Prevalence of pre-eclampsia and adverse pregnancy outcomes in women with pre-existing cardiomyopathy: a multi-centre retrospective cohort study

Pre-eclampsia is associated with postnatal cardiac dysfunction; however, the nature of this relationship remains uncertain. This multicentre retrospective cohort study aimed to determine the prevalence of pre-eclampsia in women with pre-existing cardiac dysfunction (left ventricular ejection fraction < 55%) and explore the relationship between pregnancy outcome and pre-pregnancy cardiac phenotype. In this cohort of 282 pregnancies, pre-eclampsia prevalence was not significantly increased (4.6% [95% C.I 2.2–7.0%] vs. population prevalence of 4.6% [95% C.I. 2.7–8.2], p = 0.99); 12/13 women had concurrent obstetric/medical risk factors for pre-eclampsia. The prevalence of preterm pre-eclampsia (< 37 weeks) and fetal growth restriction (FGR) was increased (1.8% vs. 0.7%, p = 0.03; 15.2% vs. 5.5%, p < 0.001, respectively). Neither systolic nor diastolic function correlated with pregnancy outcome. Antenatal ß blockers (n = 116) were associated with lower birthweight Z score (adjusted difference − 0.31 [95% C.I. − 0.61 to − 0.01], p = 0.04). To conclude, this study demonstrated a modest increase in preterm pre-eclampsia and significant increase in FGR in women with pre-existing cardiac dysfunction. Our results do not necessarily support a causal relationship between cardiac dysfunction and pre-eclampsia, especially given the population’s background risk status. The mechanism underpinning the relationship between cardiac dysfunction and FGR merits further research but could be influenced by concomitant ß blocker use.

1. Our understanding of the relationship between cardiac and placental function, to inform future preventative and therapeutic strategies; 2. Counselling of women with cardiac disease and their families, before and during pregnancy.

Results
The study cohort included 282 pregnancies from 244 women (Fig. 1). Supplementary Table S1 describes the spread of participants from different sites. Results were derived from the 282 pregnancies but were not altered by only including each woman's first pregnancy.
Relationship between cardiac parameters and pregnancy outcome. Severity of left ventricular (LV) impairment did not correlate with prevalence of pre-eclampsia (Supplementary Table S5, p = 0.35), SGA (p = 0.24), FGR (p = 0.67), or preterm delivery < 34 weeks (p = 0.26). LV impairment severity also did not correlate with birthweight Z score or gestation at delivery. Ischaemic heart disease was not associated with pre- Table 2. Echocardiography measures of cardiac structure and function prior to pregnancy or before 12 weeks' gestation. Frequencies: N (%). Mean ± standard deviation. *Median (range). Mild, moderate and severe valvular abnormalities were included; trivial and physiological regurgitation/stenosis were excluded. Echocardiography data was not available for all women, therefore the number included in the analysis (N) is recorded for each parameter. SD Standard deviation, LVIDd Left ventricular internal diameter in end-diastole, LVIDs Left ventricular internal diameter in end-systole, PWd Posterior wall thickness in end-diastole, IVSd Interventricular septal wall thickness in end-diastole, LVM Left ventricular mass, LVMi LVM indexed to body surface area, RWT Relative wall thickness, E/A Early to late diastolic filling ratio, E/E' Early diastolic filling to early diastolic mitral annular velocity ratio, TAPSE Tricuspid annular plane systolic excursion.

Mean ± SD/median (range)/N (%) N
Cardiac outcomes. Major adverse cardiovascular events (MACE) occurred in 3/282 (1.1%) pregnancies: one woman with LV non-compaction cardiomyopathy had a transient ischaemic attack and there were two maternal deaths (drug overdose and valvular thrombosis one month postpartum associated with a mechanical aortic valve). Thirty-six (12.8%) women developed acute heart failure and 14/282 (5.0%) developed pulmonary oedema. Sustained arrhythmia complicated 13/282 (4.6%) pregnancies. Table 5 summarises the prevalence of   www.nature.com/scientificreports/ adverse cardiac outcomes according to severity and cause of cardiac dysfunction. Acute heart failure was most common in those with DCM (19.5%) and severely impaired LVEF (41.9%).

Discussion
This study describes a large retrospective cohort of pregnancies affected by pre-existing maternal heart disease. Pre-eclampsia prevalence was not increased compared to the general population, however preterm pre-eclampsia, SGA and FGR prevalence were. Routinely indicated preterm and early term delivery and Caesarean sections were common in this cohort. The severity of LV impairment did not correlate with any pregnancy outcome and there was only one case of pre-eclampsia amongst the pregnancies complicated by severely impaired baseline LVEF. Antenatal ß blocker use was consistently associated with adverse pregnancy outcome, including increased SGA and FGR and reduced birthweight centile, despite adjustment for confounders. In those who were prescribed ß blockers, bisoprolol was the most commonly used agent.
Adverse cardiac events, although less frequent than previous reports in the literature 38,39 , were by no means uncommon, thereby endorsing close antenatal and postnatal surveillance in this high-risk group. Women with valvular disease were at particular increased risk of MACE and those with severely impaired LVEF had the highest risk of acute heart failure.
This was a relatively large multicentre study comprising data from 13 sites across the UK and Australia. Inclusion of 282 pregnancies affected by maternal cardiomyopathy allowed correlation of pre-existing cardiac parameters with pregnancy outcome. To our knowledge, this is the first study of women with pre-existing cardiac disease, in which the primary outcome is pre-eclampsia, thereby ensuring adjustment for pre-eclampsia risk factors, where appropriate. Although the retrospective nature of the study has its limitations, variables were pre-specified and confirmed by the clinical care team following careful review of clinical records. Heterogeneity of the cohort was compensated by subgroup analyses of women with DCM (thereby limiting confounding effects of structural heart disease on cardiac output (CO), LV geometry and function); these subgroup analyses demonstrated consistent findings with the whole cohort.
Unfortunately, background prevalence data for adverse pregnancy outcomes were not available from all sites; for this reason, the prevalence of SGA, FGR, preterm delivery and preterm FGR was estimated from fiveyear birth data from Saint Mary's Hospital, Manchester. Although a tertiary centre with a high-risk population, Saint Mary's Hospital was deemed an appropriate comparator as it contributed a large proportion of the cohort (99/282) and 11/13 of the sites are tertiary centres for Cardiology or Obstetrics. Pre-eclampsia is not reliably coded in UK hospital maternity information systems and therefore comparisons of rates of pre-eclampsia could only be made to published studies from comparable populations [45][46][47] . To compensate for this limitation, the influence and proportion of nulliparity and pre-eclampsia risk factors were explored.
If the link between cardiac dysfunction and pre-eclampsia is due to a problem with cardiovascular supply rather than demand, CO would be a useful pre-pregnancy parameter to determine this. Unfortunately, CO is not routinely reported in echocardiography and therefore it is not possible to explore the link between CO and pregnancy outcome, within this dataset. Additionally, the relatively mild LV functional impairment seen in this cohort (49.6% had LVEF 50-54%) may not have been enough to cause a significant drop in CO, thereby limiting any potential effect on uteroplacental perfusion. On the other hand, severity of LV impairment did not correlate with any measure of placental dysfunction, including pre-eclampsia, indicating a lack of causation.
Finally, for the purpose of this study, pre-eclampsia and FGR were considered clinical proxies for placental dysfunction, in the absence of confirmatory placental histology. This is due to the widely accepted theory of their mutual placental origin [31][32][33][34] , however this limits the ability to link pre-pregnancy cardiac parameters with distinct placental pathologies.
Pre-eclampsia prevalence was not increased in this cohort. However, routinely indicated early delivery in these women could have masked term pre-eclampsia. Additionally, frequent use of ß blockers could have masked late hypertension, thereby preventing a diagnosis of pre-eclampsia being made. On the other hand, the lack of association between systolic or diastolic function and pre-eclampsia, suggests that the cardiac dysfunction following pre-eclampsia 3,48,49 is unlikely to be solely a consequence of pre-existing impairment. In contrast, increased LVMi was weakly associated with higher pre-eclampsia rates. This likely reflects pre-existing comorbidities, supported by the loss of relationship between LVMi and pre-eclampsia after adjustment for booking MAP and pre-eclampsia risk factors.
The high SGA and FGR rates in this cohort could be a consequence of reduced uteroplacental blood supply due to the underlying cardiomyopathy 50 or concurrent medication (ß blockers) 51,52 , or contributed to by high smoking rates (20%). Alternatively, despite its ß1 cardio-selective nature 53 , bisoprolol could have a direct effect on the placental vasculature. This is supported by evidence of ß1 receptors 54,55 in placental vasculature and placental vasoconstriction seen following exposure to ß blockers in vitro 56,57 . The potential negative effect of antenatal ß blocker use on fetal growth has long been considered 51,58-61 . A recent meta-analysis including 13 cohort studies demonstrated a significant increase in SGA associated with antenatal ß blocker use (OR 1.72 [95% C.I. 1.59-1.85], p < 0.001) 58 . It has been proposed that ß blocker subtypes are associated with varying risk 51,59 . Labetalol, which is an α and ß antagonist and partial ß2 agonist 57,62,63 , is commonly used as a first-line antihypertensive in pregnancy 44 . It is possible that the partial ß2 agonistic properties of labetalol induce vasodilation in placental and umbilical vasculature, thereby favourably increasing placental blood flow 57,64,65 . However atenolol, which selectively blocks ß1 adrenergic receptors, is not recommended in pregnancy 44 60,66,67 . The impact of bisoprolol, which was the most commonly prescribed ß blocker in this cohort, on fetal growth is less understood. The rationale for ß blocker use in the context of cardiac dysfunction is to protect the heart against the deleterious effects of increased adrenergic activity, by reducing heart rate, blood pressure and myocardial oxygen demand 68 . It is therefore likely that continued antenatal use of ß blockers indicates a particular cardiac phenotype or degree of severity. However, the relationship between ß blockers and birthweight Z score persisted after adjustment for FGR risk factors and cardiac phenotype, indicating a direct mechanistic link between the two.
The relationship between antenatal heparin exposure and FGR was unexpected due to the wealth of existing data demonstrating no harmful effect of antenatal heparin on fetal growth [69][70][71][72] . Given the loss of significance after adjustment for confounders, this is unlikely to represent a causal relationship.
The lack of association between any measure of pre-pregnancy cardiac impairment and birthweight Z score/ FGR makes a causal role of cardiac dysfunction in the development of FGR unlikely. Furthermore, if preterm FGR in this cohort shared the presumed aetiology of preterm pre-eclampsia, in which early placentation is affected by defective spiral artery remodelling 31 , the prevalence of co-existing hypertension (i.e. pre-eclampsia) should be higher. A third of women with early-onset FGR developed pre-eclampsia in this cohort, compared with 52-60% women in the early-onset FGR cohorts in TRUFFLE 73 and STRIDER 74 . The lower-than-expected rate of pre-eclampsia in women with FGR suggests that late placental failure, rather than early placentation defects, may be a more significant cause of FGR in this cohort. This would also be supported by the association with ß blockers affecting third trimester growth 51 . In order to explore this further, measures of early placentation (including uterine artery Doppler, pregnancy-associated plasma protein-A, placental growth factor and placental pathology) need to be investigated in future cohorts.
In conclusion, this study provides valuable information to aid clinicians with pre-conception and antenatal counselling for women with cardiomyopathy. These women can be reassured that their risk of pre-eclampsia does not appear to be significantly increased, however serial ultrasound scanning is likely warranted to monitor for FGR. Preconception counselling should include information on the increased risk of acute heart failure in pregnancy for those with pre-existing cardiomyopathy (in particular severely impaired LVEF). The mechanism linking FGR and cardiac dysfunction remains unknown, however it could be attributed to reduced uteroplacental perfusion as a consequence of the underlying cardiac disease or concomitant ß blocker use. Further study is required to explore the effect of bisoprolol on the placenta. Finally, the absence of dose-effect demonstrated by lack of correlation between severity of cardiac dysfunction and pregnancy outcome does not support a causal role of cardiovascular dysfunction in the development of pre-eclampsia. Further study is needed to explore the mechanistic link between cardiac dysfunction and FGR.

Methods
This was a multicentre retrospective cohort study, including 12 UK sites and one Australian site. Research was limited to use of previously collected, non-identifiable information. The need for informed consent was waived by the HRA and Australian Human Research Ethics Committee, as identifiable patient data were not accessed outside of the primary clinical care team. All methods were carried out in accordance with the "Caldicott Principles", the Data Protection Act and the General Data Protection Regulation. Patients were not involved in the conduct of this study. Study population. Women aged ≥ 16 years with pre-existing LV systolic impairment (LVEF < 55%), who had a pregnancy between January 2008 and December 2020, were included in the study. Women were excluded if they delivered before 22 weeks' gestation or insufficient data were available. Data were collated from 13 sites in England, Scotland and Australia (Fig. 3).
Eligible participants were identified using different methods across sites, including via cardiac obstetric databases, clinic lists and ICD-10 codes (including heart failure and cardiomyopathy). Eligibility was checked following review of echocardiography reports, online clinical reports, clinic letters and case notes. Each site was given identical excel spreadsheets with pre-determined data fields to complete (Supplementary Table S10). Minimum data criteria included presence/absence of pre-eclampsia and evidence of LVEF < 55% pre-pregnancy or < 12 weeks' gestation.
Cardiac classifications. LV impairment was categorised, as per British Society of Echocardiography (BSE) guidelines 75 , as borderline (50-54%), impaired (36-49%) and severely impaired (≤ 35%). DCM was defined as a combination of dilated left ventricle (LV internal diameter in end-diastole [LVIDd] > 5.2 cm) 76 and systolic dysfunction, or evidence of DCM diagnosis by a cardiologist in the case notes. DCM was further categorised into familial, idiopathic, acquired (secondary to infection, chemotherapy, alcohol or iron overload) and previous peripartum cardiomyopathy (PPCM). As per the American Heart Association (AHA) 77 Supplementary Table S11. Echocardiography parameters were used from the most recent pre-pregnancy scan or, when this was not available, < 12 weeks' gestation.
Obstetric classifications. Pre-eclampsia was confirmed by documented diagnosis in the case notes or clinic letters. All cases met the International Society for the Study of Hypertension in Pregnancy (ISSHP) criteria for diagnosis 81 : new or worsening hypertension > 20 weeks and proteinuria or other suggestive features (abnormal haematological or biochemical parameters or FGR). Severe pre-eclampsia was defined as maximum blood pressure ≥ 160/110 mmHg, alanine aminotransferase > 100U/L, creatinine > 100 µmol/L or platelets < 100 × 10 9 /L. Data for birthweight centile customisation was not available for all women. Therefore, the World Health Organization (WHO) population Z score was used 82 . Small-for-gestational-age (SGA; birthweight < 10th centile) equated to a Z score < − 1.282 and FGR (birthweight < 3rd centile) 83 equated to a Z score < − 1.881 82 .
Population pre-eclampsia prevalence of 4.6% was derived from Abalos et al. 's systematic review 45 . Preterm pre-eclampsia prevalence (requiring delivery < 37 weeks; 0.7%) was derived from the ASPRE trial 46 , in which 4.0% of the population were high-risk for pre-eclampsia, according to NICE 44 . Population rates of SGA (18.2%), FGR (9.5%), preterm delivery (< 37 weeks; 8.2%) and preterm FGR (< 37 weeks; 1.5%) were derived from 5-year data (2016-2020) from Saint Mary's Hospital, Manchester, UK 84 . Outcomes. The primary outcome was to determine the prevalence of pre-eclampsia in women with preexisting cardiac impairment, compared with the general population. Pre-specified secondary outcomes included: (1) the prevalence of FGR and SGA in women with pre-existing cardiac impairment, compared with the general population; the prevalence of pre-eclampsia, FGR and SGA depending on (2) primary cardiac diagnosis and (3) severity of LV impairment (by LVEF); (4) the relationship between gestation at birth/birthweight Z score and primary cardiac diagnosis/severity of LV impairment/other echocardiography parameters. An appropriate published core outcome set was not available and therefore not used in this study.