Performance of machine-learning approach for prediction of pre-eclampsia in a middle-income country.

OBJECTIVE: Pre-eclampsia (PE) is a serious complication of pregnancy associated with maternal and fetal morbidity and mortality. As current prediction models have limitations and may not be applicable in resource-limited settings, we aimed to develop a machine-learning (ML) algorithm that offers a potential solution for developing accurate and efficient first-trimester prediction of PE. METHODS: We conducted a prospective cohort study in Mexico City, Mexico to develop a first-trimester prediction model for preterm PE (pPE) using ML. Maternal characteristics and locally derived multiples of the median (MoM) values for mean arterial pressure, uterine artery pulsatility index and serum placental growth factor were used for variable selection. The dataset was split into training, validation and test sets. An elastic-net method was employed for predictor selection, and model performance was evaluated using area under the receiver-operating-characteristics curve (AUC) and detection rates (DR) at 10% false-positive rates (FPR). RESULTS: The final analysis included 3050 pregnant women, of whom 124 (4.07%) developed PE. The ML model showed good performance, with AUCs of 0.897, 0.963 and 0.778 for pPE, early-onset PE (ePE) and any type of PE (all-PE), respectively. The DRs at 10% FPR were 76.5%, 88.2% and 50.1% for pPE, ePE and all-PE, respectively. CONCLUSIONS: Our ML model demonstrated high accuracy in predicting pPE and ePE using first-trimester maternal characteristics and locally derived MoM. The model may provide an efficient and accessible tool for early prediction of PE, facilitating timely intervention and improved maternal and fetal outcome. © 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Eficiencia de un enfoque de aprendizaje automático para la predicción de la preeclampsia en un país de ingresos medios OBJETIVO: La preeclampsia (PE) es una complicación grave del embarazo asociada a morbilidad y mortalidad materna y del feto. Dado que los modelos de predicción actuales tienen limitaciones y pueden no ser aplicables en situaciones con recursos limitados, se propuso desarrollar un algoritmo de aprendizaje automático (AA) que ofrezca una solución con potencial para desarrollar una predicción precisa y eficiente de la PE en el primer trimestre. MÉTODOS: Se realizó un estudio de cohorte prospectivo en Ciudad de México para desarrollar un modelo de predicción de la PE pretérmino (PEp) en el primer trimestre utilizando AA. Para la selección de variables se utilizaron las características maternas y los múltiplos de la mediana (MdM) obtenidos localmente para la presión arterial media, el índice de pulsatilidad de la arteria uterina y el factor de crecimiento placentario sérico. El conjunto de datos se dividió en subconjuntos de datos de entrenamiento, de validación y de test estadístico. Se empleó un método de red elástica para la selección de predictores, y el rendimiento del modelo se evaluó mediante el área bajo la curva de características operativas del receptor (ABC) y las tasas de detección (TD) con tasas de falsos positivos (TFP) del 10%. RESULTADOS: El análisis final incluyó a 3050 mujeres embarazadas, de las cuales 124 (4,07%) desarrollaron PE. El modelo de AA mostró una buena eficiencia, con un ABC de 0,897, 0,963 y 0,778 para la PEp, la PE de aparición temprana (PEat) y cualquier tipo de PE (todas las PE), respectivamente. Las TD con TFP del 10% fueron del 76,5%, 88,2% y 50,1% para la PEp, PEat y todas las PE, respectivamente. CONCLUSIONES: Nuestro modelo de AA demostró una alta precisión en la predicción de la PEp y la PEat utilizando características maternas del primer trimestre y MdM calculados localmente. El modelo puede proporcionar una herramienta eficiente y accesible para la predicción temprana de la PE, facilitando la intervención oportuna y la mejora de los resultados maternos y del feto.

Comorbidity, poverty and social vulnerability as risk factors for mortality in pregnant women with confirmed SARS-CoV-2 infection: analysis of 13 062 positive pregnancies including 176 maternal deaths in Mexico.

OBJECTIVE: Mortality in pregnancy due to coronavirus disease 2019 (COVID-19) is a current health priority in developing countries. Identification of clinical and sociodemographic risk factors related to mortality in pregnant women with COVID-19 could guide public policy and encourage such women to accept vaccination. We aimed to evaluate the association of comorbidities and socioeconomic determinants with COVID-19-related mortality and severe disease in pregnant women in Mexico. METHODS: This is an ongoing nationwide prospective cohort study that includes all pregnant women with a positive reverse-transcription quantitative polymerase chain reaction result for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) from the Mexican National Registry of Coronavirus. The primary outcome was maternal death due to COVID-19. The association of comorbidities and socioeconomic characteristics with maternal death was explored using a log-binomial regression model adjusted for possible confounders. RESULTS: There were 176 (1.35%) maternal deaths due to COVID-19 among 13 062 consecutive SARS-CoV-2-positive pregnant women. Maternal age, as a continuous (adjusted relative risk (aRR), 1.08 (95% CI, 1.05-1.10)) or categorical variable, was associated with maternal death due to COVID-19; women aged 35-39 years (aRR, 3.16 (95% CI, 2.34-4.26)) or 40 years or older (aRR, 4.07 (95% CI, 2.65-6.25)) had a higher risk for mortality, as compared with those aged < 35 years. Other clinical risk factors associated with maternal mortality were pre-existing diabetes (aRR, 2.66 (95% CI, 1.65-4.27)), chronic hypertension (aRR, 1.75 (95% CI, 1.02-3.00)) and obesity (aRR, 2.15 (95% CI, 1.46-3.17)). Very high social vulnerability (aRR, 1.88 (95% CI, 1.26-2.80)) and high social vulnerability (aRR, 1.49 (95% CI, 1.04-2.13)) were associated with an increased risk of maternal mortality, while very low social vulnerability was associated with a reduced risk (aRR, 0.47 (95% CI, 0.30-0.73)). Being poor or extremely poor were also risk factors for maternal mortality (aRR, 1.53 (95% CI, 1.09-2.15) and aRR, 1.83 (95% CI, 1.32-2.53), respectively). CONCLUSION: This study, which comprises the largest prospective consecutive cohort of pregnant women with COVID-19 to date, has confirmed that advanced maternal age, pre-existing diabetes, chronic hypertension, obesity, high social vulnerability and low socioeconomic status are risk factors for COVID-19-related maternal mortality. © 2021 International Society of Ultrasound in Obstetrics and Gynecology.

Increased levels of soluble fms-like tyrosine kinase-1 are associated with adverse outcome in pregnant women with COVID-19.

OBJECTIVE: In addition to the lungs, the placenta and the endothelium can be affected by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Soluble fms-like tyrosine kinase-1 (sFlt-1) and placental growth factor (PlGF) are markers of endothelial dysfunction and could potentially serve as predictors of severe coronavirus disease 2019 (COVID-19). We aimed to investigate the association of serum concentrations of sFlt-1 and PlGF with the severity of COVID-19 in pregnancy. METHODS: This was a prospective cohort study carried out in a tertiary care hospital in Mexico City, Mexico. Symptomatic pregnant women with a positive reverse-transcription quantitative polymerase chain reaction test for SARS-CoV-2 infection who fulfilled the criteria for hospitalization were included. The primary outcome was severe pneumonia due to COVID-19. Secondary outcomes were intensive care unit (ICU) admission, viral sepsis and maternal death. sFlt-1 levels were expressed as multiples of the median (MoM). The association between sFlt-1 and each adverse outcome was explored by logistic regression analysis, adjusted for gestational age for outcomes occurring in more than five patients, and the predictive performance was assessed by receiver-operating-characteristics-curve analysis. RESULTS: Among 113 pregnant women with COVID-19, higher sFlt-1 MoM was associated with an increased probability of severe pneumonia (adjusted odds ratio (aOR), 1.817 (95% CI, 1.365-2.418)), ICU admission (aOR, 2.195 (95% CI, 1.582-3.047)), viral sepsis (aOR, 2.318 (95% CI, 1.407-3.820)) and maternal death (unadjusted OR, 5.504 (95% CI, 1.079-28.076)). At a 10% false-positive rate, sFlt-1 MoM had detection rates of 45.2%, 66.7%, 83.3% and 100% for severe COVID-19 pneumonia, ICU admission, viral sepsis and maternal death, respectively. PlGF values were similar between women with severe and those with non-severe COVID-19 pneumonia. CONCLUSION: sFlt-1 MoM is higher in pregnant women with severe COVID-19 and has the capability to predict serious adverse pregnancy events, such as severe pneumonia, ICU admission, viral sepsis and maternal death. © 2021 International Society of Ultrasound in Obstetrics and Gynecology.

Evidence of possible SARS-CoV-2 vertical transmission according to World Health Organization criteria in asymptomatic pregnant women.

OBJECTIVE: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vertical transmission has been investigated extensively. Recently, the World Health Organization (WHO) published strict criteria to classify the timing of mother-to-child transmission of SARS-CoV-2 into different categories. The aim of this study was to investigate the possibility of vertical transmission in asymptomatic SARS-CoV-2-positive women. METHODS: Pregnant women attending for delivery at a perinatology center in Mexico City, Mexico, who had a SARS-CoV-2-positive nasopharyngeal swab 24-48 h before delivery, were asymptomatic at the time of the test and had an obstetric indication for Cesarean section were eligible for inclusion in this study. Amniotic fluid was collected during Cesarean delivery, and neonatal oral and rectal swabs were collected at birth and at 24 h after birth. SARS-CoV-2 detection was carried out using real-time reverse-transcription polymerase chain reaction in all samples. Relevant medical information was retrieved from clinical records. The WHO criteria for classifying the timing of mother-to-child transmission of SARS-CoV-2 were applied to the study population. RESULTS: Forty-two SARS-CoV-2-positive asymptomatic pregnant women fulfilled the inclusion criteria. Twenty-five (59%) women developed mild disease after discharge. Neonatal death occurred in three (7%) cases, of which one had a positive SARS-CoV-2 test at birth and none had coronavirus disease 2019-related symptoms. There were five (12%) cases with strong evidence of intrauterine transmission of SARS-CoV-2, according to the WHO criteria, as amniotic fluid samples and neonatal samples at birth and at 24 h after birth were positive for SARS-CoV-2. Our results also showed that 40-60% of infected neonates would have been undetected if only one swab (oral or rectal) was tested. CONCLUSION: This study contributes evidence to reinforce the potential for vertical transmission of SARS-CoV-2 even in asymptomatic women and highlights the importance of testing more than one neonatal sample in order to increase the detection rate of SARS-CoV-2 in affected cases. © 2021 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Prolactin selectively inhibits the LPS-induced chemokine secretion of human foetal membranes.

Background: Inflammation is a condition that jeopardizes the continuity of pregnancy because it increases the secretion of chemokines that favor the migration of leukocytes from maternal and fetal circulations to the cervix, placenta, and the chorioamniotic membranes. During pregnancy, the level of prolactin (PRL) in the amniotic fluid is high; there is evidence to suggest that PRL contributes to maintain a privileged immune environment in the amniotic cavity. We test the effect of prolactin on the secretion profile of chemokines in human fetal membranes.Methods: Nine fetal membranes collected from healthy nonlabouring cesarean deliveries at term. We placed whole membrane explants in a two-chamber culture system. Choriodecidua and amniotic chambers were pretreated with 250, 500, 1000, or 4000 ng/ml of PRL for 24 h, then choriodecidua was cotreated with 500 ng/ml of lipopolysaccharide (LPS) and PRL for 24 h. We used ELISA to measure secreted levels of four chemokines (RANTES, monocyte chemoattractant protein 1 (MCP-1), MIP-1α, and IL-8) in both amnion and choriodecidua regions.Results: In comparison with basal conditions, LPS treatment induced significantly higher secretion of RANTES, MCP-1, and MIP-1α, but not of IL-8. RANTES was mainly produced by choriodecidua and cotreatment with PRL significantly decreased its LPS-induced secretion. MCP-1 was primarily produced by the amnion and its secretion was only inhibited by 4000 ng/ml of PRL. Both membrane regions produced MIP-1α, which was significantly inhibited at 1000 and 4000 ng/ml PRL concentrations. IL-8 showed no significant changes regardless of PRL concentration.Conclusion: PRL inhibits the differential secretion of proinflammatory chemokines by human fetal membranes.

Progesterone suppresses the lipopolysaccharide-induced pro-inflammatory response in primary mononuclear cells isolated from human placental blood.

Progesterone is an essential hormone that induces deep immune adaptations favoring pregnancy maintenance. We aimed at evaluating the effects of progesterone on the synthesis of pro- and anti-inflammatory cytokines by mononuclear cells isolated from human placental blood stimulated with lipopolysaccharide, emulating an infection-inflammation environment. Mononuclear cells isolated form human placental blood were obtained from nine women undergoing elective cesarean delivery at term (not in labor), isolated by density gradient sedimentation, cultured and co-stimulated with lipopolysaccharide (500 ng/ml) from Escherichia coli in the presence or not of progesterone (0.01, 0.1, or 1.0 µM) for 24 h. Culture supernatants were assayed for pro-inflammatory (IL-1ß, TNFα, IL-6), anti-inflammatory (IL-10) cytokines, chemokines (IL-8, MIP-1α) and total MMP-9 by ELISA. In comparison with basal conditions, lipopolysaccharide treatment induced IL-1ß, TNFα, IL-6, IL-8, MIP-1α, and MMP-9 synthesis. lipopolysaccharide co-treatment with progesterone significantly decreased the bacterial endotoxin-induced IL-1ß, TNF-α, IL-6, IL-8, and MIP-1α secretion. In contrast, co-treatment with progesterone increased the level of IL-10 secreted to the culture medium. The present results support the concept that progesterone can modulate--partially--the inflammatory response of professional immune cells isolated from placental blood. Therefore, progesterone might be part of the natural compensatory mechanism that limits the cytotoxic effects associated with an intrauterine infection process during gestation.

[The effect of corifollitropin alfa on in vitro fertilization-ICSI patients with previous failure with an FSH/HMG protocol: Preliminary report in Mexico]. / Efecto de la corifolitropina alfa en pacientes de fertilización in vitro-ICSI con falla previa en un protocolo de FSH/HMG: experiencia preliminar en México.

BACKGROUND: The daily application of drugs, often in high doses, is a factor of stress for the infertile couple. During the last decade corifollitropin alpha has allowed a friendlier scheme comparable to traditional protocols (rFSH-HMG) results. OBJECTIVE: To compare the results of corifollitropin alpha in patients with a previous cycle of IVF-ICSI with traditional scheme ovarian stimulation. MATERIALS AND METHODS: Observational, retrospective cohort study type that infertile couples were included. RESULTS: No significant differences in the dose used HFRS (2023U/ total ± 712 vs 636 U/total ± 307) and serum estradiol day shooting HGCr (1972 pg/dL vs 1107 ± 1152 pg/dL ± 775). A higher pregnancy rate was found corifollitropin alpha perhaps because it was a second attempt at in vitro fertilization. CONCLUSIONS: Reproductive outcomes in a cycle of ovarian stimulation with corifollitropin are comparable with the results of a traditional ovarian stimulation cycle. It is important to broaden the experience of the drug indication in Mexican patients.

In vitro progesterone modulation on bacterial endotoxin-induced production of IL-1ß, TNFα, IL-6, IL-8, IL-10, MIP-1α, and MMP-9 in pre-labor human term placenta.

BACKGROUND: During human pregnancy, infection/inflammation represents an important factor that increases the risk of developing preterm labor. The purpose of this study was to determine if pre-treatment with progesterone has an immunomodulatory effect on human placenta production of endotoxin-induced inflammation and degradation of extracellular matrix markers. METHODS: Placentas were obtained under sterile conditions from pregnancies delivered at term before the onset of labor by cesarean section. Explants from central cotyledons of 10 human placentas were pre-treated with different concentrations of progesterone (0.01, 01, 1.0 µM) and then stimulated with 1000 ng/mL of LPS of Escherichia coli. Cytokines TNFα, IL-1ß, IL-6, IL-8, MIP-1α, IL-10 concentrations in the culture medium were then measured by specific ELISA. Secretion profile of MMP-9 was evaluated by ELISA and zymogram. Statistical differences were determined by one-way ANOVA followed by the appropriate ad hoc test; P < 0.05 was considered statistically significant. RESULTS: In comparison to the explants incubated with vehicle, the LPS treatment led to a significant increase in the level of all cytokines. In comparison to the explants treated only with LPS, pre-treatment with 0.01-1.0 µM progesterone significantly blunted (73, 56, 56, 75, 25, 48 %) the secretion of TNF-α, IL-1ß, IL-6, IL-8, MIP-1α, IL-10, respectively. The MMP-9 induced by LPS treatment was inhibited only with the highest concentration of progesterone. Mifepristone (RU486) blocked the immunosuppressive effect of progesterone. CONCLUSIONS: The present results support the concept that progesterone could be part of the compensatory mechanism that limits the inflammation-induced cytotoxic effects associated with an infection process during gestation.

Evidence of an immunosuppressive effect of progesterone upon in vitro secretion of proinflammatory and prodegradative factors in a model of choriodecidual infection.

OBJECTIVE: To evaluate whether progesterone (P4) is able to modulate the secretion of tumour necrosis factor α (TNF-α), interleukin-1ß (IL-1ß), IL-6, IL-8, IL-10 and matrix metalloproteinase-9 (MMP-9) after choriodecidual stimulation with lipopolysaccharide (LPS). DESIGN: Chorioamnionitis-elicited preterm delivery is associated with an uncontrolled secretion of proinflammatory cytokines that may induce MMPs, which modify the fine immunological and structural equilibrium at the fetal-maternal interface. SETTING: Instituto Nacional de Perinatología 'Isidro Espinosa de los Reyes', Mexico City. SAMPLE: Twelve human fetal membranes at term from healthy patients were placed in a two-chamber culture system. METHODS: Choriodecidual and amniotic regions were preincubated with 1.0, 0.1, or 0.01 µmol/l P4 for 24 hours; after which the choriodecidual region was costimulated with 1000 ng/ml of LPS for 24 hours. MAIN OUTCOME MEASURES: Descriptive statistics were obtained for each variable. Data distribution was tested for normality using Kolmogorov-Smirnoff and Shapiro-Wilk tests. When distribution was normal, Student's t test was used to analyse for differences among groups. Mann-Whitney's U test was used when data were not normally distributed. RESULTS: Pretreatment with 1.0 µmol/l P4 significantly blunted the secretion of TNF-α, IL-1ß, IL-6, IL-8 and IL-10. MMP-9 was inhibited with 0.1 µmol/l P4. Mifepristone (RU486) blocked the immunosuppressive effect of P4, suggesting a P4 effect mediated by its receptor. CONCLUSION: These results offer evidence to support the concept that P4 can protect the fetal-placental unit through a compensatory mechanism that partially limits the secretion of proinflammatory and prodegradative modulators.

PP134. l-Arginine supplementation induces the expression of genes related to antioxidant defense in cultures of human vascular endothelial cells: Protective role for preeclampsia.

INTRODUCTION: Recently, it has been proposed that supplementation with l-Arginine reduces the incidence of preeclampsia in high risk women, but the molecular mechanisms involved in the protective effect need to be determined. In addition, a critical role of l-Arginine in endothelial cell survival during oxidative stress, and the participation of neutrophils in the induction of oxidative stress during preeclampsia have been suggested. OBJECTIVES: To address if supplementation with l-arginine provides antioxidant defense in human vascular endothelial cells. METHODS: Human vascular endothelial cells (HUVECs) were isolated from umbilical cord veins obtained from healthy women underwent cesarean sections at term, with no evidence of hypertension disorders through the pregnancy. HUVECs were cultured in EndoGro media with LS supplement kit and 1% antibiotic with (n=10) or without 200uM l-Arginine (n=10). Confluent HUVECs were stimulated with neutrophils activated with 50umol/L arachidonic acid (1:16 ratio of neutrophil/cells). After incubation, cells were rinsed in PBS and harvested for RNA and protein extraction. Reverse transcription was performed using the RT(2) First Strand kit, and expression gene profiling was generated using the RT(2) Profiler PCR Array Human Oxidative Stress and Antioxidant Defense that includes the expression profile of 84 genes related to the oxidative pathway. Expression results were analyzed with the RT(2) Profiler PCR Array Data Analysis Template v3.0 and two different lists of fold change in gene expression were generated: (1) HUVEC+neutrophils vs HUVEC+l-Arginine + neutrophils and (2) HUVEC vs HUVEC+neutrophils. Validation of the expression assays was performed using western blots or ELISAS for proteins expressed by selected genes. RESULTS: Fold up- or down gene regulation are shown in Table 1. Forty six genes involved in oxidative stress defense were significantly up-regulated in HUVECs supplemented with l-arginine when were exposed to neutrophils. Interestingly, almost the same genes were down-regulated in non-supplemented HUVECs after neutrophil exposure. CONCLUSION: Supplementation with l-Arginine upregulates the expression of genes related to antioxidant defense in primary cultures of endothelial cells. This finding provides a novel insight about the molecular mechanisms involved in the protective role of l-Arginine during preeclampsia.

Fetal membranes exhibit selective leukocyte chemotaxic activity during human labor.

One of the characteristics of the labor process in women is leukocyte recruitment into reproductive tissues. These migrating cells may play a role in the induction of functional and biochemical changes associated with the rupture of fetal membranes during labor. This study was undertaken to assess whether human fetal membranes induce leukocyte chemotaxis during labor as well as to identify and characterize leukocyte chemoattractants secreted by these tissues. Leukocyte chemotactic activity of fetal membrane extracts obtained from women with full-term pregnancies and spontaneous active labor was compared with extracts from women without labor. The number and phenotype of attracted leukocytes were analyzed by flow cytometry. Chemokines were quantified using a Multiplex system and were identified by immunofluorescence histochemistry. Although all tested extracts induced chemotaxis of leukocytes, those prepared from women undergoing labor induced higher responses. Polymorphonuclear leukocyte chemotaxis increased approximately three-fold in response to extract from fetal membranes with labor. The same extracts elicited a significant increase in attracted monocytes (36-fold) as well as T and B lymphocytes, and NK cells (all five-fold) when compared to extracts from women without labor. This enhanced chemotactic activity was associated with the presence of IL-8, MCP-1, IP-10 and MIP-1alpha. We conclude that fetal membrane extracts obtained from women during labor exhibit selective chemotaxis for specific leukocyte subpopulations in vitro. This process may contribute to a microenvironment composed of specific leukocytes that promotes and amplifies biochemical changes in the fetal membranes during labor.

Identification of a calcium-dependent matrix metalloproteinase complex in rat chorioallantoid membranes during labour.

The induction of the expression of matrix metalloproteinases (MMPs) and their extracellular activation are key processes in connective tissue degradation in the chorioallantoid membrane during rat labour. However, the regulatory mechanisms remain largely unknown. Here, we report the identification of a calcium-dependent high molecular weight complex composed of MMP-9, MMP-3, MMP-2, tissue inhibitor of metalloproteinase 1 (TIMP-1) and TIMP-2, identified by zymography and western blotting. Molecular sieve chromatography confirmed the presence of a complex of MMPs and TIMPs with an exclusion volume >670 kDa. Differential scanning calorimetry of the complex confirmed the existence of a macromolecular complex that unfolds with a broad transition; it is denatured over a wide range of temperatures and has a T(m) of 72 degrees C in the presence of Ca(2+). When denatured in the absence of Ca(2+), there were at least eight transitions with T(m)s that corresponded to pro-MMP-9, MMP-9, pro-MMP-3, MMP-3, pro-MMP-2, MMP-2, TIMP-1 and TIMP-2. Co-localization of the same molecular components was demonstrated by confocal microscopy using cell-depleted chorioallantoid membranes. The assembly and disassembly of the complex can be reproduced at physiological concentrations of Ca(2+). This complex provides a potential mechanism for the enzymatic regulation of MMPs, which may participate in connective tissue degradation leading to the rupture of the fetal membranes during labour.