Heart Failure in Pregnant Women With Cardiac Disease
Heart Failure in Pregnant Women With Cardiac Disease
In this large worldwide registry of pregnant women with underlying cardiac disease, we investigated timing and predictors of HF. HF was the most common complication, occurring in 13% of the patients. We showed that the onset of HF depended on the underlying cardiac diagnosis, with HF most frequently diagnosed in the second or third trimester, or shortly after delivery. HF was found most often in women with poor prepregnancy cardiac function, with a diagnosis of cardiomyopathy or pulmonary hypertension. Patients with HF had a higher rate of adverse maternal and fetal outcomes. Furthermore, this is the first study to identify specific predictors for the occurrence of HF.
In this registry, the rates of HF in various diagnoses slightly differ from reported rates in the literature. For simple diagnoses, such as mitral regurgitation, aortic coarctation, aortic abnormalities and shunt lesions, rates of HF are high in this registry when compared to the literature. This may be partially explained by the high percentage of pulmonary hypertension in some of the lesions, such as mitral stenosis and/or regurgitation and uncorrected shunt lesions. Yap et al described a higher rate of complications in patients with uncorrected shunts, in patients with atrial septal defects and ventricular septal defect, but none of the women developed HF. We reported a HF rate of 3.8% in patients with atrial switch procedure for transposition of the great arteries which is relatively low compared to previously reported rates of 2.7%, 4.1% and 7.1%.
In our univariable analysis, several factors were associated with an increased or low risk of HF (Table 2). The factors cardiomyopathy, NYHA class ≥3, WHO ≥3, pre-pregnancy HF and pulmonary hypertension remained significantly associated in the multivariate analysis. The presence of a left-sided lesion and medication use prior to pregnancy showed a weak association. The loss of several of the factors of the univariable analysis suggests that their risk was indirectly mediated through a second factor. For example, the relationship of HF with developing countries was probably due to more severe disease, including a higher prevalence of pulmonary hypertension. Of those factors that remained significant, the strongest were prepregnancy HF and poor functional class and, in addition, high risk of pregnancy as represented by high WHO class. These are useful parameters in counselling of women with heart disease considering pregnancy. Interestingly, WHO class was a predictor of HF in the multivariable analysis, even though this classification was designed to predict the risk of any cardiovascular complication and not just of HF. In the prospective study of Siu et al, EF <40% predicted complications. We found that EF and fractional shortening were strong univariable predictors of HF in the subgroup of patients in which these data were available, however, these variables could not be tested in the multivariable model due to missing data. Pulmonary hypertension has also been recognised as a high-risk condition and predictor for cardiovascular events in previous studies, However, pulmonary hypertension did not predict complications in the studies of Drenthen et al and Siu et al, probably because few patients with pulmonary hypertension were included in their studies. In this registry, we included patients from developing countries where the prevalence of pulmonary hypertension is relatively high, therefore, we could identify pulmonary hypertension as a predictor of HF.
In our series, the presence of a mechanical valve was not a predictor of HF, but these patients are mainly at risk for other complications, such as haemorrhage and valve thrombosis. Similarly, IHD was not a predictor of HF, possibly because left ventricular function may have been almost normal in most of these patients. The number of IHD patients was very small and more data are needed to draw conclusions regarding this patient group. Patients with CHD had a lower risk than patients with VHD, IHD or cardiomyopathy, but compared with the rate of HF in the normal healthy population, this risk is still increased. Patients with right-sided lesions and cyanotic lesions (mostly corrected) had a lower risk than patients with left-sided lesions.
Biomarkers, such as B-type natriuretic peptide (BNP), are established markers of HF. However, their role during pregnancy in women with heart disease is incompletely studied. In the study by Tanous et al. BNP levels were associated with cardiovascular events during pregnancy. Importantly, BNP levels lower than 100 pg/mL had a negative predictive value of 100% for identifying events during pregnancy. However, since in a large proportion of patients the BNP level was only measured at time of the event and not before this, additional studies are clearly warranted to show the value of BNP in prepregnancy risk models. In this registry, we did not collect data on biomarkers.
To date, data on the timing of HF in pregnant women with heart disease are scarce. The peripartum period is regarded as high-risk period because of cardiac stress due to pain and anxiety as well as fluid overload. While peripartum cardiomyopathy by definition occurs in the months around delivery, patients with VHD are reported to present with HF during pregnancy as well as in the peripartum period.– In our study, there appeared to be two peaks, one at the end of the second and beginning of the third trimester, and the other around delivery. Within this pattern, there were distinct clusters of diagnostic groups. Women with abnormalities causing pulmonary hypertension, such as shunt lesions and mitral stenosis, typically went into HF before 30 weeks gestation. In those with most forms of cardiomyopathy, HF was diagnosed peripartum. The first peak, corresponding to 23–30 weeks occurred when most of the important haemodynamic changes had taken place. Stroke volume then has reached its maximum (up to 130% of normal) for a number of weeks, but heart rate is just starting to increase. The second peak occurred around delivery, corresponding with peripartum haemodynamic changes. Peripartum cardiac output increases with an additional 25%, and after delivery, autotransfusion from the uterus will further increase circulatory volume thereby stressing both the left and RV. Firm conclusions for all diagnostic groups cannot be made, some of the diagnostic groups were small.
Pre-eclampsia during pregnancy was associated with HF with an OR of 7.1. In previously healthy women who develop pre-eclampsia, diastolic and systolic left ventricular function abnormalities have been demonstrated, but these rarely develop into HF. However, in women with pre-existing heart disease, the added strain of pre-eclampsia precipitates HF resulting in a rate as high as 30% of the patients. This is an important novel finding of our study, which indicates that patients with heart disease who develop pre-eclampsia should be monitored carefully for the development of HF. One-third of the HF associated with pre-eclampsia was in patients with peripartum cardiomyopathy, which is a known association. However, two-thirds of the HF occurring in patients with pre-eclampsia occurred in patients with other underlying diseases. HF was also associated with endocarditis, which likely was a cause of HF. Caesarean section rates were high in patients with HF, with the majority having a CS for cardiac reasons. Women with HF were often delivered preterm probably to shorten the period of volume load and to be able to institute more aggressive therapy for the treatment of HF, however, the decision for early delivery may have a negative impact on the offspring in the longer term. On the other hand, fetal death and intrauterine growth retardation occurred more often in patients with HF, which may keenly illustrate the difficult balance between early delivery and prolonging pregnancy in this high-risk situation. Reassuringly, neonatal death rates were not different.
Some of the parameters previously described in the literature were not collected in this database, such as the severity of left ventricular outflow tract obstruction (peak aortic gradient >50 mm Hg or aortic valve area <1.0 cm). Therefore, we could neither confirm nor contradict the value of these previously identified predictors. Echocardiographic and laboratory data (such as right ventricular systolic pressure) were not available in a majority of the patients and, therefore, could not be involved in the multivariable analysis. As with other international registries, the input and quality of data was checked in only 5–10% of cases. Additionally, some centres had much higher volumes than others. Since our dataset had limitations, necessarily some of the definitions (such as pulmonary hypertension) deviated from current guidelines, therefore, all data and comments on this matter must be seen in this perspective. We did not collect detailed information on the severity of HF, although we do know that all patients needed treatment. Details on type of treatment and length of hospital stay could, however, not be analysed. Importantly, the use of predictors has limitations in estimating the risk of pregnancy in individual patients. Always, predictors identified in multiple studies must be taken into account together with the results of disease-specific studies. Although we showed that timing of HF was dependent on underlying heart disease, some of the subgroups were small. Consequently, our findings need to be confirmed in future large studies. As with all registries, there was some missing information, this was about 4%.
Discussion
In this large worldwide registry of pregnant women with underlying cardiac disease, we investigated timing and predictors of HF. HF was the most common complication, occurring in 13% of the patients. We showed that the onset of HF depended on the underlying cardiac diagnosis, with HF most frequently diagnosed in the second or third trimester, or shortly after delivery. HF was found most often in women with poor prepregnancy cardiac function, with a diagnosis of cardiomyopathy or pulmonary hypertension. Patients with HF had a higher rate of adverse maternal and fetal outcomes. Furthermore, this is the first study to identify specific predictors for the occurrence of HF.
Rate of HF in Relation to Different Underlying Cardiac Diagnoses
In this registry, the rates of HF in various diagnoses slightly differ from reported rates in the literature. For simple diagnoses, such as mitral regurgitation, aortic coarctation, aortic abnormalities and shunt lesions, rates of HF are high in this registry when compared to the literature. This may be partially explained by the high percentage of pulmonary hypertension in some of the lesions, such as mitral stenosis and/or regurgitation and uncorrected shunt lesions. Yap et al described a higher rate of complications in patients with uncorrected shunts, in patients with atrial septal defects and ventricular septal defect, but none of the women developed HF. We reported a HF rate of 3.8% in patients with atrial switch procedure for transposition of the great arteries which is relatively low compared to previously reported rates of 2.7%, 4.1% and 7.1%.
Predictors
In our univariable analysis, several factors were associated with an increased or low risk of HF (Table 2). The factors cardiomyopathy, NYHA class ≥3, WHO ≥3, pre-pregnancy HF and pulmonary hypertension remained significantly associated in the multivariate analysis. The presence of a left-sided lesion and medication use prior to pregnancy showed a weak association. The loss of several of the factors of the univariable analysis suggests that their risk was indirectly mediated through a second factor. For example, the relationship of HF with developing countries was probably due to more severe disease, including a higher prevalence of pulmonary hypertension. Of those factors that remained significant, the strongest were prepregnancy HF and poor functional class and, in addition, high risk of pregnancy as represented by high WHO class. These are useful parameters in counselling of women with heart disease considering pregnancy. Interestingly, WHO class was a predictor of HF in the multivariable analysis, even though this classification was designed to predict the risk of any cardiovascular complication and not just of HF. In the prospective study of Siu et al, EF <40% predicted complications. We found that EF and fractional shortening were strong univariable predictors of HF in the subgroup of patients in which these data were available, however, these variables could not be tested in the multivariable model due to missing data. Pulmonary hypertension has also been recognised as a high-risk condition and predictor for cardiovascular events in previous studies, However, pulmonary hypertension did not predict complications in the studies of Drenthen et al and Siu et al, probably because few patients with pulmonary hypertension were included in their studies. In this registry, we included patients from developing countries where the prevalence of pulmonary hypertension is relatively high, therefore, we could identify pulmonary hypertension as a predictor of HF.
In our series, the presence of a mechanical valve was not a predictor of HF, but these patients are mainly at risk for other complications, such as haemorrhage and valve thrombosis. Similarly, IHD was not a predictor of HF, possibly because left ventricular function may have been almost normal in most of these patients. The number of IHD patients was very small and more data are needed to draw conclusions regarding this patient group. Patients with CHD had a lower risk than patients with VHD, IHD or cardiomyopathy, but compared with the rate of HF in the normal healthy population, this risk is still increased. Patients with right-sided lesions and cyanotic lesions (mostly corrected) had a lower risk than patients with left-sided lesions.
Biomarkers, such as B-type natriuretic peptide (BNP), are established markers of HF. However, their role during pregnancy in women with heart disease is incompletely studied. In the study by Tanous et al. BNP levels were associated with cardiovascular events during pregnancy. Importantly, BNP levels lower than 100 pg/mL had a negative predictive value of 100% for identifying events during pregnancy. However, since in a large proportion of patients the BNP level was only measured at time of the event and not before this, additional studies are clearly warranted to show the value of BNP in prepregnancy risk models. In this registry, we did not collect data on biomarkers.
Timing
To date, data on the timing of HF in pregnant women with heart disease are scarce. The peripartum period is regarded as high-risk period because of cardiac stress due to pain and anxiety as well as fluid overload. While peripartum cardiomyopathy by definition occurs in the months around delivery, patients with VHD are reported to present with HF during pregnancy as well as in the peripartum period.– In our study, there appeared to be two peaks, one at the end of the second and beginning of the third trimester, and the other around delivery. Within this pattern, there were distinct clusters of diagnostic groups. Women with abnormalities causing pulmonary hypertension, such as shunt lesions and mitral stenosis, typically went into HF before 30 weeks gestation. In those with most forms of cardiomyopathy, HF was diagnosed peripartum. The first peak, corresponding to 23–30 weeks occurred when most of the important haemodynamic changes had taken place. Stroke volume then has reached its maximum (up to 130% of normal) for a number of weeks, but heart rate is just starting to increase. The second peak occurred around delivery, corresponding with peripartum haemodynamic changes. Peripartum cardiac output increases with an additional 25%, and after delivery, autotransfusion from the uterus will further increase circulatory volume thereby stressing both the left and RV. Firm conclusions for all diagnostic groups cannot be made, some of the diagnostic groups were small.
Pregnancy Outcome in Patients With HF
Pre-eclampsia during pregnancy was associated with HF with an OR of 7.1. In previously healthy women who develop pre-eclampsia, diastolic and systolic left ventricular function abnormalities have been demonstrated, but these rarely develop into HF. However, in women with pre-existing heart disease, the added strain of pre-eclampsia precipitates HF resulting in a rate as high as 30% of the patients. This is an important novel finding of our study, which indicates that patients with heart disease who develop pre-eclampsia should be monitored carefully for the development of HF. One-third of the HF associated with pre-eclampsia was in patients with peripartum cardiomyopathy, which is a known association. However, two-thirds of the HF occurring in patients with pre-eclampsia occurred in patients with other underlying diseases. HF was also associated with endocarditis, which likely was a cause of HF. Caesarean section rates were high in patients with HF, with the majority having a CS for cardiac reasons. Women with HF were often delivered preterm probably to shorten the period of volume load and to be able to institute more aggressive therapy for the treatment of HF, however, the decision for early delivery may have a negative impact on the offspring in the longer term. On the other hand, fetal death and intrauterine growth retardation occurred more often in patients with HF, which may keenly illustrate the difficult balance between early delivery and prolonging pregnancy in this high-risk situation. Reassuringly, neonatal death rates were not different.
Limitations
Some of the parameters previously described in the literature were not collected in this database, such as the severity of left ventricular outflow tract obstruction (peak aortic gradient >50 mm Hg or aortic valve area <1.0 cm). Therefore, we could neither confirm nor contradict the value of these previously identified predictors. Echocardiographic and laboratory data (such as right ventricular systolic pressure) were not available in a majority of the patients and, therefore, could not be involved in the multivariable analysis. As with other international registries, the input and quality of data was checked in only 5–10% of cases. Additionally, some centres had much higher volumes than others. Since our dataset had limitations, necessarily some of the definitions (such as pulmonary hypertension) deviated from current guidelines, therefore, all data and comments on this matter must be seen in this perspective. We did not collect detailed information on the severity of HF, although we do know that all patients needed treatment. Details on type of treatment and length of hospital stay could, however, not be analysed. Importantly, the use of predictors has limitations in estimating the risk of pregnancy in individual patients. Always, predictors identified in multiple studies must be taken into account together with the results of disease-specific studies. Although we showed that timing of HF was dependent on underlying heart disease, some of the subgroups were small. Consequently, our findings need to be confirmed in future large studies. As with all registries, there was some missing information, this was about 4%.
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