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Objective: To assess whether women with a genetic predisposition to medical conditions known to increase pre‐eclampsia risk have an increased risk of pre‐eclampsia in pregnancy. Design: Case–control study. Setting and population: Pre‐eclampsia cases (n = 498) and controls (n = 1864) in women of European ancestry from five US sites genotyped on a cardiovascular gene‐centric array. Methods: Significant single‐nucleotide polymorphisms (SNPs) from 21 traits in seven disease categories (cardiovascular, inflammatory/autoimmune, insulin resistance, liver, obesity, renal and thrombophilia) with published genome‐wide association studies (GWAS) were used to create a genetic instrument for each trait. Multivariable logistic regression was used to test the association of each continuous scaled genetic instrument with pre‐eclampsia. Odds of pre‐eclampsia were compared across quartiles of the genetic instrument and evaluated for significance. Main outcome measures: Genetic predisposition to medical conditions and relationship with pre‐eclampsia. Results: An increasing burden of risk alleles for elevated diastolic blood pressure (DBP) and increased body mass index (BMI) were associated with an increased risk of pre‐eclampsia (DBP, overall OR 1.11, 95% CI 1.01–1.21, P = 0.025; BMI, OR 1.10, 95% CI 1.00–1.20, P = 0.042), whereas alleles associated with elevated alkaline phosphatase (ALP) were protective (OR 0.89, 95% CI 0.82–0.97, P = 0.008), driven primarily by pleiotropic effects of variants in the FADS gene region. The effect of DBP genetic loci was even greater in early‐onset pre‐eclampsia cases (at <34 weeks of gestation, OR 1.30, 95% CI 1.08–1.56, P = 0.005). For other traits, there was no evidence of an association. Conclusions: These results suggest that the underlying genetic architecture of pre‐eclampsia may be shared with other disorders, specifically hypertension and obesity. A genetic predisposition to increased diastolic blood pressure and obesity increases the risk of pre‐eclampsia. A genetic predisposition to increased diastolic blood pressure and obesity increases the risk of pre‐eclampsia. [ABSTRACT FROM AUTHOR]

Background: Major depressive disorder and the use of serotonin reuptake inhibitors (SRIs) in pregnancy have been associated with preterm birth. Studies that have attempted to separate effects of illness from treatment have been inconclusive. We sought to explore the separate effects of SRI use and major depressive episodes in pregnancy on risk of preterm birth.Methods: We conducted a prospective cohort study of 2793 pregnant women, oversampled for a recent episode of major depression or use of an SRI. We extracted data on birth outcomes from hospital charts and used binary logistic regression to model preterm birth (<37 weeks' gestation). We used ordered logistic regression to model early (<34 weeks' gestation) or late (34-36 weeks) preterm birth, and we used nominal logistic regression to model preterm birth antecedents (spontaneous preterm labor/preterm premature rupture of membranes/preterm for medical indications/term).Results: Use of an SRI, both with (odds ratio = 2.1 [95% confidence interval = 1.0-4.6]) and without (1.6 [1.0-2.5]) a major depressive episode, was associated with preterm birth. A major depressive episode without SRI use (1.2 [0.68-2.1]) had no clear effect on preterm birth risk. None of these exposures was associated with early preterm birth. Use of SRIs in pregnancy was associated with increases in spontaneous but not medically indicated preterm birth.Conclusions: SRI use increased risk of preterm birth. Although the effect of a major depressive episode alone was unclear, symptomatic women undergoing antidepressant treatment had elevated risk. [ABSTRACT FROM AUTHOR]

New technology is in the wings to help detect preterm premature rupture of membranes, improve ultrasound imaging, provide noninvasive prenatal genetic screening, and speed up the diagnosis of intra-amniotic infection. [ABSTRACT FROM AUTHOR]

Postterm birth seems to get a lot less attention than preterm birth when clinicians are discussing the risks of complications and death. But unlike babies born too soon, timely delivery can almost entirely prevent the risks--including stillbirth--linked with prolonged pregnancy. [ABSTRACT FROM AUTHOR]

To many patients, tattoos and nipple rings are art. To clinicians, they're a potential source of infections, airway obstruction, keloids, granulomas, and allergic reactions. This overview will help you assess patients' risks. [ABSTRACT FROM AUTHOR]

OBJECTIVE: This purpose of this study was to investigate the association between vaginal microflora, concentrations of interleukin-1beta (IL-1beta), and its natural receptor antagonist (IL-1ra) in the cervicovaginal discharge, and spontaneous preterm birth.Study design Vaginal samples collected at 18 to 22 weeks' gestation from 207 women were analyzed to study qualitative and quantitative microbiologic aspects of vaginal microflora and IL-1beta and IL-1ra concentrations. RESULTS: Among women colonized with anaerobic Gram-negative rods and/or Gardnerella vaginalis, an elevated IL-1beta concentration, or a diminished IL-1ra:IL-1beta ratio were associated with preterm delivery. A cut-off IL-1ra:IL-1beta ratio of <8632:1 optimally discriminated the subjects with subsequent spontaneous preterm deliveries from subjects who delivered at term, with a sensitivity of 78%, specificity of 51%, positive predictive value of 21%, and negative predictive value of 95%. CONCLUSION: A disproportionate increase in IL-1beta over IL-1ra in response to vaginal colonization with anaerobic Gram-negative rods and/or G. vaginalis at 18 to 22 weeks' gestation is associated with spontaneous preterm delivery. [ABSTRACT FROM AUTHOR]

Although controversial, delivery is usually recommended for all women with severe preeclampsia--regardless of gestational age. But premature delivery can pose a major threat to the periviable fetus. When is it appropriate to expectantly manage severe preeclampsia? [ABSTRACT FROM AUTHOR]

While cervical incompetence is an important contributor to many preterm births before 28 weeks, cerclage is not always the appropriate remedy. Candidates should be selected with care and the procedure contemplated only after consideration of benefits and risks to both mother and fetus and in-depth patient counseling. [ABSTRACT FROM AUTHOR]

The author discusses a study about the use of progesterone in the treatment of preterm birth (PTB). The author highlights the results of the study which revealed that there was no significant difference between progesterone supplemented and placebo groups. The author notes the strengths and weaknesses of the randomized controlled trial (RCT).

Abstract Background The onset of birth in humans, like other apes, differs from non-primate mammals in its endocrine physiology. We hypothesize that higher primate-specific gene evolution may lead to these differences and target genes involved in human preterm birth, an area of global health significance. Methods We performed a comparative genomics screen of highly conserved noncoding elements and identified PLA2G4C, a phospholipase A isoform involved in prostaglandin biosynthesis as human accelerated. To examine whether this gene demonstrating primate-specific evolution was associated with birth timing, we genotyped and analyzed 8 common single nucleotide polymorphisms (SNPs) in PLA2G4C in US Hispanic (n = 73 preterm, 292 control), US White (n = 147 preterm, 157 control) and US Black (n = 79 preterm, 166 control) mothers. Results Detailed structural and phylogenic analysis of PLA2G4C suggested a short genomic element within the gene duplicated from a paralogous highly conserved element on chromosome 1 specifically in primates. SNPs rs8110925 and rs2307276 in US Hispanics and rs11564620 in US Whites were significant after correcting for multiple tests (p < 0.006). Additionally, rs11564620 (Thr360Pro) was associated with increased metabolite levels of the prostaglandin thromboxane in healthy individuals (p = 0.02), suggesting this variant may affect PLA2G4C activity. Conclusions Our findings suggest that variation in PLA2G4C may influence preterm birth risk by increasing levels of prostaglandins, which are known to regulate labor.

Background: Angiogenic imbalances, characterized by an excess of antiangiogenic factors (soluble fms-like tyrosine kinase 1) and reduced angiogenic factors (vascular endothelial growth factor and placental growth factor), contribute to the mechanisms of disease in preeclampsia. The ratio of soluble fms-like tyrosine kinase 1 to placental growth factor has been used as a biomarker for preeclampsia, but the cutoff values may vary with gestational age and assay platform., Objective: This study aimed to compare multiples of the median of the maternal plasma soluble fms-like tyrosine kinase 1 to placental growth factor ratio, soluble fms-like tyrosine kinase 1, placental growth factor, and conventional clinical and laboratory values in their ability to predict preeclampsia with severe features., Study Design: We conducted a cohort study across 18 United States centers involving hospitalized individuals with hypertension between 23 and 35 weeks' gestation. Receiver operating characteristic curve analyses of maternal plasma biomarkers, highest systolic or diastolic blood pressures, and laboratory values at enrollment were performed for the prediction of preeclampsia with severe features. The areas under the curve were compared, and quasi-Poisson regression models were fitted to estimate relative risks. The primary outcome was preeclampsia with severe features within 2 weeks of enrollment. Secondary outcomes were a composite of severe adverse maternal outcomes (elevated liver enzymes, low platelets count, placental abruption, eclampsia, disseminated intravascular coagulation, and pulmonary edema) and a composite of severe adverse perinatal outcomes (birth weight below the third percentile, very preterm birth [<32 weeks' gestation], and fetal or neonatal death)., Results: Of the 543 individuals included in the study, preeclampsia with severe features within 2 weeks was observed in 33.1% (n=180) of them. A receiver operating characteristic curve-derived cutoff of 11.5 multiples of the median for the soluble fms-like tyrosine kinase 1 to placental growth factor plasma ratio provided good sensitivity (90.6%), specificity (76.9%), positive predictive value (66.0%), negative predictive value (94.3%), positive likelihood ratio (3.91), negative likelihood ratio (0.12), and accuracy (81.4%) for preeclampsia with severe features within 2 weeks. This cutoff was used to compare test positive cases (≥ cutoff) and test negative cases (< cutoff). Preeclampsia with severe features (66.0% vs 5.7%; P<.001) and composites of severe adverse maternal (8.11% vs 2.7%; P=.006) or perinatal (41.3% vs 10.14%; P=.001) outcomes within 2 weeks were more frequent in test positive cases than in test negative cases. A soluble fms-like tyrosine kinase 1 to placental growth factor plasma ratio ≥11.5 multiples of the median was independently associated with preeclampsia with severe features (adjusted incidence rate ratio, 9.08; 95% confidence interval, 6.11-14.06; P<.001) and a composite of severe adverse perinatal outcomes (adjusted incidence rate ratio, 9.42; 95% confidence interval, 6.36-14.53; P<.001) but not with a composite of severe adverse maternal outcomes (adjusted incidence rate ratio, 2.20; 95% confidence interval, 0.95-5.54; P=.08). The area under the curve for the soluble fms-like tyrosine kinase 1 to placental growth factor plasma ratio in multiples of the median (0.91; 95% confidence interval, 0.89-0.94) for preeclampsia with severe features within 2 weeks was significantly higher (P<.001 for all comparisons) than either plasma biomarker alone or any other parameter with the exception of absolute soluble fms-like tyrosine kinase 1 to placental growth factor plasma ratio values., Conclusion: A soluble fms-like tyrosine kinase 1 to placental growth factor plasma ratio ≥11.5 multiples of the mean among hospitalized patients with hypertension between 23 and 35 week's gestation predicts progression to preeclampsia with severe features and severe adverse perinatal outcomes within 2 weeks., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Preterm birth remains a worldwide health concern due to ongoing challenges in prediction and prevention. Current predictors are limited by poor performance, need for invasive sampling, and an inability to identify patients in a timely fashion to allow for effective intervention. The multiple etiologies of preterm birth often have an inflammatory component. Thus, a deeper understanding of the inflammatory mechanisms involved in preterm birth may provide opportunities to identify new predictors of preterm birth. This review will discuss the multiple etiologies of preterm birth, their links to inflammation, current predictors available, and new directions for the field.

Expression quantitative trait loci (eQTL) analysis measures the contribution of genetic variation in gene expression on complex traits. Although this methodology has been used to examine gene regulation in numerous human tissues, eQTL research in solid tissues is relatively lacking. We conducted eQTL analysis on placentas collected from an East Asian population in an effort to identify gene regulatory mechanisms in this tissue. Placentas (n = 102) were collected at the time of cesarean delivery. mRNA was extracted, sequenced with NGS, and compared with matched maternal and fetal DNA arrays performed using maternal and neonatal cord blood. Linear regression modeling was performed using tensorQTL. Fine-mapping along with epigenomic annotation was used to select putative functional variants. We identified 2,703 coding genes that contained at least one eQTL with statistical significance (false discovery rate <0.05). After fine-mapping, we found 108 previously unreported eQTL variants with posterior inclusion probability >0.1. Of these, 19% were located in genomic regions with evidence from public placental epigenome suggesting that they may be functionally relevant. For example, variant rs28379289 located in the placenta-specific regulatory region changes the binding affinity of transcription factor leading to higher expression of LGALS3, which is known to affect placental function. This study expands the knowledge base of regulatory elements within the human placenta and identifies 108 previously unreported placenta eQTL signals, which are listed in our publicly available GMI eQTL database. Further studies are needed to identify and characterize genetic regulatory mechanisms that affect placental function in normal pregnancy and placenta-related diseases., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024. Published by Elsevier Inc.)

Sepsis caused by bloodstream infection (BSI) is a major healthcare burden and a leading cause of morbidity and mortality worldwide. Timely diagnosis is critical to optimize clinical outcome, as mortality rates rise every hour treatment is delayed. Blood culture remains the "gold standard" for diagnosis but is limited by its long turnaround time (1-7 days depending on the organism) and its potential to provide false-negative results due to interference by antimicrobial therapy or the presence of mixed (i.e., polymicrobial) infections. In this paper, we evaluated the performance of resistance and pathogen ID/BSI, a direct-from-specimen molecular assay. To reduce the false-positivity rate common with molecular methods, this assay isolates and detects genomic material only from viable microorganisms in the blood by incorporating a novel precursor step to selectively lyse host and non-viable microbial cells and remove cell-free genomic material prior to lysis and analysis of microbial cells. Here, we demonstrate that the assay is free of interference from host immune cells and common antimicrobial agents at elevated concentrations. We also demonstrate the accuracy of this technology in a prospective cohort pilot study of individuals with known sepsis/BSI status, including samples from both positive and negative individuals., Importance: Blood culture remains the "gold standard" for the diagnosis of sepsis/bloodstream infection (BSI) but has many limitations which may lead to a delay in appropriate and accurate treatment in patients. Molecular diagnostic methods have the potential for markedly improving the management of such patients through faster turnaround times and increased accuracy. But molecular diagnostic methods have not been widely adopted for the identification of BSIs. By incorporating a precursor step of selective lysis of host and non-viable microorganisms, our resistance and pathogen ID (RaPID)/BSI molecular assay addresses many limitations of blood culture and other molecular assay. The RaPID/BSI assay has an approximate turnaround time of 4 hours, thereby significantly reducing the time to appropriate and accurate diagnosis of causative microorganisms in such patients. The short turnaround time also allows for close to real-time tracking of pathogenic clearance of microorganisms from the blood of these patients or if a change of antimicrobial regimen is required. Thus, the RaPID/BSI molecular assay helps with optimization of antimicrobial stewardship; prompt and accurate diagnosis of sepsis/BSI could help target timely treatment and reduce mortality and morbidity in such patients., Competing Interests: A.S. is an employee of HelixBind. A.R.R. is an advisor to HelixBind.

Background: Ferroptosis plays a key role in placental development and physiology, and abnormal ferroptosis has been implicated in trophoblast injury leading to preeclampsia (PE). We hypothesize that leukocytes isolated from PE exhibit increased ferroptosis and that extracellular vesicles contain long non-coding (lnc) RNA/mRNAs that modulate oxidative stress and iron toxicity in vascular endothelial cells., Methods: We measured the expression of key regulators of ferroptosis in leukocytes and extracellular vesicles as well as circulating biomarkers of iron homeostasis and oxidative stress in plasma from women with/without PE at different timepoints during pregnancy. For markers that were dysregulated, we assessed their temporal correlation with established markers of disease activity and marker of endothelial activation. For markers dysregulated in early pregnancy, we assessed their ability to predict the development of PE., Results: We found decreased lncRNA/mRNAs in leukocytes, but not extracellular vesicles, in PE that may modulate oxidative stress and iron toxicity. This decrease in anti-ferroptotic markers does not appear to be related to maternal disease activity or plasma oxidative stress status but rather to attenuated anti-inflammatory expression in these cells. Circulating ferritin was elevated in PE, supporting the hypothesis that PE represents a disbalance in iron homeostasis. Low lncRNA taurine upregulated gene 1 RNA levels in leukocytes at 22-24 weeks were strongly associated with the development of PE., Conclusions: Our findings suggest that maternal leukocytes in PE show decreased anti-ferroptotic activity that correlates with anti-inflammatory expression. Moreover, some of these changes in ferroptotic activity appear to precede the development of PE., (© 2023 The Authors. Journal of Internal Medicine published by John Wiley & Sons Ltd on behalf of Association for Publication of The Journal of Internal Medicine.)

Iron overload is associated with pregnancy complications. Ferroportin (FPN) is the only known iron exporter in mammalian cells. We hypothesize that FPN is functionally important in ferrotopsis, a process of iron-dependent non-apoptotic programmed cell death, and may have a critical role to play in pregnancy success. We investigated the expression of FPN in placenta/fetal membranes by immunohistochemistry in tissues collected from pregnancies with/without preeclampsia (PE) and spontaneous preterm birth (SPTB). FPN was highly expressed in both trophoblasts and decidual cells found in placenta/fetal membranes. Staining was significantly reduced in fetal membranes from SPTB versus healthy pregnancies (P = 0.046). FPN expression in immortalized human endometrial stromal cells (HESC) increased with in vitro decidualization induction using 1 μM of medroxyprogesterone acetate and 0.5 mM of dibutyryl-cAMP. In addition, both HESC cells and immortalized extravillous trophoblast SW71 cells with FPN knockdown showed significant sensitivity to ferroptosis inducer, erastin (P < 0.001 and P = 0.009, respectively). The survival of both HESC and SW71 cells was not negatively affected by iron supplementation with ferric ammonium citrate in the medium. However, SW71 cells were more sensitive than HESC cells to physiologic iron in the presence of a non-lethal dose of erastin (P < 0.001). Taken together, our data demonstrating increased sensitivity of FPN knockdown HESC and SW71 cells to erastin and increased sensitivity of trophoblasts to iron overload under ferroptotic stress support the hypothesis that FPN protects against ferroptosis during pregnancy., Competing Interests: Declaration of Competing Interest The authors disclose that there are no financial or non-financial interests that are directly or indirectly related to the work submitted for publication., (Copyright © 2023 Society for Biology of Reproduction & the Institute of Animal Reproduction and Food Research of Polish Academy of Sciences in Olsztyn. Published by Elsevier B.V. All rights reserved.)

Background: Circulating extracellular vesicles (EVs) are increased in preeclampsia (PE) and are associated with severity and progression. We examined in this exploratory cohort study if the mRNAs and long noncoding RNAs (lncRNAs) in plasma-derived EVs were dysregulated in PE compared to normal pregnancy and display different temporal patterns during gestation., Methods: We isolated EVs from plasma at weeks 22-24 and 36-38 in women with and without PE (n=7 in each group) and performed RNA-seq, focusing on mRNAs and lncRNAs. We validated highly expressed mitochondrial and platelet-derived RNAs discovered from central pathways in 60 women with/without PE. We examined further one of the regulated RNAs, noncoding mitochondrially encoded tRNA alanine (MT-TA), in leukocytes and plasma to investigate its biomarker potential and association with clinical markers of PE., Results: We found abundant levels of platelet-derived and mitochondrial RNAs in EVs. Expression of these RNAs were decreased and lncRNAs increased in EVs from PE compared to without PE. These findings were further validated by qPCR for mitochondrial RNAs MT-TA, MT-ND2, MT-CYB and platelet-derived RNAs PPBP, PF4, CLU in EVs. Decreased expression of mitochondrial tRNA MT-TA in leukocytes at 22-24 weeks was strongly associated with the subsequent development of PE., Conclusions: Platelet-derived and mitochondrial RNA were highly expressed in plasma EVs and were decreased in EVs isolated from women with PE compared to without PE. LncRNAs were mostly increased in PE. The MT-TA in leukocytes may be a useful biomarker for prediction and/or early detection of PE., (© 2023. The Author(s).)

Introduction: Postpartum hemorrhage (PPH) is a significant cause of maternal mortality worldwide, particularly in low- and middle-income countries. It is essential to develop effective prediction models to identify women at risk of PPH and implement appropriate interventions to reduce maternal morbidity and mortality. This study aims to predict the occurrence of postpartum hemorrhage using machine learning models based on antenatal, intrapartum, and postnatal visit data obtained from the Kenya Antenatal and Postnatal Care Research Collective cohort., Method: Four machine learning models - logistic regression, naïve Bayes, decision tree, and random forest - were constructed using 67% training data (1,056/1,576). The training data was further split into 67% for model building and 33% cross validation. Once the models are built, the remaining 33% (520/1,576) independent test data was used for external validation to confirm the models' performance. Models were fine-tuned using feature selection through extra tree classifier technique. Model performance was assessed using accuracy, sensitivity, and area under the curve (AUC) of the receiver operating characteristics (ROC) curve., Result: The naïve Bayes model performed best with 0.95 accuracy, 0.97 specificity, and 0.76 AUC. Seven factors (anemia, limited prenatal care, hemoglobin concentrations, signs of pallor at intrapartum, intrapartum systolic blood pressure, intrapartum diastolic blood pressure, and intrapartum respiratory rate) were associated with PPH prediction in Kenyan population., Discussion: This study demonstrates the potential of machine learning models in predicting PPH in the Kenyan population. Future studies with larger datasets and more PPH cases should be conducted to improve prediction performance of machine learning model. Such prediction algorithms would immensely help to construct a personalized obstetric path for each pregnant patient, improve resource allocation, and reduce maternal mortality and morbidity., Competing Interests: SS, SR and NN are employees of CognitiveCare Inc.'s wholly owned subsidiary. SYS, SG and MT are founding team members and employees of CognitiveCare Inc. CognitiveCare Inc. has a patent pending for a maternal and infant health intelligence and cognitive insight (MIHIC) system and score to predict the risk of maternal, fetal and infant morbidity and mortality. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2023 Shah, Saxena, Rani, Nelaturi, Gill, Tippett Barr, Were, Khagayi, Ouma, Akelo, Norwitz, Ramakrishnan, Onyango and Teltumbade.)

Background and Purpose: A recent international expert consensus opinion suggested that metabolic dysfunction-associated fatty liver disease (MAFLD) replaces nonalcoholic fatty liver disease (NAFLD), since MAFLD is a better predictor of cardiovascular disease. We estimated the prevalence of FLD in fertile females and evaluated the clinical impact of either NAFLD or MAFLD on maternal and fetal outcomes during subsequent pregnancy., Methods: The study population included fertile females who underwent health examinations and became pregnant within 1 year of health examination. Hepatic steatosis was defined as a fatty liver index of ≥ 30. The fertile females were divided into four groups: neither-FLD, NAFLD-only, MAFLD-only, and both-FLDs. During subsequent pregnancy, the risks of adverse pregnancy outcomes, including gestational diabetes, pregnancy-associated hypertension, preterm birth, and low birthweight, were compared among the four groups., Results: The study population comprised 762,401 females, including 720,606 with neither-FLD, 318 with NAFLD-only, 14,371 with MAFLD-only, and 27,106 with both-FLDs. Compared to females with neither-FLD, the risk of adverse pregnancy outcomes was higher in females with any FLD, with an adjusted OR of 1.73 (95% CI 1.25-2.41) in the NALFD-only group, 2.65 (2.53-2.77) in the MAFLD-only group, and 2.39 (2.31-2.48) in the both-FLDs group. Pregnancy outcomes (cesarean delivery, gestational diabetes, and low birthweight) were worse in females with MAFLD compared with NAFLD., Conclusion: Any form of FLD is a risk factor for adverse pregnancy outcomes. These data suggest that MAFLD is associated with a higher risk of adverse pregnancy outcomes for both mother and fetus than NAFLD., (© 2022. Asian Pacific Association for the Study of the Liver.)

Serotonin Reuptake Inhibitors (SRIs) are often used as first line therapy for depression and other psychiatric disorders. SRI use during pregnancy is associated with preterm premature rupture of membranes (PPROM) and subsequent preterm birth. The objective of this study was to investigate the mechanism(s) responsible for SRI-associated PPROM. Putative mechanisms underlying PPROM include fetal membrane (FM) inflammation, increased apoptosis, and/or accelerated senescence, the later which may be reversed by statins. Human FM explants from normal term deliveries without labor, infection, or antidepressant use were treated with or without the SRI, fluoxetine (FLX), either alone or in the presence of a p38 MAPK inhibitor or the statins, simvastatin or rosuvastatin. FMs were also collected from women either unexposed or exposed to FLX during pregnancy. FLX significantly increased FM p38 MAPK activity and secretion of inflammatory IL-6. Inhibition of p38 MAPK reduced FM IL-6 secretion in response to FLX. Statins did not reduce the SRI-induced FM IL-6 production. FMs from women exposed to FLX during pregnancy expressed elevated levels of p38 MAPK activity compared to matched unexposed women. FMs exposed to FLX did not exhibit signs of increased apoptosis and/or accelerated senescence. These results indicate that the SRI, FLX, may induce sterile FM inflammation during pregnancy through activation of the p38 MAPK pathway, and in the absence of apoptosis and senescence. These findings may better inform clinicians and patients as they weigh the risks and benefits of SRI antidepressant treatment during pregnancy., (Copyright © 2022 Elsevier B.V. All rights reserved.)

BACKGROUND: Among women with hypertensive disorders of pregnancy, biomarkers may stratify risk for developing preeclampsia with severe features (sPE). METHODS: Across 18 U.S. centers, we prospectively measured the ratio of serum soluble fms-like tyrosine kinase 1 (sFlt-1) to placental growth factor (PlGF) in pregnant women hospitalized between 23 and 35 weeks of gestation. The primary outcome was predicting sPE, and secondary outcomes included predicting adverse outcomes within 2 weeks. The prognostic performance of the sFlt-1:PlGF ratio was assessed by using a derivation/validation design. RESULTS: A total of 1014 pregnant women were evaluated; 299 were included in the derivation cohort and 715 in the validation cohort. In the derivation cohort, the median sFlt-1:PlGF ratio was 200 (interquartile range, 53 to 458) among women who developed sPE compared with 6 (interquartile range, 3 to 26) in those who did not (P<0.001). The discriminatory ratio of ≥40 was then tested in the validation cohort and yielded a 65% positive (95% confidence interval [CI], 59 to 71) and a 96% negative (95% CI, 93 to 98) predictive value for the primary outcome. The ratio performed better than standard clinical measures (area under the receiver-operating characteristic curve, 0.92 versus <0.75 for standard-of-care tests). Compared with women with a ratio <40, women with a ratio ≥40 were at higher risk for adverse maternal outcomes (16.1% versus 2.8%; relative risk, 5.8; 95% CI, 2.8 to 12.2). CONCLUSIONS: In women with a hypertensive disorder of pregnancy presenting between 23 and 35 weeks of gestation, measurement of serum sFlt-1:PlGF provided stratification of the risk of progressing to sPE within the coming fortnight. (Funded by Cedars-Sinai Medical Center and Thermo Fisher Scientific; ClinicalTrials.gov NCT03815110.)

Background & Aims: Recently, metabolic dysfunction-associated fatty liver disease (MAFLD), rather than nonalcoholic fatty liver disease (NAFLD), was proposed to better describe liver disease associated with metabolic dysfunction (MD). In this study, we attempted to investigate the impact of MAFLD on pregnancy complications., Methods: The current study is a secondary analysis of a multicenter prospective cohort designed to examine the risk of NAFLD during pregnancy. In the first trimester, enrolled pregnant women were evaluated for hepatic steatosis by liver ultrasonography, and blood samples were collected for biochemical measurements. The study population was divided into 3 groups: no NAFLD, hepatic steatosis but without metabolic dysfunction (non-MD NAFLD), and MAFLD. The primary outcome was the subsequent development of adverse pregnancy outcomes, including gestational diabetes mellitus, pregnancy-associated hypertension, preterm birth, and fetal growth abnormalities., Results: The study population consisted of 1744 pregnant women, including 1523 with no NAFLD, 43 with non-MD NAFLD, and 178 with MAFLD. The risk of subsequent development of adverse pregnancy outcomes was higher in MAFLD than in non-MD NAFLD (adjusted odds ratio, 4.03; 95% CI, 1.68-9.67), whereas the risk was not significantly different between no NAFLD and non-MD NAFLD. Among women with no NAFLD, the presence of MD increased the risk of adverse pregnancy outcomes. However, women with MAFLD were at higher risk for adverse pregnancy outcomes than women with no NAFLD without MD or those with no NAFLD with MD., Conclusions: In pregnant women, MAFLD may be associated with an increased risk of subsequent adverse pregnancy outcomes., (Copyright © 2022 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Clinical guidelines recommend several risk factors to identify women in early pregnancy at high risk of developing pregnancy-associated hypertension. However, these variables result in low predictive accuracy. Here, we developed a prediction model for pregnancy-associated hypertension using graph-based semi-supervised learning. This is a secondary analysis of a prospective study of healthy pregnant women. To develop the prediction model, we compared the prediction performances across five machine learning methods (semi-supervised learning with both labeled and unlabeled data, semi-supervised learning with labeled data only, logistic regression, support vector machine, and random forest) using three different variable sets: [a] variables from clinical guidelines, [b] selected important variables from the feature selection, and [c] all routine variables. Additionally, the proposed prediction model was compared with placental growth factor, a predictive biomarker for pregnancy-associated hypertension. The study population consisted of 1404 women, including 1347 women with complete follow-up (labeled data) and 57 women with incomplete follow-up (unlabeled data). Among the 1347 with complete follow-up, 2.4% (33/1347) developed pregnancy-associated HTN. Graph-based semi-supervised learning using top 11 variables achieved the best average prediction performance (mean area under the curve (AUC) of 0.89 in training set and 0.81 in test set), with higher sensitivity (72.7% vs 45.5% in test set) and similar specificity (80.0% vs 80.5% in test set) compared to risk factors from clinical guidelines. In addition, our proposed model with graph-based SSL had a higher performance than that of placental growth factor for total study population (AUC, 0.71 vs. 0.80, p &lt; 0.001). In conclusion, we could accurately predict the development pregnancy-associated hypertension in early pregnancy through the use of routine clinical variables with the help of graph-based SSL., (© 2022. The Author(s).)

Background/aims: To develop an early prediction model for gestational diabetes mellitus (GDM) using machine learning and to evaluate whether the inclusion of nonalcoholic fatty liver disease (NAFLD)-associated variables increases the performance of model., Methods: This prospective cohort study evaluated pregnant women for NAFLD using ultrasound at 10-14 weeks and screened them for GDM at 24-28 weeks of gestation. The clinical variables before 14 weeks were used to develop prediction models for GDM (setting 1, conventional risk factors; setting 2, addition of new risk factors in recent guidelines; setting 3, addition of routine clinical variables; setting 4, addition of NALFD-associated variables, including the presence of NAFLD and laboratory results; and setting 5, top 11 variables identified from a stepwise variable selection method). The predictive models were constructed using machine learning methods, including logistic regression, random forest, support vector machine, and deep neural networks., Results: Among 1,443 women, 86 (6.0%) were diagnosed with GDM. The highest performing prediction model among settings 1-4 was setting 4, which included both clinical and NAFLD-associated variables (area under the receiver operating characteristic curve [AUC] 0.563-0.697 in settings 1-3 vs. 0.740-0.781 in setting 4). Setting 5, with top 11 variables (which included NAFLD and hepatic steatosis index), showed similar predictive power to setting 4 (AUC 0.719-0.819 in setting 5, P=not significant between settings 4 and 5)., Conclusion: We developed an early prediction model for GDM using machine learning. The inclusion of NAFLDassociated variables significantly improved the performance of GDM prediction. (ClinicalTrials.gov Identifier: NCT02276144).

We evaluated the relationship between maternal cholesterol levels and its biologically active precursors and metabolites in the first trimester and subsequent risk for small-for-gestational-age birthweight (SGA). This is a secondary analysis of a prospective cohort study which enrolled healthy singleton pregnancies (n = 1337). Maternal fasting blood was taken in the first trimester and followed up till delivery. The lipid parameters were compared between women who delivered SGA neonates (SGA-group, birthweight < 10th percentile, n = 107) and women who did not (non-SGA-group, n = 1230). In addition, metabolic signatures of cholesterol were evaluated in a subset consisting of propensity-score matched SGA (n = 56) and control group (n = 56). Among lipid parameters, maternal high-density lipoprotein cholesterol (HDL-C) levels were significantly lower in SGA-group than in non-SGA-group (p = 0.022). The risk for SGA was negatively correlated with maternal serum HDL-C quartiles (p = 0.003), and this association remained significant after adjustment for confounding variables. In metabolic signatures of cholesterol, the cholesterol/lathosterol ratio in SGA-group was significantly higher than non-SGA-group [(2.7 (1.6-3.7) vs. 2.1 (1.5-2.9), respectively; p = 0.034)], suggesting increased endogenous cholesterol biosynthesis. We demonstrated that dyslipidemia and increased cholesterol biosynthesis led to delivery of SGA neonates even in early pregnancy., (© 2021. The Author(s).)