Short abstract
Background
Plasma brain natriuretic peptide levels were prospectively studied in pregnant women with heart disease.
Methods
Fifty pregnant women with heart disease and 25 controls were evaluated at 24 weeks or under, 30–32 weeks, 34 weeks or more of gestation, and 6 weeks postpartum. Adverse maternal cardiac events were hospitalization for worsening heart failure, stroke, and death.
Results
Thirty-eight (76%) women had rheumatic heart disease. Plasma brain natriuretic peptide levels were (in cases and controls) 118.3 ± 46.5 pg/ml and 66.3 ± 15.9 pg/ml (at 24 weeks or under), 124.8 ± 30.4 pg/ml and 68.4 ± 16.5 pg/ml (30–32 weeks), 135.8 ± 34.9 pg/ml and 68.6 ± 15.6 pg/ml (34 weeks or more), and 110.1 ± 21.9 pg/ml and 65.0 ± 16.1 pg/ml (6 weeks postpartum) (p = .0001). Eighteen women had adverse events. Of these, only 1 had a level less than 100 pg/ml, 12 were between 100 and 200 pg/ml, and 5 more than 200 pg/ml.
Conclusions
Plasma brain natriuretic peptide levels were higher in women with heart disease at all periods of gestation as well as six weeks postpartum. No woman with a plasma brain natriuretic peptide levels of 98 pg/ml or less had an adverse event.
Keywords: Brain natriuretic peptide, pregnancy, heart disease
Introduction
Maternal heart disease complicates around 2–4% of pregnancies and is one of the major causes of maternal deaths.1,2 The hemodynamic stress of pregnancy predisposes women to various complications including heart failure, pulmonary edema, arrhythmias, and even fetal and maternal death. It is important to risk stratify pregnant women with heart disease and identify those at high risk for complications.3–5 Current parameters for risk stratification, for example, the New York Heart Association (NYHA) class, clinical features and echocardiography, various risk scores like CARPREG I and II, ZAHARA, and the modified World Health Organization classification, though useful, have their limitations.5–8 For example, some patients with severe mitral stenosis deteriorate and develop refractory heart failure, while others tolerate their pregnancy reasonably well. This is because these parameters do not evaluate the adequacy of maternal cardiac adaptation during pregnancy. Biomarkers like plasma brain natriuretic peptide (BNP) may improve the predictive ability if added to those prediction tools.
BNP is a biomarker of heart failure and predictor of mortality in patients with underlying heart disease.9 During uncomplicated pregnancy plasma BNP levels remain unchanged.10 In pregnant women with either rheumatic or congenital heart disease, it is expected that the plasma BNP would increase in relation to the degree of cardiac dysfunction. However, only a few studies have examined the utility of biomarkers in assessing the adaptation of the heart to the hemodynamic load of pregnancy.10–15 Rheumatic heart disease is the commonest cardiac disorder in pregnant women in India.1,16,17 Data on the usefulness of plasma BNP during pregnancy are especially sparse in women with rheumatic heart disease. The purpose of this prospective study was to evaluate the changes in plasma BNP in pregnant women with heart disease and determine whether plasma BNP predicts the outcome of these women.
Materials and methods
This prospective study was conducted in the Postgraduate Institute of Medical Education and Research, Chandigarh, a large tertiary care hospital. The study was approved by the Institute Ethics Committee, and written informed consent was taken from all patients and controls. Fifty pregnant women with heart disease registered in the cardio-obstetric clinic between the ages of 20 to 35 years were recruited. Only women with echocardiographically-proven heart disease were registered in the clinic. All patients were managed by a multidisciplinary team including both obstetricians and cardiologists. Women with valvular heart disease, congenital heart disease, left ventricular systolic dysfunction, or pulmonary hypertension were included in the study. The recruitment was not in a sequential manner. Echocardiography was used to confirm the underlying cardiac disease in all cases. Twenty-five healthy normotensive pregnant women attending the general obstetric outpatient clinic were taken as controls for determining baseline values in the healthy Indian pregnant population. All controls had normal echocardiographic examination at time of recruitment. Patients with renal disease and serum creatinine greater than 1.5 mg/dL, preeclampsia or eclampsia, underlying lung disease, twin pregnancy, and severe anemia were excluded.
Plasma BNP measurement, NYHA class categorization, clinical evaluation, and echocardiography were serially carried out during the antenatal and postpartum period in all women at 24 weeks or under, 30–32 weeks, 34 weeks or more of gestation, and 6 weeks postpartum. Approximately 3–4 ml of blood was collected in plain vials. The serum samples were preserved at −80°C. BNP levels were measured using ELISA kit (Ray BioHuman BNP Enzyme Immunoassay Kit). Patients were divided into three groups based on plasma BNP levels. First were those with normal plasma BNP levels of less than 100 pg/ml. The second group had mildly raised levels of 100–200 pg/ml, and the third group had levels of over 200 pg/ml.
Echocardiographic parameters including left ventricular size, wall thickness, and left ventricular ejection fraction were recorded. Valves were assessed for any stenosis or regurgitation which was quantified. Pulmonary artery pressures were measured using tricuspid regurgitation jet velocity. Any congenital heart disease was documented, and right and left ventricular outflow tract obstruction was measured.
Adverse maternal cardiac events were defined as hospitalization for worsening heart failure, stroke, and death. Cardiac events were ascertained by evaluation of clinical status by a multidisciplinary team including a cardiologist. Other reasons for hospitalization like preterm labor, intrauterine growth restriction, and switching over of anticoagulation from warfarin to heparin and vice versa in women with prosthetic valves were not considered adverse events.
Differences in clinical and echocardiographic variables between patients with high and normal BNP levels or adverse maternal cardiac events were determined with χ2, Fisher exact, or Student’s t test (paired t test and independent t test) as appropriate. A posteriori, the study had a power of over 95% to detect a difference in the detected plasma BNP levels between the two groups. A receiver operating characteristic (ROC) curve was drawn to estimate the sensitivity, specificity, and the cutoff values of BNP for predicting the presence of heart disease at different gestations and in the postpartum period.
Results
The mean age of women with heart disease was 26.3 ± 3.1 (range: 20–32) years while that of controls was 26.2 ± 3.2 (range: 20–34) years (Table 1). Of the 50 women with heart disease, 38 (76%) had rheumatic heart disease, 8 (16%) had congenital heart disease, 3 (6%) had dilated cardiomyopathy while 1 (2%) had primary pulmonary hypertension (Table 1). Mitral valve involvement was the most common in the rheumatic heart disease women with 19 having mitral stenosis and 12 having mitral regurgitation. Most of the women were in NYHA class I and II at baseline (Figure 1). Thirty-three women were taking some cardiac medication at enrollment. All were taking diuretics. Other drugs included anticoagulants, beta blockers, and digoxin.
Table 1.
Baseline demographic and clinical profile of 50 women with cardiac diseases and 25 controls.
| Baseline variables | Women with cardiac diseases | Healthy pregnant controls |
|---|---|---|
| Age (years) | 26.4 ± 3.1 | 26.2 ± 3.2 |
| Body weight (kg) | 52.2 ± 6.3 | 52.2 ± 7.2 |
| Period of gestation at recruitment | 17.5 ± 5.2 | 13.2 ± 5.4 |
| Nulligravida | 13 (26%) | 18 (36%) |
| Cardiac medications | 33 (66%) | 0 |
| Rheumatic heart disease | 38 | 0 |
| Severe mitral stenosis | 11 (22%) | 0 |
| Moderate mitral stenosis | 8 (16%) | 0 |
| Post-valve replacement | 3 (6%) | 0 |
| Severe mitral regurgitation | 5 (10%) | 0 |
| Moderate mitral regurgitation | 7 (14%) | 0 |
| Aortic stenosis | 2 (4%) | 0 |
| Aortic regurgitation | 2 (4%) | 0 |
| Congenital heart disease | 8 | 0 |
| Eisenmenger syndrome | 1 (2%) | 0 |
| Tetralogy of Fallot | 1 (2%) | 0 |
| Coarctation of aorta (corrected) | 1 (2%) | 0 |
| Ventricular septal defect | 1 (2%) | 0 |
| Atrial septal defect | 1 (2%) | 0 |
| Ebstein’s anomaly | 1 (2%) | 0 |
| Patent ductus arteriosus (closed) | 1 (2%) | 0 |
| Severe pulmonary stenosis | 1 (2%) | 0 |
| Others | 4 | 0 |
| Dilated cardiomyopathy | 3 (6%) | 0 |
| Primary pulmonary hypertension | 1 (2%) | 0 |
Figure 1.
NYHA class of patients with cardiac disease at different stages of pregnancy. NYHA: New York Heart Association.
Plasma BNP was significantly higher in women with cardiac diseases compared to controls at all time points (Table 2). This indicates that women with cardiac diseases had higher plasma BNP levels even in early pregnancy, and the levels remained elevated at six weeks postpartum. Mean BNP levels were elevated in valvular and congenital heart disease as well as in patients with dilated cardiomyopathy (Table 3).
Table 2.
Plasma BNP levels at different periods of gestation and postpartum.
| BNP | Mean ± SD BNP levels (pg/ml) of women with cardiac disease | Mean ± SD BNP levels (pg/ml) of controls | p value |
|---|---|---|---|
| ≤24 weeks | 118.3 ± 46.5 | 66.3 ± 15.9 | .0001 |
| 30–32 weeks | 124.8 ± 30.4 | 68.4 ± 16.5 | .0001 |
| ≥34 weeks | 135.8 ± 34.9 | 68.6 ± 15.6 | .0001 |
| 6 weeks postpartum | 110.1 ± 21.9 | 64.9 ± 16.1 | .0001 |
BNP: brain natriuretic peptide; SD: standard deviation.
Table 3.
Mean BNP levels estimated in different categories of heart diseases at different gestations.
| Cardiac disease | Mean plasma BNP levels (pg/ml) |
|||||
|---|---|---|---|---|---|---|
| ≤24 weeks | 30–32 weeks | ≥34 weeks | 6 weeks postpartum | Minimum | Maximum | |
| Valvular heart disease | 129.8 | 138.8 | 149.8 | 111.9 | 88.4 | 381.7 |
| Congenital heart disease | 118.5 | 124.3 | 135.0 | 110.4 | 78.9 | 272.6 |
| Others | 90.3 | 104.3 | 114.9 | 101.8 | 82.4 | 143.7 |
BNP: brain natriuretic peptide.
To estimate the sensitivity and specificity of plasma BNP for predicting presence of heart disease during pregnancy, a ROC curve was drawn between plasma BNP of all the 50 women with known cardiac diseases and 25 controls at different periods of gestation and at six weeks postpartum (Table 4). The results from the ROC curve showed that BNP levels have different sensitivity and specificity and cutoff values at different periods of gestation and at six weeks postpartum. Maximum specificity was in third trimester. The maximum cutoff value for presence of heart disease was 87.6–97.2 pg/ml at different periods of gestation and six weeks postpartum (Table 4).
Table 4.
ROC curve for the ability of BNP levels to identify cardiac disease, in the cohort of 50 women with cardiac disease and 25 controls at different periods of gestation and six weeks postpartum.
| Variables of ROC curve | BNP levels pg/ml |
|||
|---|---|---|---|---|
| ≤24 weeks | 30–32 weeks | ≥ 34 weeks | 6 weeks pp | |
| Sensitivity (%) | 85.2 | 92.3 | 88.5 | 78.6 |
| Specificity | 95.8 | 97.9 | 95.7 | 93.0 |
| Cutoff value (pg/ml) | 89.3 | 96.7 | 97.2 | 87.6 |
| Area under curve | 0.977 | 0.992 | 0.988 | 0.966 |
BNP: brain natriuretic peptide; ROC: receiver operating characteristic.
Of the 50 women with known cardiac diseases, 32 (64%) underwent an uncomplicated antenatal period with outpatient follow-up. Their delivery and postpartum period remained uneventful, and they were discharged stable with a minimal hospital stay. Eighteen (32%) women with known cardiac diseases were hospitalized for worsening heart failure. Of these, 2 developed cardiac decompensation at less than 24 weeks of gestation, 1 at 30–32 weeks, and 15 after 34 weeks of gestation. Two of these 18 patients died. No woman included in the study had a stroke. Of the 50 cases, 31 (62%) underwent normal vaginal delivery while 17 (34%) underwent caesarean section, of which 16 were for obstetric indications. One woman with primary pulmonary hypertension underwent caesarean section as her condition was deteriorating. There were two (4%) medical terminations of pregnancy. Of these, one woman with severe mitral stenosis (mitral valve area 0.6 cm2) underwent a medical termination of pregnancy in the first trimester due to heart failure and pulmonary edema. The second medical termination of pregnancy was carried out in a severely symptomatic woman with primary pulmonary hypertension.
All the 25 controls had an uncomplicated antenatal course with minimal hospital stay. Among controls, 21 (84%) underwent full-term normal vaginal delivery and 4 (16%) underwent cesarean section for fetal indications. There were no termination of pregnancy in controls.
There were two deaths in the study. One was a woman with Eisenmenger syndrome. She underwent caesarean section at 33 weeks of gestation, remained hemodynamically unstable and died five days post-caesarean due to heart failure. Her BNP levels in the three time frames of pregnancy were 217, 263, and 272 respectively. The second woman who died had severe mitral stenosis with aortic stenosis. She was severely symptomatic during pregnancy and underwent caesarean section since she had two previous caesarean sections and was in labor. She remained symptomatic in NYHA class IV and died 10 days post-caesarean of cardiogenic shock. Her BNP levels in the three periods of gestation were 128, 130, and 202 pg/ml respectively.
Outcomes and complications of the three groups with plasma BNP levels such as <100 pg/ml, 100–200 pg/ml, and >200 pg/ml were compared (Table 5). At less than 24 weeks of gestation, two women had maternal cardiac decompensation and underwent medical termination of pregnancy. Both had plasma BNP levels over 200 pg/ml. Only one woman had maternal cardiac decompensation between 30–32 weeks of gestation. She had undergone double valve replacement and had prosthetic aortic valve stenosis and moderate left ventricular systolic dysfunction. She had a placental abruption and preterm delivery at 30 weeks of gestation. Her BNP level was 127 pg/ml at 24 weeks, 209 pg/ml at 30 weeks, and 256 pg/ml after 34 weeks of gestation. After 34 weeks of gestation, 15 women were hospitalized for adverse cardiac events. Of these, 8 had mitral stenosis, 2 had dilated cardiomyopathy, 1 had Eisenmenger syndrome, 1 had Ebstein's anomaly, 1 had tetralogy of Fallot, 1 had severe pulmonary stenosis, and 1 was post-mitral valve replacement with normal left ventricular systolic function. Of these, only 1 had plasma BNP less than 100 pg/ml, 12 had levels between 100 and 200 pg/ml, and 2 had levels of more than 200 pg/ml. Both patients with plasma BNP levels over 200 pg/ml died post-delivery of heart failure. One post-mitral valve replacement woman became NYHA class III at term, and the plasma BNP level was only 99 pg/ml. No woman with heart disease and plasma BNP of 98 pg/ml or under had any adverse event, while all women with plasma BNP levels over 200 pg/ml developed heart failure. The highest plasma BNP (381 pg/ml) was noted in a severely symptomatic patient with primary pulmonary hypertension who underwent medical termination of pregnancy in the first trimester.
Table 5.
Acute decompensated heart failure by BNP level at different gestations.
| Gestation | Plasma BNP<100 pg/mln = decompensated/total | Plasma BNP100–200 pg/mln = decompensated/total | Plasma BNP>200 pg/mln = decompensated/total |
|---|---|---|---|
| ≤24 weeks | 0/13 | 0/34 | 2/3 |
| 30–32 weeks | 0/6 | 0/40 | 1/2 |
| ≥34 weeks | 1/5 | 12/40 | 2/3a |
Note: BNP: brain natriuretic peptide.
aOne patient had decompensated heart failure at 30 weeks and had a premature delivery and was in NYHA class II at 34 weeks of gestation.
Mitral stenosis was the commonest lesion in this cohort affecting 19 of the 50 women. Sixteen women with mitral stenosis had peak plasma BNP levels of 100–200 pg/ml, 2 had peak plasma BNP levels of more than 200 pg/ml, while only 1 had plasma BNP levels of under 100 pg/ml. Nine of these 19 patients had cardiac decompensation. Of these nine women, two had plasma BNP levels of over 200 pg/ml, while seven had plasma BNP levels of 100–200 pg/ml. All patients with mitral stenosis were booked in the cardio-obstetric clinic and were on regular treatment. These plasma BNP levels thus reflect medically-treated women with mitral stenosis.
The second most common lesion was mitral regurgitation which was present in 12 (24%) women. All these women had normal left ventricular systolic function with a left ventricular ejection fraction of ≥60%. All these patients tolerated pregnancy well, and none had cardiac decompensation. Eleven women had peak plasma BNP levels of 100–200 pg/ml while 1 had a level of 99 pg/ml.
Discussion
This study found that plasma BNP levels were significantly higher in women with cardiac disease compared to controls at all periods of gestation as well as six weeks postpartum. Women with mild increases in plasma BNP levels did well, while those with the highest levels were at high risk of developing heart failure. This study reflects plasma BNP levels of a group of women predominantly having rheumatic heart disease being monitored during pregnancy in a cardio-obstetric clinic. All women had normal renal function. Plasma BNP levels were measured in each trimester of pregnancy and six weeks postpartum and not at the time of cardiac decompensation. These therefore reflect baseline plasma BNP levels rather than the expected spike at the time of the acute deterioration.
Plasma BNP levels in all the 25 healthy normotensive women did not increase significantly as the pregnancy advanced and also did not show any significant change in the postpartum period. This suggests that the normal heart adapts well to the hemodynamic changes of pregnancy. Plasma BNP levels were around double in women with cardiac disease as compared to controls at all periods of gestation and also postpartum. Increased plasma BNP levels were also seen in women with heart disease patients who tolerated pregnancy well and did not show any cardiac decompensation. Pregnancy increases preload, thereby increases stress on ventricles.4 This peaks at 32–34 weeks of gestation. The decrease in plasma BNP levels at six weeks postpartum indicates that the hemodynamic adaptation which occurred during pregnancy normalized by the end of six weeks.
This study shows that plasma BNP level of over 200 pg/ml at any time during pregnancy is a warning signal. All women with levels over 200 pg/ml developed cardiac decompensation either in the same trimester or later in pregnancy. None of the women with plasma BNP levels of under 200 pg/ml decompensated in the first or second trimester. Women with plasma BNP levels under 200 pg/ml decompensate only in the third trimester, whereas those with plasma BNP levels over 200 pg/ml may decompensate as early as the first trimester. Forty women with heart disease had plasma BNP levels of 100–200 pg/ml after 34 weeks of gestation. Twelve of these had cardiac decompensation. Only one of the five women with heart disease and plasma BNP levels of under 100 pg/ml after 34 weeks of gestation developed cardiac decompensation. Her plasma BNP level was 99 pg/ml. A previous study showed that that plasma BNP levels under 100 pg/ml had a negative predictive value for adverse events.10
Thus, women with plasma BNP levels over 200 pg/ml at any period of gestation are at high risk for heart failure and should be hospitalized. Women with plasma BNP levels of 99–200 pg/ml are also at risk of decompensation in the third trimester and need close monitoring. Plasma BNP levels of 98 pg/ml or under are a predictor of good outcomes, and these women are unlikely to develop heart failure. These results are consistent with a previous study of 78 patients with heart disease in which none of the patients with plasma BNP levels <100 pg/ml had adverse events.7 Around 30% of women with plasma BNP levels of 100–200 pg/ml in the third trimester developed decompensation. Plasma BNP levels have not been included in risk stratification for women with heart disease even in recent guidelines and find only a passing mention.18 Plasma BNP levels, however, are useful in identifying low risk as well as very high-risk women and should be incorporated in future risk scores and guidelines.
Although other heart diseases have been reported, rheumatic heart disease is the most common heart disease affecting pregnant women in India.1,16,17,19 This was also reflected in this study. Mitral stenosis was the commonest lesion in this cohort affecting over a third of women. Mitral stenosis does not stress the left ventricle. In fact, it has the opposite effect with the left ventricle being underfilled. However, even women with mitral stenosis showed raised plasma BNP levels during pregnancy.20,21 A possible reason for the raised plasma BNP levels in patients with mitral stenosis is the likely co-existent pulmonary hypertension and resultant right ventricular stress. The second most common lesion was mitral regurgitation, occurring in 24% of women. All these women had normal left ventricular systolic function with a left ventricular ejection fraction of 60% or greater, and 11 of the 12 women had plasma BNP 100–200 pg/ml. All tolerated pregnancy well, and none had cardiac decompensation. This is because patients with mitral regurgitation and normal left ventricular systolic function tolerate pregnancy well due to peripheral vasodilatation.
Conclusions
Plasma BNP levels were significantly higher in women with heart disease as compared to controls at all periods of gestation as well as six weeks postpartum. Women with cardiac disease and plasma BNP levels of 98 pg/ml or under did not have any adverse events, whereas all patients with plasma BNP levels greater than 200 pg/ml developed decompensated heart failure.
Contributorship
Karanvir Singh, Pooja Sikka, Vanita Suri, Madhu Khullar and Rajesh Vijayvergiya were involved in planning the study protocol. Karanvir Singh, Pooja Sikka, Rishikesh Prasad, Madhu Khullar and Rajesh Vijayvergiya were involved in data collection. All authors contributed to data analysis. Karanvir Singh, Pooja Sikka, Vanita Suri, Madhu Khullar and Rajesh Vijayvergiya contributed to writing of the research work which was approved by all authors.
Declaration of conflicting interests
The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article
Ethical approval
Written informed consent was obtained from all the women and controls. Ethical approval was obtained for this study from the Institute Ethics Committee.
Funding
The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: Intramural funding provided by the Postgraduate Institute of Medical Education and Research, Chandigarh.
Guarantor
Pooja Sikka.
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