Evaluation Cardiac Function With Echo and BNP in Obstetrical Patients With/Without Cardiac Disease

The incidence of cardiac disease during pregnancy is about 2 percent, and is the leading
cause of non-obstetrical maternal mortality (1). Women with known cardiac disease and
suspected cardiac dysfunction have been monitored and evaluated during pregnancy, labor,
delivery, and post partum with electrocardiogram, long-term rhythm recording, and
echocardiogram (2). Physiological changes that occur in normal pregnancy include a 43%
increase in cardiac output, 45 to 50% increase in intravascular volume, 14% decrease in
serum colloid osmotic pressure, and 28% decrease in the colloid osmotic pressure to
pulmonary capillary wedge pressure ratio. These hemodynamic changes are believed to maintain
adequate uteroplacental perfusion, meet the increased oxygen and nutritional demands
throughout gestation and to protect against sudden hemodynamic changes precipitated by blood
loss, decreased venous return to the heart, and hypotension (3).

B-type natriuretic peptide [BNP] is released from ventricular myocardium in response to
increased ventricular wall tension or stretch. A rapid assay for the measurement of serum
BNP levels has been developed and is in clinical use for the evaluation of dyspnea related
to ventricular dysfunction. Serum BNP determination has been described as having a higher
level of diagnostic accuracy for congestive heart failure as a cause for dyspnea than any
other single historical, physical, or laboratory finding. When used in conjunction with
other clinical information, the rapid assay for serum BNP levels is useful in establishing
or excluding cardiac dysfunction as a cause for acute onset dyspnea (4). During
uncomplicated pregnancy, serum BNP levels remain the same as levels seen in non-pregnant
women. Among patients with severe preeclampsia, serum BNP levels have been observed to rise
to eight times baseline values. Decreased left ventricular ejection fraction and percentage
of fractional shortening within myocardium was observed in the preeclampsia group compared
to the normal pregnancy group. The degree of structural and functional change was linearly
related to the degree of elevation of cardiac natriuretic peptides, including B-type
natriuretic peptide levels (5).

Preliminary clinical experience indicates that serum BNP levels obtained by a commercially
available rapid assay method may be related to the degree of ventricular dysfunction among
obstetrical patients with acute dyspnea associated with preeclampsia, tocolysis therapy, or
an underlying history of cardiopulmonary disease (6). The purpose of this protocol is to
determine prospectively if the measurement of serum BNP levels will correlate with cardiac
function changes noted on echocardiography and clinically among pregnant women with a
history of cardiac disease. This group is to be compared to a group of pregnant women with
no history of cardiac disease.

Specific Objectives

The specific objectives of this study include the following:

1. Establish a cohort of subjects that have a history of heart disease that have a
diagnosis of cardiac disease, either congenital or acquired, that are pregnant and wish
to continue their pregnancies through to delivery.

2. Provide standard obstetrical and cardiac care for these subjects and their fetuses as
would be indicated by the type, nature, and degree of cardiac disease present from the
first trimester until after delivery.

3. Study interventions to include a series of echocardiograms to begin at the time of
pregnancy diagnosis and proceed until the end of the post partum time frame. These
studies will take place in the first, second, third trimesters, during labor, two to
three days after delivery, and six weeks post partum.

4. With each echocardiogram a serum BNP level will be drawn and measured for correlation
with the findings noted on echocardiography.

5. Additional data may be collected if an individual subject were to require additional
evaluations with echocardiography and/or BNP serum measurements based on clinical
indications.

6. Establish a cohort of control subjects with no history of cardiac disease that will
have echocardiography and serum BNP measurements on the same schedule described for
subjects with a history of cardiac disease for comparison.

7. At the completion of the study, a description of physiologic changes in cardiac
function in the cardiac disease cohort attributable to the subjects' history of cardiac
disease versus those attributable to the normal physiologic changes of pregnancy will
be available.

8. At the completion of the study, a description of changes in the serum levels of BNP
will reflect cardiac dysfunction.

Study Design

This study protocol employs a prospective cohort design. A group of woman with a history of
cardiac disease and pregnancy will be identified as potential subjects for a study cohort.
Each potential subject will have an initial assessment of her cardiac history, condition,
and functional status. A detailed review of her complete medical, surgical, gynecologic, and
obstetrical history will be obtained as dictated by standard care. Appropriate management
for each potential subject's medical and obstetrical care will be initiated and undertaken
by accepted clinical practice. Potential subjects for this cohort will be obstetrical
patients either cared for directly by or in consultation with the Regional Perinatal Center,
Division of Maternal Fetal Medicine, Department of Obstetrics & Gynecology, SUNY Upstate
Medical University.

A second group of women with no history of cardiac disease and pregnancy will also be
identified as potential subjects for a control cohort. Each potential subject will also have
an initial assessment of her medical, surgical, gynecologic, and obstetrical history as
dictated by standard care. Appropriate management for each potential subject's medical and
obstetrical care will be initiated and undertaken by accepted clinical practice. Potential
subjects for this cohort will be obstetrical patients either cared for directly by or in
consultation with the Regional Perinatal Center, Division of Maternal Fetal Medicine,
Department of Obstetrics & Gynecology, SUNY Upstate Medical University.

In addition to the management given as part of standard medical and obstetrical care, each
subject from both cohorts will have a series of serum BNP measurements and echocardiograms.
A serum BNP measurement and echocardiogram will be obtained during the first, second, and
third trimesters, during the course of labor or delivery, 48 to 72 hours post-delivery, and
6 to 8 weeks post-delivery. Additional studies will be obtained as indicated by standard
clinical indications. Serum BNP measurements will be made through laboratory services
available at SUNY Upstate Medical University or Crouse Hospital. Echocardiogram studies will
be performed at Cardiology P.C. or Pediatric Cardiology at SUNY Upstate Medical University.

A standard form will be used for each subject to record the results of the serum BNP
measurements, results of the maternal echocardiograms, and details of the clinical course
experienced by each subject during the course of her pregnancy, labor, delivery, and
post-delivery care. Complications related to cardiac function as well as other medical and
obstetrical complications will also be recorded. Please see the attached standard data
collection form for details.

At the conclusion of the study, a comparison will be made between the cohort of women with
cardiac disease and the cohort of woman without cardiac disease. Specific comparison will be
made in regard to serum BNP levels, cardiac function as measured on echocardiography, and
clinical course.

Statistical Methods, Data Analysis, Interpretation

There are no prior published reports regarding the use of a rapid serum BNP assay to
evaluate cardiac function during pregnancy for women with known cardiac disease. From June
1, 2003 to May 31, 2004, the Regional Perinatal Center at SUNY Upstate Medical University
provided obstetrical care and consultation for 55 patients with ICD-9 Code 648.63, cardiac
disease in pregnancy. Since this is a pilot study, it is anticipated that 20 subjects for
the cardiac disease cohort can be followed over the course of 1 to 2 years, along with a
control cohort.

Specific measurements that will be obtained by echocardiography and recorded as measures of
cardiac function will include:

- Estimated left ventricular ejection fraction

- Estimated left ventricular wall thickness

- Estimated cardiac output

- Right and left atrial chamber volumes

- Right and left ventricular chamber volumes

- Estimated pulmonary artery pressure

Serum BNP measurements will be obtained and recorded as units of picograms/milliliter.
Approximately 3-4 milliliters of blood is obtained per assay in a standard lavender-top tube
by standard blood sampling methods. The rapid quantitative assay for BNP will be run on the
Triage® BNP Test (International) of Biosite Diagnostics, Incorporated, San Diego,
California.

Measurements of serum BNP will be correlated with clinical course and objective measures of
cardiac function as determined by echocardiography. A linear relationship between the
elevation of serum BNP measurement and degree of cardiac dysfunction is expected. Elevated
serum BNP and cardiac dysfunction demonstrated on echocardiogram should also correlate with
the clinical estimate of NYHA functional status and the degree of congestive failure.

Inclusion Criteria:

Potential subjects for the cardiac disease in pregnancy cohort:

1. At least 18 years of age

2. Cardiac disease as per Clark's Maternal Mortality Associated with Pregnancy: Group 1
(mortality less than 1%) atrial septal defect, ventricular septal defect, patent
ductus arteriosus, pulmonic or tricuspid valve disease, corrected tetrology of
Fallot, bioprosthetic valve, mitral stenosis with NYHA class I and II functional
status Group 2 (mortality 5-15%) mitral stenosis with NYHA class III and IV
functional status, aortic stenosis, coarctation of aorta without valvular
involvement, uncorrected tetrology of Fallot, previous myocardial infarction, Marfan
syndrome with normal aorta, mitral stenosis with atrial fibrillation, artificial
valve Group 3 (mortality 25-50%) pulmonary hypertension, coarctation of aorta with
valvular involvement, Marfan syndrome with aortic involvement (7)

3. Other significant cardiac disease not listed above

4. Other medical disorders, such as diabetes mellitus, chronic hypertension, asthma,
other endocrine disorders, et cetera, will be acceptable

5. Diagnosis of a least a single intrauterine pregnancy, multiple gestation acceptable

Potential subjects for pregnancy without cardiac disease cohort:

1. At least 18 years of age

2. Absence of significant cardiac disease, minor cardiac disorders such as mitral valve
prolapse without arrythmia

3. Other medical disorders, not directly related to cardiac disease, such as diabetes
mellitus, chronic hypertension, asthma, other endocrine disorders et cetera, will be
acceptable

4. Diagnosis of at least a single intrauterine pregnancy, multiple gestation acceptable

Exclusion Criteria:

1. Less than 18 years of age

2. Non-viable pregnancy such as a threatened spontaneous miscarriage, or ectopic
pregnancy

3. Planned termination of pregnancy, either elective or medically indicated based on
history

4. Inability to complete informed consent process or participate in the study protocol