Evaluation of Metabolic Acid-base Abnormalities in Pre-eclamptic Women Applying the Stewart-Fencl Approach

Studies evaluating acid/base imbalances are scarce in pre-eclamptics, and tools to
thoroughly evaluate them are lacking. The detection of metabolic acidosis has been proposed
as a diagnostic criterion for a severe disease state8, 11, however other studies entirely
reject the presence of any metabolic acid-base disorder in pre-eclampsia10. One reason for
this controversy may lie in the fact that no study performed a full comprehensive acid base
analysis. Whereas some measured plasma pH, HCO3 and BE8, 11 others focused on AG1 or AG and
HCO32, 10 only. Merely one study corrected the AG for low albumin1, and no study focused on
independent variables. While some of the cited reports were based on retrospective chart
review without differentiating mild and severe disease state1, 2, the few prospective
studies available were of low sample size including a total number of 311 or 98women with
severe pre-eclampsia. As indicated above, it is totally legitimate to use the traditional
approach to describe changes in hydrogen ion concentration and HCO3. The
Hendersson-Hasselbach equation does differentiate well between respiratory and metabolic
acid-base changes. However, it is unable to quantify metabolic causes15. SBE quantifies net
change in metabolic acid-base status in vivo, but does not tell us about mechanisms16. The
AG is insufficient to detect unmeasured anions17, 18, but when corrected for low albumin it
does not detect all unmeasured cations16.

Intravascular volume depletion and disorders of electrolytes and albumin are common findings
in pre-eclampsia1, 2 and the impact of such disorders on acid-base homeostasis has been
increasingly acknowledged in the last decade3, 19. Decreased serum albumin has an
alkalinizing effect on plasma, resulting in hypoalbuminemic alkalosis. Furthermore,
derangements in volume, sodium and chloride homeostasis, as well as the accumulation of
unmeasured anions, are common findings in pre-eclampsia7 and may result in multiple
acid-base disorders. The presence of hyponatremia or hyperchloremia has an acidifying effect
on blood pH, whereas hypernatremia or hypochloremia lead to alkalosis. The accumulation of
unmeasured anions, such as lactate or uric acid, will lead to acidemia, if not otherwise
compensated3, 20.

We hypothesize that with comprehensive analysis, clinically significant and complex
metabolic derangements might be discovered in preeclamptics that will potentially impact
their care plan. To our knowledge, this will be the first time that the Stewart-Fencl
methodology will be used to determine causes of acid-base status in pre-eclamptics, which
takes into account the multiple, potentially opposing, electrochemical disturbances observed
in this patient population.

Specific Aims

Aim 1: Prevalence

The primary aim is a description of the prevalence of acid-base disorders in pregnant women
with pre-eclampsia at three time points:

1. at time of diagnosis with mild pre-eclampsia,

2. at time of progression to severe pre-eclampsia, and

3. at time of delivery. Pregnant women without pre-eclampsia will be used as a comparison
group for (a) and (b) for testing whether the.prevalence of acid-base disorders is
higher in pre-eclampsia than in pregnancy without pre-eclamsia.

Aim 2: Changes over time in acid base status This aim is to describe and test change over
three time points in the prevalence of acid-base disorders among those women who progress
from mild to severe pre-eclampsia, and change from initial diagnosis to delivery among women
whose pre-eclampsia remains mild.

Aim 3: Acid-base as clinical predictor This aim will test whether acid-base variables at
time of diagnosis with mild pre-eclampsia predict which women will progress to severe
pre-eclampsia and/or need an urgent delivery.

Significance (Note—include significance in relation to translational health science)

Pre-eclampsia complicates 2-8% of pregnancies, and is a major contributor to fetal and
maternal morbidity/mortality worldwide5, 21, 22.

The only cure for pre-eclampsia is delivery. However, especially remote from term, the
premise that delaying delivery to allow for the fetus to continue to grow and thrive in
utero is a big part of what expectant management is trying to achieve. The challenge remains
to this day to balance the benefits of a prompt delivery (undeniably benefiting the mother)
versus allowing the fetus to remain in utero (although if placental insufficiency is severe
and endothelial dysfunction critical, the baby may well be better off delivered).
Unfortunately, there are no strict criteria (hemodynamic, metabolic or other) or any
predictive model that may guide obstetricians in the decision to proceed with a prompt
delivery or allow prudent expectant management. Therefore, management is mostly guided by
expert opinion-based guidelines, which do not accurately predict adverse maternal events23,
24. The fullPIERS-model, recently published results from a large clinical trial, considers
gestational age, chest pain or dyspnea, oxygen saturation, platelet count, serum creatinine
levels and aspartate transaminase concentration, to predict adverse maternal outcome with a
sensitivity of 75% and a specificity of 87%25. However, for most of these predictors the
worst values recorded during the first 48 hours of study were used to predict complications
within the same 48 hour time frame26. In practice, a model based exclusively on information
available at admission is still needed. The data evaluated by the proposed Stewart-method
would add to the physiologic understanding of the disease, would be easy to obtain at
admission and possibly discover new predictors for adverse maternal and perinatal events.

Research Approach

In this prospective case-control study, previously normotensive women diagnosed with mild
pre-eclampsia as defined by the American Association of Hypertension 27 will be enrolled.
Blood samples from women with pre-eclampsia and healthy controls will be gathered, and
plasma pH, HCO3- and BE will be measured. According to the Stewart-Fencl methodology these
parameters are dependent variables of the following four factors 12, 28:

- The difference of strong cation and anion concentration, or 'strong ion difference'
(SID)

- The pCO2

- The concentration of weak acids, which are mainly albumin and phosphate (Atot)

- The presence of other acids, so called unmeasured anions (UMA) or strong ion group
(SIG)

Based on that concept, BE can be defined by:

(A) plasma dilution/concentration (=changes in Na+-concentration, (BENa+)) (B) changes in
chloride concentration (BECl-) (C) changes in albumin concentration (BEAlb) (D) changes in
lactate (BELac) (E) changes in unmeasured anions (BEUMA). BE = BENa+ + BECl- + BEAlb + BELac
+ BEUMA

Each component will be identified and quantified as described by Gilfix et al.17. (A
detailed explanation can be found in the Appendix of this application).

Statistical Analysis Because of the descriptive and exploratory nature of this pilot study,
no controls for multiple comparisons will be made. Any results from this study will be
interpreted as hypothesis generating, to justify a larger further study.

Aim 1: Prevalence The primary aim is a description of the prevalence of acid-base disorders
in pregnant women with pre-eclampsia at three time points: (a) at time of diagnosis with
mild pre-eclampsia, (b) at time of progression to severe pre-eclampsia, and (c) at time of
delivery, in comparison to pregnant women without pre-eclampsia.

For each of the BE measures, abnormal will be defined as differing from +/-2mEq/l or more.
If any one of the BE measures is abnormal, the woman will be classified as having an
acid-base disorder. Descriptive displays (tables and/or bar charts) will be used to
describe the percent of women with an acid-disorder at each of (a) to (b) and in control
women. In addition, we will describe how many of these cases have offsetting disorders so
that the total BE is normal, i.e. they would not have been identified by the traditional
approach. Further displays will describe the prevalence of abnormal values for each of the
5 components separately. In addition, we will explore the utility of displaying means and
SDs of each of the 5 BE components.

Logistic regression will be used to test for differences in prevalence of acid-base disorder
in pre-eclampsia versus controls, at each of (a) and (b) time points, while controlling for
gestational age as a covariate. Linear regression will be used to test for differences in
the means of each of the BE components between pre-eclampsia and controls, controlling for
gestational age.

Aim 2: Changes over time in acid base status This aim is to describe and test change over
three time points in the prevalence of acid-base disorders among those women who progress
from mild to severe pre-eclampsia, and change from initial diagnosis to delivery among women
whose pre-eclampsia remains mild.

Mixed models for binary outcome data, using for example xtlogit in Stata, will be used to
test for changes over time in prevalence. Further analyses will use mixed models for
continuous outcomes to test for changes in means of the individual BE scores over time.

Aim 3: Acid-base as clinical predictor This aim will test whether acid-base variables at
time of diagnosis with mild pre-eclampsia predict which women will progress to severe
pre-eclampsia and/or need an urgent delivery. A chi-square test can be used to test whether
the fraction of women progressing to sever pre-eclampsia is different in those with abnormal
versus normal acid-base at time of diagnosis of mild pre-eclampsia. Further analysis will
use logistic regression analyses to test whether the 5 BE components predict probability of
progression. Potential confounding variables such as medications (e.g furosemide) used to
control symptoms or severity of the disease will also be evaluated to see whether
controlling for these variables changes the association of acid-base variables with risk of
progression.

We will further explore a variety of neonatal and maternal outcome variables for a possible
association with acid-base predictors. Please find those secondary outcome variables
described in detail in the appendix of the revised application. Please find also clarified
if variables are categorical or continuous.

• Sample size

In this pilot study, power will be good if the effect size is moderately large. For
example, for the primary analysis of Aim 1 there will be 86% power if the prevalence of
acid-base abnormality is 45% in severe pre-eclampsia compared to 5% in controls (n=25 each
group). Power will be 88% if prevalence is 35% in mild pre-eclampsia (n=100) versus 5% in
controls. Power will be poor for a more modest effect sizes, however that is to be expected
in a small pilot study - the goal is not to provide a definitive test of hypotheses but
rather to provide preliminary data to justify a later well-powered study.

Inclusion Criteria:

Women diagnosed with mild or severe pre-eclampsia

Exclusion Criteria:

Women in labor or presenting with chronic pulmonary disease, collagen disorders, history
of lithium intoxication or history of methanol, ethanol or salicylates ingestion, urinary
tract infection, chorioamnionitis, intrauterine fetal death, a body mass index (BMI) > 50
kg/m2 or acute asthma will be excluded.