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DOI 10.1515/jpm-2013-0285J. Perinat. Med.

2014; 42(5): 617627

Johannes Stubert*, Stefanie Ullmann, Max Dieterich, Doreen Diedrich and Toralf Reimer

Clinical differences between early- and late-onset


severe preeclampsia and analysis of predictors for
perinatal outcome
Abstract
Aims: To analyze the clinical differences between earlyand late-onset cases of severe preeclampsia and to evaluate
parameters that could help to predict perinatal outcome.
Methods: Over a period of 6 years, all cases of severe
preeclampsia (n=68) at our institution were included in
a retrospective cohort analysis. Differences between early
(<34 weeks, n=44) and late (34 weeks, n=24) onset of
the disease were evaluated. Risk factors for low 5-min
Apgar score (7), small-for-gestational-age (SGA) infants
and neonatal acidosis (umbilical arterial pH <7.20) were
identified and considered in a multiple logistic regression
model.
Results: Early- and late-onset severe preeclampsia differed from each other remarkably. Perinatal outcome
was unfavorable in early-onset disease and seemed to be
mainly a result of premature delivery and development of
fetal growth restriction. Abnormal uterine Doppler velocimetry increased the risk of low 5-min Apgar values [odds
ratio (OR) 8.0, P=0.012] and preterm birth <34+0 weeks
(OR 17.9, P<0.001). An increased resistance of the umbilical artery was associated with a higher risk for SGA birth
weight (OR 4.9, P=0.010).
Conclusion: Preeclampsia is a heterogeneous syndrome
even if only severe cases were analyzed. Abnormal Doppler flow characteristics facilitated the identification of
patients who were at increased risk for worse perinatal
outcome.
Keywords: Early onset; late onset; perinatal outcome;
severe preeclampsia.
*Corresponding author: Johannes Stubert, MD, Department of
Obstetrics and Gynecology, University of Rostock, Suedring 81,
18059 Rostock, Germany, Tel.: +49 38144018475,
Fax: +49 38144014599, E-mail: johannes.stubert@uni-rostock.de
Stefanie Ullmann, Max Dieterich and Toralf Reimer: Department
of Obstetrics and Gynecology, University of Rostock, Suedring 81,
18059 Rostock, Germany
Doreen Diedrich: Institute for Statistics and Informatics in Medicine
and Ageing Research, University of Rostock, 18057 Rostock, Germany

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.

618Stubert etal., Differences between early- and late-onset severe preeclampsia

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

Stubert etal., Differences between early- and late-onset severe preeclampsia619


Table 1Maternal characteristics 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)

Age (years)

MeanSD

Minimummaximum

Gravidity

Median

Minimummaximum

Parity

Median

Minimummaximum

Body mass index (kg/m2)

MeanSD

Minimummaximum

Obesity (BMI >30 kg/m2)

Chronic hypertension (n)

Thrombophilia (n)

Nicotine abuse (n)

Diabetes mellitus type 1 (n)

Chronic renal disease (n)

Highest systolic blood pressure (mm Hg)


MeanSD

Minimummaximum

Highest diastolic blood pressure (mm Hg)


MeanSD

Minimummaximum

Proteinuria (mg/day)

MeanSD

Minimummaximum

Proteinuria >35 g/day (n)

Proteinuria >5 g/day (n)

Missing data (n)

Concomitant HELLP syndrome (n)

Platelets (109/L)

MeanSD

Minimummaximum

AST (U/L)

MeanSD

Minimummaximum

CrP (mg/L)

MeanSD

Minimummaximum

Gestational age at delivery

Mean (weeks+days)SD (days)

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

vs. 0.130.34) as well as a higher mean rate of elective


terminated pregnancies (0.180.49 vs. 0.0) was seen in
the EO preeclampsia group. The short-term maternal
outcome was excellent, and we did not observe any cases
of eclampsia or maternal death in our cohort.

Neonatal and placental characteristics


Generally, perinatal outcome was more unfavorable in the
EO group than in the LO group (Table 2). Preeclampsia
ended in preterm parturition (<37+0 weeks) in 93.2% of

620Stubert etal., Differences between early- and late-onset severe preeclampsia


Table 2Neonatal characteristics of patients with severe preeclampsia and differentiation between early and late onset.
Characteristics

Birth weight (g)

MeanSD

Minimummaximum

Percentile of birth weight (n)


SGA (<10th percentile)

LGA (>90th percentile)

5-min Apgar score

Median

Minimummaximum

Apgar 7 (n)

Umbilical arterial blood pH

MeanSD

Minimummaximum

pH 7.20 (n)

pH 7.197.10 (n)

pH 7.097.00 (n)

pH <7.00 (n)

Neonatal acidosis (UApH <7.20)


Base excess (mmol/L)

MeanSD

Minimummaximum

Gestational age (n)

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

the EO and in 41.7% of the LO cases (P<0.001). The rate


of birth weight below the 10th percentile was significantly
higher (34.1% vs. 20.8%, P=0.017) and 5-min Apgar scores
were significantly lower (8 vs. 9, P<0.001) in EO diseases.
We found no differences between pH of the UA (7.27
vs. 7.31, P=0.097) and the rate of neonatal acidosis with
pH <7.20 (11.4% vs. 4.2%, P=0.413).
Lower 5-min Apgar scores were significantly correlated to lower gestational age at birth (r=0.61, P<0.001).
Abnormal UtADV (r=0.40, P=0.002), use of general anesthesia (r=0.31, P=0.014) and redistribution of circulation
in the MCA (r=0.29, P=0.042) were less strong, but also
significantly correlated with lower 5-min Apgar values.
SGA birth weight was observed in 29.4% (20/68) of all
newborns, and 85.0% (17/20) of those fulfilled the criteria
of IUGR. Therefore the majority of SGA infants could be
regarded as IUGRs.
No differences between EO and LO preeclampsia
were found with respect to percentiles of placental weight
(Table 3). In both groups, about half of all placentas were

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

Stubert etal., Differences between early- and late-onset severe preeclampsia621


Table 3Placental characteristics 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)

Placenta weight (g)

MeanSD

Minimummaximum

Percentile of placental weight (n)


>90th percentile

<10th percentile

Missing data (n)

Birth weight/placental weight ratio


MeanSD

Minimummaximum

>90th percentile (n)

<10th percentile (n)

Missing data (n)

Amnion fluid index (n)

Oligohydramnion (AFI 5)

Polyhydramnion (AFI >18)

Missing data (n)

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

Italic emphasis of P-values represents statistical significance with P<0.05.


a
Students t-test.
b
Mann-Whitney U-test.
c
Pearsons 2-test for homogeneity.

was responsible for 67.9% of preterm births <34+0 weeks.


Predominantly fetal indications for delivery were found
in the remaining 32.1%. Overall, about 22% of deliveries
were predominantly indicated by fetal threat without differences between EO and LO preeclampsia (Table 4).
Induction of lung maturation using betamethasone
(212 mg/48 h) was performed in 75.0% (33/44) of patients

with an EO preeclampsia. Ten of the remaining 11 patients


with EO preeclampsia were delivered after 34 weeks of
gestation. About one third of all patients with EO preeclampsia were delivered after >34+0 weeks.
Mode of delivery was a cesarean section in almost
all cases (94.1%). Mode of anesthesia did not differ
between EO and LO preeclampsia. General anesthesia was

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

Induction of lung maturation, n (%)

Indication for delivery, nb

Maternal (<34+0 weeks)

Maternal (34+0 weeks)

Predominantly fetal (<34+0 weeks)


Predominantly fetal (34+0 weeks)
Antihypertensive treatment, n (%)

Oral

Intravenous

Mode of delivery, n (%)

Cesarean

Vaginal

Anesthesia for cesarean delivery, n (%)


Spinal/peridural

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

Pearsons 2-test for homogeneity.


Maternal indications were HELLP syndrome, uncontrollable hypertension and imminent eclampsia; fetal indications were pathological fetal
heart rate, severe Doppler pathology of UA and/or MCA.

622Stubert etal., Differences between early- and late-onset severe preeclampsia


Table 5Adjusted odds ratios for perinatal outcome parameters using logistic regression analysis.
Outcome parameter
5-min Apgar score 7

SGA

Neonatal acidosis (UApH <7.20)

Explanatory variable

Adjusted ORa

95% CI

P-value

Chronic hypertension

General anesthesia

Abnormal UtADV

Delivery <34+0 weeks

Placenta weight <10th percentile


Abnormal UA velocimetry

Placenta weight <10th percentile


Oligohydramnion (AFI <8)

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

Italic emphasis of P-values represents statistical significance with P<0.05.


Adjusted for gestational age, BMI and maternal age.
b
Adjusted for BMI and maternal age.
a

performed in 48.4% of all cesarean deliveries. Neonates


delivered using general anesthesia had an increased risk
of a 5-min Apgar score 7, but the effect was no longer significant after adjustment for gestational age (Table 5).

Doppler flow characteristics


We found significant differences between both groups considering maternal as well as fetal flow patterns (Table6).
With respect to the evaluable cases, Doppler flow analysis
revealed abnormal UtADV in 71.8% of the EO, but only in

11.8% of the LO preeclampsias (P<0.001). Therefore, only


53.6% of all severe preeclampsias revealed an abnormal
UtADV.
An increased impedance of the UA, regarding the
evaluable cases, was observed in 42.5% of EO and 11.8%
of LO preeclampsias (P=0.032). A similar trend was found
for a decreased PI in the MCA. Pathological uterine flow
curves were not correlated to an increased PI of the umbilical artery (r=0.14, P=0.337). Of all patients with reduced
or absent flow in the UA, 33.3% did not reveal an abnormal UtADV. In contrast, pathological flow patterns of the
UA and the MCA were significantly correlated (r=0.34,

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

Uterine artery (resistance index), n

Normal or unilateral increase

Bilateral increase (95th percentile)

Missing data (n)

Uterine artery, postsystolic incision (n)

Normal or unilateral

Bilateral

Missing data (n)

Uterine artery (pathological flow pattern), n


Normal or unilateral

Bilateral

Missing data (n)

Umbilical artery (pulsatility index), n

95th percentile
>95th percentile

Missing data (n)

Middle cerebral artery (pulsatility index), n


5th percentile

<5th percentile

Missing data (n)

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

Italic emphasis of P-values represents statistical significance with P<0.05.


Pearsons 2-test.

0.001

<0.001

0.032

0.143

Stubert etal., Differences between early- and late-onset severe preeclampsia623

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).

Risk factor analysis for perinatal outcome


Table 7 shows the ORs of potential explanatory variables
with respect to the three perinatal outcome parameters:
low 5-min Apgar score (7), SGA and neonatal acidosis
(UApH <7.20). If a significant difference was observed,
further analysis by logistic regression with adjustment
for gestational age, maternal body mass index (BMI) and
maternal age was performed (Table 5). Preterm birth was
adjusted only for BMI and maternal age. Preterm birth,
chronic hypertension, abnormal UtADV and placenta
weight <10th percentile were significant risk factors for

low 5-min Apgar values. After adjustment, only preterm


birth <34+0 weeks remained a significant risk factor.
Moreover, an abnormal UtADV was a significant risk factor
for preterm delivery <34+0 weeks (OR 17.9, 95% CI 4.375.1,
P<0.001). Chronic hypertension (OR 5.7, 95% CI 1.818.1,
P=0.003) and abnormal MCA velocimetry (OR 8.7, 95%CI
1.646.1, P=0.011) were also associated with an increased
risk of a preterm birth <34+0 weeks. Placental hypotrophy (weight <10th percentile) did not increase the risk of
preterm birth (OR 1.4, 95% CI 0.53.8, P=0.550). Therefore,
low 5-min Apgar values mainly resulted from premature
parturition and the remaining risk factors were predominantly predictors of preterm birth with the highest OR for
abnormal UtADV.
All significant risk factors for the delivery of SGA newborns were typical indicators of placental insufficiency,
which is demonstrated by the high proportion of IUGRs in
this group. In contrast, manifestation of SGA infants was
not correlated with the grade of severity of preeclampsia
(systolic and diastolic blood pressure, proteinuria, HELLP
syndrome). Also, neither preterm birth <34+0 weeks nor
abnormal UtADV was a risk factor for the development
of SGA. Neonatal acidosis was generally rare, and only
chronic hypertension was identified as a significant risk
factor.

Table 7Crude odds ratios for perinatal outcome parameters.


Outcome parameter
5-min Apgar score 7

SGA

Neonatal acidosis (UApH <7.20)

Explanatory variable

Crude OR

95% CI

P-value

Chronic hypertension

General anesthesia

Abnormal UtADV

Abnormal ACM velocimetry

Abnormal UA velocimetry

Delivery <34+0 weeks

Placenta weight <10th percentile


Oligohydramnion (AFI <8)

Chronic hypertension

General anesthesia

Abnormal UtADV

Abnormal ACM velocimetry

Abnormal UA velocimetry

Delivery <34+0 weeks

Placenta weight <10th percentile


Oligohydramnion (AFI <8)

Chronic hypertension

General anesthesia

Abnormal UtADV

Abnormal ACM velocimetry

Abnormal UA velocimetry

Delivery <34+0 weeks

Placenta weight <10th percentile


Oligohydramnion (AFI <8)

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

Italic emphasis of P-values represents statistical significance with P<0.05.

624Stubert etal., Differences between early- and late-onset severe preeclampsia

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

Stubert etal., Differences between early- and late-onset severe preeclampsia625

uterine factor for the development of EO preeclampsia


may exist. An iatrogenic damage of the endometrium by
curettage could be a possible risk factor for the development of EO preeclampsia.
Recent studies showed that the presence of an abnormal UtADV was predictive for an impaired perinatal
outcome in cases of manifest EO as well as LO preeclampsias [9, 12, 16, 19].
Our data supported these results as abnormal UtADV
was associated with an increased risk of lower 5-min
Apgar values. When data were adjusted for gestational
age, the increase in risk was no longer significant. This
may suggest that abnormal UtADV is mostly predictive
for EO preeclampsia and consecutive preterm birth with
subsequently adverse fetal outcome. This is in accordance
with a study analyzing data from a prospective trial on
patients with severe EO preeclampsia [11]. In a multivariate analysis, gestational age was the unique significant
parameter influencing the risk of adverse fetal outcome.
Nonetheless, in practice, abnormal UtADV is a helpful
predictive parameter for pregnancy complications and for
recognition of an increased fetal risk [5, 8]. In contrast,
severity of preeclampsia did not reveal good prediction of
fetal outcome [20, 24] and if fetal outcome was compared
between patients with preeclampsia and normotensive
IUGR after adjustment for gestational age differences were
neither significant for stay on neonatal intensive care unit
nor for neonatal death [35].
An interesting new approach for prediction of adverse
pregnancy outcome including perinatal parameters was
recently reported by Rana et al. [27]. By analyzing the
antiangiogenic soluble fms-like tyrosine kinase 1 and
the angiogenic placental growth factor, they reported
increased risk for maternal and fetal adverse outcome if
the ratio of both factors was increased. Unfortunately, they
only reported of combined adverse outcome and the most
common event was the parameter indicated delivery.
Finally, the ratio was predictive for the remaining duration of pregnancy with only short interval if the ratio was
high. In cases of early onset disease, the parameter may be
useful for the estimation of risk for premature birth.

As our study is a retrospective analysis, it has some


notable limitations. Criteria for delivery were not always
clearly evaluable, especially if a combination of fetal
abnormalities (e.g., non-reassuring fetal heart rate) and
severe maternal symptoms was often co-incident. Moreover, Doppler measurements were not available for all
patients. However, our data represented the current clinical practice out of study conditions.
In conclusion, patients with EO and LO preeclampsia showed differences even if only severe manifestations were analyzed. EO patients had more frequently
abnormal flow patterns of maternal and fetal perfusion
with increased rate of SGA newborns. However, about
one third of patients with severe preeclampsia developed
symptoms after 34+0 weeks and the rate of SGA infants
was also high in this group despite the low incidence
of Doppler abnormalities. Perinatal outcome was unfavorable in EO diseases and mainly seemed to be related
to premature birth as well as to a higher incidence of
growth restriction. In contrast, severity of preeclampsia was not directly relevant for perinatal outcome. An
abnormal UtADV was predictive for lower 5-min Apgar
values and preterm birth, but was not indicative for
SGA. The presence of an abnormal UA Doppler, with
increased resistance, was a significant risk factor for the
development of SGA neonates. The short-term maternal
outcome was excellent in both groups, although our
study did not evaluate the long-term risks of preeclamptic mothers including the assessment of cardiovascular
diseases.
Author contributions: Johannes Stubert: Study conception, manuscript writing and statistical analysis. Stefanie Ullmann: Data assessment, data analysis and proof
reading. Max Dieterich: Manuscript writing and proof
reading. Doreen Diedrich: Statistical analysis. Toralf
Reimer: Study conception and proof reading.

Received October 21, 2013. Accepted January 6, 2014. Previously


published online April 26, 2014.

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