Pregnancy after deceased donor vs living donor kidney transplant: associated obstetric and graft outcomes.

BACKGROUND: Outside of pregnancy, recipients of a deceased donor kidney transplant experience worse graft and overall survival compared with recipients of a living donor kidney transplant. In pregnancy, it is unknown whether the type of donor graft modifies either graft health in the peripartum period or pregnancy outcomes. OBJECTIVE: This study aimed to define characteristics and outcomes in pregnancy based on donor type in kidney transplant recipients. STUDY DESIGN: This was a retrospective cohort study of adult kidney transplant recipients who received their graft between 2000 and 2019 with a subsequent pregnancy enrolled in the Transplant Pregnancy Registry International. The primary outcome was graft loss within 2 years of delivery. The secondary outcomes included severe maternal morbidity and neonatal composite morbidity. Univariate, multivariable logistic regression, and Cox proportional-hazards models were constructed for statistical analysis, with recipients of a living unrelated donor as the referent. RESULTS: Overall, 638 pregnant patients after kidney transplant had pregnancy outcomes that met our inclusion criteria. Of these patients, 168 (26.3%) received a graft from a deceased donor, 310 (48.6%) received a graft from a living related donor, and 160 (25.1%) received a graft from a living unrelated donor. Recipients of a deceased donor were more likely to be nulliparous, have an unplanned pregnancy, and self-identify as non-White. Moreover, recipients of a deceased donor were more likely to experience urinary tract infections (deceased donor: 21.8%; living related donor: 10.1%; living unrelated donor: 20.6%; P=.018). Severe maternal morbidity (deceased donor: 3.4%; living related donor: 2.8%; living unrelated donor: 7.2%) and neonatal composite morbidity (deceased donor: 8.4%; living related donor: 17.1%; living unrelated donor: 14.4%) did not differ by donor type. Deceased donor transplant was associated with graft loss within 2 years of delivery (deceased donor: 6.7%; living related donor: 3.7%; living unrelated donor: 1.3%; adjusted odds ratio, 7.52; 95% confidence interval, 1.53-60.8) and long-term graft loss from transplant (adjusted hazard ratio, 2.08; 95% confidence interval, 1.10-3.95). CONCLUSION: Although our study demonstrated an association between deceased donor transplant and graft loss after pregnancy, it did not provide evidence that pregnancy itself causes graft loss. Recipients of a deceased donor kidney transplant should not be discouraged from pursuing pregnancy based on their donor type, but these patients should undergo preconception counseling with a discussion of their individualized obstetrical and graft risks, close intrapartum monitoring for infection and hypertensive disease, and continued surveillance for at least 2 years after delivery with a multidisciplinary obstetrics and transplant team.

Outcomes of pregnancy in autoimmune hepatitis: A population-based study.

BACKGROUND AND AIMS: Autoimmune hepatitis (AIH) disproportionately affects young women, which may have implications in pregnancy. However, data on pregnancy outcomes in women with AIH are limited. APPROACH AND RESULTS: Using weighted discharge data from the United States National Inpatient Sample from 2012 to 2016, we evaluated pregnancies after 20 weeks gestation and compared outcomes in AIH to other chronic liver diseases (CLD) or no CLD in pregnancy. The association of AIH with maternal and perinatal outcomes was assessed by logistic regression. Among 18,595,345 pregnancies, 935 (<0.001%) had AIH (60 with cirrhosis) and 120,100 (0.006%) had other CLD (845 with cirrhosis). Temporal trends in pregnancies with AIH remained stable from 2008 to 2016 with 1.4-6.8/100,000 pregnancies per year (p = 0.25). On adjusted analysis, the odds of gestational diabetes (GDM) and hypertensive complications (pre-eclampsia, eclampsia, or hemolysis, elevated liver enzymes, low platelets) were significantly higher in AIH compared to other CLD (GDM: OR 2.2, 95% CI: 1.5-3.9, p < 0.001; hypertensive complications: OR: 1.8, 95% CI: 1.0-3.2, p = 0.05) and also compared to no CLD in pregnancy (GDM: OR: 2.4, 95% CI: 1.6-3.6, p < 0.001; hypertensive complications: OR: 2.4, 95% CI: 1.3-4.1, p = 0.003). AIH was also associated with preterm births when compared with women without CLD (OR: 2.0, 95% CI: 1.2-3.5, p = 0.01). AIH was not associated with postpartum hemorrhage, maternal, or perinatal death. CONCLUSIONS: Rates of pregnancy in women with AIH have remained stable in recent years, although AIH is associated with notable maternal and perinatal risks, such as GDM, hypertensive complications, and preterm birth. Whether these risks are influenced by steroid use and/or AIH disease activity warrants evaluation. These data support a low risk of postpartum hemorrhage and favorable survival of mothers and infants.

Society for Maternal-Fetal Medicine Consult Series #66: Prepregnancy evaluation and pregnancy management of patients with solid organ transplants.

The rate of solid organ transplant in reproductive-aged patients has increased in the past 3 decades. Concurrently, the range of medical immunosuppressive agents has increased, making it safer for reproductive-aged individuals who have received transplants to attempt and continue a pregnancy. In this Consult, we review the general considerations and contemporary approach to medical and obstetrical management of pregnant solid organ transplant recipients, discuss the perinatal outcomes and incidence of graft rejection specific to the most common types of organ transplants, and provide management recommendations based on the available evidence. The following are Society for Maternal-Fetal Medicine recommendations: (1) we recommend that all solid organ transplant recipients capable of pregnancy be offered prepregnancy counseling as part of the pretransplant evaluation and before any posttransplant pregnancy (Best Practice); (2) we recommend deferring pregnancy for at least 1 year (except for lung transplant recipients in which case a 2-year deferral is recommended) following solid organ transplant or any episode of acute cellular rejection (GRADE 1B); (3) we recommend that solid organ transplant recipients have stable allograft function and optimal control of chronic medical comorbidities before attempting pregnancy (GRADE 1B); (4) we recommend that solid organ transplant recipients of reproductive age use highly effective contraception when on mycophenolate or other immunosuppressive agents with known teratogenic risk (GRADE 1A); (5) we recommend that solid organ transplant recipients contemplating pregnancy transition to an appropriate immunosuppressive regimen before attempting pregnancy to establish stable medication dosing and allograft function (GRADE 1C); (6) we recommend close monitoring of serum drug levels during pregnancy and the postpartum period to guide immunosuppressive therapy dosing (GRADE 1C); (7) we recommend that solid organ transplant recipients who are pregnant or contemplating pregnancy receive all indicated vaccinations before and during pregnancy (GRADE 1C); (8) given the risk of fetal and neonatal sequelae secondary to cytomegalovirus infection in pregnancy, we suggest that solid organ transplant recipients ideally complete any indicated antiviral prophylaxis or treatment before pursuing pregnancy (GRADE 2B); (9) we recommend daily low-dose aspirin prophylaxis to reduce the risk for preeclampsia in pregnant solid organ transplant recipients and to reduce the risk for renal allograft failure in renal transplant recipients (GRADE 1C); (10) as for all pregnant people, we recommend that pregnant solid organ transplant recipients have access to mental health specialists and receive screening for depression during pregnancy and the postpartum period (Best Practice); (11) because of the increased incidence of fetal growth restriction and common coexisting medical morbidities, we recommend serial assessment of fetal growth every 4 to 6 weeks throughout gestation after the anatomic survey (GRADE 1C); (12) we suggest antenatal surveillance from 32 weeks of gestation unless other fetal or maternal factors are identified in which case initiation of surveillance at an earlier gestational age is indicated (GRADE 2C); (13) we recommend that renal function be assessed before pregnancy or in early pregnancy in all solid organ transplant recipients (kidney and non-kidney) (GRADE 1C); (14) we suggest individualized delivery timing for pregnant solid organ transplant recipients and to consider delivery at between 37+0/7 and 39+6/7 weeks of gestation; in the absence of other indications, we suggest delivery by 39+6/7 weeks gestation for pregnant solid organ transplant recipients (GRADE 2B); (15) given that a trial of labor is associated with a high success rate and lower neonatal morbidity without increasing maternal morbidity or compromising graft survival, we recommend that cesarean delivery be reserved for medical obstetrical indications in solid organ transplant recipients (GRADE 1C); (16) we recommend that blood pressure targets in pregnant renal transplant recipients with chronic hypertension follow guidelines for nonpregnant recipients with a target blood pressure of ≤130/80 mm Hg (GRADE 1C); (17) we recommend monthly urine cultures to screen for asymptomatic bacteriuria with treatment if positive to protect the graft in pregnant renal transplant recipients (GRADE 1C); (18) we recommend that pregnancies in pancreas-kidney transplant recipients be managed in a similar way as those of renal transplant recipients alone (GRADE 1C); (19) we recommend characterizing the underlying condition that led to liver transplantation and assessing baseline renal function in pregnant liver transplant recipients. (GRADE 1C); (20) because of the cardiovascular demand of pregnancy and the unique physiological implications of cardiac transplantation, we recommend that pregnant heart transplant recipients receive multidisciplinary care with cardiology, cardiac and/or obstetrical anesthesiology, and maternal-fetal medicine specialists (Best Practice); and (21) we recommend careful delivery planning to minimize hemodynamic stress (including considering operative vaginal delivery to minimize Valsalva) and suggest continuous intrapartum or intraoperative electrocardiographic monitoring for heart transplant recipients (GRADE 1C).

Pregnancies With Cirrhosis Are Rising and Associated With Adverse Maternal and Perinatal Outcomes.

INTRODUCTION: Cirrhosis incidence in pregnancies from outside the United States (US) is rising, although contemporary data including maternal and perinatal outcomes within the United States are lacking. METHODS: Using discharge data from the racially diverse US National Inpatient Sample, temporal trends of cirrhosis in pregnancies were compared with noncirrhotic chronic liver disease (CLD) or no CLD. Outcomes included preterm birth, postpartum hemorrhage, hypertensive complications (preeclampsia, eclampsia, and/or hemolysis, elevated liver enzymes, and low platelets syndrome), and maternal or fetal death. Logistic regression was adjusted for age, race, multiple gestation, insurance status, and prepregnancy metabolic comorbidities. RESULTS: Among 18,573,000 deliveries from 2012 to 2016, 895 had cirrhosis, 119,875 had noncirrhotic CLD, and 18,452,230 had no CLD. Pregnancies with cirrhosis increased from 2.5/100,000 in 2007 to 6.5/100,000 in 2016 (P = 0.01). On adjusted analysis, cirrhosis was associated with hypertensive complications (vs no CLD, OR 4.9, 95% confidence intervals [CI] 3.3-7.4; vs noncirrhotic CLD, OR 4.4, 95% CI 3.0-6.7), postpartum hemorrhage (vs no CLD, OR 2.8, 95% CI 1.6-4.8; vs noncirrhotic CLD, OR 2.0, 95% CI 1.2-3.5), and preterm birth (vs no CLD, OR 3.1, 95% CI 1.9-4.9; vs noncirrhotic CLD, OR 2.0, 95% CI 1.3-3.3, P ≤ 0.01). Cirrhosis was statistically associated with maternal mortality, although rarely occurred (≤ 1%). DISCUSSION: In this racially diverse, US population-based study, pregnancies with cirrhosis more than doubled over the past decade. Cirrhosis conferred an increased risk of several adverse events, although maternal and perinatal mortality was uncommon. These data underscore the need for reproductive counseling and multidisciplinary pregnancy management in young women with cirrhosis.

Rates of Cesarean Conversion and Associated Predictors and Outcomes in Planned Vaginal Twin Deliveries.

OBJECTIVE: Twin vaginal deliveries (VDs) are often performed in the operating room (OR) given the risk of conversion to cesarean delivery (CD) for the aftercoming twin. We aim to investigate the rates of conversion to CD for planned twin VDs and identify predictors and outcomes of conversion. STUDY DESIGN: A retrospective cohort study of all women who underwent a planned twin VD at two large academic medical centers over 4 years. Demographic and outcome data were chart abstracted. Various statistical tests were used to evaluate the influence of perinatal variables on mode of delivery and identify possible predictors of conversion. RESULTS: Eight hundred and eighty-five twin deliveries were identified, of which 725 (81.9%) were possible candidates for VD. Of those, 237 (32.7%) underwent successful VD of twin A. Ninety-five (40.1%) had a nonvertex second twin at time of delivery. Conversion to CD occurred in 10 planned VDs (4.2%). Conversions were higher with spontaneous labor (relative risk [RR]: 2.1; 95% confidence interval [CI] 1.6-2.7; p = 0.003), and having an intertwin delivery interval greater than 60 minutes (RR: 5.1; 95% CI: 2.5-10.8; p < 0.001). Nonvertex presentation of twin B, type of delivery provider, or years out in practice of delivery provider were not significantly different between groups. There were no significant differences in neonatal outcomes between VD and conversion groups. There was a significant association between use of forceps for twin B and successful VD (p = 0.02), with 84.6% in the setting of a nonvertex twin B. CONCLUSION: Successful VD was achieved in planned VD of twins in 95.8% of cases, and there were no significant differences in maternal and fetal outcomes between successful VD and conversion to CD for twin B. With the optimal clinical scenario and shared decision-making, performing vaginal twin deliveries in labor and delivery rooms should be discussed. KEY POINTS: · There is a propensity to perform twin vaginal deliveries in the operating room.. · Rates of conversion to cesarean section are very low.. · There are no significant differences in perinatal outcomes with conversion..

Non-alcoholic fatty liver disease in pregnancy is associated with adverse maternal and perinatal outcomes.

BACKGROUND & AIMS: The prevalence of non-alcoholic fatty liver disease (NAFLD) is rising in young adults, with potential implications for reproductive-aged women. Whether NAFLD during pregnancy confers more serious risks for maternal or perinatal health is unclear. METHODS: Using weighted discharge data from the US national inpatient sample, we evaluated temporal trends of NAFLD in pregnancies after 20 weeks gestation, and compared outcomes to pregnancies with other chronic liver diseases (CLDs) or no CLD. Study outcomes included preterm birth, postpartum hemorrhage, hypertensive complications (pre-eclampsia, eclampsia, and/or hemolysis, elevated liver enzymes, and low platelets syndrome), and maternal or fetal death. NAFLD prevalence was estimated by calendar year and temporal trends tested by linear regression. Outcomes were analyzed by logistic regression adjusted for age, race, multiple gestation, and pre-pregnancy diabetes, obesity, dyslipidemia and hypertension. RESULTS: Among 18,574,225 pregnancies, 5,640 had NAFLD and 115,210 had other, non-NAFLD CLD. Pregnancies with NAFLD nearly tripled from 10.5/100,000 pregnancies in 2007 to 28.9/100,000 in 2015 (p <0.001). Compared to the other groups, patients with NAFLD during pregnancy more frequently experienced gestational diabetes (7-8% vs. 23%), hypertensive complications (4% vs. 16%), postpartum hemorrhage (3-5% vs. 6%), and preterm birth (5-7% vs. 9%), all p values ≤0.01. On adjusted analysis, compared to no CLD, NAFLD was associated with hypertensive complications, preterm birth, postpartum hemorrhage and possibly maternal (but not fetal) death. CONCLUSION: The prevalence of NAFLD in pregnancy has nearly tripled in the last decade and is independently associated with hypertensive complications, postpartum hemorrhage and preterm birth. NAFLD should be considered a high-risk obstetric condition, with clinical implications for pre-conception counseling and pregnancy care. LAY SUMMARY: The prevalence of non-alcoholic fatty liver disease (NAFLD) in pregnancy has almost tripled over the past 10 years. Having NAFLD during pregnancy increases risks for both the mother and the baby, including hypertensive complications of pregnancy, bleeding after delivery, and preterm birth. Thus, pre-conception counseling is warranted with consideration of high-risk obstetric management among women with NAFLD in pregnancy.

Fetal Myocardial Function as Assessed by N-Terminal Fragment Brain Natriuretic Protein in Premature Fetuses Exposed to Intra-amniotic Inflammation.

OBJECTIVE: This study aimed to determine the relationship between fetal exposure to intra-amniotic infection/inflammation (IAI) and fetal heart ventricular function as assessed by circulatory levels of N-terminal fragment brain natriuretic protein (NT-proBNP) and the Tei index. STUDY DESIGN: We analyzed 70 samples of paired amniotic fluid (AF) and cord blood retrieved from mothers who delivered preterm at <34 weeks as follows: Yes-IAI (n = 36) and No-IAI (n = 34). IAI was diagnosed by amniocentesis and AF mass spectrometry. Fetal exposure to inflammation was determined through the evaluation of cord blood haptoglobin (Hp) switch-on status and level, and interleukin (IL)-6 levels by Western blotting and enzyme-linked immunosorbent assay, respectively. Fetal heart function was assessed by cord blood NT-proBNP immunoassay and fetal echocardiogram (Tei index). RESULTS: IAI was characterized by significantly higher levels of AF (p < 0.001) and umbilical cord IL-6 (p = 0.004). Cord blood Hp levels and frequency of switch-on status were higher in fetuses exposed to IAI (p < 0.001, both). Fetuses exposed to IAI did not have higher levels of NT-proBNP. Following correction for gestational age and race, neither cord blood NT-proBNP nor the Tei index was significantly different in fetuses with Hp switched-on status (p > 0.05, both). CONCLUSION: Fetal myocardial left ventricular function does not seem to be significantly impaired in fetuses born alive due to IAI if delivery of the fetus occurs immediately following the diagnosis of IAI.

In utero Partial Exchange Transfusion Combined with in utero Blood Transfusion for Prenatal Management of Twin Anemia-Polycythemia Sequence.

Monochorionic twin pregnancies are at risk of unique complications due to placental sharing and vascular connections between placental territories assigned for each twin. Twin anemia-polycythemia sequence (TAPS) is an infrequent but potentially dangerous complication of abnormal placental vascular connections. TAPS occurs due to very-small-caliber (< 1 mm) abnormal placental vascular connections which lead to chronic anemia in the donor twin and polycythemia in the recipient twin. TAPS may occur spontaneously or following fetoscopic laser photocoagulation of communicating placental vessels for twin-twin transfusion syndrome. One of the hallmarks of TAPS is the absence of polyhydramnios and oligohydramnios. The postnatal diagnosis is based on significant hemoglobin discrepancy between the twins. Middle cerebral artery peak systolic velocity Doppler ultrasound allows for the prenatal diagnosis of TAPS. The optimal prenatal treatment and intervention timing has not been established. Here, we report 3 spontaneous TAPS cases diagnosed and managed in the prenatal period with a combination of in utero blood transfusion for the anemic twin (donor) and in utero partial exchange transfusion for the polycythemic twin (recipient). These cases contribute to the limited outcome data of this underutilized method for the management of TAPS.

Living Donation and Pregnancy-Related Complications: State of the Evidence and Call To Action for Improved Risk Assessment.

Living kidney donation and living liver donation significantly increases organ supply to make lifesaving transplants possible, offering survival benefits to the recipients and cost savings to society. Of all living donors, 40% are women of childbearing age. However, limited data exist regarding the effect of donation on future pregnancies and of pregnancy-related complications on postdonation outcomes. In February 2023, the American Society of Transplantation Women's Health Community of Practice held a virtual Controversies Conference on reproductive health, contraception, and pregnancy after transplantation and living donation. Experts in the field presented the available data. Smaller breakout sessions were created to discuss findings, identify knowledge gaps, and develop recommendations. We present the conference findings related to living donation. The evidence reviewed shows that gestational hypertension and gestational diabetes mellitus before kidney donation have been associated with an increased risk of developing postdonation hypertension and diabetes mellitus, respectively, without increasing the risk of developing an eGFR <45 ml/min after donation. The risk of preeclampsia in living kidney donors increases to 4%-10%, and low-dose aspirin may help reduce that risk. Little is known about the financial burden for living donors who become pregnant, their risk of postpartum depression, or the optimal time between donation and conception. The data on living liver donors are even scarcer. The creation of a registry of donor candidates may help answer many of these questions and, in turn, educate prospective donors so that they can make an informed choice.

Autoantibody-mediated IL-6-dependent endothelin-1 elevation underlies pathogenesis in a mouse model of preeclampsia.

Preeclampsia (PE) is a life-threatening hypertensive disorder of pregnancy. Elevated circulating endothelin-1 (ET-1) is associated with the disease. However the molecular basis of increased ET-1 production and its role in PE are unknown. This study aimed to investigate the causative factors, pathological role of elevated ET-1 production in PE, and the underlying mechanisms. In this study, we found that IgG from women with PE, in contrast to IgG from normotensive pregnant women, induced preproET-1 mRNA expression via angiotensin II type 1 receptor activation in kidneys and placentas in pregnant mice. The ET-A receptor-specific antagonist BQ123 significantly attenuated autoantibody-induced hypertension, proteinuria, and renal damage in pregnant mice, demonstrating that autoantibody-induced ET-1 production contributes to pathophysiology. Mechanistically, we discovered that IL-6 functioned downstream of TNF-α signaling, contributing to increased ET-1 production in pregnant mice. IL-6 blockade inhibited preeclamptic features in autoantibody-injected pregnant mice. Extending the data to human studies, we found that IL-6 was a key cytokine underlying ET-1 induction mediated by IgG from women with PE in human placental villous explants and that endothelial cells are a key source of ET-1. Overall, we provide human and mouse studies showing that angiotensin II type I receptor-agonistic autoantibody is a novel causative factor responsible for elevated ET-1 production and that increased TNF-α/IL-6 signaling is a key mechanism underlying increased ET-1 production and subsequent maternal features. Significantly, our findings revealed novel factors and signaling cascades involved in ET-1 production, subsequent disease symptom development, and possible therapeutic intervention in the management of PE.

Experiences of Preconception Counseling among Pregnant Women with Preexisting Diabetes: Opportunities to Improve Patient-Centered Care.

Available research suggests that patients with diabetes do not regularly receive preconception counseling, but information on patients' experiences of counseling is scant. We conducted a qualitative study involving semi-structured interviews with 22 patients between October 2020 and February 2021. Pregnant patients with preexisting diabetes were recruited from a specialty diabetes and pregnancy clinic at a large academic medical center in Northern California. Interviews were transcribed, coded, and analyzed using an inductive and deductive content analysis approach. A total of 27% reported they did not have any pregnancy-related discussions with a health care provider before pregnancy. Of those that did, many sought out counseling; this was often connected to how "planned" the pregnancy was. Few participants, nearly all with type 1 diabetes, reported having a formal preconception care visit. Participants described receiving information mostly about the risks associated with diabetes and pregnancy. While participants who sought out counseling generally reported their providers were supportive of their desire for pregnancy, there were a few exceptions, notably all among patients with type 2 diabetes. The varied experiences of participants indicate gaps in the delivery of pre-pregnancy counseling to patients with diabetes and suggest counseling may vary based on diabetes type. There are opportunities to improve the patient-centeredness of counseling.

Complete Molar Pregnancies with a Coexisting Fetus: Pregnancy Outcomes and Review of Literature.

Objective The objective of the study was to review the obstetric outcomes of complete hydatidiform molar pregnancies with a coexisting fetus (CHMCF), a rare clinical entity that is not well described. Materials and Methods We performed a retrospective case series with pathology-confirmed HMCF. The cases were collected via solicitation through a private maternal-fetal medicine physician group on social media. Each contributing institution from across the United States ( n = 9) obtained written informed consent from the patients directly, obtained institutional data transfer agreements as required, and transmitted the data using a Health Insurance Portability and Accountability Act of 1996 (HIPAA) compliant modality. Data collected included maternal, fetal/genetic, placental, and delivery characteristics. For descriptive analysis, continuous variables were reported as median with standard deviation and range. Results Nine institutions contributed to the 14 cases collected. Nine (64%) cases of CHMCF were a product of assisted reproductive technology and one case was trizygotic. The median gestational age at diagnosis was 12 weeks and 2 days (9 weeks-19 weeks and 4 days), and over half were diagnosed in the first trimester. The median human chorionic gonadotropin (hCG) at diagnosis was 355,494 mIU/mL (49,770-700,486 mIU/mL). Placental mass size universally enlarged over the surveillance period. When invasive testing was performed, insufficient sample or no growth was noted in 40% of the sampled cases. Antenatal complications occurred in all delivered patients, with postpartum hemorrhage (71%) and hypertensive disorders of pregnancy (29%) being the most frequent outcomes. Delivery outcomes were variable. Four patients developed gestational trophoblastic neoplasia. Conclusion This series is the largest report of obstetric outcomes for CHMCF to date and highlights the need to counsel patients about the severe maternal and fetal complications in continuing pregnancies, including progression to gestational trophoblastic neoplastic disease. Key Points CHMCF is a rare obstetric complication and may be associated with the use of assisted reproductive technology.Universally, patients with CHMCF who elected to manage expectantly developed antenatal complications.The risk of developing gestational trophoblastic neoplasia after CHMCF is high, and termination of the pregnancy did not decrease this risk.

Angiotensin receptor agonistic autoantibody-mediated tumor necrosis factor-alpha induction contributes to increased soluble endoglin production in preeclampsia.

BACKGROUND: Preeclampsia is a prevalent life-threatening hypertensive disorder of pregnancy. The circulating antiangiogenic factor, soluble endoglin (sEng), is elevated in the blood circulation of women with preeclampsia and contributes to disease pathology; however, the underlying mechanisms responsible for its induction in preeclampsia are unknown. METHODS AND RESULTS: Here, we discovered that a circulating autoantibody, the angiotensin receptor agonistic autoantibody (AT(1)-AA), stimulates sEng production via AT(1) angiotensin receptor activation in pregnant mice but not in nonpregnant mice. We subsequently demonstrated that the placenta is a major source contributing to sEng induction in vivo and that AT(1)-AA-injected pregnant mice display impaired placental angiogenesis. Using drug screening, we identified tumor necrosis factor-alpha as a circulating factor increased in the serum of autoantibody-injected pregnant mice contributing to AT(1)-AA-mediated sEng induction in human umbilical vascular endothelial cells. Subsequently, among all the drugs screened, we found that hemin, an inducer of heme oxygenase, functions as a break to control AT(1)-AA-mediated sEng induction by suppressing tumor necrosis factor-alpha signaling in human umbilical vascular endothelial cells. Finally, we demonstrated that the AT(1)-AA-mediated decreased angiogenesis seen in human placenta villous explants was attenuated by tumor necrosis factor-alpha-neutralizing antibodies, soluble tumor necrosis factor-alpha receptors, and hemin by abolishing both sEng and soluble fms-like tyrosine kinase-1 induction. CONCLUSIONS: Our findings demonstrate that AT(1)-AA-mediated tumor necrosis factor-alpha induction, by overcoming its negative regulator, heme oxygenase-1, is a key underlying mechanism responsible for impaired placental angiogenesis by inducing both sEng and soluble fms-like tyrosine kinase-1 secretion from human villous explants. Our results provide important new targets for diagnosis and therapeutic intervention in the management of preeclampsia.

Postpartum anticoagulation in women with mechanical heart valves.

BACKGROUND: Women with mechanical heart valves (MHV) requiring anticoagulation (AC) are at high risk for hemorrhagic complications. Despite guidelines to manage antenatal and peripartum AC, there are few evidence-based recommendations to guide the initiation of postpartum AC. We reviewed our institutional experience of pregnant women with MHV to lay the groundwork for recommendations of immediate postpartum AC therapy. STUDY DESIGN: This descriptive retrospective cohort used ICD-9 and -10 codes to identify pregnant women with MHV on AC at the Yale-New Haven Hospital from 2007 to 2018. All identified patients were confirmed by chart review. Delivery hospitalization and the immediate postpartum AC management were reviewed. Maternal complications recorded were postpartum hemorrhage, transfusion, wound hematoma, intra-abdominal bleeding, stroke, valve thrombosis, and death. Further, immediate neonatal outcomes were detailed. RESULTS: Forty-two pregnant women with nonnative heart valves were identified during the study period. From those pregnant women, nine had an MHV and were anticoagulated throughout gestation. Of 19 total pregnancies, 14 met the inclusion criteria. The median gestational age of the delivered pregnancies was early term (37w2d). Nine deliveries were via cesarean (64%). The median time to restart AC after birth was 6 hours. After six deliveries (43%), AC was initiated ≤6 hours postpartum. Hemorrhagic complications occurred in six cases (43%), including wound and intra-abdominal hematomas. Four cases (29%) required blood transfusion. No maternal strokes, thrombotic events, or deaths were recorded. Five (38.5%) neonates required admission to the neonatal intensive care unit. CONCLUSION: MHV in pregnancy was rare but was associated with significant maternal morbidity, particularly postpartum hemorrhagic complications. We noted significant variability in the timing of restarting postpartum AC and in the selected agents. Pooled institutional data and an interdisciplinary approach are recommended to minimize competing risks and sequelae of valve thrombosis and obstetrical hemorrhage and, thereby, to optimize maternal outcomes and develop evidence-based guidelines for postpartum AC management.

Gottesfeld-Hohler Memorial Foundation Zika Virus Think Tank Summary.

At a think tank bringing together experts on fetal neuroimaging, obstetric infectious diseases, and public health, we discussed trends in all of these areas for Zika virus. There is a wide variety of imaging findings in affected fetuses, influenced by timing of infection and probably host factors. The resources for diagnosis and interventions also vary by location with the hardest hit areas often having the fewest resources. We identified potential areas for both research and clinical collaboration as the Zika virus epidemic continues to evolve.