Keywords
mild preeclampsia - preeclampsia without severe features - gestational hypertension
- chronic hypertension in pregnancy - superimposed preeclampsia - liver enzymes -
platelet count - preeclampsia with severe features
The safety and cost effectiveness of the outpatient management of gestational hypertension
and preeclampsia without severe features has been validated in multiple studies and
is currently supported by the American College of Obstetricians and Gynecologists
(ACOG).[1]
[2]
[3]
[4] Prerequisites for outpatient management include reasonable assurance of patient
willingness to comply with frequent maternal and fetal evaluation and maternal understanding
of warning symptoms of preeclampsia with severe features.[1]
Current recommendations for outpatient management of gestational hypertension and
preeclampsia without severe features include at least one clinic visit each week.[1] Maternal evaluation should include review of symptomatology associated with severe
preeclampsia, blood pressure measurement, and weekly laboratory testing (platelet
count, serum creatinine, and liver transaminases).[1]
[4] The recommendation for weekly laboratory testing is based on expert opinion, with
the goal of early detection of severe preeclampsia and associated end-organ damage.[1]
[4]
The utility of weekly laboratory testing in the outpatient management of preeclampsia
is currently unclear and has not been investigated to date. The objective of the current
study was to determine if there is an association between weekly laboratory testing
for severe features of preeclampsia and decreased maternal morbidity in patients managed
outpatient for gestational hypertension and preeclampsia without severe features.
Materials and Methods
This is a multicenter, retrospective, cohort study performed at two tertiary care
teaching hospitals. All patients diagnosed with gestational hypertension, preeclampsia
without severe features, and chronic hypertension with superimposed preeclampsia without
severe features at LSU Health Shreveport, Shreveport, LA and The University of Tennessee
Medical Center, Knoxville, TN between January 1, 2012, and August 18, 2018, were evaluated
for inclusion.
The Institutional Review Board at the LSU Health Shreveport, Shreveport, LA approved
the study, and The University of Tennessee Medical Center, Knoxville, TN obtained
independent approval through their Institutional Review Board. International Classification of Diseases, Ninth and Tenth Revision codes were used to obtain a list of patients with the diagnosis of gestational hypertension,
preeclampsia without severe features, or chronic hypertension without severe features.
Linked neonatal charts were reviewed to obtain neonatal outcome data.
Patients were included in the final analysis if they had a singleton pregnancy between
230/7 and 366/7 weeks; were diagnosed with gestational hypertension, preeclampsia without severe
features, or chronic hypertension with superimposed preeclampsia without severe features;
and were treated as an outpatient following diagnosis. All patients at each study
site which met the inclusion criteria during the study period were included in the
study. Patients were excluded if they were treated inpatient from diagnosis until
delivery, if they had a multiple gestation, and if they had preexisting liver or renal
disease with abnormal baseline liver function or renal function laboratory values.
Most patients in the study cohort were diagnosed during a short inpatient admission.
During this brief inpatient stay, each patient was deemed a candidate for outpatient
management by a maternal–fetal medicine specialist due to stability of hypertensive
disorder and assessment of reliability of the patient to follow-up with twice weekly
evaluation.
The primary outcome of the study was a composite of maternal morbidity including one
or more of the following: severe features of preeclampsia at delivery, HELLP syndrome,
placental abruption, eclampsia, maternal death, and maternal intensive care unit (ICU)
admission. Secondary outcomes included indication for delivery (37 weeks, severe uncontrolled
maternal blood pressure, maternal symptomatology associated with severe preeclampsia,
abnormal laboratory values, fetal indication, spontaneous labor, or other), gestational
age at diagnosis, gestational age at delivery, latency from diagnosis to delivery,
and compliance with scheduled outpatient visits.
As the focus of our study is the utilization of laboratory values, we understood the
possibility of ascertainment bias during data collection for the indication for delivery.
For this reason, an additional secondary outcome evaluated was the presence of abnormal
laboratory values at delivery which was defined as thrombocytopenia (platelet count < 100,000 × 109/L), impaired liver function (liver enzymes twice the upper limit of normal), and
renal insufficiency (serum creatinine 1.1 mg/dL or doubling of baseline creatinine).
As these numbers are objective measures of end-organ dysfunction, they are not subject
to bias.
Patients were divided into two groups for comparison. The first group was managed
outpatient with weekly laboratory testing (laboratories group) and the second group
was managed outpatient without weekly laboratory testing (no laboratories group).
ACOG published its Hypertension in Pregnancy Task Force Report in November 2013 which recommended weekly laboratory assessment in the outpatient
management of hypertensive disorders of pregnancy. The majority of the no laboratories
group was managed prior to this time, before weekly laboratory testing became standard
of care, or throughout early 2014 before this practice had been fully adopted at the
study sites.
The diagnosis of gestational hypertension, preeclampsia without severe features, or
chronic hypertension with superimposed preeclampsia was based on ACOG criteria at
the time of diagnosis at both sites.[1] The current diagnostic criteria are as follows: Gestational hypertension is defined
as systolic blood pressure more than 140 mm Hg or diastolic blood pressure more than
90 mm Hg on two separate occasions more than 4 hours apart without associated proteinuria
or other signs of end-organ dysfunction.[1] Preeclampsia without severe features criteria contains identical blood pressure
criteria but with associated proteinuria defined as protein–creatinine ratio more
than 0.3 or 24-hour urine protein more than 300 mg.[1] Chronic hypertension with superimposed preeclampsia is diagnosed with a sudden increase
in blood pressure or proteinuria in a patient with preexisting hypertension.[5]
Statistical analysis was performed using GraphPad Prism 7 (La Jolla, CA). All continuous
data were compared using t-test and all categorical data were compared using chi-square or Fisher's exact test.
A p-value of < 0.05 was considered statistically significant. All tests were considered
based on a two-sided alternative hypothesis.
Results
A total of 204 patients met inclusion criteria and are included in the final analysis:
120 patients in the laboratories group and 84 patients in the no laboratories group.
The LSU Health Shreveport, Shreveport, LA contributed 100 patients, and The University
of Tennessee Health Science Center, Knoxville, TN contributed 104 patients to the
study cohort. Demographics between the two groups were compared and are shown in [Table 1]. Patients in the laboratories group were older and more likely to have chronic hypertension.
As the laboratories group had a significantly higher rate of chronic hypertension,
this group also had a significantly higher rate of superimposed preeclampsia without
severe features. Patients in the no laboratories group were more likely to have the
diagnosis of gestational hypertension. All other demographic categories were similar
between the two study groups.
Table 1
Maternal characteristics of 204 patients with mild gestational hypertension, mild
preeclampsia, and chronic hypertension with mild superimposed preeclampsia managed
as an outpatient
|
Laboratories (N = 120)
|
No laboratories (N = 84)
|
p-Value
|
|
Age (y)
|
28.8 (24–34)
|
26.6 (22–31.7)
|
0.02
|
|
Body mass index (kg/m2)
|
35.7 (29.3–41.1)
|
34.9 (27.2–40.9)
|
0.51
|
|
White
|
60 (50)
|
45 (53.6)
|
0.67
|
|
Black
|
56 (46.7)
|
38 (45.2)
|
0.89
|
|
Hispanic
|
4 (3.3)
|
1 (1.2)
|
0.65
|
|
Nulliparity
|
35 (29.2)
|
21 (25)
|
0.53
|
|
Smoking
|
22 (18.3)
|
17 (22.1)
|
0.86
|
|
History of preeclampsia
|
33 (27.5)
|
23 (27.3)
|
0.99
|
|
On antihypertensive medications
|
30/44 (68.2)
|
9/17 (52.9)
|
0.37
|
|
Total diabetes
|
38 (31.6)
|
19 (22.6)
|
0.20
|
|
Pregestational diabetes
|
18/38 (47.4)
|
9/19 (47.4)
|
0.99
|
|
Gestational diabetes
|
20/38 (52.6)
|
10/19 (52.6)
|
0.99
|
|
Renal disease
|
6 (5)
|
6 (7.1)
|
0.56
|
|
Intrauterine growth restriction
|
19 (15.8)
|
8 (9.5)
|
0.19
|
|
Diagnosis
|
|
Gestational hypertension
|
19 (15.8)
|
27 (32.2)
|
0.006
|
|
Preeclampsia without severe features
|
57 (47.5)
|
40 (47.6)
|
0.99
|
|
cHTN with SIPE without severe features
|
44 (36.7)
|
17 (20.2)
|
0.01
|
Abbreviations: cHTN, chronic hypertension; SIPE, superimposed preeclampsia.
Note: Data are mean (interquartile range) or n (%).
Delivery outcomes were similar between the two groups with a few important differences
([Table 2]). Significant findings were that the laboratories group had a mean gestational age
at diagnosis that was 1 week earlier than the no laboratories group and they also
had a mean gestational age at delivery that was 4 days earlier than the no laboratories
group. This explains the higher rate of neonatal intensive care unit (NICU) admission
in the laboratories group. The groups had similar lengths of latency from diagnosis
to delivery, however. Compliance with outpatient visits was similar between the two
groups, and overall compliance was 83.7%. Mode of delivery, birth weight, and 5-minute
Apgar score < 7 were also similar between the two groups. There was one stillbirth
in the study cohort, which was in the laboratories group in a patient with preeclampsia
without severe features who maintained 100% compliance with her follow-up visits.
Table 2
Delivery information and neonatal outcomes of 204 patients with mild gestational hypertension,
mild preeclampsia, and chronic hypertension with mild superimposed preeclampsia managed
as an outpatient
|
Laboratories (N = 120)
|
No laboratories (N = 84)
|
p-Value
|
|
GA at diagnosis (d)
|
330/7 (312/7–346/7)
|
340/7 (330/7–352/7)
|
0.003
|
|
GA at delivery (wk)
|
362/7 (355/7–371/7)
|
366/7 (360/7–373/7)
|
0.008
|
|
Latency (d)
|
22.7 (13–30)
|
19.7 (10–22.7)
|
0.15
|
|
Spontaneous vaginal delivery
|
44 (36.7)
|
34 (40.5)
|
0.66
|
|
Primary cesarean delivery
|
40 (33.3)
|
25 (29.7)
|
0.65
|
|
Repeat cesarean delivery
|
34 (28.3)
|
22 (26.1)
|
0.75
|
|
Operative vaginal delivery
|
2 (1.6)
|
3 (3.6)
|
0.40
|
|
Birth weight (g)
|
2,762 (2,380–3,190)
|
2,901 (2,410–3,280)
|
0.14
|
|
Stillbirth
|
1 (0.8)
|
0 (0)
|
0.99
|
|
NICU admission
|
41 (34.2)
|
17 (20.2)
|
0.03
|
|
5-min Apgar score < 7
|
3 (2.5)
|
1 (1.2)
|
0.64
|
Abbreviations: GA, gestational age; NICU, neonatal intensive care unit.
Note: Data are mean (interquartile range), n (%).
Primary outcome data are shown in [Table 3]. The primary outcome of composite maternal morbidity was more common in the laboratories
group than the no laboratories group. A total of 53 patients in the laboratories group
(44.2%) versus 24 patients in the no laboratories group (28.5%) experienced the primary
outcome (p = 0.02). Analysis of the individual outcomes included in the composite morbidity
revealed that the only outcome experienced in either group was the presence of severe
features at delivery. No patient in the 204-patient cohort experienced HELLP syndrome,
placental abruption, eclampsia, maternal death, or maternal ICU admission.
Table 3
Primary outcome: composite maternal morbidity of 204 patients with mild gestational
hypertension, mild preeclampsia, and chronic hypertension with mild superimposed preeclampsia
managed as an outpatient
|
Laboratories (N = 120)
|
No laboratories (N = 84)
|
p-Value
|
|
Composite maternal morbidity
|
53 (44.2)
|
24 (28.5)
|
0.02
|
|
Individual outcomes
|
|
Severe features at delivery
|
53 (44.2)
|
24 (28.5)
|
0.02
|
|
HELLP syndrome
|
0 (0)
|
0 (0)
|
1
|
|
Placental abruption
|
0 (0)
|
0 (0)
|
1
|
|
Eclampsia
|
0 (0)
|
0 (0)
|
1
|
|
Maternal death
|
0 (0)
|
0 (0)
|
1
|
|
Maternal ICU admission
|
0 (0)
|
0 (0)
|
1
|
Abbreviation: ICU, intensive care unit.
Indications for delivery were similar between the two groups with no statistically
significant differences ([Fig. 1]). The most common indication for delivery in both groups was reaching 37 weeks,
the gestational age at which delivery is recommended by ACOG for gestational hypertension,
preeclampsia without severe features, and chronic hypertension with superimposed preeclampsia
without severe features.[1]
[4] No patient in the study cohort was delivered for the indication of abnormal laboratory
values as defined.
Fig. 1 Indications for delivery in 204 patients managed as an outpatient for mild gestational
hypertension: weekly laboratory group versus no laboratory group. BP, blood pressure;
labs, laboratory values. *Abnormal laboratory values defined as platelet count < 100,000 × 109/L,
liver transaminases twice the upper limit of normal, and serum creatinine 1.1 mg/dL
or doubling of baseline creatinine. No statistically significant differences between
the two groups with regard to any indication for delivery (defined as p < 0.05).
The presence of abnormal laboratory values at delivery was evaluated as an additional
secondary outcome. Only one patient in the study cohort had abnormal laboratory values
at delivery. This patient had preeclampsia without severe features and was seen in
antenatal testing clinic where she was scheduled to receive a biophysical profile,
have her blood pressure checked, and be evaluated by a maternal–fetal medicine specialist.
On intake, she was noted to have a severe range blood pressure, defined as > 160 mm
Hg systolic. On her clinical assessment, she also reported a severe headache, unresponsive
to medication she had taken at home prior to her presentation. She was diagnosed with
preeclampsia with severe features and immediately sent to the labor and delivery unit
for assessment and subsequent delivery. Her admission laboratory values showed thrombocytopenia
with platelet count of < 100,000 × 109/L with normal liver transaminases and creatinine. For this particular patient, her
severe blood pressure and symptomatology were the primary indications for delivery
with thrombocytopenia being an incidental finding.
Due to the demographic differences, as well as the differences in the composite outcome
between the two groups, we performed an additional secondary outcome investigating
the differences in latency period and the development of severe features according
to each individual hypertensive disorder. Mean latency was slightly longer in the
gestational hypertension group (24.4 days) compared with preeclampsia without severe
features (20.5 days) and chronic hypertension with superimposed preeclampsia without
severe features (20.9 days). The development of severe features, however, was twice
as likely in the group with chronic hypertension with superimposed preeclampsia without
severe features (37 of 61 patients, 60.7%) compared with either gestational hypertension
(10 of 46 patients, 21.7%) or preeclampsia without severe features (30 of 97 patients,
30.9%), p < 0.001 for both comparisons. The development of severe features in the gestational
hypertension group compared with the preeclampsia without severe features group was
not different, p = 0.25.
Discussion
Our multicenter, retrospective study is the first to investigate the clinical utility
of weekly laboratory testing in the outpatient management of gestational hypertension
and preeclampsia without severe features to our knowledge. Our extensive literature
review spanning PubMed, Medline, Google Scholar, and Embase did not reveal any prior
studies specifically investigating this topic. The comparison of patients who were
managed without laboratory testing to those managed with laboratory testing showed
that the group managed without laboratory testing did not have less favorable maternal
or fetal outcomes. In our 204-patient cohort, no patient was delivered primarily due
to an abnormality in laboratory values, and only 1 patient had abnormal laboratories
at the time of delivery (thrombocytopenia only).
Patients in the laboratories group were older and had higher rates of chronic hypertension,
which subsequently led to findings of higher rates of superimposed preeclampsia without
severe features, earlier age at both diagnosis and delivery, as well as higher rates
of NICU admission. Patients in our cohort with the diagnosis of chronic hypertension
with superimposed preeclampsia had twice the rate of development of severe features
compared with preeclampsia without severe features or gestational hypertension. Additionally,
prior studies support that chronic hypertension in pregnancy has been associated with
a higher risk of both maternal and fetal morbidity and mortality. The laboratories
group is a higher risk population than the no laboratories group in our comparison,
so the differences in outcomes reported is not surprising.[5]
The laboratories group was found to have a higher rate of the composite maternal morbidity,
but the only outcome noted in either group of the study cohort was the development
of severe features. No patient developed HELLP syndrome, placental abruption, eclampsia,
maternal death, or maternal ICU admission. In our cohort, the decision to treat each
patient as an outpatient was made at the discretion of a maternal–fetal medicine specialist.
Our overall compliance with outpatient management was high at 83.7%. Additionally,
the majority of patients included in our study were diagnosed with hypertensive disorders
after 30 weeks of gestation. Our original study design was set to include patients
diagnosed as early as 230/7 weeks, but only 16 of the patients in our cohort were diagnosed at less than 30 weeks.
Patients with multiple risk factors for preeclampsia are more likely to develop early
onset and/or severe features of preeclampsia.[6] Our study cohort self-selected to include mostly patients diagnosed with hypertensive
disorders at a later gestational age. Patients diagnosed in the third trimester were
more likely to be viewed as appropriate for management in the outpatient setting.
Our study findings may not be applicable to patients diagnosed in the second trimester.
We hypothesize that our appropriate selection of patients to be treated outpatient,
close monitoring, and high patient compliance allowed early recognition of severe
signs and symptoms of preeclampsia with subsequent delivery prior to the development
of less favorable outcomes included in the composite.
While the laboratories group had a higher rate of development of severe features,
this group also had a higher rate of chronic hypertension. Physiologic changes in
pregnancy can cause blood pressure increases in the late second and early third trimesters
in patients with chronic hypertension.[7] It is often difficult to distinguish between physiologic elevations in blood pressure
and the development of superimposed preeclampsia. When a patient's blood pressures
are persistently in the severe range, they are often treated as preeclampsia with
severe features despite the absence of other severe signs or symptoms.[5]
[7] Maternal headache refractory to medication is another diagnostic criterion for preeclampsia
with severe features, but it is also a common complaint in pregnancy.[8] Headache as an isolated symptom of preeclampsia with severe features has not been
associated with adverse outcomes in the literature.[8] Physicians being aware of increased risk of adverse outcomes with superimposed preeclampsia
are more likely to act on increasing blood pressure or maternal symptoms in these
individuals.[5] The laboratories group had a 7% higher reported rate of severe blood pressures and
a 4% higher rate of maternal symptomatology prompting delivery, which could explain
the higher rate of severe features in the laboratories group.
Indications for delivery were similar between the two groups. The most significant
finding in our study cohort is that no patient was delivered for the primary indication
of abnormal laboratory values. Schoen et al reported in a cohort of 198 patients with
superimposed preeclampsia treated outpatient, 16 (8.1%) of patients were delivered
for the primary indication of abnormal laboratory values.[3] As previously discussed, superimposed preeclampsia carries a higher risk of progression
to severe disease. Our population had an overall lower number of patients with superimposed
preeclampsia and a higher rate of preeclampsia without severe features and gestational
hypertension, so our overall study population is relatively lower risk and would be
expected to have a lower rate of laboratory abnormalities. Valent et al reported a
similar rate of 9.5% of patients being delivered for abnormal laboratory values, but
this cohort only included patients managed inpatient which is not comparable to our
relatively lower risk cohort.[9] We strengthened our reporting of delivery indication by also reporting that only
one patient in our cohort had abnormal laboratory values at delivery.
Strengths of this study include a large number of patients managed at two tertiary
teaching hospitals with an even racial distribution which makes the results generalizable.
Major medical conditions were not excluded unless baseline signs of end-organ dysfunction
were present. As the population effected by hypertensive disorders of pregnancy generally
has multiple medical comorbidities, this also makes the results generalizable. The
main weakness of this study is the retrospective, nonrandomized study design. Over
the course of the study period, the recommendations for management of hypertensive
disorders as well as diagnostic criteria changed,[1]
[4] and the physicians at the study sites became more comfortable treating these hypertensive
disorders outpatient. A prospective trial at these two sites would likely yield a
much higher number of patients over a similar time period.
We do not advise a change in the current standard of care regarding weekly laboratory
testing in the outpatient management of gestational hypertension, preeclampsia without
severe features, and superimposed preeclampsia without severe features based on our
findings. Our study does suggest that in a carefully selected, compliant patient population,
the clinical evaluation regarding maternal blood pressure and symptomatology was used
more often in the management of these patients. Elevated maternal blood pressure and/or
maternal symptomatology associated with severe preeclampsia may be present before
laboratory findings of end-organ dysfunction in this group. Our study findings also
suggest that the diagnosis of chronic hypertension with superimposed preeclampsia
is a higher risk group and may warrant more intensive follow-up than the diagnoses
of preeclampsia without severe features and gestational hypertension.
In conclusion, our study suggests that weekly laboratory testing may have minimal
clinical utility in the outpatient management of hypertensive disorders of pregnancy.
Larger, prospective randomized trials are needed to determine the appropriate timing
and frequency of laboratory testing in this population with a specific focus on stratifying
the need for laboratories based on the particular hypertensive disorder that is diagnosed.
