Agnostic identification of plasma biomarkers for postpartum hemorrhage risk.

BACKGROUND: Postpartum hemorrhage is difficult to predict, is associated with significant maternal morbidity, and is the leading cause of maternal mortality worldwide. The identification of maternal biomarkers that can predict increased postpartum hemorrhage risk would enhance clinical care and may uncover mechanisms that lead to postpartum hemorrhage. OBJECTIVE: This retrospective case-control study employed agnostic proteomic profiling of maternal plasma samples to identify differentially abundant proteins in controls and postpartum hemorrhage cases. STUDY DESIGN: Maternal plasma samples were procured from a cohort of >60,000 participants in a single institution's perinatal repository. Postpartum hemorrhage was defined as a decrease in hematocrit of ≥10% or receipt of transfusion within 24 hours after delivery. Postpartum hemorrhage cases (n=30) were matched by maternal age and delivery mode (vaginal or cesarean) with controls (n=56). Mass spectrometry was used to identify differentially abundant proteins using integrated peptide peak areas. Statistically significant differences between groups were defined as P<.05 after controlling for multiple comparisons. RESULTS: By study design, cases and controls did not differ in race, ethnicity, gestational age at delivery, blood type, or predelivery platelet count. Cases had slightly but significantly lower predelivery and postdelivery hematocrit and hemoglobin. Mass spectrometry detected 1140 proteins, including 77 proteins for which relative abundance differed significantly between cases and controls (fold change >1.15, P<.05). Of these differentially abundant plasma proteins, most had likely liver or placental origins. Gene ontology term analysis mapped to protein clusters involved in responses to wound healing, stress response, and host immune defense. Significantly differentially abundant proteins with the highest fold change (prostaglandin D2 synthase, periostin, and several serine protease inhibitors) did not correlate with predelivery hematocrit or hemoglobin but identified postpartum hemorrhage cases with logistic regression modeling revealing good-to-excellent area under the operator receiver characteristic curves (0.802-0.874). Incorporating predelivery hemoglobin with these candidate proteins further improved the identification of postpartum hemorrhage cases. CONCLUSION: Agnostic analysis of maternal plasma samples identified differentially abundant proteins in controls and postpartum hemorrhage cases. Several of these proteins are known to participate in biologically plausible pathways for postpartum hemorrhage risk and have potential value for predicting postpartum hemorrhage. These findings identify candidate protein biomarkers for future validation and mechanistic studies.

When Are Pregnant Patients Receiving Tranexamic Acid during Delivery Hospitalization in the United States?

OBJECTIVE: The World Health Organization recommends tranexamic acid (TXA) in the management of postpartum hemorrhage (PPH). However, the role of TXA in PPH prevention and the optimal timing of TXA administration remain unknown. Our objective was to describe the timing of TXA administration, differences in timing of TXA administration by mode of delivery, and current trends in TXA administration in the United States. STUDY DESIGN: We conducted a descriptive study of trends in TXA administration using the Cerner Real-World Database. We identified 1,544,712 deliveries occurring at greater than 24 weeks' gestation from January 1, 2016, to February 21, 2023. Demographic data were collected including gestational age, mode of delivery, and comorbidities. The timing of TXA administration and differences in TXA timing by mode of delivery were also collected. RESULTS: In our cohort, 21,433 patients (1.39%) received TXA. The majority of patients who received TXA were between ages 25 and 34 years old (55.3%), White (60.7%), and delivered between 37 and 416/7 weeks (81.4%). The TXA group had a higher prevalence of medical comorbidities including obesity (32.9 vs. 19.0%, p < 0.00001), preeclampsia (19.6 vs. 6.81%, p < 0.00001), and pregestational diabetes (3.27 vs. 1.36%, p < 0.00001). Among women who received TXA, 15.4% received it within 3 hours before delivery. Among patients who received TXA after delivery, 23.6% received TXA within 3 hours after delivery, whereas 35.7% received TXA between 10 and 24 hours after delivery. A total of 80.4% of patients who received TXA before delivery had a cesarean delivery. CONCLUSION: While TXA is most commonly administered after delivery, many patients are receiving TXA prior to delivery in the United States without clear evidence to guide the timing of administration. A randomized trial is urgently needed to determine the safety and efficacy of TXA when administered prior to delivery. KEY POINTS: · TXA is used in the treatment of PPH.. · The role of TXA in prevention of PPH is unclear.. · Fewer than 2% of patients in the United States receive TXA at delivery.. · TXA administration before delivery in the United States is rising..

The correlation of non-invasive hemoglobin testing and lab hemoglobin in surgical patients: A systematic review and meta-analysis.

BACKGROUND: The decision regarding intraoperative transfusion has traditionally been based on hemodynamic instability and estimated blood loss. We performed a systematic review to determine the validity of the oximetry method compared to standard of care for hemoglobin measurement. METHODS: A systematic literature review was conducted, and several libraries were searched from inception to March 31,2023. The primary outcome was comparing the mean difference between laboratory-derived hemoglobin and non-invasive, point-of-care hemoglobin measurement. Subgroup analysis included comparing the mean difference in the pediatric population and among female patients. RESULTS: A total of 276 studies were identified, and 37 were included. We found that the pooled mean difference varied qualitatively between adult and pediatric population (p value for heterogeneity <0.001). In adult populations, lab hemoglobin measurements were on average slightly higher than non-invasive measurements (mean difference = 0.23; 95% CI -0.13, 0.59), though there was greater heterogeneity across studies (I2 = 97%, p value = <0.001). In the pediatric population, most studies showed lab hemoglobin to be slightly lower (mean difference = -0.42; 95% CI -0.87 to 0.03). CONCLUSIONS: In general, there was no clinically significant difference in mean hemoglobin among adult and pediatric populations. The percentage of female participants had no effect on the mean difference in hemoglobin.

Pharmacoethics and pregnancy: Overcoming the therapeutic orphan stigma.

There is paucity of evidence to support clinical decision making and counselling related to medication use in pregnancy. Despite multiple efforts from legislative bodies and advocacy groups, the inclusion of pregnant women in clinical drug trials assessing efficacy and safety remains scarce. Pregnancy can be complicated by multiple comorbidities that require pharmacological intervention; these interventions primarily target the pregnant woman but also sometimes have secondary effects for the foetus. The US Food and Drug Administration has issued multiple guidance documents on incorporating pregnant women in clinical trials to aid pharmaceutical companies in designing a protocol to ensure safety and adherence to ethical standards. Advances in paediatric pharmacology studies provide lessons for researchers on the best practice of designing clinical trials with inclusion of patients from special populations. In this review, we present the status of pregnant women in clinical trials, highlighting the ethical stigma and possible future directives.

Impact of anemia and thrombocytopenia on postpartum hemorrhage risk among women with term singleton pregnancy.

Both thrombocytopenia (platelet count < 150 × 103/µL) and anemia have been associated with postpartum hemorrhage (PPH). However, the impact of thrombocytopenia on PPH risk among women with mild and severe anemia is unknown. We sought to evaluate the association between thrombocytopenia and anemia in increasing risk of PPH. We performed a secondary analysis of a retrospective cohort of pregnant women from 19 hospitals across the United States from 2016 to 2021. Women who had a term singleton pregnancy and hematocrit (Hct) ≤ 33% at delivery were included in the study. The primary outcome was PPH (defined as blood loss ≥ 1000 mL or blood transfusion). We also analyzed the effect of severe anemia (Hct < 28%) on the association between PPH and thrombocytopenia. Chi-squared tests and Fisher's exact tests were used for categorical variables and an independent t-test was used for continuous variables. There were 20,808 women who met our inclusion criteria, of which 1793 (8.6%) had platelet count < 150 × 103/µL. The prevalence of PPH was 6.4%. Compared with women with normal platelet count, those with thrombocytopenia had 1.3-fold higher odds of PPH [6.8% vs. 4.5%, adjusted OR 1.3 (1.1-1.7)]. Platelet count ≥ 150 × 103/µL was associated with decreased odds of PPH among patients with hct between 28 and 33% and hct < 28%. In conclusion, anemic women with term singleton pregnancies who delivered with thrombocytopenia had a higher frequency of PPH. Normal platelet count at delivery was protective against PPH in the setting of anemia regardless of severity.

Recent trends in tranexamic acid use during postpartum hemorrhage in the United States.

INTRODUCTION: Postpartum hemorrhage (PPH) was the second leading cause of maternal death, accounting for approximately 14% of all pregnancy-related deaths between 2017 and 2019 in the United States. Several large multi-center studies have demonstrated decreased PPH rates with the use of tranexamic acid (TXA). Little data exists regarding the prevalence of TXA use in obstetric patients. METHODS: We identified over 1.2 million US pregnancies between January 1, 2015 and June 30, 2021, with and without PPH by International Statistical Classification of Disease and Related Health Problems, Tenth Revision codes using Cerner Real-World Database™. TXA use and patient characteristics were abstracted from the electronic medical record. RESULTS: During delivery, TXA was used approximately 1% of the time (12,394 / 1,262,574). Pregnant patients who did and did not receive TXA during delivery had similar demographic characteristics. Pregnant patients who underwent cesarean delivery (4,356 / 12,394), had a term delivery (10,199 / 12,394), and had comorbid conditions were more likely to receive TXA during hospitalization for delivery. The majority of TXA was use was concentrated in Arizona, Colorado, Idaho, New Mexico, Nevada, Utah, and Wyoming. During the study period the use of TXA increased in both patients with PPH and those without. CONCLUSION: The data illustrate a rapid increase in the use of TXA after 2017 while the total number of pregnancies remained relatively constant. The observed increase in TXA use may reflect changing practicing patterns as the support for use of TXA in the setting of PPH prophylaxis increases.

Tranexamic acid for the prevention of postpartum hemorrhage: a cost-effectiveness analysis.

Postpartum hemorrhage is a significant contributor to maternal mortality worldwide and in the United States. Tranexamic acid (TXA) has been shown to reduce PPH complications although it is not routinely recommended for use as prophylaxis to date. To estimate the cost-effectiveness of alternative risk-dictated strategies utilizing prophylactic tranexamic acid for the prevention of postpartum hemorrhage. We constructed a microsimulation-based Markov decision-analytic model estimating the cost-effectiveness of three alternative risk-dictated strategies for tranexamic acid prophylaxis versus the no prophylaxis in a cohort of 3.8 million pregnant women delivering in the United States. Each strategy differentially modified risk-specific hemorrhage probabilities by preliminary estimates of tranexamic acid's prophylactic efficacy. Outcome measures included incremental costs, quality-adjusted life-years, and outcomes averted. Costs and benefits were considered from the healthcare system and societal perspectives over a lifetime time horizon. All intervention strategies were dominant versus no prophylaxis, implying that they were simultaneously more effective and cost-saving. Prophylaxing delivering women irrespective of hemorrhage risk produced the most favorable results overall, with estimated cost savings greater than $690 million and up to 149,505 PPH cases, 2,933 hysterectomies, and 70 maternal deaths averted, per annual cohort. Threshold analysis suggested that tranexamic acid is likely to be cost-saving for health systems at costs below $190 per gram. Our findings suggest that routine prophylaxis with tranexamic acid would likely result in substantial cost-savings and reductions in adverse maternal outcomes in this context. This study is a cost-effectiveness analysis demonstrating cost-savings and reduction in adverse maternal outcomes with routine tranexamic acid as prophylaxis for post-partum hemorrhage.

Optimal use of intravenous tranexamic acid for hemorrhage prevention in pregnant women.

BACKGROUND: Every 2 minutes, there is a pregnancy-related death worldwide, with one-third caused by severe postpartum hemorrhage. Although international trials demonstrated the efficacy of 1000 mg tranexamic acid in treating postpartum hemorrhage, to the best of our knowledge, there are no dose-finding studies of tranexamic acid on pregnant women for postpartum hemorrhage prevention. OBJECTIVE: This study aimed to determine the optimal tranexamic acid dose needed to prevent postpartum hemorrhage. STUDY DESIGN: We enrolled 30 pregnant women undergoing scheduled cesarean delivery in an open-label, dose ranging study. Subjects were divided into 3 cohorts receiving 5, 10, or 15 mg/kg (maximum, 1000 mg) of intravenous tranexamic acid at umbilical cord clamping. The inclusion criteria were ≥34 week's gestation and normal renal function. The primary endpoints were pharmacokinetic and pharmacodynamic profiles. Tranexamic acid plasma concentration of >10 µg/mL and maximum lysis of <17% were defined as therapeutic targets independent to the current study. Rotational thromboelastometry of tissue plasminogen activator-spiked samples was used to evaluate pharmacodynamic profiles at time points up to 24 hours after tranexamic acid administration. Safety was assessed by plasma thrombin generation, D-dimer, and tranexamic acid concentrations in breast milk. RESULTS: There were no serious adverse events including venous thromboembolism. Plasma concentrations of tranexamic acid increased in a dose-proportional manner. The lowest dose cohort received an average of 448±87 mg tranexamic acid. Plasma tranexamic acid exceeded 10 µg/mL and maximum lysis was <17% at >1 hour after administration for all tranexamic acid doses tested. Median estimated blood loss for cohorts receiving 5, 10, or 15 mg/kg tranexamic acid was 750, 750, and 700 mL, respectively. Plasma thrombin generation did not increase with higher tranexamic acid concentrations. D-dimer changes from baseline were not different among the cohorts. Breast milk tranexamic acid concentrations were 1% or less than maternal plasma concentrations. CONCLUSION: Although large randomized trials are necessary to support the clinical efficacy of tranexamic acid for prophylaxis, we propose an optimal dose of 600 mg in future tranexamic acid efficacy studies to prevent postpartum hemorrhage.

Population pharmacokinetics and pharmacodynamics of Tranexamic acid in women undergoing caesarean delivery.

AIMS: The population pharmacokinetics (PK) and pharmacodynamics (PD) of tranexamic acid (TXA) have not been studied to prevent postpartum haemorrhage (PPH) in pregnant women. It is unclear which TXA dose assures sufficient PPH prevention. This study investigated population PK/PD of TXA in pregnant women who underwent caesarean delivery to determine the optimal prophylactic doses of TXA for future studies. METHODS: We analysed concentration (PK) and maximum lysis (PD) data from 30 pregnant women scheduled for caesarean delivery who received 5, 10 or 15 mg/kg of TXA intravenously using population approach. RESULTS: TXA PK was best described by a two-compartment model with first-order elimination and the following parameters: clearance (between-subject variability) of 9.4 L/h (27.7%), central volume of 10.1 L (47.4%), intercompartmental clearance of 22.4 L/h (66.7%), peripheral volume of 14.0 L (13.1%) and additive error of 1.4 mg/L. The relationship between TXA concentration and maximum lysis was characterized by a sigmoid Emax model with baseline lysis of 97%, maximum inhibition of 89%, IC50 of 6.0 mg/L (65.3%), hill factor of 8.5 (86.3%) and additive error of 7.3%. Simulations demonstrated that 500 and 650 mg of TXA maintained therapeutic targets for 30 minutes and 1 hour, respectively, in 90% of patients. CONCLUSION: This is the first population PK and PD study of TXA in pregnant women undergoing caesarean delivery. Our analysis suggests that a 650 mg dose provides adequate PPH prophylaxis up to 1 hour, which is less than the currently used 1000 mg of TXA in pregnant women.

Hemorrhage Risk Assessment on Admission: Utility for Prediction of Maternal Morbidity.

OBJECTIVE: Hemorrhage is a major cause of maternal morbidity and mortality prompting creation of innovative risk assessment tools to identify patients at highest risk. We aimed to investigate the association of hemorrhage risk assessment with maternal morbidity and to evaluate maternal outcomes after implementation of the risk assessment across hospital sites. STUDY DESIGN: We conducted a retrospective cohort analysis of a multicenter database including women admitted to labor and delivery from January 2015 to June 2018. The Association of Women's Health, Obstetric and Neonatal Nurses risk assessment tool was used to categorize patients as low, medium, or high risk for hemorrhage. Multivariate logistic regression was used to describe the association between hemorrhage risk score and markers of maternal morbidity and evaluate maternal outcomes before and after standardized implementations of the risk assessment tool. RESULTS: In this study, 14,861 women were categorized as low risk (26%), 26,080 (46%) moderate risk, and 15,730 (28%) high risk (N = 56,671 births). For women with high-risk scores, the relative risk (RR) ratio compared with low-risk women was 4.9 (RR: 95% confidence interval [CI]: 3.2-7.4) for blood transfusion and 5.2 (RR: 95% CI: 4.6-5.9) for estimated blood loss (EBL) ≥ 1,000 mL. For the second objective, 110,633 women were available for pre- and postimplementation analyses (39,027 and 71,606, respectively). A 20% reduction in rates of blood transfusion (0.5-0.4%, p = 0.02) and EBL ≥ 1,000 mL (6.3-5.9%, p = 0.014) was observed between pre- and postimplementations of the admission hemorrhage risk assessment tool. CONCLUSION: Women who were deemed high risk for hemorrhage using a hemorrhage risk assessment tool had five times higher risk for blood transfusion and EBL ≥ 1,000 mL compared with low-risk women. Given the low incidence of the outcomes explored, the hemorrhage risk assessment works moderately well to identify patients at risk for peripartum morbidity. KEY POINTS: · This study aimed to understand the utility of the AWOHNN hemorrhage risk assessment tool for predicting hemorrhage-related morbidity and to evaluate maternal outcomes before and after tool implementations.. · A high score using a hemorrhage risk assessment tool on admission is associated with five times higher risk for blood transfusion and/or estimated blood loss ≥ 1,000 mL, compared with a low score.. · Use of a hemorrhage risk assessment tool works moderately well to identify patients at highest risk for hemorrhage-related morbidity..

Expanding Access to Fetal Telecardiology During the COVID-19 Pandemic.

Background: This study aims to describe one center's experience in expanding a fetal telecardiology program through collaborative work with maternal fetal medicine (MFM) clinics with the goal of safely reaching mothers during the COVID-19 pandemic. We sought to define the extent of fetal telehealth conversion at a large fetal cardiac care center and evaluate the diagnostic accuracy for studies performed. Methods: At our center, fetal telemedicine expanded from one MFM site before the pandemic to four additional sites by May 2020. A retrospective review of fetal telecardiology visits between March 15 and July 15, 2020, was performed. The chart was reviewed for confirmation of diagnosis postnatally. Results: With pandemic onset, there was a large increase in the number of telemedicine visits with a total of 122 mothers seen between five MFM clinics. Fourteen mothers (11.5%) had abnormal fetal echocardiograms requiring additional follow-up, and seven mothers (5.8%) had a fetal echocardiogram suspicious for a critical congenital heart disease (CCHD). All the fetal echocardiograms suspicious for CCHD were confirmed on postnatal echocardiogram. To our knowledge, none of the normal fetal echocardiograms were found to have congenital heart disease postnatally. Conclusions: In response to the COVID-19 pandemic, we rapidly transitioned to fetal telecardiology using a variety of formats. This has reduced potential infectious exposure for pregnant mothers and minimized contact between physicians without compromising diagnostic accuracy. In our experience, the expansion of a telemedicine program requires strong initial infrastructure, prior relationships with MFM providers, and appropriate training among obstetric sonographers.

Blood type association with bleeding outcomes at delivery in a large multi-center study.

Postpartum hemorrhage is a leading cause of maternal death globally. Recent studies have associated Type-O group to increased risk of bleeding. We aimed to determine if women with Type-O blood are at higher risk of PPH. This is a retrospective cohort analysis of a multi-center database included women admitted to labor and delivery from January 2015 to June 2018. All deliveries resulting in live birth were included. Association between Type-O and non Type-O were examined using chi-square test and fishers exact test. Prevalence of postpartum hemorrhage, estimated blood loss, drop in hematocrit and red blood cell transfusion were compared. The matched sample included 40,964 Type-O and the same number of no Type-O. The overall prevalence of postpartum hemorrhage was 6.4%, and there was no difference in the prevalence of PPH among Type-O compared to non Type-O (6.38% vs. 6.37% respectively; p = 0.96). There was no difference in hematocrit drop and estimated blood loss between Type-O and non Type-O in all deliveries. However, in cesarean delivery there was a significant difference in blood loss among the two groups. Finally, Type-O had 1.09-fold increased risk for transfusion compared to non Type O (95% CI 0.9-1.34). There is an association between Type-O group and risk of bleeding in women undergoing cesarean delivery. More prospective studies, taking into account coagulation profile, platelet count and tissue factors, are needed to draw a conclusion on whether ABO system can be considered a heritable risk of postpartum hemorrhage.

National trends in tranexamic acid use in the peripartum period, 2015-2019.

BACKGROUND: The purpose of this study was to measure trends in the use of tranexamic acid (TXA) during delivery in the United States and to evaluate demographic data and morbidity outcomes among these patients. METHODS: This retrospective cohort study includes data from 19 hospitals in the Universal Health Services network. We compared rates of TXA use between January 2015 and June 2019 across geographic sectors. We also evaluated associations of demographic variables and perinatal outcomes of women who received TXA. RESULTS: 209 cases of TXA use were found from analysis of 101,564 deliveries. TXA use increased over time and rates were higher in the West than in Central and East; the slope of increase over years did not differ between regions. Women who received TXA were more likely to have a history of postpartum hemorrhage (59 (28.2%) vs. 2290 (2.2%), P < 0.0001) but were not more likely to have a chronic disease, including diabetes mellitus, hypertension and heart disease. Women who received TXA were more likely to have estimated blood loss greater than or equal to 1000 mL (adjusted odds ratio (aOR) 15.3; 95% CI 11.1-21.1; P < 0.0001). Likelihood of venous thromboembolism was not significantly increased in TXA recipients (aOR 2.0; 95% CI 0.3-14.6; P = 0.49). CONCLUSION: Increasing national trends of TXA use in the peripartum period was observed, with variable increases by geographic region. Likelihood of venous thromboembolism was not significantly increased among women who received TXA. Increasing TXA use throughout the country suggests that updated hemorrhage guidelines from national obstetrical organizations can shape clinical practice.

Fetal acute cerebral vasoreactivity to maternal hyperoxia in low-risk pregnancies: a cross-sectional study.

OBJECTIVE: To establish whether fetal cerebral vasoreactivity (CVRO2 ), following maternal hyperoxia, is predicted by fetal cerebral and uteroplacental Doppler pulsatility indices (PI) at baseline, fetal pulmonary vasoreactivity to oxygen (PVRO2 ), gestational age (GA), or sex. METHODS: Pulsatility index of middle (MCA), anterior (ACA), posterior cerebral (PCA), umbilical (UA), uterine (UtA), and branch of the pulmonary arteries (PA) were obtained, by ultrasound, before (baseline), during (hyperoxia) and after 15 minutes of maternal administration of 8 L/min of 100% oxygen, through a non-rebreathing face mask, in normal singleton pregnancies within 20 to 38 weeks' gestation. CVRO2 was defined as changes greater than zero in z score of PI of the cerebral arteries from baseline to hyperoxia. Logistic modeling was applied to identify CVRO2 predictors. RESULTS: A total of 97 pregnancies were eligible. In the overall population, median z scores of PI of MCA, ACA, and PCA did not differ between study phases. Based on the logistic model, baseline z scores for cerebral PI and GA were the best predictors of CVRO2 . CONCLUSIONS: In low-risk pregnancies, fetal CVRO2 to hyperoxia does not occur uniformly but depends on cerebral PI and GA at baseline. These findings may provide useful reference points when oxygen is administered in high-risk pregnancies.

Anatomical and physiological alterations of pregnancy.

The extensive metabolic demands of pregnancy require specific physiological and anatomical changes. These changes affect almost all organ systems, including the cardiovascular, respiratory, renal, gastrointestinal, and hematologic system. The placenta adds another layer of complexity. These changes make it challenging for clinicians to understand presenting signs and symptoms, or to interpret laboratory and radiological tests. Furthermore, these physiological alterations can affect the pharmacokinetics and pharmacodynamics of drugs. Drug safety in lactation is only supported by limited evidence. In addition, the teratogenic effects of medications are often extrapolated from animals, which further adds uncertainties. Unfortunately, pregnant women are only rarely included in clinical drug trials, while doses, regimens, and side effects are often extrapolated from studies conducted in non-pregnant populations. In this comprehensive review, we present the changes occurring in each system with its effects on the pharmacokinetic variables. Understanding these physiological changes throughout normal pregnancy helps clinicians to optimize the health of pregnant women and their fetuses. Furthermore, the information on pregnancy-related physiology is also critical to guide study design in this vulnerable 'orphan' population, and provides a framework to explore pregnancy-related pathophysiology such as pre-eclampsia.

Fetal intracranial hemorrhage: role of fetal MRI.

OBJECTIVE: To date, prenatal diagnosis of intracranial hemorrhage (ICH) is mainly based on ultrasound (US) findings rather than magnetic resonance imaging (MRI). We aimed to investigate the role of MRI in the diagnosis of fetal ICH among pregnancies referred to fetal MRI and to characterize the topography of fetal ICH using MRI. METHODS: We retrospectively identified fetal ICH cases diagnosed by MRI from 2008 to 2015 and reviewed their prenatal and postnatal medical records. RESULTS: Of the 2638 MRIs performed during the study period, 36 had ICH (median age 27 weeks). The most common US indication for MRI was a suspected cerebral anomaly (86%): 20 (55%) fetuses were referred for ventriculomegaly, 8 (22%) for ICH, and the other 8 had a variety of different indications. We distinguished two broad topographic patterns: (1) those related to hemorrhage of the periventricular germinal matrix (GMH, n = 24; 67%) and (2) those not related to GMH (non-GMH, n = 12; 33%). GMH fetuses were referred to MRI later (median 28 vs 22 weeks, p = 0.005). Intrauterine demise was more frequent in non-GMH (58% vs 4%, p < 0.001). CONCLUSION: Magnetic resonance imaging is an important tool in prenatal diagnosis of ICH, especially when US describes nonspecific intracranial abnormalities. GMH occurs more frequently and later in pregnancy than non-GMH. © 2017 John Wiley & Sons, Ltd.

Development of a Generic Fetal Physiologically Based Pharmacokinetic Model and Prediction of Human Maternal and Fetal Organ Concentrations of Cefuroxime.

BACKGROUND AND OBJECTIVE: Physiologically based pharmacokinetic (PBPK) models for pregnant women have recently been successfully used to predict maternal and umbilical cord pharmacokinetics (PK). Because there is very limited opportunity for conducting clinical and PK investigations for fetal drug exposure, PBPK models may provide further insights. The objectives of this study were to extend a whole-body pregnancy PBPK model by multiple compartments representing fetal organs, and to predict the PK of cefuroxime in the maternal and fetal plasma, the amniotic fluid, and several fetal organs. METHODS: To this end, a previously developed pregnancy PBPK model for cefuroxime was updated using the open-source software Open Systems Pharmacology (PK-Sim®/MoBi®). Multiple compartments were implemented to represent fetal organs including brain, heart, liver, lungs, kidneys, the gastrointestinal tract (GI), muscles, and fat tissue, as well as another compartment lumping organs and tissues not explicitly represented. RESULTS: This novel PBPK model successfully predicted cefuroxime concentrations in maternal blood, umbilical cord, amniotic fluid, and several fetal organs including heart, liver, and lungs. Further model validation with additional clinical PK data is needed to build confidence in the model. CONCLUSIONS: Being developed with an open-source software, the presented generic model can be freely re-used and tailored to address specific questions at hand, e.g., to assist the design of clinical studies in the context of drug research or to predict fetal organ concentrations of chemicals in the context of fetal health risk assessment.

Venous Thromboembolism Risk Factors in Women With Obesity Who Undergo Cesarean Delivery.

Venous thromboembolism (VTE) is a leading cause of maternal mortality. Obesity and cesarean delivery are established risk factors for pregnancy-related VTE. We identified additional risk factors among patients with obesity who underwent a cesarean delivery to identify those who need VTE prophylaxis. We conducted a secondary analysis of data from the Maternal-Fetal Medicine Units Network (MFMU) Cesarean Registry Database using a case-control design. Cases were identified as women with obesity having a pre-pregnancy body mass index of >30 kg/m2, who underwent cesarean delivery and subsequently developed deep venous thrombosis (DVT) or pulmonary embolism (PE). These women were compared to a control group of women with obesity who underwent cesarean delivery but did not develop DVT or PE. Analysis of risk factors associated with VTE was performed using Chi-Square test and Fisher's exact test. We identified 43 VTE cases and 172 controls in the MFMU database. Increased risk of VTE was noted in women with endometritis (OR of 4.58 [95% CI: 1.86-11.2, P = .0004]), receiving a blood transfusion (OR 17.07 [95% CI: 4.46-65.3, P = .0001]), having a coagulopathy (OR 27.73 [95% CI: 3.24-237.25, P = .0003]), and urinary tract infection (OR 2.39 [95% CI: 1.08-5.28, P = .03]). Important risk factors for VTE in women with obesity who undergo cesarean delivery include endometritis, intra- or post-operative transfusion, coagulopathy, and urinary tract infection. The presence of one or more of these factors may help guide provider decision-making regarding whether to administer thromboprophylaxis.