs 4.1%, p = 0.01), AST > 70 IU/L (12.3% vs 5.3%, p = 0.02), BUN > 25 mg/dL (27.4% vs 8.1%, p = 0.001), SK > 1.1 mg/dL (29.2% vs 6.5%, p = 0.001) and Albumin <3 g/dL (65.1% vs 10.2%, p = 0.001), need for ICU admission (76.4% vs 36.6%, p = 0.001), mechanical ventilation (48.1% vs 21.1%, p = 0.001), and occurrence of complications (72.6% vs 57.7%, p = 0.006). Stage 2 CH in pregnancy was associated with an increased risk of maternal death (OR: 7.22; 95% CI: 1.43-36.36; p = 0,016). Stage 2 CH was also associated with worse perinatal outcome, in terms of lower birth weight (1635 ±â€¯863.27 vs 2063.74 ±â€¯935.43, p = 0.001), lower Apgar score (p = 0.001), and number of intra uterine complications such as: IUGR, stillbirth, and placental abruption (27.4% vs 11.8%, p = 0.001). CONCLUSIONS: Stage 2 CH in pregnancy is associated with worse maternal and perinatal outcomes compared with stage 1. Intervention to prevent disease progression to stage 2 before pregnancy may improve maternal and perinatal outcomes during pregnancy.