BACKGROUND:The hemodynamic changes during pregnancy can be challenging in women with underlying heart disease, particularly in women with impaired left ventricular function (LVF, left ventricular ejection fraction <40%). OBJECTIVES:The aim of this study was to describe the cardiac, obstetric, and fetal outcomes of pregnancy in women with impaired LVF. METHODS:ROPAC (Registry Of Pregnancy and Cardiac disease) includes an international, prospective, observational cohort of pregnancies in women with heart disease. Cardiac, obstetric, and fetal outcomes were analyzed in 251 patients with impaired LVF. The primary endpoint was the occurrence of major adverse cardiac events (MACE) including maternal death, supraventricular or ventricular arrhythmias, heart failure, aortic dissection, endocarditis, ischemic coronary event, and other thromboembolic events. Logistic regression was used to determine variables associated with poor outcomes. RESULTS:Median follow-up duration was 7 (6-11) months. Maternal mortality occurred in 6/251 (2.4%, 1%-5%) and heart failure in 67/251 (27%, 21%-33%) patients. Ventricular tachyarrhythmias occurred in 11/251 (4%, 2%-8%) patients. Eighty-one of 251 (32%, 27%-38%) patients experienced at least one MACE during pregnancy or up to 6 months postpartum. Obstetric complications were common, including preterm birth in 67/251 (27%, 22%-33%) and low birthweight in 65/251 (26%, 21%-32%). Patients with cardiomyopathy were at higher risk of cardiovascular complications with 4.3% mortality and nearly 40% risk of MACE during pregnancy. Prepregnancy signs of heart failure (OR: 2.67; 1.3-5.6), atrial fibrillation (OR: 6.32; 3.0-13.3), and an NYHA functional class >II (OR: 6.06; 2.2-16.6) were associated with poor cardiac outcomes. CONCLUSIONS:Women with impaired LVF are at increased risk of complications, particularly heart failure, tachyarrhythmias, and premature delivery with low birth weight.

Abstract Extravillous trophoblasts (EVTs) are a trophoblast subpopulation critical for feto-maternal tolerance during early pregnancy, primarily using HLA-G to exert immunomodulatory effect, and possessing N-glycomic profiles distinct from other trophoblast subpopulations. However, whether the N-glycosylation confers distinct immunological properties to EVTs remains poorly understood. To investigate this, we employed JEG-3, a human choriocarcinoma cell line having the capacity to produce pregnancy-related hormones and expressing both HLA-C and HLA-G resembling placental EVTs, as an in vitro EVT model, alongside cell line JAR which exhibits villous trophoblast phenotypes distinct from JEG-3. Both cell lines were treated with kifunensine or swainsonine, inhibitors of α-mannosidases, to remodel their N-glycosylation patterns. This led to significant remodelling of their N-glycomic profiles, with JEG-3 cells showing an increased level of polylactosamine chains and decreased levels of α-2,6-sialylation and core α-1,6-fucosylation. Western blot analysis showed that inhibiting α-mannosidases altered only the composition of N-glycans on cell-surface HLA-G, without affecting the overall abundance of cell-surface HLA-G. In kifunensine-treated JEG-3 cells that predominantly express oligomannose type N-glycans, an intracellular accumulation of unfolded HLA-G fragments, increased hCG secretion, and down-regulations of EVT markers GATA3 and KRT7 were observed compared to untreated control, while swainsonine treatment did not impact N-glycan expression. Cytotoxicity assays using NK-92 as effector cells showed that the de-sialylation of JEG-3 by neuraminidase treatment led to increased NK-92 mediated killing. JEG-3 cell sustained its EVT immunological properties through generating bioequivalent N-glycans, exemplified by NK-92 cells pre-conditioned with used culture media of kifunensine-treated JEG-3 cells displaying reduced cytotoxicity toward NK-sensitive lymphoblast cell line K562, an effect not observed with swainsonine-treated JEG-3 cells. This model suggests that EVTs immunological properties are dependent on specific N-glycomic profiles that are maintained by unique N-glycosylation homeostasis, and overall improves our understanding of how EVTs maintain their immunomodulatory effect at the maternal-fetal interface.

BACKGROUND:Pregnancy exacerbates left ventricular outflow tract (LVOT) gradients due to increased cardiac output (CO). This is amplified in patients with LVOT obstruction (LVOTO). Ascertaining whether gestational elevations in LVOT gradients are transient haemodynamic responses that regress postpartum, or predictors of disease progression or adverse outcomes, is critical. METHODS:A retrospective, observational study was conducted between 2009 and 2023 in two tertiary centres. Clinical and echocardiographic data were collected preconception, antenatally, and postpartum. Key measurements included peak and mean LVOT gradients, left ventricular ejection fraction, and aortic valve area. The primary endpoint was the need for postpartum intervention, while the secondary endpoints were a composite of adverse clinical outcomes and postpartum intervention. RESULTS:A total of 78 women with LVOTO (109 pregnancies) were included. Gestational increases in LVOT gradients were transient, regressing to baseline levels postpartum for most. Postpartum intervention was required in 11% of pregnancies within a median of 6.3 (4.4-9.2) years. Predictors of the primary endpoint were baseline LVOTO severity (HR = 29.6, p < 0.01), antenatal LVOTO severity (HR = 21.1, p < 0.01), and postpartum LVOTO severity (HR = 18.3, p < 0.01). While patients with inherently severe LVOTO at baseline (n = 8, 10%) had a significantly increased risk of postpartum intervention, those with transiently severe LVOTO during pregnancy did not. CONCLUSIONS:Pregnancy causes an increase in LVOT gradients but no significant disease progression warranting either antenatal or postpartum intervention, except in patients who had severe LVOTO preconception. The development of pregnancy-specific echocardiographic thresholds for severity is a critical need to prevent misdiagnoses and optimise maternal outcomes.

BACKGROUND:Women with left ventricular outflow tract obstruction (LVOTO) are at risk of adverse pregnancy outcomes, which have been related to the severity of the LVOTO. However, the physiological adaptations of pregnancy increase the gradient across an LVOTO, often altering the clinical perception of risk. Here, we examined how the LVOTO gradient changes during pregnancy, investigating whether a greater increase in the gradient is associated with worse pregnancy outcome and whether any increase in the gradient is transient, reversing after the end of the pregnancy. METHODS:The study was conducted at three tertiary centres. Data were collected from 125 pregnancies in 100 women with a range of causes of LVOTO, including bicuspid aortic valve (n=71), trileaflet aortic stenosis (n=23), prosthetic valve replacement (n=18) and subvalvular stenosis (n=8). Measurements included echocardiographic parameters (peak and mean LVOT gradients, left ventricular ejection fraction) and pregnancy outcomes. The primary endpoints were the change in gradient and pregnancy outcomes. RESULTS:The mean (19.5±11.9 mm Hg to 23.8±14.9 mm Hg) and peak (31.6±19.2 mm Hg to 40.6±27.7 mm Hg) gradients increased significantly during pregnancy and in a minority of cases this rise persisted postpartum. Pregnancy complications were unrelated to baseline gradient severity or the increase in gradient observed during pregnancy. Counter to our hypothesis, there was no association between the increase in gradient and adverse pregnancy outcomes. CONCLUSIONS:The physiological changes of pregnancy resulted in an increase in the gradient across the LVOTO, which was not associated with any adverse obstetric outcomes. In some cases, the increase in the gradient only partially reversed after pregnancy, implying that pregnancy may induce a structural change in the lesion, giving rise to LVOTO.

Intrauterine infection and inflammation are major causes of preterm labor, yet antibiotics alone often fail to prevent preterm birth despite achieving microbial clearance. Interleukin1 (IL1) is a key mediator of intra-amniotic inflammation and functional progesterone withdrawal, processes linked to labor initiation. We tested whether IL1 blockade with the clinically approved IL1 receptor antagonist, anakinra, could reduce inflammation and preterm labor in a Rhesus macaque model of intra-amniotic Escherichia coli infection followed by delayed antibiotic treatment. Here we show that anakinra reduced the incidence of preterm labor by 40% (p=0.07), attenuated inflammation in the fetal membranes and cervix, and preserved progesterone receptor-B abundance in the fetal membranes. These effects were most pronounced in animals protected from preterm labor. Our findings in a relevant model support the translational potential of combining IL1 blockade with antibiotics for infection-associated preterm labor.

Abstract Glycosylation of proteins is arguably the most diverse post-translational modification that is altered in almost all cancer types, which has been demonstrated to play a crucial role in creating an immunosuppressive microenvironment that promotes immune tolerance and evasion. However, the biosynthesis of N -linked glycan is mediated by a series of enzymatic reactions catalysed by glycosyltransferases and glycosidases in a template-independent manner, hindering our understanding of specific structure-function relationships and roles of specific glycans on specific proteins. Here we use HLA class I-negative cell line K562, a known reference target for NK-mediated cytolysis, to establish a model investigating how cell surface glycan dynamics influence its susceptibility to cytolysis mediated by NK-92 cells. Treatment of K562 cells with kifunensine, swainsonine, 2F-peracetyl-fucose, or 3Fax-peracetyl Neu5Ac, inhibitors of N -linked glycan processing, resulted in drastic alterations in cell surface carbohydrate phenotype, as could be shown by flow cytometric analysis of the lecti N binding properties of the cells. Despite these clear changes in carbohydrate phenotype, only K562 cells treated with either kifunensine or 3Fax-peracetyl Neu5Ac exhibited higher susceptibility to the cytolysis medidated by NK-92 cells accompanied with an increased CD107a expression by NK-92 cells. Although K562 cells overexpressing gene MGAT3 exhibited a decreased NK-susceptibility, we further found that this decrease was not exclusively determined by the overexpression of gene MGAT3 product bisecting β1,4-GlcNAc, because the treatment of 3Fax-peracetyl Neu5Ac reversed the resistance of K562 cell against NK-92 cell in despite of expressing higher levels of bisecting β1,4-GlcNAc. Expressing HLA-G on cell surface as extravillous trophoblast did not change the NK-susceptibility of K562 cells, despite evidence that HLA-G molecules expressed by K562 cells can bind to inhibitory receptor ILT2 expressed on NK-92 cell surface. These findings suggest that the level of terminal sialylation, outweighing other components in N -linked glycan, determines the NK-susceptibility of K562 cell, offering a new strategy to weaken the resistance of cancer cells so that the immune system can maximise the elimination.

OBJECTIVES:To investigate the optimal valve substitute for young women requiring aortic valve replacement (AVR), allowing improved future valve-related outcomes for mother and foetus during pregnancy. METHODS:A systematic search was performed for publications between 1998 and 2025 reporting women experiencing pregnancy after AVR with a pulmonary autograft (Ross-procedure), homograft, bioprosthesis (xenograft), or mechanical valve. Pooled proportions were calculated to determine maternal, valvular and foetal outcomes during pregnancy using generalized linear mixed models. RESULTS:Thirteen studies reporting 356 pregnancies in 251 women (pooled mean age at pregnancy 29.1 ± 4.8 years) after AVR with a pulmonary autograft (70 women, 119 pregnancies), homograft (73 women, 99 pregnancies), bioprosthesis (37 women, 50 pregnancies), or mechanical valve (71 women, 88 pregnancies) were included. During pregnancy, valve-related reintervention in women with a bioprosthesis was 2.7% (95% CI, 0.4-16.9) at 5.1 ± 2.5 years after AVR. This was not observed in women with pulmonary autografts (7.7 ± 4.2 years after AVR) and homografts (4.1 ± 3.3 years after AVR). Reintervention for valve thrombosis (4.9% [95% CI, 1.6-14.0]) and maternal death (1.1% [95% CI, 0.2-7.6]) occurred only in women with mechanical valves (8.1 ± 4.5 years after AVR). Pooled probability of liveborn delivery was 71.7% (95% CI, 59.2-81.6) in women with a mechanical valve, compared to 90.6% (95% CI, 72.4-97.3), 92.3% (95% CI, 56.0-99.1), and 82.9% (95% CI, 53.3-95.4) in women with an autograft, homograft, and bioprosthesis respectively. CONCLUSIONS:Maternal mortality and valve thrombosis during pregnancy occurred only in women with mechanical valves. Although no statistical comparisons were made, pregnancies in women with pulmonary autograft, homograft or bioprosthesis showed acceptable maternal and foetal outcomes. These descriptive findings provide foundations for further investigation of tissue-valve function before, during and after pregnancy, aiming for more support of current guidelines.

Women with pre-existing cardiomyopathy experience high maternal and fetal complication rates when undergoing pregnancy. Different cardiomyopathy phenotypes and genetics can influence the presentation during pregnancy and help inform risk profile and management.This case series demonstrates the differing course of pregnancy in dilated, hypertrophic and arrhythmogenic cardiomyopathy. The main complications managed were arrhythmia, rising left ventricular outflow tract obstruction and heart failure. The cases highlight important pre-conception considerations, the use of biomarkers, and pharmacological and device management during pregnancy, delivery and post-partum.It is important to recognise that cardiomyopathies represent a heterogeneous group of conditions with differing phenotypes which need individualised specialist care during pregnancy. Risk stratification and management by an expert multidisciplinary team are recommended to support these women to attain good maternal and fetal outcomes.

Background and Aims Pregnancy in women with a prosthetic heart valve is considered high risk, primarily due to the need for effective anticoagulation. However, data on the relationship between anticoagulation practices and pregnancy outcomes are very limited. Methods The Registry of Pregnancy and Cardiac disease is a global registry that prospectively enrolled pregnancies in women with a prosthetic heart valve between January 2018 and April 2023. Detailed data on anticoagulation, including dosage and monitoring, and cardiovascular, pregnancy, and perinatal outcomes were collected. Results In total, 613 pregnancies were included of which 411 pregnancies were in women with a mechanical valve and 202 were in women with a biological valve. The chance of an uncomplicated pregnancy with a live birth in women with a mechanical valve was 54%, compared with 79% in women with a biological valve (P < .001). Thromboembolic and haemorrhagic complications most frequently occurred when low-molecular weight heparin (LMWH)-based regimens were used. Valve thrombosis occurred in 24 (6%) women, and a prosthetic valve in mitral position was associated with valve thrombosis (odds ratio 3.3; 95% confidence interval 1.9-8.0). A thromboembolic event occurred in 12 (10%) women with anti-Xa monitoring and in 9 (21%) women without (P = .060). Foetal death occurred in 20% of all pregnancies. Conclusions More favourable outcomes were found in women with a biological valve compared with a mechanical valve. In women with a mechanical valve, the use of LMWH was associated with an increased risk of thromboembolic complications. A mitral prosthetic valve was identified as a predictor for valve thrombosis. The benefit could not be confirmed nor refuted, in terms of reduced thromboembolic events, from using anti-Xa level monitoring in women on LMWH.

This protocol was developed as part of Dr Brendan Browne's 'Origins of Labour' PhD project in collaboration with the Borne Uterine Mapping Project (BUMP) feasibility study; specifically for the goal of storing human tissues of the uterine environment (obtained at Caesarean section) to later analyse using RNA-seq and SWATH-MS. Samples of eight different tissue types were collected; namely myometrium (upper segment basalis region, upper segment parietalis region, and lower segment), decidua (basalis and parietalis region), amnion, chorion, and placenta. Cervicovaginal swab samples were also collected (and cervical length measurements were acquired using a transvaginal ultrasound (TVUS) scanner).

BACKGROUND:Spontaneous preterm birth, defined as delivery before 37 weeks of gestation, remains a global cause of neonatal illness and death, yet treatments for preterm labor remain limited. We hypothesized that KV7 channels in the uterus (myometrium), could be a therapeutic target for preventing or treating preterm labor. The aim was to characterize KV7 channel subtypes in human myometrium present after labor onset, and to use a preterm birth mouse model to provide proof-of-principal evidence that activating these channels in vivo can delay preterm delivery. METHODS:This experimental study integrated studies of human myometrial tissue (term and preterm pregnancies, n = 159 across experiments), with a RU486-induced preterm birth mouse model (C57BL/6 J, n = 6-9 per experimental group), and ex vivo fetal ductus arteriosus preparations (CD-1 mice, n = 10 per group). Molecular and protein profiling, isometric tension recordings, and functional pharmacology were used to characterize KV7 mediated regulation of human and mouse uterine contractility. In vivo dosing studies in mice assessed the effects of KV7 activators (retigabine and ML213) on delivery timing (n = 6-9). RESULTS:We show that KV7 channels and ancillary units (KCNE1-5), are expressed in pregnant human myometrium, prior to and after the onset of labor. KCNQ4 and KCNE4 transcripts are also present in myometrium taken at preterm gestations ( ± labor). KV7.2-5 activators markedly reduce spontaneous contractions in human and mouse myometrium in vitro and significantly delay preterm birth in vivo with limited impact on fetal ductus arteriosus function. CONCLUSIONS:These findings support KV7 activation as a promising approach to suppress uterine contractility and hence delay preterm birth, highlighting a potential new direction for either drug repurposing or therapeutic development.

Peripartum cardiomyopathy is increasingly recognised and diagnosed in clinical practice. Over the past two decades, a substantial amount of new knowledge on this condition has been accrued, including a better understanding of the pathophysiology, genetic predisposition for a proportion of patients, diagnostic tools, management with a disease-specific therapy, and predictors of outcome. Peripartum cardiomyopathy occurs globally in all ethnic groups and should be suspected in any women who are peripartum presenting with symptoms and signs indicative of heart failure towards the end of pregnancy or in the months following delivery. Verification of left ventricular systolic dysfunction (ejection fraction <45%) is crucial for the diagnosis of peripartum cardiomyopathy and the exclusion of other causes of heart failure, such as pre-existing cardiomyopathy, valvular heart disease, or congenital heart disease. Peripartum cardiomyopathy is a disease with considerable maternal and neonatal morbidity and mortality, with only half of women experiencing complete myocardial recovery within 6 months of the onset of symptoms. This Seminar summarises current knowledge of peripartum cardiomyopathy genetics, pathophysiology, diagnostic approaches, medical management, and outcome. Furthermore, we provide guidance on both risk stratification by use of a novel score to predict recovery and on the outcomes of a subsequent pregnancy.

OBJECTIVES:Heart valve replacement during pregnancy is sometimes unavoidable, and the need for anticoagulation further complicates these procedures. Our study describes cases of valve replacement in pregnancy enrolled in the Registry Of Pregnancy And Cardiac disease (ROPAC) III and gives an overview of the published literature. METHODS:We performed a systematic review with new data from the ROPAC III and data available in the literature. ROPAC III is a global, prospective, observational registry that included pregnant women with 1 or more prosthetic valves between January 2018 and April 2023. Electronic databases were searched for studies enrolling pregnant women who underwent valve replacement during pregnancy with a fetus in utero. The primary outcomes were maternal and fetal death. Mixed-effect logistic regression models were used to identify predictors for maternal and fetal mortality. RESULTS:A valve replacement was performed in 11 pregnancies. The mother and fetus died in 1 case, and in 2 cases, reversible postoperative complications occurred. We found 74 cases in the literature and calculated an overall maternal and fetal death rate of 9% and 34%, respectively. All maternal deaths occurred in women with a replacement of a prosthetic valve in mitral position. We found valve replacement in the 1st trimester (OR 10.0) and acute malfunctioning of an existing prosthetic valve (OR 19.7) as predictors for maternal mortality, and replacement of an existing prosthetic valve (OR 4.8) as predictor for fetal mortality. CONCLUSIONS:Valve replacement during pregnancy carries a high maternal and fetal death, especially in women who need a replacement of an existing prosthetic valve.

Background:Innate lymphoid cells (ILCs) are prominent in the human uterine mucosa and play physiological roles in pregnancy. ILC3 are the second-most common ILC subset in the uterine mucosa, but their role remains unclear. Methods:Here we define two subsets of lineage-negative CD56+ CD117+ CRTH2-uterine ILC3, distinguished by their expression of CD127. Results:The CD127- subset is most numerous and active during menstruation and immediately after parturition, suggesting a role in the repair of the uterine mucosa (called endometrium outside of pregnancy); the CD127+ subset is most numerous and active immediately after menstruation, as the endometrium regenerates. In healthy endometrium, ILC3 are spatially associated with glandular epithelial and endothelial cells, which both express receptors for the ILC3-derived cytokines, IL-22 and IL-8. In the eutopic endometrium of people with endometriosis, ILC3 are located further from glandular epithelial and endothelial cells suggesting that these cells may be less exposed to ILC3 products, potentially with negative consequences for endometrial regeneration. Conclusion:Our findings highlight the dynamic nature of ILC3 in the uterine mucosa and suggest their primary role is in repair and regeneration. An improved understanding of uterine ILC3 will inform future research on endometrial health and disease.

ObjectiveTo compare differences in maternal hemodynamics, measured non-invasively by impedance cardiography and mean arterial blood pressure (MAP)-at rest and with high-intensity exercise-between pregnant women with corrected congenital heart disease (CHD) and low-risk (LR) pregnant controls, and to correlate these findings with umbilical artery Doppler in the third trimester, estimated fetal weight (EFW) and birth weight (BW).MethodsProspective longitudinal study with hemodynamic exercise studies and fetal ultrasound between 30 and 34 weeks' gestation. Approval was obtained from London South East Research Ethics Committee.ResultsThere were no differences in heart rate (HR), stroke volume (SV), or cardiac output (CO) at rest between the two groups. HR at peak exercise was significantly lower in the CHD group, and MAP was significantly higher at rest and immediately after exercise. In the CHD group there was a significant association between CO at peak exercise and BW. In the LR group there was a significant association between peak CO with exercise and the abdominal circumference/EFW ratio and between HR at rest and BW. There were no differences in the Doppler indices between groups. There was a statistically significant association between uterine artery Doppler pulsatility index and BW in the LR group, but not in the CHD group.ConclusionsThere was no difference between Doppler indices in the third trimester between a LR population and a population with corrected CHD with no or minimal functional impairment. This suggests that factors other than defective placentation may be causing the lower BW in the CHD population.

Cardio-obstetrics is a growing subspecialty focused on the prevention, diagnosis, and management of high-risk pregnancies in women with cardiac disease, a condition affecting 1-4 % of pregnancies and a leading cause of indirect maternal mortality in developed countries. The prevalence of maternal cardiac disease is rising as a result of increasing maternal age, obesity, comorbidities, and improved survival of individuals with congenital heart disease. Artificial intelligence (AI) is increasingly used in cardiology to enhance early diagnosis, risk stratification, and treatment planning, offering promising tools to support the diagnostic and therapeutic complexities of maternal cardiac disease. This review explores current applications of AI in cardio-obstetrics and highlights potential opportunities and barriers to its future integration in clinical care.