Abstract
Aims
Women with congenital heart disease (CHD) are at risk of pregnancy-related adverse outcomes (PRAO). The purpose of this study was to assess temporal changes in cardiac structure and function (cardiac remodelling) during pregnancy, and the association with PRAO in women with CHD.
Methods and results
Retrospective study of pregnant women with CHD and serial echocardiograms (2003–2021). Cardiac structure and function were assessed at pre-specified time points: prepregnancy, early pregnancy, late pregnancy, and postnatal period. PRAO was defined as the composite of maternal cardiovascular, obstetric, and neonatal complications. The study comprised 81 women with CHD (age, 29 ± 5 years). Compared to the baseline echocardiogram, there was a relative increase in right ventricular systolic pressure (RVSP) (relative change 13 ± 5%, P < 0.001, in early pregnancy; and 18 ± 5%, P < 0.001, in late pregnancy). There was a relative decrease in right ventricle free wall strain (RVFWS) (relative change −11 ± 3%, P < 0.001, in late pregnancy; and −11 ± 4%, P = 0.003, in postnatal period), and a relative decrease in RVFWS/RVSP (relative change, −10 ± 5%, P = 0.02 in early pregnancy, −26 ± 7%, P < 0.001, in late pregnancy, and −14 ± 5%, P < 0.001, in postnatal period). Baseline right ventricular to pulmonary arterial (RV–PA) coupling, and temporal change in RV–PA coupling were associated with PRAO, after adjustment for maternal age and severity of cardiovascular disease.
Conclusion
Women with CHD had a temporal decrease in RV systolic function and RV–PA coupling, and these changes were associated with PRAO. Further studies are required to delineate the aetiology of deterioration in RV–PA coupling during pregnancy, and the long-term implications of right heart dysfunction observed in the postnatal period.
Keywords: pregnancy, outcome, risk stratification
Introduction
The average age of adults with congenital heart disease (CHD) is about 30–35 years, and half of these patients are women.1–4 Based on these estimates, more than one-quarter of adults with CHD are of childbearing age, and hence, providing optimal cardiovascular care during pregnancy is important in this population.1–4 Several studies have described risk factors associated with cardiovascular, obstetric, and neonatal complications during pregnancy, and proposed strategies to modify these risk factors in order to improve pregnancy-related outcomes in this population.5–7 These studies provide the foundation for guideline recommendations used for risk stratification, counselling, and management of pregnancy in women with cardiovascular disease.8–10 Previous studies have assessed different aspects of cardiac function such as cardiac output, ventricular systolic function, and ventricular diastolic function, in women with cardiovascular disease, and the relationship between these indices and clinical outcomes.11–14 However, data about comprehensive assessment of temporal changes in cardiac structure and function during pregnancy are lacking.
Transthoracic echocardiography is the first-line imaging modality for structural heart disease because of its relatively low cost, accessibility, no known contraindications, and the absence of adverse effects on the patient or the fetus.15–17 As a result, it is the ideal imaging tool for the assessment of temporal changes in cardiac structure and function during pregnancy. The purpose of this study was, therefore, to assess temporal changes in cardiac structure and function (cardiac remodelling) during pregnancy using transthoracic echocardiography, and the relationship between cardiac remodelling and outcomes in women with CHD.
Methods
Study population
This is a retrospective cohort study of women (age, ≥18 years) with CHD that received care during pregnancy at Mayo Clinic, Rochester, Minnesota from 1 January 2003 to 31 December 2021. Patients with Fontan palliation, and those with systemic right ventricle (RV) were excluded, to minimize heterogeneity and confounding. From this cohort, we selected consecutive patients that had echocardiograms at the following time points: (i) within 24 months prior to pregnancy (baseline echocardiogram); (ii) within the first two trimesters (early pregnancy echocardiogram); (iii) third trimester (late pregnancy echocardiogram); (iv) more than 6 months after delivery (postnatal echocardiogram). In women that had multiple pregnancies within the study period, we selected the first pregnancy that met the study inclusion criteria.
The CHD patients that met the inclusion criteria were divided into anatomic subgroups as follows: (i) left heart lesions (coarctation of aorta, aortic valve stenosis, subaortic stenosis); (ii) right heart lesion (pulmonary valve stenosis, tetralogy of Fallot, pulmonary atresia with intact ventricular septum, Ebstein anomaly); (iii) septal defects/shunt lesions (atrial septal defect/partial anomalous pulmonary venous return, partial atrioventricular canal defect, ventricular septal defect); and (iv) others (transposition of great arteries status post arterial switch operation or Rastelli operation). The severity of cardiovascular disease was assessed using the Word Health Organization (WHO) severity classification as previously described.18 The Mayo Clinic Institutional Review Board approved this study.
We selected a control group of non-pregnant women without structural heart disease of similar age (±3 years) from the Mayo Adult Congenital Heart Disease Biobank (MACHD-Biobank) project that underwent echocardiogram within the same period, to serve as a reference group for the comparisons of baseline echocardiographic indices. The MACHD-Biobank project is a prospective database of adults with CHD as well age- and sex-matched control group of patients without structural heart disease.
Study objectives
(i) Define the baseline cardiac structure and function of women with CHD, and compare these indices to the control group, and normative values. (ii) Assess temporal change in cardiac structure and function (cardiac remodelling) during pregnancy using the prepregnancy echocardiogram as the baseline. (iii) Assess the relationship between cardiac structure and function, and pregnancy-related adverse outcomes (PRAO). The exploratory objective was to assess the relationship between temporal change in cardiac indices (from baseline echocardiogram to early pregnancy echocardiogram) and PRAO.
Pregnancy-related adverse outcomes were defined as the composite outcome of maternal cardiovascular complications, obstetric complications, and neonatal complications.19 Maternal cardiovascular complications were defined as sustained atrial or ventricular arrhythmias, ischaemic, or haemorrhagic stroke, heart failure hospitalization, urgent invasive cardiac procedures during pregnancy or within 6 months after delivery, or cardiovascular death during pregnancy.5–7 Obstetric complications were defined as gestational hypertension, pre-eclampsia, eclampsia haemolysis-elevated liver enzymes-low platelets syndrome, or postpartum haemorrhage. Neonatal complications were defined as premature birth (< 37 weeks of gestation), small-for-gestational-age birth weight (< 10th percentile), intraventricular haemorrhage, foetal, or neonatal death.5–7
Assessment of cardiac structure and function
A comprehensive assessment of cardiac structure and function was performed using 2D, Doppler and speckle-tracking echocardiography according to contemporary guidelines.15,17,20 Offline image analyses and measurements were performed by experienced research sonographers.
For this study, we assessed cardiac structure and function using the following indices: (i) Right atrial (RA) size and function: RA volume index and RA reservoir strain. (ii) RV size and function: RV end-diastolic area index and RV free wall strain (RVFWS). (iii) RV afterload: RV systolic pressure (RVSP) and RVFWS/RVSP ratio. RVSP was used as a measure of RV global afterload, while RVFWS/RVSP ratio was used as a measure of RV to pulmonary arterial (RV–PA) coupling. (iv) Left atrial (LA) size and function: LA volume index and LA reservoir strain. (v) Left ventricular (LV) size and function: LV end-diastolic volume index and LV global longitudinal strain. (vi) LV afterload: Valvuloarterial impedance; effective arterial elastance index, and systemic vascular resistance index. Valvuloarterial impedance, a measure of LV global afterload, was calculated as aortic valve Doppler mean gradient + systolic blood pressure)/Doppler-derived LV stroke volume index.21 Effective arterial elastance index, a measure of pulsatile arterial afterload, was calculated as (0.9 × systolic blood pressure)/Doppler-derived LV stroke volume index.21 Systemic vascular resistance, a measure of non-pulsatile arterial afterload, was calculated as (80 × mean arterial pressure)/Doppler-derived LV cardiac index.21 Supplementary data online, Table S1 shows the echocardiographic indices cardiac structure and function, and normative values.15,17,22–25
Statistical analysis
Data were presented as mean ± standard deviation, median (interquartile range), and count (%). Between-group comparisons were performed using unpaired t-test, and Fisher’s exact test. Temporal changes in cardiac indices were calculated as relative changes from baseline echocardiogram as follows: (indices from baseline echocardiogram minus indices from pregnancy or postnatal echocardiogram)/indices from baseline echocardiogram and expressed as %-change. Separate analyses were performed for the different CHD subgroups (right heart lesions vs. left heart lesions). The relationship between the cardiac indices obtained from baseline echocardiogram and PRAO was assessed using univariable logistic regression analysis, and each model was adjusted for maternal age and WHO risk classification. The WHO risk classification was modelled as a categorical variable using WHO Class I as the reference group. Separate analyses were performed to determine the relationship between temporal change in cardiac indices (from baseline echocardiogram to early pregnancy echocardiogram) and PRAO, using logistic regression as described above. All statistical analyses were performed with BlueSky Statistics software (version. 7.10; BlueSky Statistics LLC, Chicago, IL, USA), and JMP statistical software (version 17.1.0, JMP Statistical Discovery LLC, NC). P value < 0.05 was considered to be statistically significant for all analyses.
Results
Baseline characteristics
There were 81 women with CHD that met the study inclusion criteria, and Table 1 shows the baseline clinical characteristics of the cohort. The mean age at the time of pregnancy was 29 ± 5 years, the median number of prior pregnancies was 2 (1–2), and the median number of prior live births was 1 (0–2). The most common CHD diagnoses were coarctation of aorta (n = 21, 38%), pulmonary valve stenosis (n = 19, 24%), and Ebstein anomaly (n = 11, 14%). Of the 81 women, 80 (99%) have had prior cardiovascular interventions (surgical n = 76, transcatheter n = 4), and the only patient without prior cardiovascular intervention had an atrial septal defect. Of the 81 patients, 11 (14%) had bioprosthetic valves, 1 (1%) had a mechanical prosthetic valve, and 4 (5%) had transvenous cardiac implantable electronic devices.
Table 1.
Baseline characteristics of patients with congenital heart disease
| N = 81 | |
|---|---|
| Congenital heart disease | |
| Coarctation of aorta | 31 (38%) |
| Pulmonary valve stenosis | 19 (24%) |
| Ebstein anomaly | 11 (14%) |
| Partial atrioventricular canal defect | 6 (7%) |
| ASD/PAPVR | 4 (5%) |
| Tetralogy of Fallot | 3 (4%) |
| d-TGAs/p ASO | 2 (3%) |
| Congenital aortic valve stenosis | 2 (3%) |
| Pulmonary atresia with IVS | 1 (1%) |
| Subaortic stenosis | 1 (1%) |
| Ventricular septal defect | 1 (1%) |
| Congenital heart disease subgroup | |
| Left heart lesions | 34 (42%) |
| Right heart lesions | 34 (42%) |
| Septal defects | 11 (14%) |
| Others | 2 (3%) |
| Modified WHO risk classification | |
| I | 30 (37%) |
| II | 46 (57%) |
| III | 5 (6%) |
| Prosthesis | |
| Bioprosthesis | 11 (14%) |
| Aortic bioprosthetic valve | 2 (3%) |
| Pulmonary bioprosthetic valve | 9 (11%) |
| Mechanical prosthesis | 1 (1%) |
| Aortic mechanical prosthesis | 1 (1%) |
| Transvenous CIED | 4 (5%) |
| Comorbidities | |
| Atrial arrhythmia history | 11 (14%) |
| Hypertension | 13 (16%) |
| Hyperlipidaemia | 9 (11%) |
| Type 2 diabetes | 2 (3%) |
| Obesity | 24 (30%) |
| Cardiac medications | |
| ACEI/ARB | 15 (19%) |
| Mineralocorticoid receptor antagonist | 2 (3%) |
| Loop diuretics | 13 (16%) |
| Beta blocker | 2 (3%) |
| Laboratory data | |
| Haemoglobin, g/dL | 12.9 ± 0.8 |
| Glomerular filtration rate, mL/min/1.73 m2 | 91 ± 24 |
Congenital heart lesions were grouped into: left heart lesions (coarctation of aorta, aortic valve stenosis, subaortic stenosis), right heart lesion (pulmonary valve stenosis, tetralogy of Fallot, pulmonary atresia with intact ventricular septum, Ebstein anomaly), septal defects (atrial septal defect/partial anomalous pulmonary venous return, partial atrioventricular canal defect, ventricular septal defect), and others (transposition of great arteries status post-arterial switch operation).
ACEI/ARB, angiotensin-converting enzyme inhibitor/angiotensin II receptor blocker; ASD, atrial septal defect; ASO, arterial switch operation; CIED, cardiac implantable electronic device; IVS, intact ventricular septum; PAPVR, partial anomalous pulmonary venous return; TGA, transposition of great arteries; WHO, World Health Organization.
Of the 81 women with CHD, 15 (19%) were on renin-angiotensin-aldosterone system antagonists prior to pregnancy, and these medications were discontinued prior to conception, or at the time of first clinic visit after conception. Of the 15 patients, renin-angiotensin-aldosterone system antagonists were restarted after pregnancy in only 8 of the patients.
The control group comprised 33 women without structural heart disease. There was no significant difference in age, body mass index, and body surface area between the CHD group and the control group (Table 2). Compared to the control group, women with CHD had worse RA function (RA reservoir strain 34 ± 19 vs. 42 ± 15%, P < 0.001), more RV dilation (RV end-diastolic area index 13.5 ± 4.3 vs. 10.3 ± 3.2 cm2/m2, P = 0.04) and RV systolic dysfunction (RVFWS −19 ± 5 vs. −24 ± 5%, P < 0.001), higher RV global afterload (RVSP 38 ± 9 vs. 22 ± 5 mmHg, P < 0.001), and worse RV–PA coupling (RVFWS/RVSP 0.52 ± 0.24 vs. −1.09 ± 0.28%/mmHg, P < 0.001). After excluding the 11 patients with Ebstein anomaly, we observed that the rest of the CHD group (n = 70) still had worse RA function (RA reservoir strain 37 ± 14 vs. 42 ± 15%, P = 0.02), worse RV systolic function (RVFWS −20 ± 5 vs. −24 ± 5%, P < 0.001), higher RV global afterload (RVSP 40 ± 8 vs. 22 ± 5 mmHg, P < 0.001), and worse RV–PA coupling (RVFWS/RVSP 0.49 ± 0.22 vs. −1.09 ± 0.28%/mmHg, P < 0.001), compared to the control group. However, the between-group difference RV size was no longer statistically significant in the subgroup analysis (RV end-diastolic area index, 12.9 ± 3.5 vs. 10.3 ± 3.2 cm2/m2; P = 0.07, for CHD group vs. control group, respectively). Similarly, the CHD group had worse left heart indices as evidenced by lower indices of LA function (LA reservoir strain 34 ± 11 vs. 43 ± 14%, P < 0.001), and LV systolic function (LV global longitudinal strain −19 ± 6 vs. −23 ± 4%, P = 0.008, Table 2).
Table 2.
Comparison of baseline indices of cardiac structure and function between the CHD and control groups
| CHD group (N = 81) |
Control group (N = 33) |
P | |
|---|---|---|---|
| Demographic indices | |||
| Age | 29 ± 5 | 31 ± 6 | 0.1 |
| Body mass index, kg/m2 | 27 ± 4 | 28 ± 5 | 0.4 |
| Body surface area, m2 | 1.78 ± 1.10 | 1.84 ± 1.12 | 0.3 |
| RA indices | |||
| RA volume index (mL/m2) | 27 ± 10 | 23 ± 8 | 0.07 |
| RA reservoir strain (%) | 34 ± 19 | 42 ± 15 | <0.001 |
| RA pressure (mmHg) | 8 ± 3 | 5 ± 2 | 0.02 |
| RV (non-systemic) indices | |||
| RV end-diastolic area index (cm2/m2) | 13.5 ± 4.3 | 10.3 ± 3.2 | 0.04 |
| RV fractional area change (%) | 42 ± 17 | 49 ± 12 | 0.08 |
| RVFWS (%) | −19 ± 5 | −24 ± 5 | <0.001 |
| ≥ Moderate tricuspid regurgitation | 18 (22%) | 0 | — |
| ≥ Moderate pulmonary regurgitation | 14 (17%) | 0 | — |
| Pulmonary mean gradient (mmHg) | 11 ± 5 | 5 ± 2 | < 0.001 |
| RV afterload | |||
| RVSP, mmHg | 38 ± 9 | 22 ± 5 | < 0.001 |
| RVFWS/RVSP, %/mmHg | 0.52 ± 0.24 | 1.09 ± 0.28 | < 0.001 |
| LA indices | |||
| LA volume index (mL/m2) | 25 ± 7 | 22 ± 9 | 0.3 |
| LA reservoir strain (%) | 34 ± 11 | 43 ± 14 | < 0.001 |
| Lateral E/e′ | 8 ± 3 | 5 ± 2 | 0.02 |
| LV (systemic) indices | |||
| LV end-diastolic volume (mL/m2) | 52 ± 19 | 49 ± 18 | 0.2 |
| LV ejection fraction (%) | 61 ± 13 | 63 ± 8 | 0.7 |
| LV global longitudinal strain (%) | −19 ± 6 | −23 ± 4 | 0.008 |
| ≥Moderate mitral regurgitation | 4 (5%) | 0 | — |
| ≥ Moderate aortic regurgitation | 1 (1%) | 0 | — |
| LV stroke volume index, mL/m2 | 39 ± 19 | 43 ± 14 | 0.2 |
| Heart rate, bpm | 68 ± 9 | 66 ± 7 | 0.3 |
| Cardiac index, l/min/m2 | 2.66 ± 0.94 | 2.83 ± 0.81 | 0.1 |
| LV afterload | |||
| Aortic mean gradient (mmHg) | 9 ± 4 | 6 ± 2 | 0.01 |
| Systolic blood pressure, mmHg | 118 ± 16 | 123 ± 18 | 0.2 |
| Pulse pressure, mmHg | 46 ± 7 | 49 ± 9 | 0.2 |
| Zva, mmHg/mL*m2 | 3.26 ± 0.85 | 3.01 ± 0.72 | 0.08 |
| EAI, mmHg/mL*m2 | 2.86 ± 0.72 | 2.63 ± 0.54 | 0.1 |
| SVRI, dyne-s/cm5*m2 | 2725 ± 503 | 26 965 ± 491 | 0.4 |
CHD, congenital heart disease; E/e′, ratio of mitral inflow pulsed wave Doppler early velocity to tissue Doppler early velocity; EAI, effective arterial elastance index; LA, left atrium; LV, left ventricle; RA, right atrium; RV, right ventricle; RVFWS, right ventricular free wall strain; RVSP, right ventricular systolic pressure; SVRI, systemic vascular resistance index; Zva, valvuloarterial impedance.
P values were derived from pairwise comparisons using Fisher’s exact test and unpaired t-test.
In the CHD group, the average RA reservoir strain was 34 ± 19% (range, 11–52%), RVFWS was −19 ± 5% (range, −12 to −26%), LA reservoir strain was 34 ± 11% (range, 19–49%), and LV global longitudinal strain was −19 ± 5% (range, −10 to −27%). According to normative values (see Supplementary data online, Table S1), 47% (38/81) had RA enlargement, 41% (32/78) had RA dysfunction, 52% (42/81) had RV dilation, 84% (67/80) had RV systolic dysfunction, 11% (9/80) had LA enlargement, 27% (21/77) had LA dysfunction, 15% (12/81) had LV enlargement, and 41% (33/81) had LV systolic dysfunction.
Temporal changes in cardiac structure and function
Of the 81 patients, 81 (100%) had an echocardiogram in early pregnancy, 74 (91%) had an echocardiogram in late pregnancy, and 81 (100%) had a postnatal echocardiogram. Table 3 shows cardiac indices from echocardiograms obtained at baseline, early pregnancy, late pregnancy, and postnatal period. Of note, all cardiac indices normalized back to baseline values at the time of postnatal echocardiogram apart from the right heart indices. Compared to the baseline echocardiogram, we observed a significant increase in RVSP in early pregnancy (relative change 13 ± 5%, P < 0.001), and late pregnancy (relative change 18 ± 5%, P < 0.001), and a decrease in RVSP back to baseline levels at postnatal echocardiogram (relative change 2 ± 3%, P = 0.2, Figures 1 and 2). Similarly, there was a significant decrease in RVFWS in late pregnancy (relative change −11 ± 3%, P < 0.001), and postnatal echocardiogram (relative change −11 ± 4%, P = 0.003), leading to a significant decrease in RVFWS/RVSP in early pregnancy (relative change −10 ± 5%, P = 0.02), late pregnancy (relative change −26 ± 7%, P < 0.001), and postnatal echocardiogram (relative change −14 ± 5%, P < 0.001, Figures 1 and 2). Similar findings were observed in the subgroup of patients with right heart lesions, as well as those with left heart lesions (see Supplementary data online, Table S2).
Table 3.
Temporal changes in cardiac structure and function
| Echocardiographic indices | Baseline (N = 81) |
Early pregnancy (N = 81) |
Late pregnancy (N = 74) | Postnatal (N = 81) |
|---|---|---|---|---|
| RA indices | ||||
| RA volume index (mL/m2) | 27 ± 10 | 29 ± 10 | 34 ± 12a | 30 ± 11 |
| RA reservoir strain (%) | 34 ± 19 | 36 ± 18 | 33 ± 12 | 32 ± 16 |
| RV (non-systemic) indices | ||||
| RV end-diastolic area index (cm2/m2) | 13.5 ± 4.3 | 15.1 ± 3.9 | 16.9 ± 4.8a | 16.3 ± 3.7a |
| RV fractional area change (%) | 42 ± 17 | 44 ± 15 | 41 ± 16 | 46 ± 10 |
| RVFWS (%) | −19 ± 5 | −20 ± 4 | −17 ± 4a | −17 ± 3a |
| ≥ Moderate tricuspid regurgitation | 18 (22%) | 18 (22%) | 19 (26%) | 18 (22%) |
| Pulmonary mean gradient (mmHg) | 11 ± 5 | 14 ± 6 | 17 ± 10a | 9 ± 4 |
| RV afterload | ||||
| RVSP, mmHg | 38 ± 9 | 43 ± 10a | 45 ± 9a | 39 ± 8 |
| RVFWS/RVSP, %/mmHg | 0.52 ± 0.24 | 0.46 ± 0.21a | 0.38 ± 0.14a | 0.42 ± 0.29a |
| LA indices | ||||
| LA volume index (mL/m2) | 25 ± 7 | 29 ± 10 | 32 ± 11a | 29 ± 11 |
| LA reservoir strain (%) | 34 ± 11 | 32 ± 9 | 29 ± 7a | 33 ± 10 |
| Lateral E/e′ | 8 ± 3 | 9 ± 4 | 9 ± 4 | 8 ± 3 |
| LV (systemic) indices | ||||
| LV end-diastolic volume (mL/m2) | 52 ± 19 | 56 ± 27 | 63 ± 22a | 50 ± 16 |
| LV ejection fraction (%) | 61 ± 13 | 64 ± 17 | 66 ± 17 | 64 ± 13 |
| LV global longitudinal strain (%) | −19 ± 6 | −20 ± 4 | −18 ± 3 | −19 ± 4 |
| ≥Mitral regurgitation | 4 (5%) | 4 (5%) | 4 (5%) | 4 (5%) |
| LV stroke volume, mL/m2 | 39 ± 19 | 48 ± 22a | 52 ± 27a | 42 ± 18 |
| Heart rate, bpm | 68 ± 9 | 76 ± 13 | 89 ± 22a | 65 ± 14 |
| Cardiac index, l/min/m2 | 2.66 ± 0.94 | 3.64 ± 1.12a | 4.63 ± 1.27a | 2.73 ± 1.02 |
| LV afterload | ||||
| Aortic mean gradient (mmHg) | 9 ± 4 | 12 ± 6 | 14 ± 5a | 11 ± 4 |
| Systolic blood pressure, mmHg | 118 ± 16 | 126 ± 19 | 115 ± 14 | 122 ± 26 |
| Pulse pressure, mmHg | 46 ± 7 | 58 ± 12a | 54 ± 13a | 44 ± 17 |
| Zva, mmHg/mL*m2 | 3.26 ± 0.85 | 2.87 ± 0.61a | 2.51 ± 0.47a | 3.12 ± 0.74 |
| EAI, mmHg/mL*m2 | 2.86 ± 0.72 | 2.51 ± 0.62a | 1.92 ± 0.45a | 2.67 ± 0.60 |
| SVRI, dyne-s/cm5*m2 | 2725 ± 503 | 2066 ± 421a | 1496 ± 317a | 2785 ± 522 |
EAI, effective arterial elastance index; E/e′, ratio of mitral inflow pulsed wave Doppler early velocity to tissue Doppler early velocity; LA, left atrium; LV, left ventricle; RA, right atrium; RV, right ventricle; RVSP, right ventricular systolic pressure; RVFWS, right ventricular free wall strain; SVRI, systemic vascular resistance index; Zva, valvuloarterial impedance.
aStatistically significant difference between indices obtained at baseline echocardiogram vs. indices obtained during pregnancy/postnatal period. Comparisons were based on paired t-test.
Figure 1.
Bar graph showing relative change in RVSP (plaid), RVFWS (red), and RVFWS/RVSP (black) in early pregnancy, late pregnancy, and postnatal echocardiograms. *Signifies statistically significant relative change from baseline values. RVSP: right ventricular systolic pressure, RVFWS: right ventricular free wall strain.
Figure 2.
Bar graph showing relative change in RVSP, RVFWS, and RVFWS/RVSP, in early pregnancy (plaid), late pregnancy (red), and postnatal echocardiogram (black). * Signifies statistically significant relative change from baseline values. RVSP: right ventricular systolic pressure, RVFWS: right ventricular free wall strain.
At the time of postnatal echocardiogram, 49% (40/81) had RA enlargement, 44% (34/78) had RA dysfunction, 58% (47/81) had RV dilation, 89% (71/80) had RV systolic dysfunction, 13% (10/80) had LA enlargement, 25% (19/77) had LA dysfunction, 16% (13/81) had LV enlargement, and 38% (31/81) had LV systolic dysfunction.
Pregnancy-related adverse outcomes
Of the 81 pregnancies, the median gestational age at the time of delivery was 38 (35–39) weeks and the median birth weight was 2916 (20 631–3964) grams. There was one twin gestation, and 42 (51%) of the 82 babies were boys. Delivery was by caesarean section in 17 (21%) cases, and the indications for caesarean section were foetal distress (n = 6), arrest/failure of progression of labour (n = 3), and repeat (elective) caesarean section (n = 8).
There were 5 maternal cardiovascular complications in four patients (sustained atrial arrhythmias n = 2, heart failure hospitalization n = 3); 10 obstetric complications in 9 patients (gestational hypertension n = 4, pre-eclampsia n = 2, postpartum haemorrhage n = 2); and 22 neonatal complications in 18 pregnancies (prematurity n = 13, small-for-gestational age birthweight 8, and foetal death n = 1). Overall, there were 37 PRAO in 25 (31%) patients. Table 4 shows the relationship between cardiac indices obtained from baseline echocardiogram and PRAO. Of the cardiac indices analysed, only RVFWS (odds ratio, 0.96; 95% confidence interval, 0.93–0.99; area under the curve, 0.642) and RVFWS/RVSP (odds ratio, 0.96; 95% confidence interval, 0.94–0.98; area under the curve, 0.661) were associated with PRAO after adjustment for maternal age and WHO risk classification. Similarly, we observed a relationship between relative change in RVFWS (from baseline echocardiogram and echocardiogram performed in early pregnancy trimester) and PRAO (odds ratio, 0.97; 95% confidence interval, 0.95–0.99; area under the curve, 0.629), and between relative change in RVFWS/RVSP (odds ratio, 0.95; 95% confidence interval, 0.93–0.97; area under the curve, 0.682), after adjustment for maternal age and WHO risk classification (Table 5).
Table 4.
Logistic regression model showing association between baseline cardiac indices and pregnancy-related adverse outcome
| Echocardiographic indices | OR (95% CI) | P | AUC |
|---|---|---|---|
| RA indices | |||
| RA volume index (mL/m2) | 0.97 (0.92–1.02) | 0.3 | 0.521 |
| RA reservoir strain (%) | 0.98 (0.95–1.01) | 0.4 | 0.544 |
| RV (non-systemic) indices | |||
| RV end-diastolic area (cm2/m2) | 1.01 (0.95–1.07) | 0.5 | 0.493 |
| RVFWS (%) | 0.96 (0.93–0.99) | 0.04 | 0.642 |
| RV afterload | |||
| RVSP, mmHg | 1.03 (0.96–1.10) | 0.3 | 0.502 |
| RVFWS/RVSP, %/mmHg | 0.96 (0.94–0.98) | 0.02 | 0.661 |
| LA indices | |||
| LA volume index (mL/m2) | 1.05 (0.94–1.13) | 0.4 | 0.573 |
| LA reservoir strain (%) | 0.98 (0.95–1.01) | 0.1 | 0.588 |
| LV (systemic) indices | |||
| LV end-diastolic volume (mL/m2) | 0.99 (0.95–1.03) | 0.7 | 0.498 |
| LV global longitudinal strain (%) | 1.02 (0.79–1.31) | 0.8 | 0.516 |
AUC, area under the curve; CI, confidence interval; LA, left atrium; LV, left ventricle; OR, odds ratio; RA, right atrium; RV, right ventricle; RVFWS, right ventricular free wall strain; RVSP, right ventricular systolic pressure
The data presented above were derived from univariable logistic regression analysis, and the univariable models were each adjusted for age and congenital heart disease group (right heart lesion, left heart lesion, septal defect, and others. Right heart lesion was used as the reference group). RVFWS and LV global longitudinal strain were modelled as absolute values (i.e. ignoring the negative sign). Models were adjusted for maternal age and WHO risk class.
Table 5.
Logistic regression model showing association between temporal change in cardiac indices and pregnancy-related adverse outcome
| Echocardiographic indices | OR (95% CI) | P | AUC |
|---|---|---|---|
| RA indices | |||
| Δ RA volume index (mL/m2) | 0.99 (0.95–1.03) | 0.4 | 0.504 |
| Δ RA reservoir strain (%) | 0.98 (0.94–1.02) | 0.4 | 0.527 |
| RV (non-systemic) indices | |||
| Δ RV end-diastolic area (cm2/m2) | 1.03 (0.92–1.12) | 0.3 | 0.498 |
| Δ RVFWS (%) | 0.97(0.95–0.99) | 0.03 | 0.629 |
| RV afterload | |||
| Δ RVSP, mmHg | 1.02 (0.97–1.06) | 0.4 | 0.511 |
| Δ RVFWS/RVSP, %/mmHg | 0.95 (0.93–0.97) | 0.01 | 0.682 |
| LA indices | |||
| Δ LA volume index (mL/m2) | 1.02 (0.96–1.10) | 0.3 | 0.536 |
| Δ LA reservoir strain (%) | 0.97 (0.92–1.02) | 0.2 | 0.541 |
| LV (systemic) indices | |||
| Δ LV end-diastolic volume (mL/m2) | 1.02 (0.97–1.02) | 0.5 | 0.481 |
| Δ LV global longitudinal strain (%) | 0.98 (0.92–1.04) | 0.4 | 0.474 |
The data presented above were derived from univariable logistic regression analysis, and the univariable models were each adjusted for age and congenital heart disease group (right heart lesion, left heart lesion, septal defect, and others. Right heart lesion was used as the reference group). Δ was calculated as relative change between baseline echocardiogram and echocardiogram performed in early pregnancy (first/second) trimester, whereby positive values signify temporal increase, while negative values signify temporal decrease in cardiac indices. Models were adjusted for maternal age and WHO risk class.
AUC, area under the curve; CI, confidence interval; LA, left atrium; LV, left ventricle; OR, odds ratio; RA, right atrium; RV, right ventricle; RVFWS, right ventricular free wall strain; RVSP, right ventricular systolic pressure.
Discussion
In this study, we assessed cardiac remodelling during pregnancy and postpartum, and the relationship between cardiac indices and PRAO. The main findings were: (i) Women with CHD had worse atrial and ventricular function, higher RV global afterload, and worse RV–PA coupling compared to a control group of women without cardiovascular disease. (ii) There was a temporal decrease in RV systolic function and RV–PA coupling during pregnancy, and these changes persisted in the postnatal period. (iii) RV systolic function and RV–PA coupling, at baseline and during follow-up, were associated with PRAO.
Pregnancy is associated with significant haemodynamic changes such as an increase in blood volume, heart rate, and stroke volume.11–14 These changes, coupled with a decrease in systemic afterload, improve haemodynamic performance and provide the additional cardiac output required to meet the metabolic demands of pregnancy.11–14 Women without cardiovascular disease tolerate these haemodynamic changes during pregnancy, without overt symptoms or change in functional status. On the other hand, women with cardiovascular disease may experience new or worsening cardiovascular symptoms during pregnancy depending on their ability to adapt to the physiological demands associated with pregnancy.5,11–14,26 This would explain the higher incidence of cardiovascular complications such as stroke, arrhythmias, and heart failure, as well as neonatal and obstetric complications, observed in women with cardiovascular disease in previous studies such as the Registry for Pregnancy and Cardiac Disease (ROPAC) study, Cardiac Disease in Pregnancy (CAPREG) study, and the Pregnancy in CHD (ZAHARA) study.5,14,26,27
Previous studies have proposed a mechanistic link between haemodynamic abnormalities during pregnancy and the occurrence of PRAO. This link is postulated to be due to suboptimal cardiovascular performance during pregnancy. One of these studies was by Wald et al., where the authors reported a decline in maternal cardiac output from baseline (prepregnancy) to the third trimester and also demonstrated a relationship between decline in maternal cardiac output and umbilical artery Doppler abnormalities and neonatal complications.11 Similarly, Pieper et al. showed that women with cardiovascular disease had abnormal uteroplacental Doppler flow (higher umbilical artery resistance index) and that abnormal uteroplacental Doppler flow was more common in women with RV systolic dysfunction.12 The current study supports the results of previous studies and also provides novel insight into the clinical implications of deterioration in RV systolic function and RV–PA coupling during pregnancy. The temporal decline in right heart indices during pregnancy cannot be entirely explained by the type of CHD lesions since a similar decline was observed both in patients with predominantly right heart lesions as well as those with left heart lesions. We postulate that this may be related to factors such as abnormal PA compliance, pulmonary vascular disease, and LV diastolic dysfunction, since these factors are known to be relatively common in women with CHD. Perhaps, the CHD patients have increased pulsatile and non-pulsatile RV afterload that are not apparent at baseline but are unmasked in the setting of the high RV stroke volume and cardiac output of pregnancy. Consistent with our results, Cornette et al. observed an increase in Doppler-derived LV filling pressures during pregnancy, while Uebing observed an increase in RV size during pregnancy in women with cardiovascular disease.13,28
Clinical implications and future directions
A potential clinical application of these findings is with regard to risk stratification and level of cardiovascular surveillance and care during pregnancy. Perhaps, women with moderate severity of cardiovascular disease (WHO II) who have abnormal RV–PA coupling at baseline, may require a higher level of cardiovascular surveillance and care during pregnancy.
Limitations
This is a retrospective single-centre study, and it is therefore prone to selection and ascertainment bias. Patients with complex CHD such as systemic RV, Fontan physiology, and cyanotic heart disease were excluded to reduce population heterogeneity in assessing temporal changes in cardiac structure and function over time. However, the prevalence of PRAO observed in the current study is consistent with estimates from previous studies, suggesting that the results of the current study could be generalised to other populations. We were unable to determine or control for the effect (or lack thereof) of discontinuation of renin-angiotensin-aldosterone system antagonists in 19% of the patients. However, considering the limited effect of renin-angiotensin-aldosterone system antagonist on right heart function in previous studies, we postulate that discontinuing these medications did not influence the observed results. Finally, we were unable to perform subgroup analyses and rigorous statistical analyses because of the small sample size.
Conclusions
Women with CHD had a temporal decrease in RV systolic function and an increase in RV global afterload during pregnancy, leading to a significant decline in RV–PA coupling. These changes persisted in the postnatal period. Baseline RV systolic function and RV–PA coupling, and temporal change in RV systolic function and RV–PA coupling were associated with PRAO, independent of the severity of cardiovascular disease (WHO risk classification). Since the assessment of RV systolic function (RV strain imaging) and RV global afterload (RVSP) can easily be added to routine clinical/echocardiographic evaluation, these indices can be integrated into clinical risk stratification protocol and could help determine the need for more intensive cardiovascular care and surveillance during pregnancy. The results of this study also provide the foundation for further studies to delineate the causes of the observed deterioration in RV–PA coupling during pregnancy, and the long-term implications of right heart dysfunction observed in the postnatal period.
Supplementary data
Supplementary data are available at European Heart Journal—Cardiovascular Imaging online.
Supplementary Material
Contributor Information
Alexander C Egbe, Department of Cardiovascular Medicine, Mayo Clinic Rochester, Mayo Clinic and Foundation, 200 First Street SW, Rochester, MN 55905, USA.
William R Miranda, Department of Cardiovascular Medicine, Mayo Clinic Rochester, Mayo Clinic and Foundation, 200 First Street SW, Rochester, MN 55905, USA.
C Charles Jain, Department of Cardiovascular Medicine, Mayo Clinic Rochester, Mayo Clinic and Foundation, 200 First Street SW, Rochester, MN 55905, USA.
Luke J Burchill, Department of Cardiovascular Medicine, Mayo Clinic Rochester, Mayo Clinic and Foundation, 200 First Street SW, Rochester, MN 55905, USA.
Kathleen A Young, Department of Cardiovascular Medicine, Mayo Clinic Rochester, Mayo Clinic and Foundation, 200 First Street SW, Rochester, MN 55905, USA.
Carl H Rose, Department of Obstetrics and Gynaecology, Mayo Clinic Rochester, Rochester, MN 55905, USA.
Snigdha Karnakoti, Department of Cardiovascular Medicine, Mayo Clinic Rochester, Mayo Clinic and Foundation, 200 First Street SW, Rochester, MN 55905, USA.
Marwan H Ahmed, Department of Cardiovascular Medicine, Mayo Clinic Rochester, Mayo Clinic and Foundation, 200 First Street SW, Rochester, MN 55905, USA.
Heidi M Connolly, Department of Cardiovascular Medicine, Mayo Clinic Rochester, Mayo Clinic and Foundation, 200 First Street SW, Rochester, MN 55905, USA.
Funding
A.C.E. was supported by National Heart, Lung, and Blood Institute (NHLBI, R01 HL158517 and R01 HL160761). The MACHD Registry was supported by the Al-Bahar Research grant.
Data availability
The data underlying this article will be shared on reasonable request to the corresponding author.
References
- 1. Diller GP, Kempny A, Alonso-Gonzalez R, Swan L, Uebing A, Li W et al. Survival prospects and circumstances of death in contemporary adult congenital heart disease patients under follow-up at a large tertiary centre. Circulation 2015;132:2118–25. [DOI] [PubMed] [Google Scholar]
- 2. Egbe AC, Miranda WR, Pellikka PA, DeSimone CV, Connolly HM. Prevalence and prognostic implications of left ventricular systolic dysfunction in adults with congenital heart disease. J Am College Cardiol 2022;79:1356–65. [DOI] [PubMed] [Google Scholar]
- 3. Verheugt CL, Uiterwaal CS, van der Velde ET, Meijboom FJ, Pieper PG, Vliegen HW et al. Gender and outcome in adult congenital heart disease. Circulation 2008;118:26–32. [DOI] [PubMed] [Google Scholar]
- 4. Tutarel O, Kempny A, Alonso-Gonzalez R, Jabbour R, Li W, Uebing A et al. Congenital heart disease beyond the age of 60: emergence of a new population with high resource utilization, high morbidity, and high mortality. Eur Heart J 2014;35:725–32. [DOI] [PubMed] [Google Scholar]
- 5. Silversides CK, Grewal J, Mason J, Sermer M, Kiess M, Rychel V et al. Pregnancy outcomes in women with heart disease: the CARPREG II study. J Am College Cardiol 2018;71:2419–30. [DOI] [PubMed] [Google Scholar]
- 6. Jimenez-Juan L, Krieger EV, Valente AM, Geva T, Wintersperger BJ, Moshonov H et al. Cardiovascular magnetic resonance imaging predictors of pregnancy outcomes in women with coarctation of the aorta. Eur Heart J Cardiovasc Imaging 2014;15:299–306. [DOI] [PubMed] [Google Scholar]
- 7. Piepoli MF, Adamo M, Barison A, Bestetti RB, Biegus J, Bohm M et al. Preventing heart failure: a position paper of the Heart Failure Association in collaboration with the European Association of Preventive Cardiology. Eur J Heart Fail 2022;24:143–68. [DOI] [PubMed] [Google Scholar]
- 8. Elkayam U, Goland S, Pieper PG, Silverside CK. High-risk cardiac disease in pregnancy: part I. J Am College Cardiol 2016;68:396–410. [DOI] [PubMed] [Google Scholar]
- 9. Elkayam U, Goland S, Pieper PG, Silversides CK. High-risk cardiac disease in pregnancy: part II. J Am College Cardiol 2016;68:502–16. [DOI] [PubMed] [Google Scholar]
- 10. Regitz-Zagrosek V, Roos-Hesselink JW, Bauersachs J, Blomstrom-Lundqvist C, Cifkova R, De Bonis M et al. 2018 ESC Guidelines for the management of cardiovascular diseases during pregnancy. Eur Heart J 2018;39:3165–241. [DOI] [PubMed] [Google Scholar]
- 11. Wald RM, Silversides CK, Kingdom J, Toi A, Lau CS, Mason J et al. Maternal cardiac output and fetal Doppler predict adverse neonatal outcomes in pregnant women with heart disease. J Am Heart Assoc 2015;4:e002414. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12. Pieper PG, Balci A, Aarnoudse JG, Kampman MA, Sollie KM, Groen H et al. Uteroplacental blood flow, cardiac function, and pregnancy outcome in women with congenital heart disease. Circulation 2013;128:2478–87. [DOI] [PubMed] [Google Scholar]
- 13. Cornette J, Ruys TP, Rossi A, Rizopoulos D, Takkenberg JJ, Karamermer Y et al. Hemodynamic adaptation to pregnancy in women with structural heart disease. Int J Cardiol 2013;168:825–31. [DOI] [PubMed] [Google Scholar]
- 14. Kampman MA, Valente MA, van Melle JP, Balci A, Roos-Hesselink JW, Mulder BJ et al. Cardiac adaption during pregnancy in women with congenital heart disease and healthy women. Heart 2016;102:1302–8. [DOI] [PubMed] [Google Scholar]
- 15. Lang RM, Badano LP, Mor-Avi V, Afilalo J, Armstrong A, Ernande L et al. Recommendations for cardiac chamber quantification by echocardiography in adults: an update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging. J Am Soc Echocardiogr 2015;28:1–39.e14. [DOI] [PubMed] [Google Scholar]
- 16. Nagueh SF, Smiseth OA, Appleton CP, Byrd BF 3rd, Dokainish H, Edvardsen T et al. Recommendations for the evaluation of left ventricular diastolic function by echocardiography: an update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging. J Am Soc Echocardiogr 2016;29:277–314. [DOI] [PubMed] [Google Scholar]
- 17. Rudski LG, Lai WW, Afilalo J, Hua L, Handschumacher MD, Chandrasekaran K et al. Guidelines for the echocardiographic assessment of the right heart in adults: a report from the American Society of Echocardiography endorsed by the European Association of Echocardiography, a registered branch of the European Society of Cardiology, and the Canadian Society of Echocardiography. J Am Soc Echocardiogr 2010;23:685–713. quiz 786-8. [DOI] [PubMed] [Google Scholar]
- 18. Thorne S, MacGregor A, Nelson-Piercy C. Risks of contraception and pregnancy in heart disease. Heart 2006;92:1520–5. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19. Egbe AC, El-Harasis M, Miranda WR, Ammash NM, Rose CH, Fatola A et al. Outcomes of pregnancy in patients with prior right ventricular outflow interventions. J Am Heart Assoc 2019;8:e011730. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20. Mitchell C, Rahko PS, Blauwet LA, Canaday B, Finstuen JA, Foster MC et al. Guidelines for performing a comprehensive transthoracic echocardiographic examination in adults: recommendations from the American Society of Echocardiography. J Am Soc Echocardiogr 2019;32:1–64. [DOI] [PubMed] [Google Scholar]
- 21. Egbe AC, Reddy YNV, Obokata M, Borlaug BA. Doppler-derived arterial load indices better reflect left ventricular afterload than systolic blood pressure in coarctation of aorta. Circ Cardiovasc Imaging 2020;13:e009672. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22. Padeletti M, Cameli M, Lisi M, Malandrino A, Zaca V, Mondillo S. Reference values of right atrial longitudinal strain imaging by two-dimensional speckle tracking. Echocardiography 2012;29:147–52. [DOI] [PubMed] [Google Scholar]
- 23. Morris DA, Krisper M, Nakatani S, Kohncke C, Otsuji Y, Belyavskiy E et al. Normal range and usefulness of right ventricular systolic strain to detect subtle right ventricular systolic abnormalities in patients with heart failure: a multicentre study. Eur Heart J Cardiovasc Imaging 2017;18:212–23. [DOI] [PubMed] [Google Scholar]
- 24. Morris DA, Takeuchi M, Krisper M, Kohncke C, Bekfani T, Carstensen T et al. Normal values and clinical relevance of left atrial myocardial function analysed by speckle-tracking echocardiography: multicentre study. Eur Heart J Cardiovasc Imaging 2015;16:364–72. [DOI] [PubMed] [Google Scholar]
- 25. Egbe AC, Miranda WR, Connolly HM. Role of echocardiography for assessment of cardiac remodeling in congenitally corrected transposition of great arteries. Circ Cardiovasc Imaging 2022;15:e013477. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26. Roos-Hesselink J, Baris L, Johnson M, De Backer J, Otto C, Marelli A et al. Pregnancy outcomes in women with cardiovascular disease: evolving trends over 10 years in the ESC Registry Of Pregnancy And Cardiac disease (ROPAC). Eur Heart J 2019;40:3848–55. [DOI] [PubMed] [Google Scholar]
- 27. Drenthen W, Boersma E, Balci A, Moons P, Roos-Hesselink JW, Mulder BJ et al. Predictors of pregnancy complications in women with congenital heart disease. Eur Heart J 2010;31:2124–32. [DOI] [PubMed] [Google Scholar]
- 28. Uebing A, Arvanitis P, Li W, Diller GP, Babu-Narayan SV, Okonko D et al. Effect of pregnancy on clinical status and ventricular function in women with heart disease. Int J Cardiol 2010;139:50–9. [DOI] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
The data underlying this article will be shared on reasonable request to the corresponding author.