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Introduction: Preterm birth, defined as birth before 37 weeks of gestation, is the leading cause of death of children under the age of five years worldwide. Globally there has been no change in the preterm birth rate between 2010 and 2020, when rates were calculated to be 9.8% and 9.9% of all livebirths, respectively. The analysis of amniotic fluid has been advocated by many to identify the mechanisms driving threatened preterm labor. Amniocentesis is largely considered to be safe, but care provider concerns about complications in the setting of threatened preterm labor (tPTL) exist. This systematic review will critically review the data regarding safety and outcomes of amniocentesis in cases of PPROM and tPTL and help in the counseling and clinical decision-making of patients and care providers alike., Methods: This systematic review was conducted in accordance with the preferred reporting items for systematic reviews and meta-analyses (PRISMA). All English language, peer-reviewed human studies where amniocentesis was used to sample the amniotic fluid of patients presenting with tPTL or PPROM and published between January 1990 and March 2022 were included. Data on the uptake rates, success rates, and safety profile associated with amniocentesis in this context of tPTL or PPROM were analyzed as part of the systematic review. Included studies compromised of randomized control trials, cohort studies, and case-control studies. Conference abstracts and abstracts with no full text were excluded., Results: 10,215 studies were returned after searches were conducted in MEDLINE, EMBASE, EMCARE, Web of Science, and SCOPUS databases using free text and Medical Subject Headings (MESH). 399 studies were assessed for eligibility with 15 studies being included in the final review. The main reason for exclusion from the review was an absence of safety data. Four studies gave information on uptake rates of amniocentesis in cases of PPROM and tPTL, with a range of 55% in an observational study to >99% in centers offering it as part of routine care. Eleven studies detailed success rates of amniocentesis, with all centers reporting >90% success rates. However, in some centers, a "successful" amniocentesis was deemed to be a retrieval of >0.5 ml. Three studies reported risks associated with amniocentesis. There were four reported complications (all transitory) in a series of 1119 cases (0.35%)., Discussion: This systematic review found that amniocentesis in cases of PPROM or threatened preterm labor is a safe and feasible procedure. These data should give care providers confidence to counsel patients appropriately.

Background: The Fontan circulation procedure is the palliative surgery of choice for patients with single ventricle physiology, many of whom are now reaching childbearing age due to advances in care. Our study examines the impact of pregnancy on women with Fontan circulation, assessing both short and long-term outcomes., Methods: We retrospectively analysed pregnancies in women with Fontan circulation at our centre from 2005 to 2023, including a matched non-pregnant, nulliparous cohort for comparison. Pregnancies lost before 18 weeks were analysed separately., Results: Among 26 pregnancies in 18 women, preterm births were common (73.1%), with 3 fetal losses and no maternal deaths. Neonatal complications included a 50% incidence of babies small for gestational age (SGA). Cardiac events occurred in 19.2% of pregnancies, primarily supraventricular arrhythmias, and 23% experienced postpartum haemorrhage. Over a median 6.1 [5.2-10.6]-year follow-up, no deaths, heart failure (HF), or Fontan-associated liver disease (FALD) developed, and functional status remained stable., Conclusions: Women with a Fontan-type circulation undergoing pregnancy had a few serious maternal cardiac events, though there was a high rate of post-partum haemorrhage. The rates of neonatal complications, particularly related to restricted growth and pre-term birth, were also high. Our findings indicate a generally positive medium-term outlook for these patients, though the impact of pregnancy on long-term survival remains unclear. Careful selection of patients with Fontan circulation during pre-pregnancy counselling may help to reduce complications during and after pregnancy., Competing Interests: Declaration of competing interest Dr. Krishnathasan and Dr. Constantine have received educational grants, personal fees and non-financial support from Jannsen-Cilag Limited. Professor Dimopoulos has received nonfinancial support from Jannsen-Cilag Limited and has been a consultant to and received grants and personal fees from Jannsen-Cilag Limited, Pfizer, GlaxoSmithKline, and Bayer/MSD. All the remaining authors have no relationships with industry to declare., (Copyright © 2024. Published by Elsevier B.V.)

Pregnancy is a period of substantial changes to the body's normal physiology, and the failure to adapt to these changes can lead to life-threatening pathology, particularly involving the cardiovascular system. In comparison to pre-pregnancy physiology, pregnant women have increased blood volume and physical demands which exert increased stress on the heart. This is important to consider in women with and without previously diagnosed cardiovascular disease, as the physiologic changes during pregnancy and postpartum can lead to sudden decompensation. The management of heart failure is particularly important as it remains the most common cardiovascular complication during pregnancy and is associated with substantial maternal and fetal morbidity and mortality. This is especially true in patients with pre-existing heart failure, who should receive counseling before conception and in certain cases be advised against pregnancy. For these reasons, healthcare professionals must be well-versed in the different strategies of diagnosis, management, treatment, and monitoring. This review will outline the pathophysiology, diagnostics, management, and general approach to heart failure in pregnant patients., Competing Interests: Declarations Competing interests The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Angiotensin-converting enzyme inhibitors (ACE-Is) and angiotensin receptor blockers (ARBs) are not recommended during the second and third trimester because of the significant risk of congenital anomalies associated with their use. However, data are scarce, especially regarding their use in the first trimester and about the impact of stopping just before pregnancy. Our study illustrates the profile of the women who used ACE-Is or ARBs during pregnancy and evaluates the impact on perinatal outcomes. The Registry of Pregnancy and Cardiac Disease is a prospective, global registry of pregnancies in women with structural heart disease. Outcomes were compared between women who used ACE-Is or ARBs and those who did not. Multivariable regression analysis was performed to assess the effect of ACE-I or ARB use on the occurrence of congenital anomalies. ACE-Is (n = 35) and/or ARBs (n = 8) were used in 42 (0.7%) of the 5,739 Registry of Pregnancy and Cardiac Disease pregnancies. Women who used ACE-Is or ARBs more often came from a low-or-middle-income country (57% vs 40%, p = 0.021), had chronic hypertension (31% vs 6%, p <0.001), or a left ventricular ejection fraction <40% (33% vs 4%, p <0.001). In the multivariable analysis, ACE-I use during the first trimester was associated with an increased risk of congenital anomaly (odds ratio 3.2, 95% confidence interval 1.0 to 9.6). Therefore, ACE-Is should be avoided during pregnancy, also in the first trimester, because of a higher risk of congenital anomalies. However, there is no need to stop long before pregnancy. Preconception counseling is crucial to discuss the potential risks of these medications, to evaluate the clinical condition and, if possible, to change or stop the medication., Competing Interests: Declaration of competing interest The authors have no competing interests to declare., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

This statement focuses on the fact that women with peripartum cardiomyopathy (PPCM) have a substantial mortality and morbidity rate. Less than 50% of patients have full recovery of their cardiac function within 6 months of diagnosis. Also, patients with recovered cardiac function often suffer from comorbidities, such as hypertension or arrhythmias, which require long-term treatment. This has major implications which extend beyond the life of the patient, as it may also substantially impact her family. Women with a new diagnosis of PPCM should be involved in the decision-making processes regarding therapies, e.g. the recommendation to abstain from breastfeeding, or the use of cardiac implantable electronic devices. Women living with PPCM face the uncertainty of not knowing for some time whether their cardiac function will recover to allow them a near-to-normal life expectancy. This not only impacts their ability to work, which may have financial implications, but may also affect mental health and quality of life for the extended family. Women living with PPCM must be informed that a future pregnancy always carries a substantial risk and, in case of poor cardiac recovery, is associated with a high morbidity and mortality. Patients with PPCM are best managed by an interdisciplinary and multiprofessional approach including e.g. a cardiologist, a gynaecologist, nurses, a psychologist, and social workers. The scope of this document encompasses contemporary challenges and approaches for the management of women diagnosed with PPCM., (© 2024 The Author(s). European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Background: Beta-blockers are commonly used drugs during pregnancy, especially in women with heart disease, and are regarded as relatively safe although evidence is sparse. Differences between beta-blockers are not well-studied., Methods: In the Registry of Pregnancy And Cardiac disease (ROPAC, n = 5739), a prospective global registry of pregnancies in women with structural heart disease, perinatal outcomes (small for gestational age (SGA), birth weight, neonatal congenital heart disease (nCHD) and perinatal mortality) were compared between women with and without beta-blocker exposure, and between different beta-blockers. Multivariable regression analysis was used for the effect of beta-blockers on birth weight, SGA and nCHD (after adjustment for maternal and perinatal confounders)., Results: Beta-blockers were used in 875 (15.2%) ROPAC pregnancies, with metoprolol (n = 323, 37%) and bisoprolol (n = 261, 30%) being the most frequent. Women with beta-blocker exposure had more SGA infants (15.3% vs 9.3%, p < 0.001) and nCHD (4.7% vs 2.7%, p = 0.001). Perinatal mortality rates were not different (1.4% vs 1.9%, p = 0.272). The adjusted mean difference in birth weight was -177 g (-5.8%), the adjusted OR for SGA was 1.7 (95% CI 1.3-2.1) and for nCHD 2.3 (1.6-3.5). With metoprolol as reference, labetalol (0.2, 0.1-0.4) was the least likely to cause SGA, and atenolol (2.3, 1.1-4.9) the most., Conclusions: In women with heart disease an association was found between maternal beta-blocker use and perinatal outcomes. Labetalol seems to be associated with the lowest risk of developing SGA, while atenolol should be avoided., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Improved survival rates for patients with a Fontan circulation has allowed more women with this complex cardiac physiology to contemplate pregnancy. However, pregnancy in women with a Fontan circulation is associated with a high risk of adverse maternal and foetal outcomes, high rates of miscarriage, and preterm delivery. Factors associated with a successful pregnancy outcome are younger age, normal body weight, absence of significant functional limitation, no Fontan-related complications, and well-functioning single ventricle physiology. Appropriate care with timely preconception counselling and regular, frequent clinical reviews by a multidisciplinary team based at a tertiary centre improves the chance of a successful pregnancy. Empowerment of patients with education on their specific congenital cardiac condition and its projected trajectory helps them make informed choices regarding their health, reproductive choices, and assists them to achieve their life goals., Competing Interests: Conflict of interest: none declared., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Aims: Data on diuretic use in pregnancy are limited and inconsistent, and consequently it remains unclear whether they can be used safely. Our study aims to evaluate the perinatal outcomes after in-utero diuretic exposure., Methods and Results: The Registry Of Pregnancy And Cardiac disease (ROPAC) is a prospective, global registry of pregnancies in women with heart disease. Outcomes were compared between women who used diuretics during pregnancy versus those who did not. Multivariable regression analysis was used to assess the impact of diuretic use on the occurrence of congenital anomalies and foetal growth. Diuretics were used in 382 (6.7%) of the 5739 ROPAC pregnancies, most often furosemide (86%). Age >35 years (odds ratio [OR] 1.5, 95% confidence interval [CI] 1.2-2.0), other cardiac medication use (OR 5.4, 95% CI 4.2-6.9), signs of heart failure (OR 1.7, 95% CI 1.2-2.2), estimated left ventricular ejection fraction <40% (OR 2.9, 95% CI 2.0-4.2), New York Heart Association class >II (OR 3.4, 95% CI 2.3-5.1), valvular heart disease (OR 6.3, 95% CI 4.7-8.3) and cardiomyopathy (OR 3.9, 95% CI 2.6-5.7) were associated with diuretic use during pregnancy. In multivariable analysis, diuretic use during the first trimester was not significantly associated with foetal or neonatal congenital anomalies (OR 1.3, 95% CI 0.7-2.6), and diuretic use during pregnancy was also not significantly associated with small for gestational age (OR 1.4, 95% CI 1.0-1.9)., Conclusions: Our study does not conclusively establish an association between diuretic use during pregnancy and adverse foetal outcomes. Given these findings, it is essential to assess the risk-benefit ratio on an individual basis to guide clinical decisions., (© 2024 The Author(s). European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

The amnion is a thin layer of fetal origin in contact with the amniotic fluid which plays a key role at the feto-maternal interface during pregnancy. Here, we present a protocol for isolation of human and Rhesusmacaque amnion cells. We describe steps for tissue dissection, cell isolation for flow cytometry analysis, and RNA isolation for RNA sequencing library preparation and analysis. This protocol can provide insights into altered immunological pathways during intrauterine infections to develop new therapeutic strategies. For complete details on the use and execution of this protocol, please refer to Presicce et al. 1 ., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Introduction: Obesity is known to be associated with cardiovascular compromise and a major risk factor for the development of hypertensive disorders in pregnancy. However, little is known about the effect of obesity on maternal cardiac function. The aim of this study was to investigate the effect of obesity on the maternal cardiovascular system., Material and Methods: This was a prospective, observational, longitudinal study. Pregnant women with booking body mass index (BMI) ≥30 kg/m 2 were compared with pregnant women with normal booking BMI 20-24.9 kg/m 2 . Participants were seen at three time points during pregnancy; 12-14, 20-24 and 30-32 weeks. At all visits, maternal blood pressure (BP) was measured, and cardiac geometry and function were assessed using two-dimensional trans-thoracic echocardiography. Multilevel linear mixed-effects models were used for all the comparisons., Results: Fifty-nine pregnant women with obesity were compared with 14 pregnant women with normal BMI. In women with obesity, the maternal BP, heart rate and cardiac output were higher and peripheral vascular resistance was lower (p < 0.01 for all comparisons) compared with normal BMI women. Women with obesity had altered cardiac geometry with higher left ventricular end diastolic diameter, intraventricular septal thickness, posterior wall diameter, relative wall thickness and left ventricular mass (p < 0.001 for all comparisons). There was also evidence of impaired diastolic indices in the obese group with a lower E/A ratio, tissue Doppler imaging E' lateral and medial and higher left atrial volume (p < 0.01 for all comparisons). Finally, women with obesity had reduced longitudinal function, as assessed by mitral plane annular systolic excursion, between the second and third trimester of pregnancy, indicating possible early cardiac dysfunction in this group., Conclusions: Obesity is associated with maternal hyperdynamic circulation, altered cardiac geometry and suboptimal diastolic function, compared with normal BMI pregnant women, and these factors may contribute to the increased risk of complications in obese pregnant women., (© 2024 The Authors. Acta Obstetricia et Gynecologica Scandinavica published by John Wiley & Sons Ltd on behalf of Nordic Federation of Societies of Obstetrics and Gynecology (NFOG).)

Background: Peripartum cardiomyopathy (PPCM) is a global disease with substantial morbidity and mortality. The aim of this study was to analyze to what extent socioeconomic factors were associated with maternal and neonatal outcomes., Methods: In 2011, >100 national and affiliated member cardiac societies of the European Society of Cardiology (ESC) were contacted to contribute to a global PPCM registry, under the auspices of the ESC EORP Programme. We investigated the characteristics and outcomes of women with PPCM and their babies according to individual and country-level sociodemographic factors (Gini index coefficient [GINI index], health expenditure [HE] and human developmental index [HDI])., Results: 739 women from 49 countries (Europe [33%], Africa [29%], Asia-Pacific [15%], Middle East [22%]) were enrolled. Low HDI was associated with greater left ventricular (LV) dilatation at time of diagnosis. However, baseline LV ejection fraction did not differ according to sociodemographic factors. Countries with low HE prescribed guideline-directed heart failure therapy less frequently. Six-month mortality was higher in countries with low HE; and LV non-recovery in those with low HDI, low HE and lower levels of education. Maternal outcome (death, re-hospitalization, or persistent LV dysfunction) was independently associated with income. Neonatal death was significantly more common in countries with low HE and low HDI, but was not influenced by maternal income or education attainment., Conclusions: Maternal and neonatal outcomes depend on country-specific socioeconomic characteristics. Attempts should therefore be made to allocate adequate resources to health and education, to improve maternal and fetal outcomes in PPCM., Competing Interests: Declaration of Competing Interest None of the authors have any conflict of interest to declare related to this manuscript., (Copyright © 2023. Published by Elsevier B.V.)

Pregnancy-associated myocardial infarction is an overall uncommon event, but can be associated with significant maternal and fetal morbidity and mortality. In contrast to myocardial infarction in the general nonpregnant population, the mechanism of pregnancy-associated myocardial infarction is most commonly due to nonatherosclerotic mechanisms such as coronary dissection, vasospasm, or thromboembolism. The diagnosis of pregnancy-associated myocardial infarction can be challenging, requiring a high index of suspicion for prompt recognition and management. Furthermore, the management of pregnancy-associated myocardial infarction can be complex due to maternal and fetal considerations and may vary based on the specific underlying mechanism of the myocardial infarction. This review aims to review the recent literature on pregnancy-associated myocardial infarction and summarize the epidemiology, mechanisms, diagnosis, and treatment strategies for this uncommon entity., Competing Interests: Disclosure: The authors have no conflicts of interest to report., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Gestational diabetes (GDM) changes the maternal metabolic and uterine environment, thus increasing the risk of short- and long-term adverse outcomes for both mother and child. Children of mothers who have GDM during their pregnancy are more likely to develop Type 2 Diabetes (T2D), early-onset cardiovascular disease and GDM when they themselves become pregnant, perpetuating a multigenerational increased risk of metabolic disease. The negative effect of GDM is exacerbated by maternal obesity, which induces a greater derangement of fetal adipogenesis and growth. Multiple factors, including genetic, epigenetic and metabolic, which interact with lifestyle factors and the environment, are likely to contribute to the development of GDM. Genetic factors are particularly important, with 30% of women with GDM having at least one parent with T2D. Fetal epigenetic modifications occur in response to maternal GDM, and may mediate both multi- and transgenerational risk. Changes to the maternal metabolome in GDM are primarily related to fatty acid oxidation, inflammation and insulin resistance. These might be effective early biomarkers allowing the identification of women at risk of GDM prior to the development of hyperglycaemia. The impact of the intra-uterine environment on the developing fetus, "developmental programming", has a multisystem effect, but its influence on adipogenesis is particularly important as it will determine baseline insulin sensitivity, and the response to future metabolic challenges. Identifying the critical window of metabolic development and developing effective interventions are key to our ability to improve population metabolic health., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Thornton, Shah, Lillycrop, Cui, Johnson and Singh.)

Cardiac disease complicates 1%-4% of pregnancies globally, with a predominance in low and middle-income countries (LMICs). Increasing maternal age, rates of obesity, cardiovascular comorbidities, pre-eclampsia and gestational diabetes all contribute to acquired cardiovascular disease in pregnancy. Additionally, improved survival in congenital heart disease (CHD) has led to increasing numbers of women with CHD undergoing pregnancy. Implementation of individualised care plans formulated through pre-conception counselling and based on national and international guidance have contributed to improved clinical outcomes. However, there remains a significant proportion of women of reproductive age with no apparent comorbidities or risk factors that develop heart disease during pregnancy, with no indication for pre-conception counselling. The most extreme manifestation of cardiac disease is cardiogenic shock (CS), where the primary cardiac pathology results in inadequate cardiac output and hypoperfusion, and is associated with significant mortality and morbidity. Key to management is early recognition, intervention to treat any potentially reversible underlying pathology and supportive measures, up to and including mechanical circulatory support (MCS). In this narrative review we discuss recent developments in the classification of CS, and how these may be adapted to improve outcomes of pregnant women with, or at risk of developing, this potentially lethal condition., (© 2023 The Authors. BJOG: An International Journal of Obstetrics and Gynaecology published by John Wiley & Sons Ltd.)

In George Wald's Nobel Prize acceptance speech for "discoveries concerning the primary physiological and chemical visual processes in the eye", he noted that events after the activation of rhodopsin are too slow to explain visual reception. Photoreceptor membrane phosphoglycerides contain near-saturation amounts of the omega-3 fatty acid docosahexaenoic acid (DHA). The visual response to a photon is a retinal cis-trans isomerization. The trans -state is lower in energy; hence, a quantum of energy is released equivalent to the sum of the photon and cis-trans difference. We hypothesize that DHA traps this energy, and the resulting hyperpolarization extracts the energized electron, which depolarizes the membrane and carries a function of the photon's energy (wavelength) to the brain. There, it contributes to the creation of the vivid images of our world that we see in our consciousness. This proposed revision to the visual process provides an explanation for these previously unresolved issues around the speed of information transfer and the purity of conservation of a photon's wavelength and supports observations of the unique and indispensable role of DHA in the visual process.

Objective: To perform a longitudinal assessment of B-type natriuretic peptide (BNP) and its association with cardiac function in low-risk pregnant women and in pregnant women with congenital heart disease (CHD)., Methods: Longitudinal study in low-risk pregnancy and pregnancy in women with CHD seen at 10-14, 18-22, and 30-34 weeks of pregnancy for BNP quantification and exercise studies using impedance cardiography (ICG)., Results: Forty-three low-risk women with longitudinal samples (129 samples, 43 in each trimester) and 30 pregnant women with CHD with convenience samples (first trimester, five samples; second trimester, 20 samples; third trimester, 21 samples) were included. Women with CHD delivered earlier by 6 days (P = 0.002) and their newborns had lower birth weight independent of gestational age (birth weight centile 30.0 vs 55.0, P = 0.005). In low-risk women, BNP levels were lower in the third trimester (P < 0.001). There were no statistically significant differences in BNP concentrations across trimesters in the CHD group, no differences in BNP concentrations between the two groups, and no significant correlations between BNP concentration in each trimester with cardiac output, stroke volume, or heart rate (at rest/with exercise)., Conclusion: This study assessed BNP longitudinally in the first, second and third trimesters in singleton low-risk pregnancy, and showed that BNP concentration decreased with advancing gestational age, with no participants with levels greater than 40.0 pg/mL in the third trimester. BNP concentrations were similar in women with and without congenital heart disease. We found no correlation between circulating levels of BNP and maternal hemodynamics at rest or with exercise measured by ICG to support its use as a marker of cardiac function., (© 2023 The Authors. International Journal of Gynecology & Obstetrics published by John Wiley & Sons Ltd on behalf of International Federation of Gynecology and Obstetrics.)

Pregnant and postnatal women are a high-risk population particularly prone to rapid progression to sepsis with significant morbidity and mortality worldwide. Moreover, severe maternal infections can have a serious detrimental impact on neonates with almost 1 million neonatal deaths annually attributed to maternal infection or sepsis. In this review we discuss the susceptibility of pregnant women and their specific physiological and immunological adaptations that contribute to their vulnerability to sepsis, the implications for the neonate, as well as the issues with antimicrobial stewardship and the challenges this poses when attempting to reach a balance between clinical care and urgent treatment. Finally, we review advancements in the development of pregnancy-specific diagnostic and therapeutic approaches and how these can be used to optimize the care of pregnant women and neonates., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Author(s).)

Objective: Ebstein's anomaly is a rare congenital cardiac condition and data regarding pregnancy outcomes in this patient group are scarce. We evaluated the maternal and perinatal risks of pregnancy in 81 women with Ebstein's anomaly., Methods: The Registry of Pregnancy and Cardiac disease is a prospective global registry of pregnancies in women with structural cardiac disease. Pregnancy outcomes in women with Ebstein's anomaly were examined. The primary outcome was the occurrence of a major adverse cardiac event (MACE) defined as maternal mortality, heart failure, arrhythmia, thromboembolic event or endocarditis. Secondary endpoints were obstetric and perinatal outcomes and the influence of pregnancy on tricuspid valve regurgitation as well as right atrial and ventricular dimensions., Results: In the 81 women with Ebstein's anomaly (mean age 29.7±6.1 years, 46.9% nulliparous), MACE occurred in 8 (9.9%) pregnancies, mostly heart failure (n=6). There were no maternal deaths. Prepregnancy signs of heart failure were predictive for MACE. Almost half of the women were delivered by caesarean section (45.7%) and preterm delivery occurred in 24.7%. Neonatal mortality was 2.5% and 4.9% of the infants had congenital heart disease. In the subgroup in which prepregnancy and postpregnancy data were available, there was no difference in tricuspid valve regurgitation grade or right atrial and ventricular dimensions before and after pregnancy., Conclusions: Most women with Ebstein's anomaly tolerate pregnancy well, but women with prepregnancy signs of heart failure are at higher risk for MACE during pregnancy and should be counselled accordingly., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Congenital heart disease (CHD) is the most common cardiac disorder in pregnancy in the western world (around 80%). Due to improvements in surgical interventions more women with CHD are surviving to adulthood and choosing to become pregnant., Areas Covered: Preconception counseling, antenatal management of CHDs and strategies to prevent maternal and fetal complications.Preconception counseling should start early, before the transition to adult care and be offered to both men and women. It should include the choice of contraception, lifestyle modifications, pre-pregnancy optimization of cardiac state, the chance of the child inheriting a similar cardiac lesion, the risks to the mother, and long-term prognosis. Pregnancy induces marked physiological changes in the cardiovascular system that may precipitate cardiac complications. Risk stratification is based on the underlying cardiac disease and data from studies including CARPREG, ZAHARA, and ROPAC., Expert Opinion: Women with left to right shunts, regurgitant lesions, and most corrected CHDs are at lower risk and can be managed in secondary care. Complex CHD, including systemic right ventricle need expert counseling in a tertiary center. Those with severe stenotic lesions, pulmonary artery hypertension, and Eisenmenger's syndrome should avoid pregnancy, be given effective contraception and managed in a tertiary center if pregnancy does happen.

This review is about the role of arachidonic acid (ArA) in foetal and early growth and development. In 1975 and '76, we reported the preferential incorporation of ArA into the developing brain of rat pups, its conservation as a principal component in the brains of 32 mammalian species and the high proportion delivered by the human placenta for foetal nutrition, compared to its parent linoleic acid (LA). ArA is quantitatively the principal acyl component of membrane lipids from foetal red cells, mononuclear cells, astrocytes, endothelium, and placenta. Functionally, we present evidence that ArA, but not DHA, relaxes the foetal mesenteric arteries. The placenta biomagnifies ArA, doubling the proportion of the maternal level in cord blood. The proportions of ArA and its allies (di-homo-gamma-linolenic acid (DGLA), adrenic acid and ω6 docosapentaenoic acid) are similar or higher than the total of ω3 fatty acids in human milk, maintaining the abundant supply to the developing infant. Despite the evidence of the importance of ArA, the European Food Standard Agency, in 2014 rejected the joint FAO and WHO recommendation on the inclusion of ArA in infant formula, although they recommended DHA. The almost universal dominance of ArA in the membrane phosphoglycerides during human organogenesis and prenatal growth suggests that the importance of ArA and its allies in reproductive biology needs to be re-evaluated urgently., Competing Interests: Declaration of Competing Interest The authors have no conflicts of interest., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Competing Interests: Conflict of interest: None declared.

Background: COVID-19 has overwhelmed health services globally. Oral antiviral therapies are licensed worldwide, but indications and efficacy rates vary. We aimed to evaluate the safety and efficacy of oral favipiravir in patients hospitalised with COVID-19., Methods: We conducted a multicentre, open-label, randomised controlled trial of oral favipiravir in adult patients who were newly admitted to hospital with proven or suspected COVID-19 across five sites in the UK (n=2), Brazil (n=2) and Mexico (n=1). Using a permuted block design, eligible and consenting participants were randomly assigned (1:1) to receive oral favipiravir (1800 mg twice daily for 1 day; 800 mg twice daily for 9 days) plus standard care, or standard care alone. All caregivers and patients were aware of allocation and those analysing data were aware of the treatment groups. The prespecified primary outcome was the time from randomisation to recovery, censored at 28 days, which was assessed using an intention-to-treat approach. Post-hoc analyses were used to assess the efficacy of favipiravir in patients aged younger than 60 years, and in patients aged 60 years and older. The trial was registered with clinicaltrials.gov, NCT04373733., Findings: Between May 5, 2020 and May 26, 2021, we assessed 503 patients for eligibility, of whom 499 were randomly assigned to favipiravir and standard care (n=251) or standard care alone (n=248). There was no significant difference between those who received favipiravir and standard care, relative to those who received standard care alone in time to recovery in the overall study population (hazard ratio [HR] 1·06 [95% CI 0·89-1·27]; n=499; p=0·52). Post-hoc analyses showed a faster rate of recovery in patients younger than 60 years who received favipiravir and standard care versus those who had standard care alone (HR 1·35 [1·06-1·72]; n=247; p=0·01). 36 serious adverse events were observed in 27 (11%) of 251 patients administered favipiravir and standard care, and 33 events were observed in 27 (11%) of 248 patients receiving standard care alone, with infectious, respiratory, and cardiovascular events being the most numerous. There was no significant between-group difference in serious adverse events per patient (p=0·87)., Interpretation: Favipiravir does not improve clinical outcomes in all patients admitted to hospital with COVID-19, however, patients younger than 60 years might have a beneficial clinical response. The indiscriminate use of favipiravir globally should be cautioned, and further high-quality studies of antiviral agents, and their potential treatment combinations, are warranted in COVID-19., Funding: LifeArc and CW+., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Protein N-linked glycosylation is a structurally diverse post-translational modification that stores biological information in a larger order of magnitude than other post-translational modifications such as phosphorylation, ubiquitination and acetylation. This gives N-glycosylated proteins a diverse range of properties and allows glyco-codes (glycan-related information) to be deciphered by glycan-binding proteins (GBPs). The intervillous space of the placenta is richly populated with membrane-bound and secreted glycoproteins. Evidence exists to suggest that altering the structural nature of their N-glycans can impact several trophoblast functions, which include those related to interactions with decidual cells. This review summarizes trophoblast-related activities influenced by N-glycan-GBP recognition, exploring how different subtypes of trophoblasts actively adapt to characteristics of the decidualized endometrium through cell-specific expression of N-glycosylated proteins, and how these cells receive decidua-derived signals via N-glycan-GBP interactions. We highlight work on how changes in N-glycosylation relates to the success of trophoblast infiltration, interactions of immunomodulators, and uterine angiogenesis. We also discuss studies that suggest aberrant N-glycosylation of trophoblasts may contribute to the pathogenesis of pregnancy complications (e.g. pre-eclampsia, early spontaneous miscarriages and hydatidiform mole). We propose that a more in-depth understanding of how N-glycosylation shapes trophoblast phenotype during early pregnancy has the potential to improve our approach to predicting, diagnosing and alleviating poor maternal/fetal outcomes associated with placental dysfunction., (© 2023 The Author(s).)

Preterm birth is the leading cause of childhood mortality and morbidity. A better understanding of the processes that drive the onset of human labour is essential to reduce the adverse perinatal outcomes associated with dysfunctional labour. Beta-mimetics, which activate the myometrial cyclic adenosine monophosphate (cAMP) system, successfully delay preterm labour, suggesting a key role for cAMP in the control of myometrial contractility; however, the mechanisms underpinning this regulation are incompletely understood. Here we used genetically encoded cAMP reporters to investigate cAMP signalling in human myometrial smooth muscle cells at the subcellular level. We found significant differences in the dynamics of the cAMP response in the cytosol and at the plasmalemma upon stimulation with catecholamines or prostaglandins, indicating compartment-specific handling of cAMP signals. Our analysis uncovered significant disparities in the amplitude, kinetics, and regulation of cAMP signals in primary myometrial cells obtained from pregnant donors compared with a myometrial cell line and found marked response variability between donors. We also found that in vitro passaging of primary myometrial cells had a profound impact on cAMP signalling. Our findings highlight the importance of cell model choice and culture conditions when studying cAMP signalling in myometrial cells and we provide new insights into the spatial and temporal dynamics of cAMP in the human myometrium.

A significant proportion of recurrent miscarriage, recurrent implantation failure and infertility are unexplained, and these conditions have been proposed to have an etiology of immunological dysfunction at the maternal-fetal interface. Uterine Natural Killer cells (uNK) comprise three subsets and are the most numerous immune cells found in the uterine mucosa at the time of implantation. They are thought to play an important role in successful pregnancy by regulation of extravillous trophoblast (EVT) invasion and spiral artery remodelling. Here, we examine the frequency, phenotype and function of uNK1-3 from the uterine mucosa of 16 women with unexplained reproductive failure compared to 11 controls with no reproductive problems, during the window of implantation. We report that KIR2DL1/S1 and LILRB1 expression is lower in the reproductive failure group for both uNK (total uNK, uNK 2 and 3) and pNK. We also show that degranulation activity is significantly reduced in total uNK, and that TNF-α production is lower in all uNK subsets in the reproductive failure group. Taken together, our findings suggest that reproductive failure is associated with global reduction in expression of uNK receptors important for interaction with HLA-C and HLA-G on EVT during early pregnancy, leading to reduced uNK activation. This is the first study to examine uNK subsets during the window of implantation in women with reproductive failure and will serve as a platform to focus on particular aspects of phenotype and function of uNK subsets in future studies. Further understanding of uNK dysregulation is important to establish potential diagnostic and therapeutic targets in the population of women with unexplained reproductive failure., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Woon, Nikolaou, MacLaran, Norman-Taylor, Bhagwat, Cuff, Johnson and Male.)

During pregnancy, interactions between uterine immune cells and cells of the surrounding reproductive tissues are thought to be vital for regulating labour. The mechanism that specifically initiates spontaneous labour has not been determined, but distinct changes in uterine immune cell populations and their activation status have been observed during labour at term gestation. To understand the regulation of human labour by the immune system, the ability to isolate both immune cells and non-immune cells from the uterus is required. Here, we describe protocols developed in our laboratory to isolate single cells from uterine tissues, which preserve both immune and non-immune cell populations for further analysis. We provide detailed methods for isolating immune and non-immune cells from human myometrium, chorion, amnion and decidua, together with representative flow cytometry analysis of isolated cell populations present. The protocols can be completed in tandem and take approximately 4-5 h, resulting in single-cell suspensions that contain viable leucocytes, and non-immune cells in sufficient numbers for single-cell analysis approaches such as flow cytometry and single cell RNA sequencing (scRNAseq)., (© The Author(s) 2022. Published by Oxford University Press.)

Tulsi (Holy basil, Ocimum tenuiflorum L., Lamiaceae), native to Asia, has become globalised as the cultural, cosmetic, and medicinal uses of the herb have been popularised. DNA barcoding, a molecular technique used to identify species based on short regions of DNA, can discriminate between different species and identify contaminants and adulterants. This study aimed to explore the values associated with Tulsi in the United Kingdom (UK) and authenticate samples using DNA barcoding. A mixed methods approach was used, incorporating social research (i.e., structured interviews) and DNA barcoding of Ocimum samples using the ITS and trnH-psbA barcode regions. Interviews revealed the cultural significance of Tulsi: including origins, knowledge exchange, religious connotations, and medicinal uses. With migration, sharing of plants and seeds has been seen as Tulsi plants are widely grown in South Asian (SA) households across the UK. Vouchered Ocimum specimens ( n = 33) were obtained to create reference DNA barcodes which were not available in databases. A potential species substitution of O. gratissimum instead of O. tenuiflorum amongst SA participants was uncovered. Commercial samples ( n = 47) were difficult to authenticate, potentially due to DNA degradation during manufacturing processes. This study highlights the cultural significance of Tulsi, despite a potential species substitution, the plant holds a prestigious place amongst SA families in the UK. DNA barcoding was a reliable way to authenticate Ocimum species.

Aims: Hypertensive disorders of pregnancy (HDP) occur in 10% of pregnancies in the general population, pre-eclampsia specifically in 3-5%. Hypertensive disorders of pregnancy may have a high prevalence in, and be poorly tolerated by, women with heart disease., Methods And results: The prevalence and outcomes of HDP (chronic hypertension, gestational hypertension or pre-eclampsia) were assessed in the ESC EORP ROPAC (n = 5739), a worldwide prospective registry of pregnancies in women with heart disease.The overall prevalence of HDP was 10.3%, made up of chronic hypertension (5.9%), gestational hypertension (1.3%), and pre-eclampsia (3%), with significant differences between the types of underlying heart disease (P < 0.05). Pre-eclampsia rates were highest in women with pulmonary arterial hypertension (PAH) (11.1%), cardiomyopathy (CMP) (7.1%), and ischaemic heart disease (IHD) (6.3%). Maternal mortality was 1.4 and 0.6% in women with vs. without HDP (P = 0.04), and even 3.5% in those with pre-eclampsia. All pre-eclampsia-related deaths were post-partum and 50% were due to heart failure. Heart failure occurred in 18.5 vs. 10.6% of women with vs. without HDP (P < 0.001) and in 29.1% of those with pre-eclampsia. Perinatal mortality was 3.1 vs. 1.7% in women with vs. without HDP (P = 0.019) and 4.7% in those with pre-eclampsia., Conclusion: Hypertensive disorders of pregnancy and pre-eclampsia rates were higher in women with CMP, IHD, and PAH than in the general population. Adverse outcomes were increased in women with HDP, and maternal mortality was strikingly high in women with pre-eclampsia. The combination of HDP and heart disease should prompt close surveillance in a multidisciplinary context and the diagnosis of pre-eclampsia requires hospital admission and continued monitoring during the post-partum period., Competing Interests: Conflict of interest: None declared., (© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Beta-blocker (BB) and calcium channel blocker (CCB) antihypertensive drugs are commonly used in pregnancy. However, data on their relative impact on maternal and foetal outcomes are limited. We leveraged genetic variants mimicking BB and CCB antihypertensive drugs to investigate their effects on risk of pre-eclampsia, gestational diabetes and birthweight using the Mendelian randomization paradigm., Methods: Genetic association estimates for systolic blood pressure (SBP) were extracted from summary data of a genome-wide association study (GWAS) on 757,601 participants. Uncorrelated single-nucleotide polymorphisms (SNPs) associated with SBP (p < 5 × 10 -8 ) in BB and CCB drug target gene regions were selected as proxies for drug target perturbation. Genetic association estimates for the outcomes were extracted from GWASs on 4743 cases and 136,325 controls (women without a hypertensive disorder in pregnancy) for pre-eclampsia or eclampsia, 7676 cases and 130,424 controls (women without any pregnancy-related morbidity) for gestational diabetes, and 155,202 women (who have given birth at least once) for birthweight of the first child. All studies were in European ancestry populations. Mendelian randomization estimates were generated using the two-sample inverse-variance weighted model., Results: Although not reaching the conventional threshold for statistical significance, genetically-proxied BB was associated with reduced risk of pre-eclampsia (OR per 10 mmHg SBP reduction 0.27, 95%CI 0.06-1.19, p = 0.08) and increased risk of gestational diabetes (OR per 10 mmHg SBP reduction 2.01, 95%CI 0.91-4.42, p = 0.08), and significantly associated with lower birthweight of first child (beta per 10 mmHg SBP reduction - 0.27, 95%CI - 0.39 to - 0.15, p = 1.90 × 10 -5 ). Genetically-proxied CCB was associated with reduced risk of pre-eclampsia and eclampsia (OR 0.62, 95%CI 0.43-0.89, p = 9.33 × 10 -3 ), and was not associated with gestational diabetes (OR 1.05, 95% CI 0.76-1.45, p = 0.76) or changes in birthweight of first child (beta per 10 mmHg SBP reduction 0.02, 95%CI - 0.04-0.07, p = 0.54)., Conclusions: While BB and CCB antihypertensive drugs may both be efficacious for lowering blood pressure in pregnancy, this genetic evidence suggests that BB use may lower birthweight. Conversely, CCB use may reduce risk of pre-eclampsia and eclampsia without impacting gestational diabetes risk or birthweight. These data support further study on the effects of BBs on birthweight., (© 2022. The Author(s).)

Uterine natural killer cells (uNK) play an important role in promoting successful pregnancy by regulating trophoblast invasion and spiral artery remodelling in the first trimester. Recently, single-cell RNA sequencing (scRNAseq) on first-trimester decidua showed that uNK can be divided into three subsets, which may have different roles in pregnancy. Here we present an integration of previously published scRNAseq datasets, together with novel flow cytometry data to interrogate the frequency, phenotype, and function of uNK1-3 in seven stages of the reproductive cycle (menstrual, proliferative, secretory phases of the menstrual cycle; first, second, and third trimester; and postpartum). We found that uNK1 and uNK2 peak in the first trimester, but by the third trimester, the majority of uNK are uNK3. All three subsets are most able to degranulate and produce cytokines during the secretory phase of the menstrual cycle and express KIR2D molecules, which allow them to interact with HLA-C expressed by placental extravillous trophoblast cells, at the highest frequency during the first trimester. Taken together, our findings suggest that uNK are particularly active and able to interact with placental cells at the time of implantation and that uNK1 and uNK2 may be particularly involved in these processes. Our findings are the first to establish how uNK frequency and function change dynamically across the healthy reproductive cycle. This serves as a platform from which the relationship between uNK function and impaired implantation and placentation can be investigated. This will have important implications for the study of subfertility, recurrent miscarriage, pre-eclampsia, and pre-term labour., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Whettlock, Woon, Cuff, Browne, Johnson and Male.)

In celebration of the centenary of the National Institute of Nutrition (NIN), Hyderabad, India (1918-2018), a symposium highlighted the progress in nutrition knowledge made over the century, as well as major gaps in implementation of that knowledge. Brain famine caused by a shortage of nutrients required for perinatal brain development has unfortunately become a global reality, even as protein-calorie famine was largely averted by the development of high yield crops. While malnutrition remains widespread, the neglect of global food policies that support brain development and maintenance are most alarming. Brain disorders now top the list of the global burden of disease, even with obesity rising throughout the world. Neurocognitive health, remarkably, is seldom listed among the non-communicable diseases (NCDs) and is therefore seldom considered as a component of food policy. Most notably, the health of mothers before conception and through pregnancy as mediated by proper nutrition has been neglected by the current focus on early death in non-neurocognitive NCDs, thereby compromising intellectual development of the ensuing generations. Foods with balanced essential fatty acids and ample absorbable micronutrients are plentiful for populations with access to shore-based foods, but deficient only a few kilometres away from the sea. Sustained access to brain supportive foods is a priority for India and throughout the world to enable each child to develop to their intellectual potential, and support a prosperous, just, and peaceful world. Nutrition education and food policy should place the nutritional requirements for the brain on top of the list of priorities., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: Obesity in pregnancy is associated with substantial risks, notably hypertensive disorders. Bariatric surgery achieves sustained weight loss and has several cardiovascular benefits, including positive effects on blood pressure, cardiac geometry, and both systolic and diastolic function. Pregnancy following bariatric surgery is also associated with improved outcomes, including a reduced risk of hypertensive disorders. The underlying mechanisms, however, remain uncertain. Maternal cardiovascular adaptation plays a vital role in maintaining a healthy pregnancy, and maladaptation has been associated with adverse pregnancy outcomes. However, to date, the maternal cardiovascular adaptation to pregnancy after bariatric surgery has not been investigated., Objective: To investigate the maternal cardiovascular adaptation to pregnancy in women with previous bariatric surgery compared with women with a similar early-pregnancy body mass index, age, and race but no history of weight loss surgery., Study Design: This was a prospective, observational, longitudinal study including pregnant women with (n=41) and without (n=41) a history of bariatric surgery. The participants were seen at 3 time points; at 12 to 14, 20 to 24, and 30 to 32 weeks of pregnancy. At each visit, the blood pressure was measured and the maternal cardiovascular system was assessed using transthoracic echocardiography. Two-dimensional speckle tracking was performed to assess the global longitudinal and circumferential strain on a subset of patients (15 in each group). Offline analysis was performed according to the European and American echocardiography guidelines. Multilevel linear mixed-effect models were used for all the comparisons., Results: Compared with the no-surgery group, women with previous bariatric surgery, had lower systolic and diastolic blood pressure, heart rate, and cardiac output across all the trimesters (P<.01 for all comparisons), with an evidence of more favorable diastolic indices, including a higher E-wave/A-wave ratio across the mitral valve (P<.001), higher mitral velocity at the lateral and medial annulus (E') (P=.01 and P=.03, respectively), and a lower left atrial volume (P<.05). Furthermore, women with previous bariatric surgery demonstrated lower global longitudinal (P<.01) and circumferential strain (P=.02), which is suggestive of better systolic function., Conclusion: Our findings indicate better cardiovascular adaptation to pregnancy in women with previous bariatric surgery than in pregnant women of a similar early-pregnancy body mass index but no history of surgery., (Crown Copyright © 2021. Published by Elsevier Inc. All rights reserved.)

Background: Maternal cardiovascular risk factors have been associated with adverse maternal and fetal outcomes. Given the difficulty in establishing causal relationships using epidemiological data, we applied Mendelian randomization to explore the role of cardiovascular risk factors on risk of developing preeclampsia or eclampsia, and low fetal birthweight., Methods: Uncorrelated single-nucleotide polymorphisms associated systolic blood pressure (SBP), body mass index, type 2 diabetes, LDL (low-density lipoprotein) with cholesterol, smoking, urinary albumin-to-creatinine ratio, and estimated glomerular filtration rate at genome-wide significance in studies of 298 957 to 1 201 909 European ancestry participants were selected as instrumental variables. A 2-sample Mendelian randomization study was performed with primary outcome of preeclampsia or eclampsia (PET). Risk factors associated with PET were further investigated for their association with low birthweight., Results: Higher genetically predicted SBP was associated increased risk of PET (odds ratio [OR] per 1-SD SBP increase 1.90 [95% CI=1.45-2.49]; P =3.23×10 -6 ) and reduced birthweight (OR=0.83 [95% CI=0.79-0.86]; P =3.96×10 -18 ), and this was not mediated by PET. Body mass index and type 2 diabetes were also associated with PET (respectively, OR per 1-SD body mass index increase =1.67 [95% CI=1.44-1.94]; P =7.45×10 -12 ; and OR per logOR increase type 2 diabetes =1.11 [95% CI=1.04-1.19]; P =1.19×10 -3 ), but not with reduced birthweight., Conclusions: Our results provide evidence for causal effects of SBP, body mass index, and type 2 diabetes on PET and identify that SBP is associated with reduced birthweight independently of PET. The results provide insight into the pathophysiological basis of PET and identify hypertension as a potentially modifiable risk factor amenable to therapeutic intervention.

Objective: Cardiac disease is a major cause of maternal mortality. Data regarding pregnancy outcomes in women with a systemic right ventricle (sRV) are scarce. We studied pregnancy outcomes in women with an sRV after the atrial switch procedure for transposition of the great arteries (TGA) or congenitally corrected TGA (CCTGA)., Methods: The ESC EORP Registry of Pregnancy and Cardiac Disease is an international prospective registry of pregnant women with cardiac disease. Pregnancy outcomes (maternal/fetal) in all women with an sRV are described. The primary end point was a major adverse cardiac event (MACE) defined as maternal death, supraventricular or ventricular arrhythmias requiring treatment, heart failure, aortic dissection, endocarditis, ischaemic coronary event and other thromboembolic events., Results: Altogether, 162 women with an sRV (TGA n=121, CCTGA n=41, mean age 28.8±4.6 years) were included. No maternal mortality occurred. In 26 women, at least one MACE occurred, heart failure in 16 (9.8%), arrhythmias (atrial 5, ventricular 6) in 11 (6.7%) and others in 4 (2.5%). Prepregnancy signs of heart failure as well as an sRV ejection fraction <40% were predictors of MACE. One woman experienced fetal loss, while no neonatal mortality was observed. No significant differences were found between women with CCTGA and TGA. In the subset of women who had an echocardiogram before and after pregnancy, no clear deterioration in sRV was observed., Conclusion: The majority of women with an sRV tolerated pregnancy well with a favourable maternal and fetal outcome. Heart failure and arrhythmias were the most common MACE., Competing Interests: Competing interests: WB reports a relationship with Proctor Abbott & Occlutech. APM reports personal fees from Novartis, personal fees from Bayer, personal fees from Fresenius, outside the submitted work., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.)

Aims: Hypertensive disorders occur in women with peripartum cardiomyopathy (PPCM). How often hypertensive disorders co-exist, and to what extent they impact outcomes, is less clear. We describe differences in phenotype and outcomes in women with PPCM with and without hypertensive disorders during pregnancy., Methods and Results: The European Society of Cardiology EURObservational Research Programme PPCM Registry enrolled women with PPCM from 2012-2018. Three groups were examined: (i) women without hypertension (PPCM-noHTN); (ii) women with hypertension but without pre-eclampsia (PPCM-HTN); (iii) women with pre-eclampsia (PPCM-PE). Maternal (6-month) and neonatal outcomes were compared. Of 735 women included, 452 (61.5%) had PPCM-noHTN, 99 (13.5%) had PPCM-HTN and 184 (25.0%) had PPCM-PE. Compared to women with PPCM-noHTN, women with PPCM-PE had more severe symptoms (New York Heart Association class IV in 44.4% vs. 29.9%, P < 0.001), more frequent signs of heart failure (pulmonary rales in 70.7% vs. 55.4%, P = 0.002), a higher baseline left ventricular ejection fraction (LVEF) (32.7% vs. 30.7%, P = 0.005) and a smaller left ventricular end-diastolic diameter (57.4 ± 6.7 mm vs. 59.8 ± 8.1 mm, P = 0.001). There were no differences in the frequencies of death from any cause, rehospitalization for any cause, stroke, or thromboembolic events. Compared to women with PPCM-noHTN, women with PPCM-PE had a greater likelihood of left ventricular recovery (LVEF ≥ 50%) (adjusted odds ratio 2.08, 95% confidence interval 1.21-3.57) and an adverse neonatal outcome (composite of termination, miscarriage, low birth weight or neonatal death) (adjusted odds ratio 2.84, 95% confidence interval 1.66-4.87)., Conclusion: Differences exist in phenotype, recovery of cardiac function and neonatal outcomes according to hypertensive status in women with PPCM., (© 2021 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

High throughput sequencing has previously identified differentially expressed genes (DEGs) and enriched signalling networks in human myometrium for term (≥37 weeks) gestation labour, when defined as a singular state of activity at comparison to the non-labouring state. However, transcriptome changes that occur during transition from early to established labour (defined as ≤3 and >3 cm cervical dilatation, respectively) and potentially altered by fetal membrane rupture (ROM), when adapting from onset to completion of childbirth, remained to be defined. In the present study, we assessed whether differences for these two clinically observable factors of labour are associated with different myometrial transcriptome profiles. Analysis of our tissue ('bulk') RNA-seq data (NCBI Gene Expression Omnibus: GSE80172) with classification of labour into four groups, each compared to the same non-labour group, identified more DEGs for early than established labour; ROM was the strongest up-regulator of DEGs. We propose that lower DEGs frequency for early labour and/or ROM negative myometrium was attributed to bulk RNA-seq limitations associated with tissue heterogeneity, as well as the possibility that processes other than gene transcription are of more importance at labour onset. Integrative analysis with future data from additional samples, which have at least equivalent refined clinical classification for labour status, and alternative omics approaches will help to explain what truly contributes to transcriptomic changes that are critical for labour onset. Lastly, we identified five DEGs common to all labour groupings; two of which (AREG and PER3) were validated by qPCR and not differentially expressed in placenta and choriodecidua., Competing Interests: The authors have declared that no competing interests exist.

Background: Cardiovascular disease is the leading cause of death during pregnancy with thoracic aortic dissection being one of the main causes. Thoracic aortic disease is commonly related to hereditary disorders and congenital heart malformations such as bicuspid aortic valve (BAV). Pregnancy is considered a high risk period in women with underlying aortopathy., Methods: The ESC EORP Registry Of Pregnancy And Cardiac disease (ROPAC) is a prospective global registry that enrolled 5739 women with pre-existing cardiac disease. With this analysis, we aim to study the maternal and fetal outcome of pregnancy in women with thoracic aortic disease., Results: Thoracic aortic disease was reported in 189 women (3.3%). Half of them were patients with Marfan syndrome (MFS), 26% had a BAV, 8% Turner syndrome, 2% vascular Ehlers-Danlos syndrome and 11% had no underlying genetic defect or associated congenital heart defect. Aortic dilatation was reported in 58% of patients and 6% had a history of aortic dissection. Four patients, of whom three were patients with MFS, had an acute aortic dissection (three type A and one type B aortic dissection) without maternal or fetal mortality. No complications occurred in women with a history of aortic dissection. There was no significant difference in median fetal birth weight if treated with a beta-blocker or not (2960 g (2358-3390 g) vs 3270 g (2750-3570 g), p value 0.25)., Conclusion: This ancillary analysis provides the largest prospective data review on pregnancy risk for patients with thoracic aortic disease. Overall pregnancy outcomes in women with thoracic aortic disease followed according to current guidelines are good., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Inflammation is thought to play a pivotal role in the onset of term and some forms of preterm labour. Although, we recently found that myometrial inflammation is a consequence rather than a cause of term labour, there are several other reproductive tissues, including amnion, choriodecidua parietalis and decidua basalis, where the inflammatory stimulus to labour may occur. To investigate this, we have obtained amnion, choriodecidual parietalis and decidua basalis samples from women at various stages of pregnancy and spontaneous labour. The inflammatory cytokine profile in each tissue was determine by Bio-Plex Pro® cytokine multiplex assays and quantitative RT-PCR. Active motif assay was used to study transcription activation in the choriodecidua parietalis. Quantitative RT-PCR was use to study the pro-labour genes (PGHS-2, PGDH, OTR and CX43) in all of the tissues at the onset of labour and oxytocin (OT) mRNA expression in the choriodecidual parietalis and decidua basalis. Statistical significance was ascribed to a P value <0.05. In the amnion and choriodecidua parietalis, the mRNA levels of various cytokines decreased from preterm no labour to term no labour samples, but the protein levels were unchanged. The choriodecidua parietalis showed increase in the protein levels of IL-1β and IL-6 in the term early labour samples. In the amnion and decidua basalis, the protein levels of several cytokines rose in term established labour. The multiples of the median derived from the 19-plex cytokine assay were greater in term early labour and term established labour samples from the choriodecidua parietalis, but only in term established labour for myometrium. These data suggest that the inflammatory stimulus to labour may begin in the choriodecidua parietalis, but the absence of any change in prolabour factor mRNA levels suggests that the cytokines may act on the myometrium where we observed changes in transcription factor activation and increases in prolabour gene expression in earlier studies., Competing Interests: The authors have declared that no competing interests exist.

Progesterone (P4) and cyclic adenosine monophosphate (cAMP) are regarded as pro-quiescent factors that suppress uterine contractions during pregnancy. We previously used human primary cells in vitro and mice in vivo to demonstrate that simultaneously enhancing myometrial P4 and cAMP levels may reduce inflammation-associated preterm labor. Here, we assessed whether aminophylline (Ami; phosphodiesterase inhibitor) and P4 can reduce myometrial contractility and contraction-associated proteins (CAPs) better together than individually; both agents are clinically used drugs. Myometrial tissues from pregnant non-laboring women were treated ex vivo with Ami acutely (while spontaneous contracting) or throughout 24-h tissue culture (±P4); isometric tension measurements, PKA assays, and Western blotting were used to assess tissue contractility, cAMP action, and inflammation. Acute (1 h) treatment with 250 and 750 μM Ami reduced contractions by 50% and 84%, respectively, which was not associated with a directly proportional increase in whole tissue PKA activity. Sustained myometrial relaxation was observed during 24-h tissue culture with 750 μM Ami, which did not require P4 nor reduce CAPs. COX-2 protein can be reduced by 300 nM P4 but this did not equate to myometrial relaxation. Ami (250 μM) and P4 (100 and 300 nM) co-treatment did not prevent oxytocin-augmented contractions nor reduce CAPs during interleukin-1β stimulation. Overall, Ami and P4 co-treatment did not suppress myometrial contractions more than either agent alone, which may be attributed to low specificity and efficacy of Ami; cAMP and P4 action at in utero neighboring reproductive tissues during pregnancy should also be considered., (© 2021 The Authors. Pharmacology Research & Perspectives published by British Pharmacological Society and American Society for Pharmacology and Experimental Therapeutics and John Wiley & Sons Ltd.)

Previously, we showed that cAMP increased COX-2 expression in myometrial cells via MAPK. Here, we have extended these observations, using primary myometrial cell cultures to show that the cAMP agonist, forskolin, enhances IL-1β-driven COX-2 expression. We then explored the role of A-kinase interacting protein (AKIP1), which modulates the effect of PKA on p65 activation. AKIP1 knockdown reversed the effect of forskolin, such that its addition inhibited IL-1β-induced COX-2 mRNA expression and reduced the IL-1β-induced increase in nuclear levels of p65 and c-jun. Forskolin alone and with IL-1β increased IκBα mRNA expression suggesting that in the context of inflammation and in the presence of AKIP1, cAMP enhances p65 activation. AKIP1 knockdown reversed these changes. Interestingly, AKIP1 knockdown had minimal effect on the ability of forskolin to repress either basal OTR expression or IL-1β-stimulated OTR mRNA expression. AKIP1 was up-regulated by IL-1β, but not stretch and was repressed by cAMP. The mRNA expression of AKIP1 increased in early labour in tandem with an increase in COX-2 mRNA and protein. AKIP1 protein levels were also increased with inflammation and stretch-induced preterm labour. Our results identify a second important cAMP effector-switch occurring at term in human myometrium and suggest that a hitherto unrecognized interaction may exist between AKIP1, NFκB and AP-1. These data add to the proposition that cAMP acts as a key regulator of human myometrial contractility., Competing Interests: The authors have declared that no competing interests exist.

Background: Pregnant women with mechanical heart valves are at significant risk of obstetric/cardiac complications. This study compares the anticoagulation management in two obstetric cardiac centres., Methods: Retrospective case-note review from Chelsea and Westminster/Royal Brompton Hospitals (CR) and Erasmus Medical Centre (EMC). Main outcome measure was mechanical heart valve thrombosis., Results: Nineteen pregnancies from CR and 25 pregnancies from EMC were included. Most women were on low-molecular-weight heparin (LMWH) throughout pregnancy at CR, whereas at EMC most had LMWH in the first trimester and vitamin K antagonists in subsequent trimesters. Peak anti-factor Xa were performed monthly at CR, levels 0.39-1.51 IU/mL (mean 0.82 IU/mL). Anticoagulation management peri-partum was inconsistent. Delivery was mainly by caesarean section at CR (74%) and vaginal delivery at EMC (64%). No maternal deaths and only one mechanical heart valve thrombosis at CR. Two mechanical heart valve thromboses and one maternal death at EMC., Conclusion: Peri-partum anticoagulation strategies, anticoagulation monitoring and mode of delivery inconsistencies reported., Competing Interests: Declaration of conflicting interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2020.)

Cyclic adenosine monophosphate (cAMP) contributes to maintenance of a quiescent (relaxed) state in the myometrium (i.e. uterine smooth muscle) during pregnancy, which most commonly has been attributed to activation of protein kinase A (PKA). PKA-mediated phosphorylation of cytosolic contractile apparatus components in myometrial smooth muscle cells (mSMCs) are known to promote relaxation. Additionally, PKA also regulates nuclear transcription factor (TF) activity to control expression of genes important to the labour process; these are mostly involved in actin-myosin interactions, cell-to-cell connectivity and inflammation, all of which influence mSMC transition from a quiescent to a contractile (pro-labour) phenotype. This review focuses on the evidence that cAMP modulates the activity of TFs linked to pro-labour gene expression, predominantly cAMP response element (CRE) binding TFs, nuclear factor κB (NF-κB), activator protein 1 (AP-1) family and progesterone receptors (PRs). This review also considers the more recently described exchange protein directly activated by cAMP (EPAC) that may oppose the pro-quiescent effects of PKA, as well as explores findings from other cell types that have the potential to be of novel relevance to cAMP action on TF function in the myometrium., (© 2021 The Author(s).)

This position paper focusses on the pathophysiology, diagnosis and management of women diagnosed with a cardiomyopathy, or at risk of heart failure (HF), who are planning to conceive or present with (de novo or previously unknown) HF during or after pregnancy. This includes the heterogeneous group of heart muscle diseases such as hypertrophic, dilated, arrhythmogenic right ventricular and non-classified cardiomyopathies, left ventricular non-compaction, peripartum cardiomyopathy, Takotsubo syndrome, adult congenital heart disease with HF, and patients with right HF. Also, patients with a history of chemo-/radiotherapy for cancer or haematological malignancies need specific pre-, during and post-pregnancy assessment and counselling. We summarize the current knowledge about pathophysiological mechanisms, including gene mutations, clinical presentation, diagnosis, and medical and device management, as well as risk stratification. Women with a known diagnosis of a cardiomyopathy will often require continuation of drug therapy, which has the potential to exert negative effects on the foetus. This position paper assists in balancing benefits and detrimental effects., (© 2021 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Introduction: Obesity rates have reached an epidemic level and bariatric surgery is the most effective method of sustainable weight loss. Pregnancy following bariatric surgery is associated with an increased prevalence of small babies. The objective of the study is to compare the fetal fat distribution, as assessed by fractional arm and thigh volume using three-dimensional ultrasonography, in pregnancies following maternal bariatric surgery with those without such history., Material and Methods: This is a prospective, longitudinal, observational study conducted in a Maternity Unit in the UK. The study included 189 pregnant women; 63 with previous bariatric surgery [27 restrictive (13 with gastric band, 14 with sleeve gastrectomy) and 36 malabsorptive procedures] and 126 with no previous surgery but similar maternal booking body mass index. Fetal arm and thigh volume were obtained at 30-33 and 35-37 weeks' gestation and fractional limb volumes were calculated using a commercially available software. Women underwent a 75 g, 2 h oral glucose tolerance test at 28-31 weeks of gestation., Results: Overall, adjusted fetal arm and thigh volume were smaller in the post-bariatric, compared to the no surgery, group and this was more marked in women who had undergone a previous sleeve gastrectomy (P < .001 and P = .002, respectively) or a malabsorptive procedure (P < .001 for both). There was a strong positive correlation between maternal fasting/post-prandial (2 h) glucose levels, at the time of the oral glucose tolerance test, and arm and thigh volume at both 30-33 and 35-37 weeks (P < .01 for all)., Conclusions: The study has demonstrated that in the third trimester of pregnancy, fetuses of women with previous bariatric surgery have smaller fractional limb volumes, therefore less soft tissue, compared to fetuses of women without such surgery and this may be related to the lower maternal glucose levels seen in the former pregnancies., (© 2020 The Authors. Acta Obstetricia et Gynecologica Scandinavica published by John Wiley & Sons Ltd on behalf of Nordic Federation of Societies of Obstetrics and Gynecology (NFOG).)

Background In the past 3 decades, the arterial switch procedure has replaced the atrial switch procedure as treatment of choice for transposition of the great arteries. Although survival is superior after the arterial switch procedure, data on pregnancy outcomes are scarce and transposition of the great arteries after arterial switch is not yet included in the modified World Health Organization classification of maternal cardiovascular risk. Methods and Results The ROPAC (Registry of Pregnancy and Cardiac disease) is an international prospective registry of pregnant women with cardiac disease, part of the European Society of Cardiology EURObservational Research Programme. Pregnancy outcomes in all women after an arterial switch procedure for transposition of the great arteries are described. The primary end point was a major adverse cardiovascular event, defined as combined end point of maternal death, supraventricular or ventricular arrhythmias requiring treatment, heart failure, aortic dissection, endocarditis, ischemic coronary events, and thromboembolic events. Altogether, 41 pregnant women (mean age, 26.7±3.9 years) were included, and there was no maternal mortality. A major adverse cardiovascular event occurred in 2 women (4.9%): heart failure in one (2.4%) and ventricular tachycardia in another (2.4%). One woman experienced fetal loss, whereas no neonatal mortality was observed. Conclusions Women after an arterial switch procedure for transposition of the great arteries tolerate pregnancy well, with a favorable maternal and fetal outcome. During counseling, most women should be reassured that the risk of pregnancy is low. Classification as modified World Health Organization risk class II seems appropriate.

Our previous work has shown myometrial PKA activity declines in term and twin-preterm labour in association with an increase in the expression of the oxytocin receptor (OTR). Here we investigate the action of cAMP/PKA in basal conditions, with the addition of progesterone (P4) and/or IL-1β to understand how cAMP/PKA acts to maintain pregnancy and whether the combination of cAMP and P4 would be a viable therapeutic combination for the prevention of preterm labour (PTL). Further, given that we have previously found that cAMP enhances P4 action we wanted to test the hypothesis that changes in the cAMP effector system are responsible for the functional withdrawal of myometrial P4 action. Myometrial cells were grown from biopsies obtained from women at the time of elective Caesarean section before the onset of labour. The addition of forskolin, an adenylyl cyclase activator, repressed basal OTR mRNA levels at all doses and P4 only enhanced this effect at its highest dose. Forskolin repressed the IL-1β-induced increase in OTR mRNA and protein levels in a PKA-dependent fashion and repressed IL-1β-activation and nuclear transfer of NFκB and AP-1. P4 had similar effects and the combination P4 and forskolin had greater effects on OTR and NFκB than forskolin alone. While PKA knockdown had no effect on the ability of P4 to repress IL-1β-induced OTR expression it reversed the repressive effect of the combination of P4 and forskolin and resulted in a greater increase than observed with IL-1β alone. These studies suggest that cAMP acts via PKA to repress inflammation-driven OTR expression, but that when PKA activity is reduced, the combination of cAMP and P4 actually enhances the OTR response to inflammation, promoting the onset of labour and suggesting that changes in the cAMP effector system can induce a functional P4 withdrawal., Competing Interests: The authors have declared that no competing interests exist.