Metabolomic profiling of serum and tongue coating of pregnant women with intrahepatic cholestasis in pregnancy.

Intrahepatic cholestasis of pregnancy (ICP) is associated with an increased risk of cesarean section and adverse fetal outcomes. Currently, ICP diagnosis depends largely on serum levels of bile acids and lacks sensitivity and specificity for accurate diagnosis. Tongue diagnosis is an important diagnostic tool in traditional Chinese medicine (TCM) and is used in our clinic as complementary treatment and personalized medicine for ICP. However, the molecular basis of the manifestation of greasy white tongue coatings in ICP remains unknown. In this study, we performed untargeted metabolomic profiling of the serum, tongue coating, and saliva of 66 pregnant women, including 22 with ICP. The metabolomic profiles of the serum and tongue coatings showed marked differences between the two clinical groups. Forty-six differentially abundant metabolites were identified, and their relative concentrations correlated with total bile acid levels. These differential metabolites included bile acids, lipids, microbiota- and diet-related metabolites, and exposomes. Conventional biochemical markers, including serum aminotransferases and bilirubin, were not significantly increased in the ICP group, whereas the total cholesterol and triglyceride levels were significantly increased as early as the first trimester. Our data provide insights into the pathophysiology of ICP and implicate the gut-liver axis and environmental exposure. Tongue coating has the potential to be a non-invasive diagnostic approach. Further studies are required to validate the clinical utility of these findings.

Elevated maternal serum bile acids level, hypertensive disorders of pregnancy and adverse fetal outcomes: a cohort study of 117,789 pregnant women in China.

BACKGROUND: Elevated maternal serum total bile acids (sTBA) level during pregnancy was associated with adverse fetal outcomes. Women with elevated sTBA could complicate with hepatic dysfunction or vascular disorders (hypertensive disorders of pregnancy, HDP), which aggravated adverse fetal outcomes. However, the relationships among sTBA level, hepatic dysfunction, HDP and adverse fetal outcomes were still illusive. OBJECTIVE: We aimed to explore whether hepatic dysfunction or vascular disorders (HDP) mediated the associations between elevated sTBA level and adverse fetal outcomes. METHODS: A large retrospective cohort study encompassing 117,789 Chinese pregnant women with singleton delivery between Jan 2014 and Dec 2022 was conducted. Causal mediation analysis was applied to assess the mediating role of hepatic dysfunction (alanine transaminase > 40 U/L) or HDP in explaining the relationship between high maternal sTBA level (≥10 µmol/L) and adverse fetal outcomes, including low birth weight (LBW), small for gestational age (SGA), and preterm birth (PTB). RESULTS: sTBA level were positively associated with LBW (adjusted odds ratio (aOR) = 1.40; [95 % confidence interval (CI): 1.24-1.59]), SGA (aOR=1.31; [95 % CI: 1.18-1.46]), and PTB (aOR=1.27; [95 % CI: 1.15-1.41]), respectively. The estimated proportions of the total associations mediated by HDP were 47 % [95 % CI: 31 %-63 %] for LBW, 24 % [95 % CI: 13 %-35 %] for SGA, and 34 % [95 % CI: 19 %-49 %] for PTB, excepting the direct effects of high sTBA level. The contribution of hepatic dysfunction as a mediator was weaker on the association between high sTBA level on fetal outcomes, as the proportions mediated and 95 % CI were 16 % [4 %-29 %], 4 % [-6%-14 %], 32 % [15 %-50 %] for LBW, SGA, and PTB, respectively. Moreover, the mediating effect of hepatic dysfunction was nearly eliminated after excluding cases of HDP in the sensitivity analysis. CONCLUSIONS: The substantial mediating effects through HDP highlighted its significant role in adverse fetal outcomes associated with elevated sTBA level. The findings also provoked new insights into understanding the mechanism and developing clinical management strategies (i.e. vascular protection) for adverse fetal outcomes associated with elevated sTBA level.

Breast Carcinogenesis during Pregnancy: Molecular Mechanisms, Maternal and Fetal Adverse Outcomes.

Breast cancer is a common type of cancer diagnosed during pregnancy, with increasing incidence over the last years, as more women choose to delay childbearing. Compared to breast cancer in general population, pregnancy-associated breast cancer (PABC) is significantly different in its terms of epidemiology, diagnostic and therapeutic management, while it exhibits particularly aggressive behavior, deriving from its unique molecular and biological profile. Although not fully elucidated, the pathophysiological basis of PABC can be traced back to a combination of hormonal and immune changes during pregnancy, breast involution and altered gene expression. There is considerable controversy in the existing literature about the influence of PABC on pregnancy outcomes, regarding both short- and long-term effects on maternal and fetal/neonatal health. The majority of PABC patients have advanced-stage disease at initial diagnosis and face a significantly poorer prognosis, with decreased survival rates. The most commonly reported adverse obstetrical-fetal events are preterm delivery and prematurity-associated neonatal morbidity, while other neonatal treatment-associated complications might also occur, even when safe therapeutic options are applied during pregnancy. The objective of the present comprehensive review was to summarize current knowledge and up-to-date evidence about the pathophysiological, molecular and biological basis of PABC, as well as its association with adverse maternal, obstetrical, fetal and neonatal outcomes.

Risk factors associated with cesarean section and adverse fetal outcomes in intrahepatic cholestasis of pregnancy.

Background: To determine the risk factors for cesarean section (CS) and adverse fetal outcomes (AFOs) in patients with intrahepatic cholestasis of pregnancy (ICP) based on the severity of maternal hypercholanemia. Methods: A hospital-based retrospective cohort study was performed between January 1, 2015, and December 31, 2019. A total of 227 nulliparous women with a singleton fetus complicated by ICP were included. The patients were divided into two groups according to the levels of total bile acids, that is, mild (10 µmol/L < total bile acids < 40 µmol/L) and severe (≥40 µmol/L). The patients' clinical characteristics and fetal outcomes were assessed. Results: Among the 227 eligible women, 177 (78.0%) were allocated to the mild group and 50 (22.0%) were in the severe group. Women with severe ICP also had a significantly higher incidence of planned and unplanned CS compared with mild ICP subjects (52.0% vs. 23.7% and 22.0% vs. 6.8%, respectively; p < 0.001). The indications for CS showed that fetal intolerance (65.4% vs. 14.3%) was higher in severe ICP compared with mild ICP (p < 0.001). Severe ICP was associated with an increased risk of preterm delivery (p < 0.001), low birthweight (p = 0.001), and neonatal intensive care unit (NICU) admission (p < 0.001). Women with severe ICP (OR 6.397, 95%CI 3.041-13.455, p < 0.001) or preeclampsia (OR 12.434, 95%CI 5.166-29.928, p < 0.001) had increased risks of AFOs compared to controls. Conclusions: Severe ICP and preeclampsia are associated with a higher incidence of AFOs.

Estimated fetal weight standards of the INTERGROWTH-21st project for the prediction of adverse outcomes: a systematic review with meta-analysis.

OBJECTIVE: To systematically review and assess the risk of bias in the literature evaluating the performance of INTERGROWTH-21st estimated fetal weight (EFW) standards to predict maternal, fetal and neonatal adverse outcomes. METHODS: Searches were performed in seven electronic databases (Scopus, Web of Science, Medline, Embase, Lilacs, Scielo and Google Scholar) using citation tools and keywords (intergrowth AND (standard OR reference OR formula OR model OR curve); all from 2014 to the last search on April 16th, 2021). We included full-text articles investigating the ability of INTERGROWTH-21st EFW standards to predict maternal, fetal or neonatal adverse outcomes in women with a singleton pregnancy who gave birth to infants with no congenital abnormalities. The study was registered on PROSPERO under the number CRD42020115462. Risk of bias was assessed with a customized instrument based on the CHARMS checklist and composed of 9 domains. Meta-analysis was performed using relative risk (RR [95%CI]) and summary ROC curves on outcomes reported by two or more methodologically homogeneous studies. RESULTS: Sixteen studies evaluating fifteen different outcomes were selected. The risk of bias was high (>50% of studies with high risk) for two domains: blindness of assessment (81.3%) and calibration assessment (93.8%). Considering all the outcomes investigated, for 95% of the results, the specificity was above 73.0%, but the sensitivity was below 64.1%. Pooled results demonstrated a higher RR of neonatal small for gestational age (6.71 [5.51-8.17]), Apgar <7 at 5 min (2.17 [1.48-3.18]), and neonatal intensive care unit admission (2.22 [1.76-2.79]) for fetuses classified <10th percentile when compared to those classified above this limit. The limitation of the study is the absence of heterogeneity exploration or publication bias investigation, whereas no outcomes were evaluated by more than five studies. CONCLUSIONS: The IG-21 EFW standard has low sensitivity and high specificity for adverse events of pregnancy. Classification <10th percentile identifies a high-risk group for developing maternal, fetal and neonatal adverse outcomes, especially neonatal small for gestational age, Apgar <7 at 5 min, and neonatal intensive care unit admission. Future studies should include blind assessment of outcomes, perform calibration analysis with continuous data, and evaluate alternative cutoff points.

Umbilical Artery Doppler Indices in Hypertensive Disorders of Pregnancy: Impact on Fetal Outcomes.

Background Hypertensive disorders of pregnancy (HDP) are associated with increased maternal and fetal risks. Doppler ultrasound indices of the umbilical artery have shown promise in predicting adverse fetal outcomes in HDP patients. This observational study investigated the correlation between abnormal umbilical artery Doppler indices and adverse fetal outcomes in HDP patients. Methodology Over a two-year period from 2020 to 2022, in Acharya Vinoba Bhave Rural Hospital, central India, we enrolled 138 pregnant women with HDP beyond 28 weeks of gestation and singleton pregnancies. Comprehensive clinical assessments, laboratory investigations, and Doppler studies of the umbilical artery were performed. Doppler indices assessed included the systolic/diastolic (S/D) ratio, resistance index (RI), and pulsatility index (PI). Adverse fetal outcomes were defined based on birth weight and neonatal intensive care unit admissions. Chi-square or Fisher's exact test was used for analyzing the relationship between qualitative data, while an independent-sample t-test was employed for quantitative data. Results Abnormal umbilical artery Doppler indices, including an elevated S/D ratio, RI, and PI, demonstrated a positive correlation with adverse fetal outcomes in HDP patients. These findings highlight the significance of umbilical artery Doppler indices as reliable indicators for anticipating adverse fetal outcomes in HDP patients. Conclusions Abnormal Doppler indices in the umbilical artery, including an elevated S/D ratio, RI, and PI, appear to be valuable predictors for adverse fetal outcomes in patients with HDP. Monitoring these indices can aid in risk stratification and improve the management of pregnancies complicated by HDP.

Uterine Artery Doppler Indices as Predictor of Adverse Fetal Outcome in Hypertensive Disorders of Pregnancy: An Observational Study.

Background Hypertensive disorders of pregnancy (HDP) pose significant risks to maternal and fetal health. The utility of Doppler indices in predicting adverse fetal outcomes in HDP patients remains an area of active research. This observational study aimed to assess the correlation between abnormal uterine artery Doppler indices and adverse fetal outcomes in HDP patients. Methods Over a two-year period, we enrolled 138 pregnant women with HDP beyond 28 weeks of gestation and singleton pregnancies. Detailed clinical assessments, laboratory investigations, and Doppler studies of the uterine artery were conducted. The Doppler indices that were assessed included the systolic/diastolic (S/D) ratio, resistance index (RI), and pulsatility index (PI). Adverse fetal outcomes were classified based on appearance, pulse, grimace, activity, and respiration (APGAR) scores, birth weight, NICU admissions, and perinatal deaths. Statistical analyses were performed to evaluate the predictive value of Doppler indices. Results Abnormal uterine artery Doppler indices, specifically an elevated S/D ratio and the presence of a diastolic notch showed a positive correlation with adverse fetal outcomes. However, Doppler indices such as PI and RI did not demonstrate a significant correlation with adverse fetal outcomes in HDP patients. These findings suggest that the S/D ratio and the presence of a diastolic notch in uterine artery Doppler studies hold potential as predictive markers for adverse fetal outcomes in HDP patients. Conclusion Uterine artery Doppler indices, specifically the S/D ratio and the presence of a diastolic notch, appear to be valuable predictors for adverse fetal outcomes in patients with hypertensive disorders of pregnancy. These findings underscore the importance of regular monitoring of uterine artery Doppler flow in the management of HDP to identify pregnancies at higher risk for adverse fetal outcomes.

An Increased Adverse Fetal Outcome Has Been Observed among Teen Pregnant Women in Rural Eastern Ethiopia: A Comparative Cross-Sectional Study.

Background: According to the World Health Organization, teenage pregnancies are high-risk due to increased risks of fetal and infant morbidity and mortality. This study compares adverse fetal outcomes between teen and adult pregnant women from rural Eastern Ethiopia. Methods: Institutional-based cross-sectional study was conducted among women visiting maternity units from surrounding rural areas. A total of 481 teenagers (13-19 years old) and 481 adults (20-34 years old) women with a singleton pregnancy were included in the study. Two hospitals and 3 health centers were selected in Eastern Hararghe Zone, Eastern Ethiopia. Comparative analysis was carried out using the log-binomial regression model to identify factors associated with adverse fetal outcomes in both categories. The results are reported in adjusted prevalence ratios with 95% confidence intervals. Results: High proportion of adverse fetal outcome was observed among teenage women than adult (34.9% vs 21%). Statistically significant difference (P < .05) in the proportion of low birth weight (21.1% vs 9.3%), preterm birth (18.7% vs 10.6%), APGAR score at 5th minute (9.3% vs 4%) were found in teenagers compared to adult women. Antenatal care attendance (APR = 0.44; 95% CI: 0.23, 0.86); eclampsia (APR = 1.96; 95% CI: 1.26, 3.06); pre-eclampsia (APR = 1.73; 95% CI: 1.12, 2.67); and wealth index (rich) (APR = 0.55; 95% CI: 0.32, 0.94) were significantly associated with adverse fetal outcomes among the teenage women. Whereas intimate partner violence (APR = 2.22; 95% CI: 1.26, 3.90); preeclampsia (APR = 3.05; 95% CI: 1.61, 5.69); antepartum hemorrhage (APR = 2.77; 95% CI: 1.73, 4.46); and hyperemesis gravderm (APR = 1.75; 95% CI: 1.09, 2.79) were significantly associated with adverse fatal outcomes among the adult women. Conclusion: teenage pregnancy is associated with a high rate of adverse fetal outcomes. Early identification and treatment of problems during antenatal follow-up should be the mainstay to avert the massive adverse fetal effects.

Acute kidney injury during pregnancy and puerperium: an Egyptian hospital-based study.

INTRODUCTION: While acute kidney injury (AKI) in pregnancy is currently a rare entity in developed countries, it is still a common occurrence in developing countries, representing a major cause of maternal and fetal morbidity and mortality. Scarce data are published regarding pregnancy-related acute kidney injury (PRAKI) in Middle Eastern and African countries. The aim of this work is to report on the frequency, the underlying causes, and the outcomes of patients with PRAKI in an Egyptian tertiary care hospital. METHODS: This is a prospective observational study that included 40 patients representing all women who presented to the Mansoura Nephrology and Dialysis Unit with PRAKI over two years. All patients were followed up for three months after hospital discharge to assess renal outcome, and till the end of pregnancy to assess the maternal and fetal outcomes. RESULTS: PRAKI was reported  in about 1% of women who presented to the obstetrics service, and accounted for 14% of all AKI patients who presented to the renal service in our hospital. Preeclampsia (PE) and obstetric hemorrhage were the commonest causes of PRAKI. Maternal mortality occurred in 22.5% of PRAKI patients. The majority of survivors (62.5%) fully recovered, while the remaining (37.5%) individuals became dialysis dependent. Unfavorable fetal events occurred in 24 pregnancies (60%). CONCLUSION: In our hospital in Mansoura, Egypt, PRAKI represents a relevant burden with potential ominous outcomes obstetric hemorrhage and preeclampsia were the major causes. Further research is needed to understand the causes and improve the outcomes of pregnancy-related AKI.

Desloratadine Use During Pregnancy and Risk of Adverse Fetal Outcomes: A Nationwide Cohort Study.

BACKGROUND: Desloratadine is a frequently used drug for the treatment of allergic disorders, which often also require treatment during pregnancy. However, information on the fetal safety of desloratadine use during pregnancy is limited. OBJECTIVE: To investigate the association between desloratadine use during pregnancy and adverse fetal outcomes. METHODS: From a cohort of 1,287,668 pregnancies identified in the Danish nationwide registries in the study period 2001 to 2016, users of desloratadine and loratadine during pregnancy were matched in a 1:1 ratio based on propensity scores to compare the risk of adverse fetal outcomes. We compared the risk of the primary outcomes major birth defects (among a total of 3348 pregnancies) and spontaneous abortion (5498 pregnancies) and the secondary outcomes preterm birth (5280 pregnancies), small size for gestational age (SGA) for birth weight (5436 pregnancies), and stillbirth (6776 pregnancies). Logistic regression was used to estimate the prevalence odds ratio (OR) of major birth defects, preterm birth, and SGA, and Cox regression to estimate the hazard ratio (HR) of spontaneous abortion and stillbirth. Sensitivity analyses included comparing with cetirizine use in pregnancy and with pregnancies unexposed to desloratadine but with prior use as additional comparator groups. RESULTS: Use of desloratadine in pregnancy was not associated with a significant increased risk of major birth defects (prevalence OR, 1.07; 95% confidence interval [CI], 0.77-1.50), spontaneous abortion (HR, 1.15; 95% CI, 0.96-1.37), preterm birth (prevalence OR, 0.84; 95% CI, 0.67-1.05), SGA (prevalence OR, 0.97; 95% CI, 0.80-1.16), or stillbirth (HR, 0.91; 95% CI, 0.31-2.70) compared with loratadine use in pregnancy. Sensitivity analyses, including those with the use of additional comparator groups, showed similar results. CONCLUSION: Use of desloratadine during pregnancy was not associated with a statistically significant increased risk of adverse fetal outcomes as compared with loratadine. Results indicate that the fetal safety profile of desloratadine is similar to the currently recommended second-generation antihistamines during pregnancy.

Polysomnographic features of pregnancy: A systematic review.

Symptoms of sleep disturbances are common among pregnant women and generally worsen across gestation. Pregnancy-related sleep disorders are not only associated with a poor quality of life of the affected mothers, but also with adverse perinatal outcomes, including perinatal depression, gestational diabetes, preeclampsia, and preterm birth. The current knowledge about the impact of sleep disorders during pregnancy largely derives from the results of sleep surveys conducted in various populations. However, the number of studies examining changes in objective sleep variables during pregnancy via polysomnography has progressively increased in recent years. Here we systematically reviewed the polysomnographic studies available in the literature with the aim to describe the sleep pattern and to identify possible markers of sleep disruption in pregnant women. Based on our analysis, subjective worsening of sleep quality across gestation is related to objective changes in sleep macrostructure, which become particularly evident in the third trimester. Pregnancy per se does not represent an independent risk factor for developing major polysomnography-assessed sleep disorders in otherwise healthy women. However, in women presenting predisposing factors, such as obesity or hypertension, physiological changes occurring during pregnancy may contribute to the onset of pathological conditions, especially sleep-disordered breathing, which must be carefully considered.

Risk factors for adverse fetal outcomes among women with early- versus late-onset intrahepatic cholestasis of pregnancy.

OBJECTIVE: To determine risk factors for adverse fetal outcomes (AFOs) among women with intrahepatic cholestasis of pregnancy (ICP) on the basis of time of onset. METHODS: In a retrospective analysis, data were obtained for all women with ICP admitted to two centers in Guangzhou, China, between February 1, 1993, and January 31, 2014. Patients were divided into group A (early-onset ICP) and group B (late-onset ICP), and were further divided on the basis of severity. The frequency of AFOs was assessed. RESULTS: Among 371 eligible women, 57 (15.4%) were in group A and 314 (84.6%) in group B. AFOs affected 20 (35.1%) women in group A and 67 (21.3%) in group B (P=0.024), and 12 (54.5%) of 22 women in group A and 21 (29.6%) of 71 in group B with severe ICP (P=0.032). Independent risk factors for AFO in group A were increased levels of serum bile acid (P=0.016) and alkaline phosphatase (P=0.004). Independent risk factors in group B were increased levels of alkaline phosphatase (P<0.001) and gamma-glutamyl transpeptidase (P=0.001). CONCLUSION: Early-onset ICP is associated with a higher frequency of AFO than is late-onset ICP, especially in severe disease. The risk factors differ between early-onset and late-onset ICP.

Pandemic A/H1N1 influenza vaccination during pregnancy: a comparative study using the EFEMERIS database.

OBJECTIVE: To evaluate the risk of adverse pregnancy outcomes following A/H1N1 vaccination in pregnant women. METHODS: This observational cohort study compared vaccinated and non-vaccinated pregnant women in EFEMERIS, a French prescription database including pregnant women. Women who ended their pregnancy in South Western France between October 21, 2009 and November 30, 2010 (the period of the French vaccination campaign) were included. Two non-vaccinated women were individually matched to each vaccinated woman by month and year of pregnancy onset. Conditional logistic regression and Cox proportional hazards regression were used to evaluate associations between each outcome (all-cause pregnancy loss, preterm delivery, small for gestational age (SGA) and neonatal pathology) and A/H1N1 vaccination during pregnancy. RESULTS: 1645 women of the 12,120 (13.6%) in the database who were administered A/H1N1 vaccine during pregnancy were compared to 3290 non-vaccinated women. Most were vaccinated in December 2009 (61%) with a non-adjuvanted vaccine (93%). The risks of pregnancy loss (adjusted HR=0.56; 95% CI=0.31-1.01), of preterm birth (adjusted HR=0.82; 95% CI=0.64-1.06), and of neonatal pathology (adjusted OR=0.70; 95% CI=0.49-1.02) did not differ between the vaccinated and the non-vaccinated groups. The rate of SGA was lower in the vaccinated group than in the non-vaccinated group (0.5% vs. 1.4%; adjusted OR=0.36; 95% CI=0.17-0.78). CONCLUSION: There was no significant association between adverse pregnancy outcomes and vaccination with a non-adjuvanted A/H1N1 vaccine during pregnancy.

Colestasis del embarazo

La colestasis intrahepática del embarazo (CIDE) se caracteriza por prurito en la segunda mitad del embarazo, prurito que no se asocia con otros problemas dermatológicos o sistémicos. El diagnóstico se confirma con la elevación de los niveles maternos de bilirrubina, enzimas hepáticas y ácidos biliares en ayunas. El pronóstico para el feto es serio, pues la CIDE está asociada con pasaje de meconio, partos prematuros y muerte fetal. El tratamiento con tabletas de ácido ursodeoxicólico (UDCA) mejora el prurito, las pruebas de laboratorio y disminuye los resultados fetales adversos. Para la embarazada, la CIDE es relativamente benigna; pero, se ha observado que en el futuro estas mujeres tienen un riesgo mayor de presentar problemas hepatobiliares, cáncer de la mama e hipotiroidismo que las mujeres que no tuvieron esta complicación. Se recomienda un seguimiento prolongado.

Intrahepatic cholestasis of pregnancy (ICP) consists in pruritus that develops in the second half of pregnancy and is not associated with other dermatological or systemic problems. ICP diagnosis is confirmed by increase in maternal serum bilirubin, liver enzymes and fasting biliary acids. ICP is associated with fetal meconium passage, prematurity and fetal death. Treatment with ursodeoxycholic acid (UDCA) improves pruritus, maternal laboratory anomalies and fetal outcomes. ICP has a relative benign maternal course but compared to women without this complication ICP women have increased risk in developing hepatobiliar problems, breast cancer and hypothyroidism. Long-term follow up is recommended.