Maternal hypertensive traits and adverse outcome in pregnancy: a Mendelian randomization study.

INTRODUCTION: Hypertensive disorders of pregnancy are associated with adverse feto-maternal outcomes. Existing evidence is mostly limited to observational studies, which are liable to confounding and bias. This study investigated the causal relevance of component hypertensive indices on multiple adverse pregnancy outcomes using Mendelian randomization. METHODS: Uncorrelated ( r2  < 0.001) genome-wide significant ( P  < 5 × 10 -8 ) single-nucleotide polymorphisms associated with SBP, DBP and pulse pressure (PP) were selected as instrumental variables. Genetic association estimates for outcomes of preeclampsia or eclampsia, preterm birth, placental abruption and hemorrhage in early pregnancy were extracted from summary statistics of genome-wide association studies in the FinnGen cohort. Two-sample, inverse-variance weighted Mendelian randomization formed the primary analysis method. Odds ratios (OR) are presented per-10 mmHg higher genetically predicted hypertensive index. RESULTS: Higher genetically predicted SBP were associated with higher odds of preeclampsia or eclampsia [OR 1.81, 95% confidence interval (CI) 1.68-1.96, P  = 5.45 × 10 -49 ], preterm birth (OR 1.09, 95% CI 1.03-1.16, P  = 0.005) and placental abruption (OR 1.33, 95% CI 1.05-1.68, P  = 0.016). Higher genetically-predicted DBP was associated with preeclampsia or eclampsia (OR 2.54, 95% CI 2.21-2.92, P  = 5.35 × 10 -40 ). Higher genetically predicted PP was associated with preeclampsia or eclampsia (OR 1.68, 95% CI 1.47-1.92, P  = 1.9 × 10 -14 ) and preterm birth (OR 1.18, 95% CI 1.06-1.30, P  = 0.002). CONCLUSION: This study provides genetic evidence to support causal associations of SBP, DBP and PP on multiple adverse outcomes of pregnancy. SBP and PP were associated with the broadest range of adverse outcomes, suggesting that optimized management of blood pressure, particularly SBP, is a key priority to improve feto-maternal health.

Direct current cardioversion in pregnancy: a multicentre study.

OBJECTIVE: Direct current cardioversion (DCCV) in pregnancy is rarely required and typically only documented in single case reports or case series. A recent UK confidential enquiry reported on several maternal deaths where appropriate DCCV appeared to have been withheld. DESIGN: Retrospective cohort study. SETTING: Seventeen UK and Ireland specialist maternity centres. SAMPLE: Twenty-seven pregnant women requiring DCCV in pregnancy. MAIN OUTCOME MEASURES: Maternal and fetal outcomes following DCCV. RESULTS: Twenty-seven women had a total of 29 DCCVs in pregnancy. Of these, 19 (70%) initial presentations were to Emergency Departments and eight (30%) to maternity settings. There were no maternal deaths. Seventeen of the women (63%) had a prior history of heart disease. Median gestation at DCCV was 28 weeks, median gestation at delivery was 35 weeks, with a live birth in all cases. The abnormal heart rhythms documented at the first cardioversion were atrial fibrillation in 12/27 (44%) cases, atrial flutter in 8/27 (30%), supraventricular tachycardia in 5/27 (19%) and atrial tachycardia in 2/27 (7%). Fetal monitoring was undertaken following DCCV on 14/29 (48%) occasions (10 of 19 (53%) at ≥26 weeks) and on 2/29 (7%) occasions, urgent delivery was required post DCCV. CONCLUSIONS: Direct current cardioversion in pregnancy is rarely required but should be undertaken when clinically indicated according to standard algorithms to optimise maternal wellbeing. Once the woman is stable post DCCV, gestation-relevant fetal monitoring should be undertaken. Maternity units should develop multidisciplinary processes to ensure pregnant women receive the same standard of care as their non-pregnant counterparts.

Prescribing for pregnancy: chronic skin diseases.

Chronic skin disease is common in women of reproductive age. Although skin can improve or remain stable during pregnancy, it is also common for existing conditions to flare and for new conditions to develop. A small number of medications used to control chronic skin disease can potentially have adverse effects on the outcome of the pregnancy. This article forms part of a series on prescribing for pregnancy and highlights the importance of achieving good control of the skin disease prior to conception and during pregnancy. It emphasises the need for patient-centred, open and informed discussions around medication options to achieve good control. During pregnancy and breastfeeding each patient should be treated as an individual in accordance with the medications that are appropriate for them, their preferences, and the severity of their skin disease. This should be done through collaborative working across primary care, dermatology and obstetric services.

Association of Hypertensive Disorders of Pregnancy With Future Cardiovascular Disease.

Conclusions and Relevance: The findings of this study provide genetic evidence supporting an association between HDPs and higher risk of coronary artery disease and stroke, which is only partially mediated by cardiometabolic factors. This supports classification of HDPs as risk factors for cardiovascular disease. Design, Setting, and Participants: A genome-wide genetic association study using mendelian randomization (MR) was performed from February 16 to March 4, 2022. Primary analysis was conducted using inverse-variance-weighted MR. Mediation analyses were performed using a multivariable MR framework. All studies included patients predominantly of European ancestry. Female-specific summary-level data from FinnGen (sixth release). Exposures: Uncorrelated (r2<0.001) single-nucleotide variants (SNVs) were selected as instrumental variants from the FinnGen consortium summary statistics for exposures of any HDP, gestational hypertension, and preeclampsia or eclampsia. Importance: Hypertensive disorders in pregnancy (HDPs) are major causes of maternal and fetal morbidity and are observationally associated with future maternal risk of cardiovascular disease. However, observational results may be subject to residual confounding and bias. Main Outcomes and Measures: Genetic association estimates for outcomes were extracted from genome-wide association studies of 122 733 cases for coronary artery disease, 34 217 cases for ischemic stroke, 47 309 cases for heart failure, and 60 620 cases for atrial fibrillation. Objective: To investigate the association of HDPs with multiple cardiovascular diseases. Results: Genetically predicted HDPs were associated with a higher risk of coronary artery disease (odds ratio [OR], 1.24; 95% CI, 1.08-1.43; P = .002); this association was evident for both gestational hypertension (OR, 1.08; 95% CI, 1.00-1.17; P = .04) and preeclampsia/eclampsia (OR, 1.06; 95% CI, 1.01-1.12; P = .03). Genetically predicted HDPs were also associated with a higher risk of ischemic stroke (OR, 1.27; 95% CI, 1.12-1.44; P = 2.87 × 10-4). Mediation analysis revealed a partial attenuation of the effect of HDPs on coronary artery disease after adjustment for systolic blood pressure (total effect OR, 1.24; direct effect OR, 1.10; 95% CI, 1.02-1.08; P = .02) and type 2 diabetes (total effect OR, 1.24; direct effect OR, 1.16; 95% CI, 1.04-1.29; P = .008). No associations were noted between genetically predicted HDPs and heart failure (OR, 0.97; 95% CI, 0.76-1.23; P = .79) or atrial fibrillation (OR, 1.11; 95% CI, 0.65-1.88; P = .71).

Sex-Specific Reproductive Factors Augment Cardiovascular Disease Risk in Women: A Mendelian Randomization Study.

Background Observational studies suggest that reproductive factors are associated with cardiovascular disease, but these are liable to influence by residual confounding. This study explores the causal relevance of reproductive factors on cardiovascular disease in women using Mendelian randomization. Methods and Results Uncorrelated (r2<0.001), genome-wide significant (P<5×10-8) single-nucleotide polymorphisms were extracted from sex-specific genome-wide association studies of age at first birth, number of live births, age at menarche, and age at menopause. Inverse-variance weighted Mendelian randomization was used for primary analyses on outcomes of atrial fibrillation, coronary artery disease, heart failure, ischemic stroke, and stroke. Earlier genetically predicted age at first birth increased risk of coronary artery disease (odds ratio [OR] per year, 1.49 [95% CI, 1.28-1.74], P=3.72×10-7) heart failure (OR, 1.27 [95% CI, 1.06-1.53], P=0.009), and stroke (OR, 1.25 [95% CI, 1.00-1.56], P=0.048), with partial mediation through body mass index, type 2 diabetes, blood pressure, and cholesterol traits. Higher genetically predicted number of live births increased risk of atrial fibrillation (OR for <2, versus 2, versus >2 live births, 2.91 [95% CI, 1.16-7.29], P=0.023), heart failure (OR, 1.90 [95% CI, 1.28-2.82], P=0.001), ischemic stroke (OR, 1.86 [95% CI, 1.03-3.37], P=0.039), and stroke (OR, 2.07 [95% CI, 1.22-3.52], P=0.007). Earlier genetically predicted age at menarche increased risk of coronary artery disease (OR per year, 1.10 [95% CI, 1.06-1.14], P=1.68×10-6) and heart failure (OR, 1.12 [95% CI, 1.07-1.17], P=5.06×10-7); both associations were at least partly mediated by body mass index. Conclusions These results support a causal role of a number of reproductive factors on cardiovascular disease in women and identify multiple modifiable mediators amenable to clinical intervention.

Implementation of a novel shared decision-making intervention in women with chronic hypertension in pregnancy: multiple-site multiple-method investigation.

BACKGROUND: Many women with chronic hypertension are conflicted about antihypertensive medication during pregnancy and some are non-adherent to prescribed medication. OBJECTIVES: Codesign, implement and evaluate a novel shared decision-making (SDM) intervention for use with pregnant women with chronic hypertension. SETTING AND PARTICIPANTS: Pregnant women with chronic hypertension and their principal healthcare professionals (obstetricians, midwives, and physicians), at three National Health Service hospital trusts with different models of care. MAIN OUTCOME MEASURES: The RE-AIM framework guided the evaluation. Primary: Decisional conflict scale, medication intention survey and women's acceptability. Secondary: Healthcare professionals' acceptability and the barriers and facilitators to SDM implementation with pregnant women with chronic hypertension. RESULTS: Fifty women participated. Nearly half (46 %; n = 23) of women were from Black and Asian backgrounds. The SDM intervention was effective at reducing decisional conflict (mean reduction from baseline 42 %, 95 % CI 35-49, p ≤ 0.05). In 36 women (72 %), the reduction was of clinical importance. 24 women (48 %) were uncertain about or planned not to take antihypertensives prior to the SDM intervention, compared to two women (4 %) after the intervention. The intervention was acceptable to women and healthcare professionals. 10 of 14 healthcare professionals felt that the in-consultation aid facilitated SDM in current antenatal contexts, a similar proportion (10/14) felt the length of consultations hindered SDM. CONCLUSION: A novel codesigned SDM intervention reduced decisional conflict and increased women's intention to take antihypertensive agents during pregnancy. This intervention could be adopted into practice for women making pregnancy decisions where there is uncertainty around the medication management option.

Safety of beta-blocker and calcium channel blocker antihypertensive drugs in pregnancy: a Mendelian randomization study.

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.

The use of fetal fibronectin and cervical length measurements in the prediction of spontaneous preterm birth in women with an Arabin pessary in situ.

OBJECTIVES: The ability to predict spontaneous PTB (sPTB) has improved greatly, allowing women at risk to be managed with prophylactic interventions such as cervical cerclage and the Arabin pessary. Cervicovaginal fetal fibronectin (qfFN) concentration and ultrasound measurement of cervical length (CL) are the two most established tools to predict sPTB. There is however limited data regarding the predictive value of qfFN and CL tests following insertion of an Arabin pessary. Our aim was therefore to determine the clinical use of qfFN and CL measurements to predict sPTB in women fitted with an Arabin pessary. STUDY DESIGN: This study is a secondary analysis on the SUPPORT trial data. Data were prospectively collected from women attending high-risk preterm surveillance clinics in 3 London centres between July 2015 and April 2020. The matched control group was pregnant women attending the same high-risk preterm surveillance clinics who had not received an Arabin pessary. Receiver operating characteristic (ROC) curves for prediction of birth by 34 and by 37 weeks' gestation were generated for qfFN and CL measurements combined for both study groups. A formal comparison of area under the curve before 34 weeks' gestation (AUC < 34 weeks) was made between the two study groups. RESULTS: At our primary endpoint of sPTB < 34 weeks' gestation, qfFN was a good predictor of sPTB in cases with an Arabin pessary in situ (AUC, 0.79, 95% CI: 0.62-0.90) and no worse than the control group who did not have an Arabin pessary, (AUC 0.74, 95% CI: 0.48-0.96). CL had good prediction for sPTB < 34 weeks' gestation in the control group (AUC 0.76, 95% CI: 0.63-0.88) but was lower and non-significant in the Arabin pessary case group (AUC 0.60, 95% CI: 0.43-0.76). CONCLUSIONS: This study showed that cervicovaginal qfFN concentration is equally reliable in the prediction of sPTB in pregnant women at increased risk of sPTB with and without an Arabin pessary in situ, and significantly better than CL measurement alone for predicting delivery before 34 weeks. This commonly used test therefore has utility in predicting sPTB in pregnant women fitted with an Arabin pessary.

Case series of COVID-19 infection in pregnancy complicated by ketoacidosis and symptomatic breathlessness.

Background: The differential diagnosis of acute shortness of breath in a pregnant woman with COVID-19 is broad. Pregnancy is a ketosis-prone state, which can result in metabolic acidosis and tachypnoea. Methods: We describe four pregnant women with COVID-19 and breathlessness where ketoacidosis was found to contribute to symptomatic tachypnoea. Results: One patient did not have associated COVID-19 pneumonitis, but presented with severe tachypnoea and metabolic acidosis; three women had pneumonitis and metabolic acidosis. Corrective treatment for the metabolic abnormalities resulted in resolution of the ketoacidosis in all cases. No women had coexistent diabetes. Conclusion: This is the first series of COVID-19 in pregnancy complicated by ketoacidosis and symptomatic tachypnoea. Ketoacidosis associated with COVID-19 is an important cause of tachypnoea requiring specific treatment, which should not be overlooked. Potential mechanisms for this are discussed with a framework for interpretation of blood gas results during pregnancy.

A national cohort study and confidential enquiry to investigate ethnic disparities in maternal mortality.

BACKGROUND: Ethnic disparities in maternal mortality were first documented in the UK in the early 2000s but are known to be widening. This project aimed to describe the women who died in the UK during or up to a year after the end of pregnancy, to compare the quality of care received by women from different aggregated ethnic groups, and to identify any structural or cultural biases or discrimination affecting their care. METHODS: National surveillance data was used to identify all 1894 women who died during or up to a year after the end of pregnancy between 2009 and 18 in the UK. Their characteristics and causes of death were described. A Confidential Enquiry was undertaken to describe the quality of care women received. The care of a stratified random sample of 54 women who died during or up to a year after the end of pregnancy between 2009 and 18, (18 from the aggregated group of Black women, 19 from the Asian aggregated group and 17 from the White aggregated group) was re-examined specifically to describe any structural or cultural biases or discrimination identified. FINDINGS: There were no major differences causes of death between women from different aggregated ethnic groups, with cardiovascular disease the leading cause of death in all groups. Multiple areas of bias were identified in the care women received, including lack of nuanced care (notable amongst women from Black aggregated ethnic groups who died), microaggressions (most prominent in the care of women from Asian aggregated ethnic groups who died) and clinical, social and cultural complexity (evident across all ethnic groups). INTERPRETATION: This confidential enquiry suggests that multiple structural and other biases exist in UK maternity care. Further research on the role of microaggressions is warranted. FUNDING: This research is funded by the National Institute for Health Research (NIHR) Policy Research Programme, conducted through the Policy Research Unit in Maternal and Neonatal Health and Care, PR-PRU-1217-21,202. MK is an NIHR Senior Investigator. SK is part funded and FCS fully funded by the National Institute for Health Research (NIHR) Applied Research Centre (ARC) West Midlands. The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care.

Placental growth factor measurements in the assessment of women with suspected Preeclampsia: A stratified analysis of the PARROT trial.

OBJECTIVE: Placental growth factor testing decreases time to recognition of preeclampsia and may reduce severe maternal adverse outcomes. This analysis aims to describe the clinical phenotype of women by PlGF concentration, and to determine the mechanism(s) underpinning the reduction in severe maternal adverse outcomes in the PARROT trial, in order to inform how PlGF testing may be optimally used within clinical management algorithms. STUDY DESIGN: This was a planned secondary analysis from the PARROT trial that compared revealed PlGF testing and management guidance with usual care in the assessment of women with suspected preterm preeclampsia. MAIN OUTCOME MEASURES: Maternal and perinatal outcomes following stratification of women by trial group, and measured PlGF concentration. RESULTS: 1006 women were included. PlGF < 100 pg/ml identified women with more marked hypertension, increased adverse maternal outcomes and preterm delivery rates, and higher rates of small for gestational age infants. There was a reduction in adverse maternal outcomes in women whose results were revealed when PlGF levels were 12-100 pg/ml compared to usual care (3.8% vs 6.9%; aOR 0.15(95% CI 0.03-0.92). There was no significant difference in gestation at delivery between concealed or revealed groups in any PlGF categories. CONCLUSION: Low PlGF concentrations are associated with severe preeclampsia. The reduction in severe adverse maternal outcomes may be mediated through quicker diagnosis and intensive surveillance, as recommended by the management algorithm for those at increased risk. PlGF is particularly beneficial in those who test 12-100 pg/ml, as these may be women with silent multi-organ disease who otherwise may go undetected.

Detection of additional abnormalities or co-morbidities in women with suspected intrahepatic cholestasis of pregnancy.

BACKGROUND: Current guidelines recommend viral, autoimmune, coagulation and liver ultrasound testing in intrahepatic cholestasis of pregnancy to exclude alternative diagnoses. METHODS: Electronic health records were searched for investigations and diagnoses in women with raised bile acid concentrations (>10 µmol/L) between January 2016 and December 2017 at two UK maternity units. RESULTS: Five hundred and thirty-one women had a raised bile acid concentration (median (IQR): 18 (13-32 µmol/L)) at a median gestation of 35.1 (IQR 31.8-37.0) weeks. Out of 531 women, 250 (47.1%) had full virology, autoimmune and ultrasound tests, and 348 (65.5%) had coagulation performed. Positive hepatitis B and C results were previously known. No new Epstein-Barr virus, cytomegalovirus or hepatitis A diagnoses were made. There were 11 positive autoimmune results, but no new diagnoses. No woman had an unexplained prolonged prothrombin time. No ultrasound liver (n = 38) or gallbladder (n = 85) abnormalities were of acute clinical significance. CONCLUSION: Intrahepatic cholestasis of pregnancy investigations provided no new diagnoses that influenced clinical management during pregnancy.

Implementation of national antenatal hypertension guidelines: a multicentre multiple methods study.

OBJECTIVE: To evaluate the implementation of National Institute for Health and Care Excellence antenatal hypertension guidelines, to identify strategies to reduce incidences of severe hypertension and associated maternal and perinatal morbidity and mortality in pregnant women with chronic hypertension. METHODS: We used a multiple method multisite approach to establish implementation of guidelines and the associated barriers and facilitators. We used a national survey of healthcare professionals (n=97), case notes review (n=55) and structured observations (n=42) to assess implementation. The barriers and facilitators to implementation were identified from semistructured qualitative interviews with healthcare professionals (n=13) and pregnant women (n=18) using inductive thematic analysis. The findings were integrated and evaluated using the Consolidated Framework for Implementation Research. SETTING AND PARTICIPANTS: Pregnant women with chronic hypertension and their principal carers (obstetricians, midwives and physicians), at three National Health Service hospital trusts with different models of care. RESULTS: We found severe hypertension to be prevalent (46% of case notes reviewed) and target blood pressure practices to be suboptimal (56% of women had an antenatal blood pressure target documented). Women were infrequently given information (52%) or offered choice (19%) regarding antihypertensives. Women (14/18) reported internal conflict in taking antihypertensives and non-adherence was prevalent (8/18). Women who were concordant with treatment recommendations described having mutual trust with professionals mediated through appropriate information, side effect management and involvement in decision making. Professionals reported needing updates and tools for target blood pressure setting and shared decision making underpinned by antihypertensive safety and effectiveness research. CONCLUSIONS: Women's non-adherence to antihypertensives is higher than anticipated. Suboptimal information provision around treatment, choice of antihypertensives and target setting practices by healthcare professionals may be contributory. Understanding the reasons for non-adherence will inform education and decision-making strategies needed to address both clinician and women's behaviour. Further research into the effectiveness and long-term safety of common antihypertensives is also required.