IJG-08354; No of Pages 4 International Journal of Gynecology and Obstetrics xxx (2015) xxx–xxx
Contents lists available at ScienceDirect
International Journal of Gynecology and Obstetrics journal homepage: www.elsevier.com/locate/ijgo
CLINICAL ARTICLE
Risk factors for heart failure during pregnancy among Chinese women with cardiac disease Qin Fu a,b, Jianhua Lin a,b,⁎ a b
Department of Obstetrics and Gynecology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China Shanghai Obstetrical Cardiology Intensive Care Center, Shanghai, China
a r t i c l e
i n f o
Article history: Received 23 October 2014 Received in revised form 15 March 2015 Accepted 18 May 2015 Keywords: Cardiac disease Heart failure Pregnancy Risk factor
a b s t r a c t Objective: To identify risk factors for heart failure (HF) during pregnancy among women with pre-existing cardiac disease. Methods: A retrospective review was conducted of pregnant women with cardiac disease who attended Shanghai Obstetrical Cardiology Intensive Care Center, China, for delivery between January 1, 1993, and December 31, 2013. Independent predictors of HF were identified by logistic regression analysis. Results: Among 1086 pregnant women with cardiac disease, 116 (10.7%) developed HF. In multivariate analysis, HF was associated with left ventricular systolic dysfunction (odds ratio [OR] 13.16, 95% confidence interval [CI] 3.62–47.80; P b 0.001), history of HF before pregnancy (OR 11.66, 95% CI 5.83–23.33; P b 0.001), twin pregnancy (OR 11.63, 95% CI 4.10–32.99; P b 0.001), sinus tachycardia (OR 4.60, 95% CI 2.77–7.62; P b 0.001), New York Heart Association functional class higher than II (OR 3.36, 95% CI 1.11–10.25; P = 0.033), and severe pulmonary arterial hypertension (OR 1.40, 95% CI 1.10–1.78; P = 0.007). Conclusion: Women with cardiac disease who wish to become pregnant should be guided by risk factors for HF. Those who do conceive should be closely monitored during pregnancy to improve outcomes and reduce maternal mortality and morbidity. © 2015 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved.
1. Introduction
2. Materials and methods
Cardiac disease is one of the leading causes of non-obstetric maternal mortality in China [1]. Heart failure (HF) is a complex clinical syndrome that can present as a severe complication among pregnant women with cardiac disease. The underlying cause of HF is structural or functional impairment of ventricular filling or ejection. Symptoms include shortness of breath, fatigue, and fluid retention [2,3]. Heart compensation mechanisms during pregnancy do not generally cause issues for healthy women, but women with cardiac disease can develop HF during pregnancy due to the hemodynamic changes. One study [4] identified independent predictive risk factors for cardiac complications (including HF) as a baseline New York Heart Association (NYHA) functional class greater than II, cyanosis, reduced left ventricular systolic function, left heart outflow tract obstruction, and a cardiac event before pregnancy. Another study [5] identified cardiomyopathy, a NYHA functional class of at least III, WHO category of at least 3, signs of HF before pregnancy, and pulmonary arterial hypertension (PAH) as predictors of HF. The aim of the present study was to identify risk factors for HF during pregnancy among Chinese women with pre-existing cardiac disease.
A retrospective analysis was conducted of pregnant women who delivered at Shanghai Obstetrical Cardiology Intensive Care Center, Shanghai, China, between January 1, 1993, and December 31, 2013. All pregnant women with cardiac disease were eligible for inclusion in the present analysis. Cardiac conditions included congenital heart disease (CHD), rheumatic heart disease, cardiomyopathy, cardiopathy induced by severe pre-eclampsia, cardiac disease associated with systemic lupus erythematosus, cardiac disease associated with hyperthyroidism, and mixed connective tissue disease accompanied by PAH. Cardiopathy induced by severe pre-eclampsia is a pregnancy-specific condition that is associated with the acute onset of HF with left ventricular dysfunction among previously healthy women. A diagnosis of severe preeclampsia was made when the systolic blood pressure was at least 160 mm Hg, the diastolic blood pressure was at least 110 mm Hg, proteinuria (≥2 g/24 hours) was noted, or there was end-organ dysfunction [6]. Women within the first 20 weeks of pregnancy were excluded from the analysis, as were those who voluntarily underwent induced abortion. Owing to the retrospective design, neither ethical approval nor informed consent was required. Shanghai Obstetrical Cardiology Intensive Care Center was opened in 1993 with the approval of the Shanghai Health Bureau. Based at Renji Hospital (affiliated with Shanghai Jiao Tong University School of Medicine), this center serves pregnant women with cardiac disease. Most patients are from Shanghai and Eastern China.
⁎ Corresponding author at: Department of Obstetrics and Gynecology, Renji Hospital, School of Medicine of Shanghai Jiaotong University, No.1630, Dongfang Road, Shanghai, 200127, China. Tel.: +86 13816109700; fax: +86 2168383073. E-mail address: [email protected] (J. Lin).
http://dx.doi.org/10.1016/j.ijgo.2015.03.040 0020-7292/© 2015 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved.
Please cite this article as: Fu Q, Lin J, Risk factors for heart failure during pregnancy among Chinese women with cardiac disease, Int J Gynecol Obstet (2015), http://dx.doi.org/10.1016/j.ijgo.2015.03.040
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Q. Fu, J. Lin / International Journal of Gynecology and Obstetrics xxx (2015) xxx–xxx
Information for the present analysis was obtained through review of the institutional database, into which data had been entered on discharge of each patient. Baseline data had been collected before pregnancy or at the first prenatal visit. Subsequent data collection occurred during follow-up until delivery. Baseline data included age, parity, weeks of pregnancy, previous cardiac events (i.e. HF or sustained symptomatic arrhythmia before pregnancy), type of cardiac disease, NYHA functional classification [7], previous cardiac surgery, cardiac medications, results of physical examinations, oxygen saturation level of the blood, and results from standard electrocardiography, dynamic (Holter) electrocardiography, and echocardiography. Neonatal events were classified as premature delivery (b37 weeks), low weight for gestational age (b 10th percentile), neonatal asphyxia (5-minute Apgar score b 7), fetal death (≥ 20 weeks), or neonatal death (within 28 days of delivery). The data were analyzed using SPSS version 17.0 (SPSS Inc, Chicago, IL, USA). Baseline data are expressed as means with standard deviations; categorical data are expressed as percentages. Comparison of enumeration data was performed using the χ2 test. Independent predictors of HF were analyzed in a logistic regression model. Univariate predictors were history of HF before pregnancy, NYHA functional class greater than II, any form of sustained symptomatic tachyarrhythmia or bradyarrhythmia requiring treatment, uncorrected shunt (atrial septal defect, ventricular septal defect, or patent ductus arteriosus), corrected or uncorrected cyanotic heart disease, moderate-to-severe pulmonary stenosis, moderate-to-severe pulmonary regurgitation, moderate-to-severe aortic stenosis, moderate-to-severe aortic insufficiency, moderate-to-severe mitral stenosis, moderate-to-severe mitral insufficiency, moderate-to-severe tricuspid insufficiency, oxygen saturation levels less than 90%, PAH (systolic pressure N50 mm Hg [moderate] or N80 mm Hg [severe]), cardiomyopathy (hypertrophic, dilated, or peripartum), mechanical valve replacement, and twin pregnancy. Potential risk factors identified in the univariate analysis were then tested in a multivariate logistic regression model. For both models, an odds ratio (OR) greater than 1.00 was indicative of a risk factor for HF. P b 0.05 was considered statistically significant.
Table 1 Baseline characteristics of the study population.a Characteristic
Age, y 18–35 1004 (92.4) b18 or N35 82 (7.6) Parity Primipara 842 (77.5) Multipara 244 (22.5) New York Heart Association functional class I–II 1065 (98.1) III 21 (1.9) Length of pregnancy at delivery, wk 20–27 51 (4.7) 28–36 215 (19.8) ≥37 820 (75.5) History of heart failure before 48 (4.4) pregnancy Previous surgical interventions 324 (29.8) Type of heart disease Congenital heart disease 789 (72.7) Rheumatic heart disease 164 (15.1) Cardiomyopathy 57 (5.2) Cardiopathy induced by pre-eclampsia 56 (5.2) Cardiac disease associated with 15 (1.4) hyperthyroidism Cardiopathy induced by systemic 4 (0.4) lupus erythematosus 1 (0.1) Mixed connective tissue disease accompanied by pulmonary arterial hypertension Cardiac medication None 768 (70.7) Digoxin 160 (14.7) Diuretic 228 (21.0) Vasodilation 134 (12.3) Antiarrhythmic 93 (8.6) Anticoagulant 46 (4.2) Comorbidities Anemia 159 (14.6) Diabetes mellitus, hypertension, 19 (1.7) or nephritis a
3. Results Overall, 1086 pregnant women with cardiac disease were identified. The main types of cardiac disease were CHD, rheumatic heart disease, cardiomyopathy, and cardiopathy induced by pre-eclampsia (Table 1). Cardiac surgery had been performed before pregnancy among 324 (29.8%) of the 1086 patients; 8 (0.7%) had undergone two operations on two different occasions and 11 (1.0%) had undergone two operations on one occasion. Surgical interventions included closure of shunts repair (204 [18.8%] patients), mitral valve replacement (40 [3.7%]) or repair (19 [1.7%]), tricuspid valve replacement (1 [0.1%]) or repair (6 [0.6%]), combined valve replacement (5 [0.5%]), relief of pulmonary stenosis (10 [0.9%]), provision of a pacemaker (3 [0.3%]), aortic balloon dilation (1 [0.1%]), aortic valve replacement (8 [0.7%]), radical correction of tetralogy of Fallot (35 [3.2%]), relief for right ventricular outflow tract obstruction (1 [0.1%]), excision of left atrial myxoma (1 [0.1%]), and correction of large blood vessel anomaly (1 [0.1%]). The operative procedures were not detailed in the medical record for 8 [0.7%] patients. In all, 318 (29.3%) patients received more than one cardiac medication (Table 1). Among the 1086 women, 116 (10.7%) developed HF. The mean age of these 116 women was 28.00 ± 4.69 years (range 16–44). Most of the women with HF were primiparas and had a NYHA functional class of I–II (Table 1). Despite active treatment, maternal deaths from HF were recorded among 12 patients (Table 2); six of these women had CHD. Patients were transferred to Shanghai Obstetrical Cardiology Intensive Care Center in a critical condition, with the exception of two patients with severe PAH and one with hypertrophic cardiomyopathy who had declined an
Total cohort With heart (n = 1086) failure (n = 116)
Without heart failure (n = 970)
101 (87.1) 15 (12.9)
903 (93.1) 67 (6.9)
80 (69.0) 36 (31.0)
762 (78.6) 208 (21.4)
106 (91.4) 10 (8.6)
959 (98.9) 11 (1.1)
23 (19.8) 65 (56.0) 28 (24.1) 28 (24.1)
28 (2.9) 150 (15.5) 792 (81.4) 20 (2.1)
6 (5.2)
318 (32.8)
31 (26.7) 27 (23.3) 11 (9.5) 44 (37.9) 1 (0.9)
758 (78.1) 137 (14.1) 46 (4.7) 12 (1.2) 14 (1.4)
1 (0.9)
3 (0.3)
1 (0.9)
0
0 98 (84.5) 116 (100.0) 87 (75.0) 19 (16.4) 4 (3.4)
768 (79.2) 62 (6.4) 112 (11.5) 47 (4.8) 74 (7.6) 42 (4.3)
38 (32.8) 0
121 (12.5) 19 (2.0)
Values are given as number (percentage).
induced abortion (suggested on the basis of a cardiac function evaluation during early pregnancy) and continued with a high-risk pregnancy. A total of 123 neonatal complications were recorded among the 116 patients with HF. The most frequent neonatal complication in this group
Table 2 Maternal deaths among patients with heart disease. Patient
Age, y
Length of pregnancy at delivery, wk a
Primary event
1 2
27 33
35+4 32+3
3 4 5 6 7
20 26 32 24 36
37+3 34+3 23+3 34+3 27+0
8 9 10 11
23 31 24 23
26+6 20+3 30+5 24+3
12
29
30+3
Severe pre-eclampsia with scoliosis Patent ductus arteriosus with severe chest deformity Peripartum cardiomyopathy CHD, PAH, Eisenmenger syndrome Peripartum cardiomyopathy Cyanotic CHD Mixed connective tissue disease accompanied by PAH Ventricular septal defect with severe PAH Arterial septal defect with severe PAH Hypertrophic cardiomyopathy CHD, repair of ventricular septal defect and mitral valve replacement, severe PAH Rheumatic heart disease, mitral valve replacement, severe PAH
Abbreviations: CHD, congenital heart disease; PAH, pulmonary arterial hypertension. a Superscript numbers indicate number of days past previous whole week.
Please cite this article as: Fu Q, Lin J, Risk factors for heart failure during pregnancy among Chinese women with cardiac disease, Int J Gynecol Obstet (2015), http://dx.doi.org/10.1016/j.ijgo.2015.03.040
Q. Fu, J. Lin / International Journal of Gynecology and Obstetrics xxx (2015) xxx–xxx
was premature delivery (Table 3). Both fetal and neonatal mortality were higher among patients with HF than among those without HF (P b 0.001 for both) (Table 3). Morbidity was recorded after premature delivery or neonatal asphyxia for 60 (51.7%) and 16 (13.8%) patients with HF, respectively, compared with 163 (16.8%) and 13 (1.3%) patients without HF (P b 0.001 for both comparisons). Low birth weight for gestational age was also more frequent among patients with HF than among those without HF (P = 0.003) (Table 3). Among the 18 twin pregnancies included in the present study, 8 (44.4%) were complicated by HF. Affected women had cardiopathy induced by pre-eclampsia (4 [50.0%] patients), peripartum cardiomyopathy (2 [25.0%]), CHD (1 [12.5%]), and rheumatic heart disease (1 [12.5%]). The point during pregnancy at which HF developed is shown in Fig. 1. The median point of onset was 34 weeks (interquartile range 28–36). HF developed within 2 days of delivery among the three women who developed this condition after delivery. In the multivariate analysis, left ventricular systolic dysfunction, history of HF before pregnancy, twin pregnancy, sinus tachycardia, NYHA functional class greater than II, and severe PAH were associated with HF (Table 4). Cardiomyopathy was identified as a potential predictor of HF in the univariate analysis (OR 2.08, 95% confidence interval 1.07–4.03; P = 0.030) but was not significantly associated with HF in the multivariate analysis. Among the 57 women with cardiomyopathy, 29 (50.9%) had hypertrophic cardiomyopathy, 23 (40.4%) had peripartum cardiomyopathy, and 5 (8.8%) had dilated cardiomyopathy. Among the 11 women with cardiomyopathy who developed HF, 8 (72.7%) had peripartum cardiomyopathy, 2 (18.2%) had dilated cardiomyopathy, and 1 (9%) had hypertrophic cardiomyopathy.
4. Discussion The present study identified sinus tachycardia, twin pregnancy, and severe PAH as novel independent predictors of HF. The findings also confirmed previously identified independent predictors—reduced left ventricular systolic function (ejection fraction b 40%), history of HF before pregnancy, and NYHA class greater than II [4,5]. Sinus tachycardia is a frequent symptom of HF and so was considered a poor prognostic indicator [8]. Nevertheless, the present study identified this condition as an independent predictive risk factor for HF. This finding could reflect the hemodynamic changes that occur during pregnancy, such as increases in blood volume (50%) and cardiac output (35%), as well as decreases in mean arterial blood pressure and peripheral vascular resistance [9,10]. Cardiac output gradually increases during pregnancy, reaching a peak in the second trimester that is maintained until term [11] because of an increased heart rate during late pregnancy [12]. This increase in heart rate contributes to limitations in ventricular systolic and diastolic function, which in turn lead to reductions in ventricular filling volume and stroke volume. Subsequent activation of components of the neurohumoral axis—such as the renin–angiotensin–aldosterone system, sympathetic nervous system, and non-osmotic vasopressin systems—causes Table 3 Neonatal complications.a,b Complication
Premature delivery Low birth weight for gestational age Fetal death Neonatal asphyxia Neonatal death a b c
Total cohort (n = 1086)
With heart failure (n = 116)
Without heart failure (n = 970)
P value
223 (20.5) 85 (7.8)
60 (51.7) 17 (14.7)
163 (16.8) 68 (7.0)
b0.001 0.003
54 (5.0) 29 (2.7) 8 (0.7)
25 (21.6) 16 (13.8) 5 (4.3)
29 (3.0) 13 (1.3) 3 (0.3)
b0.001 b0.001 b0.001
Values are given as number (percentage) unless indicated otherwise. Some neonates had more than one complication. Comparison between women with and without heart failure.
c
3
Fig. 1. Point of onset of heart failure during pregnancy.
retention of water and sodium, expansion of blood volume, and increased cardiac workload. Increased heart rate also causes increased cardiac workload, elevated myocardial oxygen consumption, and exacerbated ischemic and hypoxic myocardial injury. All these changes are conducive to the development of HF. In the present study, 64 women developed HF at 28–36 weeks of pregnancy, of whom 36 developed this condition at 28–33 weeks. This finding suggests that a gradual increase in maternal cardiac workload precipitated the onset of HF during the third trimester. In line with the present study, an investigation conducted in the Netherlands identified multiple pregnancy as a potential risk factor for cardiovascular morbidity [13]. During the second trimester, a twin pregnancy exerts more substantial effects on maternal cardiac output and peripheral resistance than does a singleton pregnancy [14]. When a twin pregnancy is complicated by cardiac disease, hemodynamic changes represented by lowered cardiac output and raised peripheral vascular resistance could lead to deterioration of cardiac function and subsequent development of HF. There were cases of successful twin pregnancy reduction for patients with heart diseases during the first trimester in the present study at Shanghai Obstetrical Cardiology Intensive Care Center. Assessment of cardiac function and reduction of multifetal pregnancy to relieve cardiac workload when necessary is recommended during the first trimester to prevent the onset of HF. The inability of patients with PAH to tolerate hemodynamic change during pregnancy could explain why this subgroup is at risk of HF and cardiac death. However, PAH was not identified as a predictor of maternal outcome in previous studies [4,15]. This finding could reflect the low prevalence of PAH in high-income countries, as well as the fact that this condition is considered a contraindication for pregnancy [16]. By contrast, Song et al. [17] found that PAH was an independent predictor of cardiac complications in South Korea, which is consistent with the results of the present study. Increased incidence of PAH is possibly linked to poor compliance with doctors’ advice and untimely treatment during pregnancy in China, which poses a huge threat to maternal and neonatal outcome. The cardiovascular risk stratification created by WHO lists PAH
Table 4 Multivariate analysis of predictors of heart failure during pregnancy. Variable
Odds ratio (95% confidence interval)
P value
Left ventricular systolic dysfunctiona History of heart failure before pregnancy Twin pregnancy Sinus tachycardia New York Heart Association functional class N II Severe pulmonary arterial hypertensionb
13.16 (3.62–47.80) 11.66 (5.83–23.33) 11.63 (4.10–32.99) 4.60 (2.77–7.62) 3.36 (1.11–10.25)
b0.001 b0.001 b0.001 b0.001 0.033
a b
1.40 (1.10–1.78)
0.007
Ejection fraction b40%. Systolic pressure ≥80 mm Hg.
Please cite this article as: Fu Q, Lin J, Risk factors for heart failure during pregnancy among Chinese women with cardiac disease, Int J Gynecol Obstet (2015), http://dx.doi.org/10.1016/j.ijgo.2015.03.040
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as a contraindication for pregnancy [18], suggesting that women with cardiac diseases complicated by severe PAH should be advised to avoid pregnancy. The present study did not identify cardiomyopathy as a predictor of HF. However, Chung et al. [19] previously reported that peripartum cardiomyopathy was the main cause of non-obstetric mortality during pregnancy. In another study [20], there were 18 (29.5%) relapses of HF during pregnancy among 61 women who had peripartum cardiomyopathy in a previous pregnancy. Relapse of HF occurred among 12 (46.2%) of the 26 pregnancies in which left ventricular ejection fraction was less than 55% before pregnancy versus 6 (17.1%) of the 35 pregnancies in which the pre-pregnancy left ventricular ejection fraction was 55% or higher [20]. That study demonstrated that patients with peripartum cardiomyopathy are at increased risk of HF relapse even when their cardiac function has been fully restored and the heart returned to its usual size [20]. Patients with peripartum cardiomyopathy who have experienced HF but not regained their original cardiac function are therefore advised to avoid another pregnancy. In the present study, neonatal complications had a higher prevalence among patients with HF than those without HF. Bhatla et al. [21] showed that there were more fetal complications, as well as more preterm and low-birth-weight neonates, among patients in NYHA class III/IV than among those in NYHA class I/II. The incidence of premature delivery was elevated among patients with HF in the present study. Most instances of premature delivery were iatrogenic and reflected a deterioration in the NYHA functional class among patients with HF. The high incidence of fetal death and neonatal asphyxia among patients with HF indicated untimely prenatal examinations of the patients and a medical situation not in line with international levels over the past 20 years, but medical advances have made it possible to decrease neonatal morbidity and perinatal mortality in recent decades. Several limitations of the present study should be considered. First, although the participants were drawn from Shanghai and Eastern China, the clinical data were limited to one center. Second, owing to the retrospective design, some potentially useful data were unavailable (e.g. socioeconomic level and education). Finally, the relationship between HF and alcohol consumption and/or tobacco smoking could not be analyzed because Chinese women tend to avoid such behaviors during pregnancy. In conclusion, the present study identified novel predictors of HF onset during pregnancy in China. On the basis of these predictors, women with cardiac disease should undergo evaluation of their disease subtype and cardiac function before becoming pregnant to determine whether or not pregnancy is safe. Should patients decide to proceed with the pregnancy, regular monitoring of risk factors is indicated to reduce maternal and neonatal complications.
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Conflict of interest The authors have no conflicts of interest.
Please cite this article as: Fu Q, Lin J, Risk factors for heart failure during pregnancy among Chinese women with cardiac disease, Int J Gynecol Obstet (2015), http://dx.doi.org/10.1016/j.ijgo.2015.03.040
Contents lists available at ScienceDirect
International Journal of Gynecology and Obstetrics journal homepage: www.elsevier.com/locate/ijgo
CLINICAL ARTICLE
Risk factors for heart failure during pregnancy among Chinese women with cardiac disease Qin Fu a,b, Jianhua Lin a,b,⁎ a b
Department of Obstetrics and Gynecology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China Shanghai Obstetrical Cardiology Intensive Care Center, Shanghai, China
a r t i c l e
i n f o
Article history: Received 23 October 2014 Received in revised form 15 March 2015 Accepted 18 May 2015 Keywords: Cardiac disease Heart failure Pregnancy Risk factor
a b s t r a c t Objective: To identify risk factors for heart failure (HF) during pregnancy among women with pre-existing cardiac disease. Methods: A retrospective review was conducted of pregnant women with cardiac disease who attended Shanghai Obstetrical Cardiology Intensive Care Center, China, for delivery between January 1, 1993, and December 31, 2013. Independent predictors of HF were identified by logistic regression analysis. Results: Among 1086 pregnant women with cardiac disease, 116 (10.7%) developed HF. In multivariate analysis, HF was associated with left ventricular systolic dysfunction (odds ratio [OR] 13.16, 95% confidence interval [CI] 3.62–47.80; P b 0.001), history of HF before pregnancy (OR 11.66, 95% CI 5.83–23.33; P b 0.001), twin pregnancy (OR 11.63, 95% CI 4.10–32.99; P b 0.001), sinus tachycardia (OR 4.60, 95% CI 2.77–7.62; P b 0.001), New York Heart Association functional class higher than II (OR 3.36, 95% CI 1.11–10.25; P = 0.033), and severe pulmonary arterial hypertension (OR 1.40, 95% CI 1.10–1.78; P = 0.007). Conclusion: Women with cardiac disease who wish to become pregnant should be guided by risk factors for HF. Those who do conceive should be closely monitored during pregnancy to improve outcomes and reduce maternal mortality and morbidity. © 2015 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved.
1. Introduction
2. Materials and methods
Cardiac disease is one of the leading causes of non-obstetric maternal mortality in China [1]. Heart failure (HF) is a complex clinical syndrome that can present as a severe complication among pregnant women with cardiac disease. The underlying cause of HF is structural or functional impairment of ventricular filling or ejection. Symptoms include shortness of breath, fatigue, and fluid retention [2,3]. Heart compensation mechanisms during pregnancy do not generally cause issues for healthy women, but women with cardiac disease can develop HF during pregnancy due to the hemodynamic changes. One study [4] identified independent predictive risk factors for cardiac complications (including HF) as a baseline New York Heart Association (NYHA) functional class greater than II, cyanosis, reduced left ventricular systolic function, left heart outflow tract obstruction, and a cardiac event before pregnancy. Another study [5] identified cardiomyopathy, a NYHA functional class of at least III, WHO category of at least 3, signs of HF before pregnancy, and pulmonary arterial hypertension (PAH) as predictors of HF. The aim of the present study was to identify risk factors for HF during pregnancy among Chinese women with pre-existing cardiac disease.
A retrospective analysis was conducted of pregnant women who delivered at Shanghai Obstetrical Cardiology Intensive Care Center, Shanghai, China, between January 1, 1993, and December 31, 2013. All pregnant women with cardiac disease were eligible for inclusion in the present analysis. Cardiac conditions included congenital heart disease (CHD), rheumatic heart disease, cardiomyopathy, cardiopathy induced by severe pre-eclampsia, cardiac disease associated with systemic lupus erythematosus, cardiac disease associated with hyperthyroidism, and mixed connective tissue disease accompanied by PAH. Cardiopathy induced by severe pre-eclampsia is a pregnancy-specific condition that is associated with the acute onset of HF with left ventricular dysfunction among previously healthy women. A diagnosis of severe preeclampsia was made when the systolic blood pressure was at least 160 mm Hg, the diastolic blood pressure was at least 110 mm Hg, proteinuria (≥2 g/24 hours) was noted, or there was end-organ dysfunction [6]. Women within the first 20 weeks of pregnancy were excluded from the analysis, as were those who voluntarily underwent induced abortion. Owing to the retrospective design, neither ethical approval nor informed consent was required. Shanghai Obstetrical Cardiology Intensive Care Center was opened in 1993 with the approval of the Shanghai Health Bureau. Based at Renji Hospital (affiliated with Shanghai Jiao Tong University School of Medicine), this center serves pregnant women with cardiac disease. Most patients are from Shanghai and Eastern China.
⁎ Corresponding author at: Department of Obstetrics and Gynecology, Renji Hospital, School of Medicine of Shanghai Jiaotong University, No.1630, Dongfang Road, Shanghai, 200127, China. Tel.: +86 13816109700; fax: +86 2168383073. E-mail address: [email protected] (J. Lin).
http://dx.doi.org/10.1016/j.ijgo.2015.03.040 0020-7292/© 2015 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved.
Please cite this article as: Fu Q, Lin J, Risk factors for heart failure during pregnancy among Chinese women with cardiac disease, Int J Gynecol Obstet (2015), http://dx.doi.org/10.1016/j.ijgo.2015.03.040
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Q. Fu, J. Lin / International Journal of Gynecology and Obstetrics xxx (2015) xxx–xxx
Information for the present analysis was obtained through review of the institutional database, into which data had been entered on discharge of each patient. Baseline data had been collected before pregnancy or at the first prenatal visit. Subsequent data collection occurred during follow-up until delivery. Baseline data included age, parity, weeks of pregnancy, previous cardiac events (i.e. HF or sustained symptomatic arrhythmia before pregnancy), type of cardiac disease, NYHA functional classification [7], previous cardiac surgery, cardiac medications, results of physical examinations, oxygen saturation level of the blood, and results from standard electrocardiography, dynamic (Holter) electrocardiography, and echocardiography. Neonatal events were classified as premature delivery (b37 weeks), low weight for gestational age (b 10th percentile), neonatal asphyxia (5-minute Apgar score b 7), fetal death (≥ 20 weeks), or neonatal death (within 28 days of delivery). The data were analyzed using SPSS version 17.0 (SPSS Inc, Chicago, IL, USA). Baseline data are expressed as means with standard deviations; categorical data are expressed as percentages. Comparison of enumeration data was performed using the χ2 test. Independent predictors of HF were analyzed in a logistic regression model. Univariate predictors were history of HF before pregnancy, NYHA functional class greater than II, any form of sustained symptomatic tachyarrhythmia or bradyarrhythmia requiring treatment, uncorrected shunt (atrial septal defect, ventricular septal defect, or patent ductus arteriosus), corrected or uncorrected cyanotic heart disease, moderate-to-severe pulmonary stenosis, moderate-to-severe pulmonary regurgitation, moderate-to-severe aortic stenosis, moderate-to-severe aortic insufficiency, moderate-to-severe mitral stenosis, moderate-to-severe mitral insufficiency, moderate-to-severe tricuspid insufficiency, oxygen saturation levels less than 90%, PAH (systolic pressure N50 mm Hg [moderate] or N80 mm Hg [severe]), cardiomyopathy (hypertrophic, dilated, or peripartum), mechanical valve replacement, and twin pregnancy. Potential risk factors identified in the univariate analysis were then tested in a multivariate logistic regression model. For both models, an odds ratio (OR) greater than 1.00 was indicative of a risk factor for HF. P b 0.05 was considered statistically significant.
Table 1 Baseline characteristics of the study population.a Characteristic
Age, y 18–35 1004 (92.4) b18 or N35 82 (7.6) Parity Primipara 842 (77.5) Multipara 244 (22.5) New York Heart Association functional class I–II 1065 (98.1) III 21 (1.9) Length of pregnancy at delivery, wk 20–27 51 (4.7) 28–36 215 (19.8) ≥37 820 (75.5) History of heart failure before 48 (4.4) pregnancy Previous surgical interventions 324 (29.8) Type of heart disease Congenital heart disease 789 (72.7) Rheumatic heart disease 164 (15.1) Cardiomyopathy 57 (5.2) Cardiopathy induced by pre-eclampsia 56 (5.2) Cardiac disease associated with 15 (1.4) hyperthyroidism Cardiopathy induced by systemic 4 (0.4) lupus erythematosus 1 (0.1) Mixed connective tissue disease accompanied by pulmonary arterial hypertension Cardiac medication None 768 (70.7) Digoxin 160 (14.7) Diuretic 228 (21.0) Vasodilation 134 (12.3) Antiarrhythmic 93 (8.6) Anticoagulant 46 (4.2) Comorbidities Anemia 159 (14.6) Diabetes mellitus, hypertension, 19 (1.7) or nephritis a
3. Results Overall, 1086 pregnant women with cardiac disease were identified. The main types of cardiac disease were CHD, rheumatic heart disease, cardiomyopathy, and cardiopathy induced by pre-eclampsia (Table 1). Cardiac surgery had been performed before pregnancy among 324 (29.8%) of the 1086 patients; 8 (0.7%) had undergone two operations on two different occasions and 11 (1.0%) had undergone two operations on one occasion. Surgical interventions included closure of shunts repair (204 [18.8%] patients), mitral valve replacement (40 [3.7%]) or repair (19 [1.7%]), tricuspid valve replacement (1 [0.1%]) or repair (6 [0.6%]), combined valve replacement (5 [0.5%]), relief of pulmonary stenosis (10 [0.9%]), provision of a pacemaker (3 [0.3%]), aortic balloon dilation (1 [0.1%]), aortic valve replacement (8 [0.7%]), radical correction of tetralogy of Fallot (35 [3.2%]), relief for right ventricular outflow tract obstruction (1 [0.1%]), excision of left atrial myxoma (1 [0.1%]), and correction of large blood vessel anomaly (1 [0.1%]). The operative procedures were not detailed in the medical record for 8 [0.7%] patients. In all, 318 (29.3%) patients received more than one cardiac medication (Table 1). Among the 1086 women, 116 (10.7%) developed HF. The mean age of these 116 women was 28.00 ± 4.69 years (range 16–44). Most of the women with HF were primiparas and had a NYHA functional class of I–II (Table 1). Despite active treatment, maternal deaths from HF were recorded among 12 patients (Table 2); six of these women had CHD. Patients were transferred to Shanghai Obstetrical Cardiology Intensive Care Center in a critical condition, with the exception of two patients with severe PAH and one with hypertrophic cardiomyopathy who had declined an
Total cohort With heart (n = 1086) failure (n = 116)
Without heart failure (n = 970)
101 (87.1) 15 (12.9)
903 (93.1) 67 (6.9)
80 (69.0) 36 (31.0)
762 (78.6) 208 (21.4)
106 (91.4) 10 (8.6)
959 (98.9) 11 (1.1)
23 (19.8) 65 (56.0) 28 (24.1) 28 (24.1)
28 (2.9) 150 (15.5) 792 (81.4) 20 (2.1)
6 (5.2)
318 (32.8)
31 (26.7) 27 (23.3) 11 (9.5) 44 (37.9) 1 (0.9)
758 (78.1) 137 (14.1) 46 (4.7) 12 (1.2) 14 (1.4)
1 (0.9)
3 (0.3)
1 (0.9)
0
0 98 (84.5) 116 (100.0) 87 (75.0) 19 (16.4) 4 (3.4)
768 (79.2) 62 (6.4) 112 (11.5) 47 (4.8) 74 (7.6) 42 (4.3)
38 (32.8) 0
121 (12.5) 19 (2.0)
Values are given as number (percentage).
induced abortion (suggested on the basis of a cardiac function evaluation during early pregnancy) and continued with a high-risk pregnancy. A total of 123 neonatal complications were recorded among the 116 patients with HF. The most frequent neonatal complication in this group
Table 2 Maternal deaths among patients with heart disease. Patient
Age, y
Length of pregnancy at delivery, wk a
Primary event
1 2
27 33
35+4 32+3
3 4 5 6 7
20 26 32 24 36
37+3 34+3 23+3 34+3 27+0
8 9 10 11
23 31 24 23
26+6 20+3 30+5 24+3
12
29
30+3
Severe pre-eclampsia with scoliosis Patent ductus arteriosus with severe chest deformity Peripartum cardiomyopathy CHD, PAH, Eisenmenger syndrome Peripartum cardiomyopathy Cyanotic CHD Mixed connective tissue disease accompanied by PAH Ventricular septal defect with severe PAH Arterial septal defect with severe PAH Hypertrophic cardiomyopathy CHD, repair of ventricular septal defect and mitral valve replacement, severe PAH Rheumatic heart disease, mitral valve replacement, severe PAH
Abbreviations: CHD, congenital heart disease; PAH, pulmonary arterial hypertension. a Superscript numbers indicate number of days past previous whole week.
Please cite this article as: Fu Q, Lin J, Risk factors for heart failure during pregnancy among Chinese women with cardiac disease, Int J Gynecol Obstet (2015), http://dx.doi.org/10.1016/j.ijgo.2015.03.040
Q. Fu, J. Lin / International Journal of Gynecology and Obstetrics xxx (2015) xxx–xxx
was premature delivery (Table 3). Both fetal and neonatal mortality were higher among patients with HF than among those without HF (P b 0.001 for both) (Table 3). Morbidity was recorded after premature delivery or neonatal asphyxia for 60 (51.7%) and 16 (13.8%) patients with HF, respectively, compared with 163 (16.8%) and 13 (1.3%) patients without HF (P b 0.001 for both comparisons). Low birth weight for gestational age was also more frequent among patients with HF than among those without HF (P = 0.003) (Table 3). Among the 18 twin pregnancies included in the present study, 8 (44.4%) were complicated by HF. Affected women had cardiopathy induced by pre-eclampsia (4 [50.0%] patients), peripartum cardiomyopathy (2 [25.0%]), CHD (1 [12.5%]), and rheumatic heart disease (1 [12.5%]). The point during pregnancy at which HF developed is shown in Fig. 1. The median point of onset was 34 weeks (interquartile range 28–36). HF developed within 2 days of delivery among the three women who developed this condition after delivery. In the multivariate analysis, left ventricular systolic dysfunction, history of HF before pregnancy, twin pregnancy, sinus tachycardia, NYHA functional class greater than II, and severe PAH were associated with HF (Table 4). Cardiomyopathy was identified as a potential predictor of HF in the univariate analysis (OR 2.08, 95% confidence interval 1.07–4.03; P = 0.030) but was not significantly associated with HF in the multivariate analysis. Among the 57 women with cardiomyopathy, 29 (50.9%) had hypertrophic cardiomyopathy, 23 (40.4%) had peripartum cardiomyopathy, and 5 (8.8%) had dilated cardiomyopathy. Among the 11 women with cardiomyopathy who developed HF, 8 (72.7%) had peripartum cardiomyopathy, 2 (18.2%) had dilated cardiomyopathy, and 1 (9%) had hypertrophic cardiomyopathy.
4. Discussion The present study identified sinus tachycardia, twin pregnancy, and severe PAH as novel independent predictors of HF. The findings also confirmed previously identified independent predictors—reduced left ventricular systolic function (ejection fraction b 40%), history of HF before pregnancy, and NYHA class greater than II [4,5]. Sinus tachycardia is a frequent symptom of HF and so was considered a poor prognostic indicator [8]. Nevertheless, the present study identified this condition as an independent predictive risk factor for HF. This finding could reflect the hemodynamic changes that occur during pregnancy, such as increases in blood volume (50%) and cardiac output (35%), as well as decreases in mean arterial blood pressure and peripheral vascular resistance [9,10]. Cardiac output gradually increases during pregnancy, reaching a peak in the second trimester that is maintained until term [11] because of an increased heart rate during late pregnancy [12]. This increase in heart rate contributes to limitations in ventricular systolic and diastolic function, which in turn lead to reductions in ventricular filling volume and stroke volume. Subsequent activation of components of the neurohumoral axis—such as the renin–angiotensin–aldosterone system, sympathetic nervous system, and non-osmotic vasopressin systems—causes Table 3 Neonatal complications.a,b Complication
Premature delivery Low birth weight for gestational age Fetal death Neonatal asphyxia Neonatal death a b c
Total cohort (n = 1086)
With heart failure (n = 116)
Without heart failure (n = 970)
P value
223 (20.5) 85 (7.8)
60 (51.7) 17 (14.7)
163 (16.8) 68 (7.0)
b0.001 0.003
54 (5.0) 29 (2.7) 8 (0.7)
25 (21.6) 16 (13.8) 5 (4.3)
29 (3.0) 13 (1.3) 3 (0.3)
b0.001 b0.001 b0.001
Values are given as number (percentage) unless indicated otherwise. Some neonates had more than one complication. Comparison between women with and without heart failure.
c
3
Fig. 1. Point of onset of heart failure during pregnancy.
retention of water and sodium, expansion of blood volume, and increased cardiac workload. Increased heart rate also causes increased cardiac workload, elevated myocardial oxygen consumption, and exacerbated ischemic and hypoxic myocardial injury. All these changes are conducive to the development of HF. In the present study, 64 women developed HF at 28–36 weeks of pregnancy, of whom 36 developed this condition at 28–33 weeks. This finding suggests that a gradual increase in maternal cardiac workload precipitated the onset of HF during the third trimester. In line with the present study, an investigation conducted in the Netherlands identified multiple pregnancy as a potential risk factor for cardiovascular morbidity [13]. During the second trimester, a twin pregnancy exerts more substantial effects on maternal cardiac output and peripheral resistance than does a singleton pregnancy [14]. When a twin pregnancy is complicated by cardiac disease, hemodynamic changes represented by lowered cardiac output and raised peripheral vascular resistance could lead to deterioration of cardiac function and subsequent development of HF. There were cases of successful twin pregnancy reduction for patients with heart diseases during the first trimester in the present study at Shanghai Obstetrical Cardiology Intensive Care Center. Assessment of cardiac function and reduction of multifetal pregnancy to relieve cardiac workload when necessary is recommended during the first trimester to prevent the onset of HF. The inability of patients with PAH to tolerate hemodynamic change during pregnancy could explain why this subgroup is at risk of HF and cardiac death. However, PAH was not identified as a predictor of maternal outcome in previous studies [4,15]. This finding could reflect the low prevalence of PAH in high-income countries, as well as the fact that this condition is considered a contraindication for pregnancy [16]. By contrast, Song et al. [17] found that PAH was an independent predictor of cardiac complications in South Korea, which is consistent with the results of the present study. Increased incidence of PAH is possibly linked to poor compliance with doctors’ advice and untimely treatment during pregnancy in China, which poses a huge threat to maternal and neonatal outcome. The cardiovascular risk stratification created by WHO lists PAH
Table 4 Multivariate analysis of predictors of heart failure during pregnancy. Variable
Odds ratio (95% confidence interval)
P value
Left ventricular systolic dysfunctiona History of heart failure before pregnancy Twin pregnancy Sinus tachycardia New York Heart Association functional class N II Severe pulmonary arterial hypertensionb
13.16 (3.62–47.80) 11.66 (5.83–23.33) 11.63 (4.10–32.99) 4.60 (2.77–7.62) 3.36 (1.11–10.25)
b0.001 b0.001 b0.001 b0.001 0.033
a b
1.40 (1.10–1.78)
0.007
Ejection fraction b40%. Systolic pressure ≥80 mm Hg.
Please cite this article as: Fu Q, Lin J, Risk factors for heart failure during pregnancy among Chinese women with cardiac disease, Int J Gynecol Obstet (2015), http://dx.doi.org/10.1016/j.ijgo.2015.03.040
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Q. Fu, J. Lin / International Journal of Gynecology and Obstetrics xxx (2015) xxx–xxx
as a contraindication for pregnancy [18], suggesting that women with cardiac diseases complicated by severe PAH should be advised to avoid pregnancy. The present study did not identify cardiomyopathy as a predictor of HF. However, Chung et al. [19] previously reported that peripartum cardiomyopathy was the main cause of non-obstetric mortality during pregnancy. In another study [20], there were 18 (29.5%) relapses of HF during pregnancy among 61 women who had peripartum cardiomyopathy in a previous pregnancy. Relapse of HF occurred among 12 (46.2%) of the 26 pregnancies in which left ventricular ejection fraction was less than 55% before pregnancy versus 6 (17.1%) of the 35 pregnancies in which the pre-pregnancy left ventricular ejection fraction was 55% or higher [20]. That study demonstrated that patients with peripartum cardiomyopathy are at increased risk of HF relapse even when their cardiac function has been fully restored and the heart returned to its usual size [20]. Patients with peripartum cardiomyopathy who have experienced HF but not regained their original cardiac function are therefore advised to avoid another pregnancy. In the present study, neonatal complications had a higher prevalence among patients with HF than those without HF. Bhatla et al. [21] showed that there were more fetal complications, as well as more preterm and low-birth-weight neonates, among patients in NYHA class III/IV than among those in NYHA class I/II. The incidence of premature delivery was elevated among patients with HF in the present study. Most instances of premature delivery were iatrogenic and reflected a deterioration in the NYHA functional class among patients with HF. The high incidence of fetal death and neonatal asphyxia among patients with HF indicated untimely prenatal examinations of the patients and a medical situation not in line with international levels over the past 20 years, but medical advances have made it possible to decrease neonatal morbidity and perinatal mortality in recent decades. Several limitations of the present study should be considered. First, although the participants were drawn from Shanghai and Eastern China, the clinical data were limited to one center. Second, owing to the retrospective design, some potentially useful data were unavailable (e.g. socioeconomic level and education). Finally, the relationship between HF and alcohol consumption and/or tobacco smoking could not be analyzed because Chinese women tend to avoid such behaviors during pregnancy. In conclusion, the present study identified novel predictors of HF onset during pregnancy in China. On the basis of these predictors, women with cardiac disease should undergo evaluation of their disease subtype and cardiac function before becoming pregnant to determine whether or not pregnancy is safe. Should patients decide to proceed with the pregnancy, regular monitoring of risk factors is indicated to reduce maternal and neonatal complications.
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Conflict of interest The authors have no conflicts of interest.
Please cite this article as: Fu Q, Lin J, Risk factors for heart failure during pregnancy among Chinese women with cardiac disease, Int J Gynecol Obstet (2015), http://dx.doi.org/10.1016/j.ijgo.2015.03.040
