Comparison Fetal Hemodynamic Measurements Antihypertensive Versus Control

Chronic hypertension is a common medical condition during pregnancy, occurring in up to 5
percent of pregnant women. There are significant maternal, fetal, and neonatal morbidity and
mortality associated with this disease [1,2]. Chronic hypertension in pregnancy has been
defined as elevated blood pressure detected and confirmed before the 20th week of gestation
or hypertension present prior to conception. Chronic hypertension is usually classified as
mild with systolic blood pressure greater than or equal to 140 mmHg or diastolic blood
pressure greater than or equal to 90 mmHg. Severe hypertension is defined as systolic blood
pressure greater than or equal to 180 mmHg or diastolic blood pressure greater than or equal
to 110 mmHg [3]. Adverse outcomes associated with chronic hypertension in pregnancy include
preterm delivery, intrauterine growth restriction (IUGR), intrauterine fetal demise (IUFD),
placental abruption, and cesarean delivery [4]. The incidence of superimposed preeclampsia
has been reported in up to 50 percent of women with severe chronic hypertension [5]. Many of
these women have medical management with anti-hypertensive medications during pregnancy.
Data is lacking regarding improvement in neonatal outcome, and there is evidence that
anti-hypertensive medications may interfere with uteroplacental blood flow and fetal growth
[3,6]. Despite a lack of support in the literature for medication in the management of
hypertension in pregnancy, current recommendations recognize a role for medication use for
at least severe chronic hypertension [1].

The umbilical arteries arise within fetal circulation from the common iliac arteries and
represent the dominant circulatory outflow of the distal aortic circulation and contribute
entirely to placental circulation. Normal umbilical artery resistance to blood flow
progressively decreases throughout pregnancy, reflecting the progressive increase in
placental mass and the increased numbers of tertiary villous small vessels of the placenta
[7]. Doppler ultrasonography is a noninvasive technique that is used to assess the
hemodynamic components of vascular impedance within the placenta. Umbilical artery Doppler
flow velocimetry has been developed to evaluate fetal condition en-utero [8]. Normally
developing and growing fetuses are characterized by high velocity diastolic umbilical artery
flow, while those with IUGR have decreased, absent, or reversed diastolic flow [9,10].
Abnormal umbilical artery flow has been defined as the presence of absent or reversed end
diastolic flow or a flow index greater than two standard deviations above the reported mean
flow index for a given gestational age [11,12]. Evaluation of umbilical artery hemodynamics
is indicated as part of standard care when IUGR or significant fetal anemia due to
iso-immunization is suspected [7,8].

A group of patients with pregnancies complicated by pregnancy-induced hypertension (PIH)
were treated with anti-hypertensive drugs labetalol and nifedipine. These subjects had
umbilical artery Doppler flow velocity and resistance index measurements at 27-32 weeks
gestation and again at 33-36 weeks gestation. An increase in resistance index measurements
was noted over time. The authors attributed this increase in umbilical artery resistance to
progression in placental impairment due disease progression rather than the medication
management of PIH [13]. Another group of patients with pregnancies complicated by
preeclampsia had significantly elevated umbilical artery systolic flow to diastolic flow
(S/D) ratios compared to a control group. When treated with an antihypertensive agent
alpha-methyldopa, there was a significant reduction in umbilical artery S/D ratios in the
group of women with preeclampsia [14]. An in-vitro study was undertaken with isolated
segments of human umbilical cords that were evaluated for measured umbilical artery
resistance. The segments were exposed to varying concentrations of common substances that
affect arterial tone and are used as antihypertensive agents such as labetalol,
alpha-methyldopa, nifedipine, and magnesium sulfate. All except alpha-methyldopa
demonstrated a dose-dependant reduction in umbilical artery resistance due to direct
umbilical artery smooth muscle relaxation [15].

The purpose of this study is to obtain information regarding umbilical and middle cerebral
artery hemodynamics during pregnancies complicated by chronic hypertension managed with
anti-hypertensive medication and compare the measured values obtained to pregnancies not
complicated by chronic hypertension. We postulate that the use of anti-hypertensive agents
during pregnancy do not significantly affect umbilical artery Doppler flow and middle
cerebral artery peak systolic velocity measurements.

Specific Objectives:

1. Establish a cohort of subjects that have a history of chronic hypertension requiring
anti-hypertensive medication during pregnancy to act as a study group

2. Establish a cohort of subjects that do not have chronic hypertension and do not take
anti-hypertensive medication during pregnancy to act as a control group

3. Obtain standard measurements of utero-placental function on two occasions during the
third trimester of pregnancy, the first between 26 to 33 weeks gestation and the second
between 34 and 40 weeks gestation

4. The measurements of utero-placental function to include estimated fetal weight, average
gestational size, amniotic fluid index, umbilical artery S/D ratio, and middle cerebral
arterial peak velocity

5. Compare the results of measurements made in both groups at two different times in the
third trimester of pregnancy to define differences potentially attributable to
medication use during pregnancy

6. Use the results of this preliminary study to estimate how many subjects would be
required to identify a statistically significant difference in fetal hemodynamic
measurements potentially attributable to anti-hypertension agent use

Study Design:

This study will employ a prospective case-control design. A group of women with a history of
chronic hypertension managed with anti-hypertensive medication will be identified as
potential subjects for the study cohort. Each potential subject will have an assessment of
her hypertension history, management, and associated vascular complications. 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 condition will be provided according to accepted practice. Potential
subjects for this cohort will be obstetrical patients cared for at 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 chronic hypertension will be identified as
potential subjects for the control cohort. Each potential subject will have 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 condition will be provided according to accepted practice. Potential
subjects for this cohort will be obstetrical patients cared for at the Regional Perinatal
Center, Division of Maternal Fetal Medicine, Department of Obstetrics & Gynecology, SUNY
Upstate Medical University.

The subjects enrolled in both cohorts are seen at the Regional Perinatal Center for
management of high-risk pregnancies. As part of intensified obstetrical care, ultrasound
evaluation of interval fetal growth with an assessment of estimated fetal weight, average
gestational size, and amniotic fluid index is standard around 28 weeks gestation and again
at about 35 weeks gestation. Umbilical artery Doppler studies are usually reserved for
fetuses with a diagnosis of suspected intrauterine growth restriction. Fetal middle cerebral
artery peak flow velocity studies are usually reserved for suspected severe fetal anemia and
have been used on an investigational basis for suspected intrauterine growth restriction. We
anticipate most subjects will not have a pregnancy complicated by IUGR, therefore performing
Doppler studies for umbilical artery S/D ratio and middle cerebral arterial peak velocity
will not be standard care. Data will be collected in a database in a single computer on site
at the Regional Perinatal Center. This computer is password protected and reserved for use
by care providers at the Perinatal Center that will be investigators for this study. The
database will record specific patient identifiers including subject name and chart number.
These specific identifiers will be removed at the completion of data collection prior to
data analysis.

Statistical Methods, Data Analysis, Interpretation:

There are few studies published regarding the use of anti-hypertensive agents during
pregnancy and the effect of these agents on umbilical artery hemodynamics. These few studies
usually involved 20 to 30 subjects. At this point, there is not enough information to
estimate how many subjects would be required to measure a statistically significant
difference potentially attributable to the use of these agents. For this preliminary study,
we will obtain 30 subjects for the study cohort and 30 subjects for the control cohort. It
is anticipated that it will take approximately one year to complete this study.

Once data collection is complete as described above, a comparison of means will be
undertaken for umbilical artery Doppler studies between the two cohorts at the first and
then again for the second gestational age measurements.

Inclusion Criteria:

1. At least 18 years of age

2. A diagnosis of chronic hypertension by at least one of these criteria including
hypertension that has persisted beyond the postpartum time frame of a prior
pregnancy, hypertension diagnosed and managed before current pregnancy, or elevated
blood pressure (systolic blood pressure > or = 140 mmHg or diastolic blood pressure >
or = 90 mmHg) prior to 20 weeks gestation requiring medication management

3. Taking medication for control of chronic hypertension prior to study entry

4. Potential subjects taking medications for control of cardiac arrythmia that fall into
the anti-hypertensive class will be considered for this cohort

Potential subjects for the control cohort:

1. At least 18 years of age

2. Absence of a diagnosis of chronic hypertension

3. Not taking medication for control of chronic hypertension or arrythmia

Exclusion Criteria:

1. Less than 18 years of age

2. Pregnancy complicated by significant fetal chromosomal anomaly, severe or multiple
fetal anomalies, early onset amniotic fluid abnormalities, preterm labor, placental
abruption, or IUGR

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