Johannes Stubert*, Stefanie Ullmann, Max Dieterich, Doreen Diedrich and Toralf Reimer
Introduction
The estimated incidence of preeclampsia is about
0.42.8% of all pregnancies in Europe [6, 10]. The vast
majority develops close to term (34 weeks of gestation) and is characterized by mild clinical signs. Only
a minority of patients present a severe clinical course
[26, 38]. Characteristically, severe preeclampsia develops early in pregnancy (<34 weeks of gestation) and
is more frequently associated with an adverse maternal and fetal outcome [15, 17, 18, 25]. Thus, it is widely
accepted to discriminate the syndromic disease preeclampsia, in respect of the time of onset, into two distinct entities, which are also characterized by a different
pathogenetic appearance [37]. An outcome analysis may
be biased if early-onset (EO) and late-onset (LO) preeclampsia are directly compared to each other because
some of the postulated differences may exclusively be
related to the different grades of severity. While mild
preeclampsia is mainly associated with a nearly unaffected clinical course, severe cases are commonly
treated by interventionist care. Safekeeping of maternal
health in preeclampsia is most relevant, and, consecutively, a termination of pregnancy by cesarean section
with consecutive preterm parturition is often mandatory. In Western Europe, with a system of intensive
perinatal care, the risk of maternal mortality as well as
serious, irreversible morbidity is very low [6]. But perinatal morbidity and mortality remain problematic due
to prematurity and the high incidence of intrauterine
growth restriction [35]. In selected cases of preeclampsia
and with respect to the severity of maternal symptoms,
expectant management may be an option to improve
perinatal outcome [4]. But parameters that enable prediction of fetal risks in preeclampsia are poorly defined.
Recent studies reported of an abnormal uterine Doppler
flow as a predictor for worse perinatal outcome in preeclampsia [12, 19]. The aim of our study was to analyze the
clinical differences between severe preeclampsia in EO
and LO cases and to evaluate parameters that could help
to predict perinatal outcome.
Methods
Patient selection and criterions of inclusion
The retrospective analysis encompassed all patients with severe preeclampsia diagnosed between January 1, 2006, and December 31, 2011, at
the Department of Obstetrics and Gynecology at the University of Rostock, Germany. Only singleton pregnancies were included. Preeclampsia
was defined as being present when blood pressure was 140/90mm Hg
(taken twice, 6 h apart) combined with a proteinuria level 300 mg
in a 24-h collection [29]. Alternatively, confirmation of proteinuria by
semiquantitative urine dipstick analysis with at least 2+ was allowed
[1]. Severe preeclampsia was defined on the basis of preeclampsia with
at least one of the following: (1) blood pressure: systolic 160mm Hg or
diastolic 110mm Hg; (2) proteinuria 5 g/24 h; (3) syndrome of hemolysis, elevated liver enzymes and low platelets (HELLP) [31, 32]. Patients
with HELLP syndrome were only included in cases of concomitant signs
of preeclampsia (hypertension and proteinuria). HELLP syndrome
was defined as being present when platelet count was <100,000/mL
(normal range: 150,000450,000/mL), haptoglobin serum levels were
<0.3 g/L (normal range: 0.32.0 g/L) and AST levels were >70 U/L (normal range: 334 U/L). Chronic hypertension was defined as blood pressure levels 140/90mm Hg prior to 20 weeks of gestation [1]. According
to the clinical onset, patients were assigned to EO preeclampsia if
disease became manifest before 34 weeks of gestation and LO preeclampsia if manifestation was 34 weeks of gestation [37]. Gestational
age was calculated from the first day of the last menstrual period and
corrected by ultrasound if measurement of the crown-rump length
during the first trimester revealed a difference of 14 days. As the
national guideline [28] recommends a correction already at a difference
of more than 7 days, all data were retrospectively reevaluated. Small
for gestational age (SGA) was defined as a birth weight less than the
10th percentile for gestational age, according to Voigt et al. [36]. Generally, intrauterine growth restriction/fetal growth restriction (IUGR/
FGR) has not been clearly defined [14, 39] in our study; in cases of SGA
with additional signs of placental insufficiency (oligohydramnion or
abnormality of uterine or umbilical artery Doppler measurements),
an IUGR was assumed. Although the majority of SGA cases fulfilled
the criteria of IUGR, we used the better-defined parameter SGA as a
correlate for IUGR, keeping in mind that few SGA newborns were not
growth restricted. Placental weight and birth weight/placental weight
ratio were classified according to Thompson etal. [33]. For ultrasound
examinations, a Voluson 730 ultrasound system (GE Medical Systems,
Milwaukee, WI, USA) was used. All measurements were performed
by one of two experienced observers following the recommendations
for Doppler ultrasonography measurements in obstetrics [2]. We used
the reference values from Schaffer [30] for analysis of Doppler indices.
Abnormal uterine artery Doppler velocimetry (UtADV) was assumed
if a bilateral increased resistance index (RI) >95th percentile and/or a
distinct postsystolic incision (notch) was detected. For the umbilical
artery (UA), a pulsatility index (PI) >95th percentile, and for the middle
cerebral artery (MCA), a PI <5th percentile, indicating a redistribution of
fetal blood flow, were defined as abnormal.
Statistical analysis
All data were stored and analyzed using the SPSS statistical package
version 19.0 (SPSS Inc., Chicago, IL, USA).
Descriptive statistics were computed for continuous and categorical variables. The statistics computed included mean, median,
standard deviation (SD), minimum, maximum and number of
available observations of continuous variables, and are presented
as meanSD; for categorical variables, frequencies and relative
frequencies are presented. Testing for differences of continuous
variables between the study groups (EO vs. LO preeclampsia) was
accomplished by the two-sample t-test for independent samples or
the Mann-Whitney U-test, as appropriate. Test selection was based
on evaluating the variables for normal distribution, employing the
Kolmogorov-Smirnov test. Comparison between the study groups
for categorical variables was done using the 2-test or the Fishers
exact test. All P values resulted from two-sided statistical tests, and
values of P<0.05 were considered to be statistically significant. For
correlation analysis, Pearsons correlations coefficient(r) was calculated if normally distributed variables were given. Otherwise, or in
cases of nonparametric data, the Spearmans correlations coefficient
was assessed. The logistic regression model was used to assess the
independence of specific perinatal outcome parameters from prognostic factors. First, univariate analyses were performed to reveal
unadjusted significant associations between prognostic variables
and outcome. Thereafter, variables yielding P values 0.05 in the
univariate analysis were entered in the multivariate model to highlight some adjusted associations between the outcome and several
covariates.
Results
Maternal characteristics
During the evaluation period of 6 years, we identified
68 patients in our tertiary care center who developed a
severe preeclampsia; they were included in our analysis (Table 1). The estimated prevalence of severe preeclampsia was low, complicating only about 0.5% of all
pregnancies in our department. Of all cases with severe
preeclampsia, 64.7% were EO, whereas about one third
were LO diseases. No differences between the EO and
the LO groups were observed regarding the criteria of
disease severity (blood pressure, proteinuria, prevalence
of HELLP syndrome or isolated elevated liver enzymes).
Preexisting risk factors for the development of preeclampsia did not differ between both groups, but patients
with EO disease tended towards a higher prevalence of
chronic hypertension [34.1% vs. 16.7%, OR 2.78, 95%
confidence interval (CI) 0.809.62, P=0.108]. The appearance of chronic hypertension was not correlated to SGA
birth weight (r=0.09, P=0.48). The mean gestational age
at delivery was significantly lower in the EO group (31+5
vs. 37+5 weeks, P<0.001). Although most patients were
primiparae, those with EO diseases had significantly
more previous pregnancies in their histories (P=0.017).
Referring to this, a higher mean abortion rate (0.360.86
Age (years)
MeanSD
Minimummaximum
Gravidity
Median
Minimummaximum
Parity
Median
Minimummaximum
MeanSD
Minimummaximum
Thrombophilia (n)
Minimummaximum
Minimummaximum
Proteinuria (mg/day)
MeanSD
Minimummaximum
Platelets (109/L)
MeanSD
Minimummaximum
AST (U/L)
MeanSD
Minimummaximum
CrP (mg/L)
MeanSD
Minimummaximum
Minimummaximum
28.66.2
1842
1
15
0
03
25.66.0
15.643.1
12 (17.6%)
19 (27.9%)
8 (11.8%)
8 (11.8%)
3 (4.4%)
5 (7.4%)
172.519.3
133230
107.312.8
80160
49875819
12228,952
10 (14.7%)
22 (32.4%)
7 (10.3%)
16 (23.5%)
181.585.8
12475
150.5290.5
13.21645.2
28.342.7
0.3186.8
33+631
24+541+3
28.96.8
1842
1
15
0
03
24.95.4
15.642.2
6 (13.6%)
15 (34.1%)
5 (11.4%)
6 (13.6%)
1 (2.3%)
4 (9.1%)
171.418.5
136230
107.514.2
80160
49365787
12228,952
8 (18.2%)
14 (31.8%)
4 (9.1%)
11 (25.0%)
174.887.3
12475
155.3266.8
18.81461.0
32.445.0
0.3186.8
31+528
24+539+6
28.05.0
2038
1
12
0
01
26.87.0
17.243.1
6 (25.0%)
4 (16.7%)
3 (12.5%)
2 (8.3%)
2 (8.3%)
1 (4.2%)
174.420.9
133215
106.99.7
90120
50856022
26321,578
2 (8.3%)
8 (33.3%)
3 (12.5%)
5 (20.8%)
193.683.4
35355
142.0334.8
13.21645.2
20.637.7
0.3135.0
37+514
34+441+3
P-value
0.505a
0.017b
0.126b
0.214a
0.321c
0.163c
0.887c
0.703c
0.545c
0.654c
0.541a
0.853a
0.804b
0.802c
0.773c
0.392a
0.318b
0.393b
<0.001b
SD=Standard deviation. Italic emphasis of P-values represents statistical significance with P<0.05.
Students t-test.
b
Mann-Whitney U-test.
c
Pearsons 2-test for homogeneity.
a
MeanSD
Minimummaximum
Median
Minimummaximum
Apgar 7 (n)
MeanSD
Minimummaximum
pH 7.20 (n)
pH 7.197.10 (n)
pH 7.097.00 (n)
pH <7.00 (n)
MeanSD
Minimummaximum
37+0 weeks
34+036+6 weeks
28+033+6 weeks
24+027+6 weeks
All severe
PE (n=68)
19971032
3604490
20 (29.4%)
4 (5.9%)
9
210
17 (25.0%)
7.290.079
6.977.43
62 (91.2%)
3 (4.4%)
2 (2.9%)
1 (1.5%)
6 (8.8%)
1.123.91
15 to +5
17 (25.0%)
23 (33.8%)
17 (25.0%)
11 (16.2%)
Early onset
(n=44)
Late onset
(n=24)
P-value
1460685
3603215
15 (34.1%)
0 (0.0%)
210
17 (38.6%)
7.270.083
6.977.38
39 (88.6%)
2 (4.5%)
2 (4.5%)
1 (2.3%)
5 (11.4%)
1.384.13
15 to +5
3 (6.8%)
13 (29.5%)
17 (38.6%)
11 (25.0%)
2981816
15804490
5 (20.8%)
4 (16.7%)
810
0 (0.0%)
7.310.068
7.107.43
23 (95.8%)
1 (4.2%)
0 (0.0%)
0 (0.0%)
1 (4.2%)
0.653.54
10 to +4
14 (58.3%)
10 (41.7%)
0 (0.0%)
0 (0.0%)
<0.001a
0.017c
<0.001b
0.097a
0.863c
0.413c
0.422b
<0.001c
UApH=Umbilical artery pH. Italic emphasis of P-values represents statistical significance with P<0.05.
Students t-test.
b
Mann-Whitney U-test.
c
Pearsons 2-test for homogeneity.
a
hypotrophic with a birth weight <10th percentile. In contrast, if birth weight/placental weight ratios were analyzed, 61.9% of all LO cases and only 39.5% (P=0.112) in
the EO group showed a ratio >90th percentile. Furthermore, all SGA infants with a LO preeclampsia displayed
a placental weight <10th percentile, whereas only 71.4% of
the cases with an EO preeclampsia did so. In our study,
28.6% (4/14) of the SGA newborns had a normal-weight
placenta, but even so fulfilled the criteria of an IUGR. For
these cases, placental hypotrophy alone was not exclusive
for the development of a SGA neonate. None of these placentas was a diabetic one. Furthermore, in both groups,
about half of all appropriate-weight newborns had a
placental weight <10th percentile (Supplementary Table).
Management of delivery
Maternal as well as fetal situation was considered for indication of delivery. Compromise of maternal well-being
All severe PE
(n=68)
Early onset
(n=44)
Late onset
(n=24)
MeanSD
Minimummaximum
<10th percentile
Minimummaximum
Oligohydramnion (AFI 5)
352.4141.3
130640
1 (1.6%)
33 (53.2%)
6
5.321.47
2.119.20
28 (47.5%)
2 (3.4%)
9
12 (17.9%)
5 (7.5%)
1
292.6116.1
130602
1 (2.5%)
22 (55.0%)
4
4.761.31
2.118.55
15 (39.5%)
2 (5.3%)
6
7 (15.9%)
2 (4.5%)
0
461.2117.2
280640
0 (0.0%)
11 (50.0%)
2
6.401.12
4.849.20
13 (61.9%)
0 (0.0%)
3
5 (21.7%)
3 (13.0%)
1
P-value
<0.001a
0.864c
<0.001b
0.112c
0.333c
Table 4Management of pregnancy and delivery of patients with severe preeclampsia and differentiation between early and late onset.
Characteristics
All severe
PE (n=68)
Early onset
(n=44)
Late onset
(n=24)
P-valuea
Oral
Intravenous
Cesarean
Vaginal
General anesthesia
35 (51.5%)
19 (27.9%)
34 (50.0%)
9 (13.2%)
6 (8.8%)
22 (30.3%)
44 (64.7%)
64 (94.1%)
4 (5.9%)
33 (51.6%)
31 (48.4%)
33 (75.0%)
19 (43.2%)
15 (34.1%)
9 (20.5%)
1 (2.3%)
17 (38.6%)
27 (61.4%)
43 (97.7%)
1 (2.3%)
21 (48.8%)
22 (51.2%)
2 (8.3%)
0 (0.0%)
19 (79.2%)
0 (0.0%)
5 (20.8%)
5 (20.8%)
17 (70.8%)
21 (87.5%)
3 (12.5%)
12 (57.1%)
9 (42.9%)
<0.001
<0.001
0.069
0.122
0.601
SGA
Explanatory variable
Adjusted ORa
95% CI
P-value
Chronic hypertension
General anesthesia
Abnormal UtADV
Chronic hypertension
2.5
2.4
2.0
15.0
4.4
4.3
6.1
11.4
17.3
0.512.5
0.610.3
0.314.3
3.371.4
0.923.3
1.017.9
1.327.8
1.871.4
1.3223.2
0.288
0.234
0.421
<0.001b
0.077
0.043
0.020
0.010
0.029
Table 6Results of Doppler measurements on patients with severe preeclampsia and differentiation between early and late onset.
Characteristics
All severe
PE (n=68)
Early onset
(n=44)
Late onset
(n=24)
P-valuea
Normal or unilateral
Bilateral
Bilateral
95th percentile
>95th percentile
<5th percentile
26 (47.3%)
29 (52.7%)
13
31 (55.4%)
25 (44.6%)
12
26 (46.4%)
30 (53.6%)
12
38 (66.7%)
19 (33.3%)
11
38 (77.6%)
11 (22.4%)
19
12 (30.8%)
27 (69.2%)
5
16 (41.0%)
23 (59.0%)
5
11 (28.2%)
28 (71.8%)
5
23 (57.5%)
17 (42.5%)
4
25 (71.4%)
10 (28.6%)
9
14 (87.5%)
2 (12.5%)
8
15 (88.2%)
2 (11.8%)
7
15 (88.2%)
2 (11.8%)
7
15 (88.2%)
2 (11.8%)
7
13 (92.9%)
1 (7.1%)
10
<0.001
0.001
<0.001
0.032
0.143
P=0.017). Uterine flow pathology was significantly correlated to lower 5-min Apgar values (r=0.40, P=0.002) and
to chronic hypertension (r=0.30, P=0.027).
Surprisingly, uterine artery blood flow was not correlated to birth weight (r=0.22, P=0.112) as well as to placental weight percentiles (r=0.17, P=0.247), although 68.8%
of the SGA newborns were associated with an abnormal
UtADV. In contrast, flow patterns of the UA were significantly correlated to birth weight percentiles (r=0.36,
P=0.006) and SGA newborns showed more frequently a
pathological UA Doppler (58.8% vs. 22.5%, P=0.08).
SGA
Explanatory variable
Crude OR
95% CI
P-value
Chronic hypertension
General anesthesia
Abnormal UtADV
Abnormal UA velocimetry
Chronic hypertension
General anesthesia
Abnormal UtADV
Abnormal UA velocimetry
Chronic hypertension
General anesthesia
Abnormal UtADV
Abnormal UA velocimetry
3.5
3.5
8.0
3.7
3.1
12.3
4.1
1.6
0.8
0.6
2.4
2.0
4.9
1.2
4.6
5.0
16.4
1.1
3.8
4.0
2.1
8.5
0.4
2.6
1.111.6
1.111.7
1.640.3
0.915.6
0.911.1
3.149.5
1.114.4
0.46.2
0.22.5
0.21.8
0.78.3
0.58.1
1.516.6
0.43.6
1.316.3
1.318.7
1.8142.9
0.25.7
0.437.0
0.532.3
0.316.4
0.976.9
0.12.4
0.415.9
0.037
0.038
0.012
0.076
0.081
<0.001
0.030
0.487
0.655
0.364
0.155
0.309
0.010
0.679
0.018
0.016
0.014
0.936
0.243
0.194
0.472
0.058
0.317
0.315
Discussion
Assuming the clinical differences between EO and LO
preeclampsia were notably found by differences in
severity, we compared only cases with severe preeclampsia. Our results showed that, even if only cases
fulfilling the criteria of severity were analyzed, some
significant differences were apparent between EO and
LO preeclampsias. Interestingly, differences were not
related to innate preeclamptic characteristics, e.g.,
grade of hypertension and proteinuria or incidence
of HELLP syndrome. Frequency of risk factors predisposing for the development of preeclampsia like renal
dysfunction, thrombophilia and diabetes or high BMI
did not differ between both groups either. All of these
factors predispose for maternal endothelial dysfunction
and therefore may support the development of severe
preeclampsia [23]. Only the appearance of chronic
hypertension tended to be more frequent in EO preeclampsias and, furthermore, was an independent risk
factor for neonatal acidosis, but was not correlated to
the development of SGA infants.
The most impressive differences between EO and
LO preeclampsia referred to the frequency of abnormal
maternal as well as fetal Doppler velocimetry and to the
incidence of SGA newborns. Generally, patients with EO
preeclampsia showed more abnormalities of uteroplacental perfusion and of fetal growth. This known correlation and the observation of abnormal UtADV and also
of the histopathological correlate a shallow trophoblast invasion in cases of fetal growth restriction
without hypertensive disorders [3] led to the hypothesis
that abnormal uteroplacental perfusion is predominantly responsible for impaired fetal growth and is not
exclusive for the development of the preeclampsia syndrome [13]. The observation that in our study only about
half of all severe preeclampsias showed an abnormal
UtADV partially supported this hypothesis. But in contrast, we neither found a correlation between abnormal
UtADV and fetal growth nor was an abnormal UtADV
associated with an increased risk for the occurrence of
SGA infants. Moreover, patients with LO preeclampsia
had a higher proportion of SGA infants than of abnormal UtADV. Therefore, in severe preeclampsia, other
factors seemed to be more important for the development of SGA, although insufficient transformation of
spiral arteries may impair placental development even
in a minor grade that cannot be visualized by an abnormal UtADV.
The strong associations with abnormal UA velocimetry as well as low placental weight suggest that a
concomitant intraplacental dysfunction may be arbitrative for fetal malnutrition in preeclampsia. The development of growth restriction in preeclampsia may also be
triggered by inherent changes in the villus structure with
subsequent increase in umbilical impedance and nutritive impairment. In accordance, we found differences
between EO and LO diseases in respect of the development of placental weight. While all SGA newborns of the
LO group had a placenta weight <10th percentile, some
of the SGA newborns of the EO group also had a normal
placenta weight. Therefore, in EO preeclampsia, SGA
may be generated not only by restricted placental growth
but in some cases also by an intraplacentally developed
nutritive malfunction. In a Norwegian population study
[7], placenta weights of preeclamptic and normotensive SGA newborns were compared, showing no differences in small placentas of the lowest decile. But 0.9%
of the preeclamptic SGA placentas and only 0.07% of
the normotensive SGA group were in the highest decentile of placental weight [7]. The OR for preeclamptic SGA
newborns with a placenta weight 90th percentile was
1.36 (95% CI 0.662.79) compared to normotensive SGA,
although it was not significant due to the low number of
patients. As preeclampsia is commonly associated with
placental infarcts, disturbance of placental microcirculation and fibrinoid villous degeneration development of
fetal growth restriction in severe EO preeclampsia may
also be triggered by these secondary structural changes
[21]. Otherwise, both groups of our study population contained many newborns with appropriate birth weights
that showed a placental weight <10th percentile, illustrating the compensatory capability of the placental nutritive function. In a recent study of the differences between
placental pathologies, the following were observed:
EO preeclampsias presented with dominating vascular
lesions of the villous tree, whereas LO preeclampsia placentas showed a more common infiltration with inflammatory cells [22]. These findings further emphasize the
differences between both entities of preeclampsia. Furthermore, the authors found higher rates of placental
hypotrophy in EO preeclampsias, but in this context the
statement is of limited information because they did not
correlate the results to birth weight percentiles.
Somewhat obvious were the differences in previous
pregnancies between EO and LO preeclampsia. History
of recurrent miscarriages (3) combined with infertility
treatment was shown to be a risk factor for preeclampsia
[34]. However, we found no data regarding elective pregnancy termination (induced abortion). As a higher rate of
gravidity in our study was found in cases of miscarriage
as well as of elective pregnancy terminations, a further
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Hernandez-Andrade E, etal. ISUOG practice guidelines: use
[39] Zhang J, Merialdi M, Platt LD, Kramer MS. Defining normal and
abnormal fetal growth: promises and challenges. Am J Obstet
Gynecol. 2010;202:5228.
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