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

2014; 42(5): 617–627

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 Introduction
Aims: To analyze the clinical differences between early-
The estimated incidence of preeclampsia is about
and late-onset cases of severe preeclampsia and to evaluate
0.4–2.8% of all pregnancies in Europe [6, 10]. The vast
parameters that could help to predict perinatal outcome.
majority develops close to term (  ≥  34 weeks of gesta-
Methods: Over a period of 6 years, all cases of severe
tion) and is characterized by mild clinical signs. Only
preeclampsia (n = 68) at our institution were included in
a minority of patients present a severe clinical course
a retrospective cohort analysis. Differences between early
[26, 38]. Characteristically, severe preeclampsia devel-
( < 34 weeks, n = 44) and late (  ≥  34 weeks, n = 24) onset of
ops early in pregnancy ( < 34 weeks of gestation) and
the disease were evaluated. Risk factors for low 5-min
is more frequently associated with an adverse mater-
Apgar score (  ≤  7), small-for-gestational-age (SGA) infants
nal and fetal outcome [15, 17, 18, 25]. Thus, it is widely
and neonatal acidosis (umbilical arterial pH  < 7.20) were
accepted to discriminate the syndromic disease preec-
identified and considered in a multiple logistic regression
lampsia, in respect of the time of onset, into two dis-
model.
tinct entities, which are also characterized by a different
Results: Early- and late-onset severe preeclampsia dif-
pathogenetic appearance [37]. An outcome analysis may
fered from each other remarkably. Perinatal outcome
be biased if early-onset (EO) and late-onset (LO) preec-
was unfavorable in early-onset disease and seemed to be
lampsia are directly compared to each other because
mainly a result of premature delivery and development of
some of the postulated differences may exclusively be
fetal growth restriction. Abnormal uterine Doppler veloci-
related to the different grades of severity. While mild
metry increased the risk of low 5-min Apgar values [odds
preeclampsia is mainly associated with a nearly unaf-
ratio (OR) 8.0, P = 0.012] and preterm birth  < 34+0 weeks
fected clinical course, severe cases are commonly
(OR 17.9, P < 0.001). An increased resistance of the umbili-
treated by interventionist care. Safekeeping of maternal
cal artery was associated with a higher risk for SGA birth
health in preeclampsia is most relevant, and, consecu-
weight (OR 4.9, P = 0.010).
tively, a termination of pregnancy by cesarean section
Conclusion: Preeclampsia is a heterogeneous syndrome
with consecutive preterm parturition is often manda-
even if only severe cases were analyzed. Abnormal Dop-
tory. In Western Europe, with a system of intensive
pler flow characteristics facilitated the identification of
perinatal care, the risk of maternal mortality as well as
patients who were at increased risk for worse perinatal
serious, irreversible morbidity is very low [6]. But peri-
outcome.
natal morbidity and mortality remain problematic due
to prematurity and the high incidence of intrauterine
Keywords: Early onset; late onset; perinatal outcome;
growth restriction [35]. In selected cases of preeclampsia
severe preeclampsia.
and with respect to the severity of maternal symptoms,
expectant management may be an option to improve
*Corresponding author: Johannes Stubert, MD, Department of perinatal outcome [4]. But parameters that enable pre-
Obstetrics and Gynecology, University of Rostock, Suedring 81, diction of fetal risks in preeclampsia are poorly defined.
18059 Rostock, Germany, Tel.: +49 38144018475, Recent studies reported of an abnormal uterine Doppler
Fax: +49 38144014599, E-mail: johannes.stubert@uni-rostock.de
flow as a predictor for worse perinatal outcome in preec-
Stefanie Ullmann, Max Dieterich and Toralf Reimer: Department
of Obstetrics and Gynecology, University of Rostock, Suedring 81, lampsia [12, 19]. The aim of our study was to analyze the
18059 Rostock, Germany clinical differences between severe preeclampsia in EO
Doreen Diedrich: Institute for Statistics and Informatics in Medicine and LO cases and to evaluate parameters that could help
and Ageing Research, University of Rostock, 18057 Rostock, Germany to predict perinatal outcome.

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618      Stubert et al., Differences between early- and late-onset severe preeclampsia
Methods
Patient selection and criterions of inclusion
The retrospective analysis encompassed all patients with severe preec-
lampsia diagnosed between January 1, 2006, and December 31, 2011, at
the Department of Obstetrics and Gynecology at the University of Ros-
tock, Germany. Only singleton pregnancies were included. Preeclampsia
was defined as being present when blood pressure was   ≥  140/90 mm 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   ≥  160 mm Hg or
diastolic   ≥  110 mm Hg; (2) proteinuria   ≥  5 g/24 h; (3) syndrome of hemol-
ysis, 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: 150,000–450,000/mL), haptoglobin serum levels were
 < 0.3 g/L (normal range: 0.3–2.0 g/L) and AST levels were  > 70 U/L (nor-
mal range: 3–34 U/L). Chronic hypertension was defined as blood pres-
sure levels   ≥  140/90 mm 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 preec-
lampsia 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]. Gen-
erally, 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 et al. [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).
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Descriptive statistics were computed for continuous and cat-
egorical variables. The statistics computed included mean, median,
standard deviation (SD), minimum, maximum and number of
available observations of continuous variables, and are presented
as mean ± SD; 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 χ2-test or the Fisher’s
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, Pearson’s correlations coefficient(r) was calcu-
lated if normally distributed variables were given. Otherwise, or in
cases of nonparametric data, the Spearman’s correlations coefficient
was assessed. The logistic regression model was used to assess the
independence of specific perinatal outcome parameters from prog-
nostic 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 high-
light 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 analy-
sis (Table  1). The estimated prevalence of severe preec-
lampsia 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 preec-
lampsia 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) 0.80–9.62, P = 0.108]. The appear-
ance 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 (0.36 ± 0.86
 Stubert et al., Differences between early- and late-onset severe preeclampsia      619

Table 1 Maternal 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)  P-value

Age (years)        
 Mean ± SD   28.6 ± 6.2  28.9 ± 6.8  28.0 ± 5.0  0.505a
 Minimum–maximum   18–42  18–42  20–38 
Gravidity        
 Median   1  1  1  0.017b
 Minimum–maximum   1–5  1–5  1–2 
Parity        
 Median   0  0  0  0.126b
 Minimum–maximum   0–3  0–3  0–1 
Body mass index (kg/m2)        
 Mean ± SD   25.6 ± 6.0  24.9 ± 5.4  26.8 ± 7.0  0.214a
 Minimum–maximum   15.6–43.1  15.6–42.2  17.2–43.1 
Obesity (BMI  > 30 kg/m2)   12 (17.6%)  6 (13.6%)  6 (25.0%)  0.321c
Chronic hypertension (n)   19 (27.9%)  15 (34.1%)  4 (16.7%)  0.163c
Thrombophilia (n)   8 (11.8%)  5 (11.4%)  3 (12.5%)  0.887c
Nicotine abuse (n)   8 (11.8%)  6 (13.6%)  2 (8.3%)  0.703c
Diabetes mellitus type 1 (n)   3 (4.4%)  1 (2.3%)  2 (8.3%)  0.545c
Chronic renal disease (n)   5 (7.4%)  4 (9.1%)  1 (4.2%)  0.654c
Highest systolic blood pressure (mm Hg)        
 Mean ± SD   172.5 ± 19.3  171.4 ± 18.5  174.4 ± 20.9  0.541a
 Minimum–maximum   133–230  136–230  133–215 
Highest diastolic blood pressure (mm Hg)       
 Mean ± SD   107.3 ± 12.8  107.5 ± 14.2  106.9 ± 9.7  0.853a
 Minimum–maximum   80–160  80–160  90–120 
Proteinuria (mg/day)        
 Mean ± SD   4987 ± 5819  4936 ± 5787  5085 ± 6022  0.804b
 Minimum–maximum   122–28,952  122–28,952  263–21,578 
 Proteinuria  > 3–5 g/day (n)   10 (14.7%)  8 (18.2%)  2 (8.3%)  0.802c
 Proteinuria  > 5 g/day (n)   22 (32.4%)  14 (31.8%)  8 (33.3%) 
 Missing data (n)   7 (10.3%)  4 (9.1%)  3 (12.5%) 
 Concomitant HELLP syndrome (n)   16 (23.5%)  11 (25.0%)  5 (20.8%)  0.773c
Platelets ( × 109/L)        
 Mean ± SD   181.5 ± 85.8  174.8 ± 87.3  193.6 ± 83.4  0.392a
 Minimum–maximum   12–475  12–475  35–355 
AST (U/L)        
 Mean ± SD   150.5 ± 290.5  155.3 ± 266.8  142.0 ± 334.8  0.318b
 Minimum–maximum   13.2–1645.2  18.8–1461.0  13.2–1645.2 
CrP (mg/L)        
 Mean ± SD   28.3 ± 42.7  32.4 ± 45.0  20.6 ± 37.7  0.393b
 Minimum–maximum   0.3–186.8  0.3–186.8  0.3–135.0 
Gestational age at delivery        
 Mean (weeks+days) ± SD (days)   33+6 ± 31  31+5 ± 28  37+5 ± 14   < 0.001b
 Minimum–maximum   24+5–41+3  24+5–39+6  34+4–41+3 

SD = Standard deviation. Italic emphasis of P-values represents statistical significance with P<0.05.
a
Student’s t-test.
b
Mann-Whitney U-test.
c
Pearson’s χ2-test for homogeneity.

vs. 0.13 ± 0.34) as well as a higher mean rate of elective
terminated pregnancies (0.18 ± 0.49 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

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

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

Characteristics   All severe   Early onset   Late onset   P-value

PE (n = 68) (n = 44) (n = 24)

Birth weight (g)        

 Mean ± SD   1997 ± 1032   1460 ± 685   2981 ± 816    < 0.001a
 Minimum–maximum   360–4490   360–3215   1580–4490  
Percentile of birth weight (n)         0.017c
 SGA ( < 10th percentile)   20 (29.4%)   15 (34.1%)   5 (20.8%)  
 LGA ( > 90th percentile)   4 (5.9%)   0 (0.0%)   4 (16.7%)  
5-min Apgar score        
 Median   9   8   9    < 0.001b
 Minimum–maximum   2–10   2–10   8–10  
 Apgar   ≤  7 (n)   17 (25.0%)   17 (38.6%)   0 (0.0%)  
Umbilical arterial blood pH        
 Mean ± SD   7.29 ± 0.079   7.27 ± 0.083   7.31 ± 0.068   0.097a
 Minimum–maximum   6.97–7.43   6.97–7.38   7.10–7.43  
 pH   ≥  7.20 (n)   62 (91.2%)   39 (88.6%)   23 (95.8%)   0.863c
 pH 7.19–7.10 (n)   3 (4.4%)   2 (4.5%)   1 (4.2%)  
 pH 7.09–7.00 (n)   2 (2.9%)   2 (4.5%)   0 (0.0%)  
 pH  < 7.00 (n)   1 (1.5%)   1 (2.3%)   0 (0.0%)  
Neonatal acidosis (UApH  < 7.20)  6 (8.8%)   5 (11.4%)   1 (4.2%)   0.413c
Base excess (mmol/L)         0.422b
 Mean ± SD   –1.12 ± 3.91   –1.38 ± 4.13   –0.65 ± 3.54  
 Minimum–maximum   –15 to +5   –15 to +5   –10 to +4  
Gestational age (n)          < 0.001c
   ≥  37+0 weeks   17 (25.0%)   3 (6.8%)   14 (58.3%)  
 34+0–36+6 weeks   23 (33.8%)   13 (29.5%)   10 (41.7%)  
 28+0–33+6 weeks   17 (25.0%)   17 (38.6%)   0 (0.0%)  
 24+0–27+6 weeks   11 (16.2%)   11 (25.0%)   0 (0.0%)  

UApH = Umbilical artery pH. Italic emphasis of P-values represents statistical significance with P<0.05.
a
Student’s t-test.
b
Mann-Whitney U-test.
c
Pearson’s χ2-test for homogeneity.

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 corre-
lated to lower gestational age at birth (r = 0.61, P < 0.001).
Abnormal UtADV (r = 0.40, P = 0.002), use of general anes-
thesia (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 con-
trast, if birth weight/placental weight ratios were ana-
lyzed, 61.9% of all LO cases and only 39.5% (P = 0.112) in
the EO group showed a ratio  > 90th percentile. Further-
more, 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 pla-
centas 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 indi-
cation of delivery. Compromise of maternal well-being

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 Stubert et al., Differences between early- and late-onset severe preeclampsia      621

Table 3 Placental characteristics of patients with severe preeclampsia and differentiation between early and late onset.

Characteristics   All severe PE  Early onset  Late onset  P-value

(n = 68) (n = 44) (n = 24)

Placenta weight (g)        

 Mean ± SD   352.4 ± 141.3  292.6 ± 116.1  461.2 ± 117.2   < 0.001a
 Minimum–maximum   130–640  130–602  280–640 
Percentile of placental weight (n)         0.864c
  > 90th percentile   1 (1.6%)  1 (2.5%)  0 (0.0%) 
  < 10th percentile   33 (53.2%)  22 (55.0%)  11 (50.0%) 
 Missing data (n)   6  4  2 
Birth weight/placental weight ratio       
 Mean ± SD   5.32 ± 1.47  4.76 ± 1.31  6.40 ± 1.12   < 0.001b
 Minimum–maximum   2.11–9.20  2.11–8.55  4.84–9.20 
  > 90th percentile (n)   28 (47.5%)  15 (39.5%)  13 (61.9%)  0.112c
  < 10th percentile (n)   2 (3.4%)  2 (5.3%)  0 (0.0%) 
 Missing data (n)   9  6  3 
Amnion fluid index (n)         0.333c
 Oligohydramnion (AFI   ≤  5)   12 (17.9%)  7 (15.9%)  5 (21.7%) 
 Polyhydramnion (AFI  > 18)   5 (7.5%)  2 (4.5%)  3 (13.0%) 
 Missing data (n)   1  0  1 

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

a
Student’s t-test.
b
Mann-Whitney U-test.
c
Pearson’s χ2-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 dif-
ferences between EO and LO preeclampsia (Table 4).
Induction of lung maturation using betamethasone
(2 × 12 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 preec-
lampsia 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 4 Management of pregnancy and delivery of patients with severe preeclampsia and differentiation between early and late onset.

Characteristics   All severe   Early onset  Late onset   P-valuea

PE (n = 68) (n = 44) (n = 24)

Induction of lung maturation, n (%)   35 (51.5%)  33 (75.0%)  2 (8.3%)   < 0.001

Indication for delivery, nb          < 0.001
Maternal ( < 34+0 weeks)   19 (27.9%)  19 (43.2%)  0 (0.0%) 
Maternal (  ≥  34+0 weeks)   34 (50.0%)  15 (34.1%)  19 (79.2%) 
Predominantly fetal ( < 34+0 weeks)   9 (13.2%)  9 (20.5%)  0 (0.0%) 
Predominantly fetal (  ≥  34+0 weeks)   6 (8.8%)  1 (2.3%)  5 (20.8%) 
Antihypertensive treatment, n (%)         0.069
 Oral   22 (30.3%)  17 (38.6%)  5 (20.8%) 
 Intravenous   44 (64.7%)  27 (61.4%)  17 (70.8%) 
Mode of delivery, n (%)         0.122
 Cesarean   64 (94.1%)  43 (97.7%)  21 (87.5%) 
 Vaginal   4 (5.9%)  1 (2.3%)  3 (12.5%) 
Anesthesia for cesarean delivery, n (%)        0.601
 Spinal/peridural   33 (51.6%)  21 (48.8%)  12 (57.1%) 
 General anesthesia   31 (48.4%)  22 (51.2%)  9 (42.9%) 
a
Pearson’s χ2-test for homogeneity.
b
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.

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

Table 5 Adjusted odds ratios for perinatal outcome parameters using logistic regression analysis.

Outcome parameter   Explanatory variable   Adjusted ORa  95% CI  P-value

5-min Apgar score   ≤  7   Chronic hypertension   2.5  0.5–12.5  0.288

  General anesthesia   2.4  0.6–10.3  0.234
  Abnormal UtADV   2.0  0.3–14.3  0.421
  Delivery  < 34+0 weeks   15.0  3.3–71.4   < 0.001b
  Placenta weight  < 10th percentile   4.4  0.9–23.3  0.077
SGA   Abnormal UA velocimetry   4.3  1.0–17.9  0.043
  Placenta weight  < 10th percentile  6.1  1.3–27.8  0.020
  Oligohydramnion (AFI  < 8)   11.4  1.8–71.4  0.010
Neonatal acidosis (UApH  < 7.20)  Chronic hypertension   17.3  1.3–223.2  0.029

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

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

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 sig-
nificant after adjustment for gestational age (Table 5).
Doppler flow characteristics
We found significant differences between both groups con-
sidering maternal as well as fetal flow patterns (Table 6).
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 umbil-
ical artery (r = 0.14, P = 0.337). Of all patients with reduced
or absent flow in the UA, 33.3% did not reveal an abnor-
mal UtADV. In contrast, pathological flow patterns of the
UA and the MCA were significantly correlated (r = 0.34,

Table 6 Results of Doppler measurements on patients with severe preeclampsia and differentiation between early and late onset.

Characteristics   All severe  Early onset  Late onset  P-valuea

PE (n = 68) (n = 44) (n = 24)

Uterine artery (resistance index), n          < 0.001

 Normal or unilateral increase   26 (47.3%)  12 (30.8%)  14 (87.5%) 
 Bilateral increase (  ≥  95th percentile)   29 (52.7%)  27 (69.2%)  2 (12.5%) 
 Missing data (n)   13  5  8 
Uterine artery, postsystolic incision (n)         0.001
 Normal or unilateral   31 (55.4%)  16 (41.0%)  15 (88.2%) 
 Bilateral   25 (44.6%)  23 (59.0%)  2 (11.8%) 
 Missing data (n)   12  5  7 
Uterine artery (pathological flow pattern), n         < 0.001
 Normal or unilateral   26 (46.4%)  11 (28.2%)  15 (88.2%) 
 Bilateral   30 (53.6%)  28 (71.8%)  2 (11.8%) 
 Missing data (n)   12  5  7 
Umbilical artery (pulsatility index), n         0.032
   ≤  95th percentile   38 (66.7%)  23 (57.5%)  15 (88.2%) 
  > 95th percentile   19 (33.3%)  17 (42.5%)  2 (11.8%) 
 Missing data (n)   11  4  7 
Middle cerebral artery (pulsatility index), n         0.143
   ≥  5th percentile   38 (77.6%)  25 (71.4%)  13 (92.9%) 
  < 5th percentile   11 (22.4%)  10 (28.6%)  1 (7.1%) 
 Missing data (n)   19  9  10 

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

a
Pearson’s χ2-test.

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 Stubert et al., Differences between early- and late-onset severe preeclampsia      623

P = 0.017). Uterine flow pathology was significantly corre-
lated 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 corre-
lated to birth weight (r = 0.22, P = 0.112) as well as to placen-
tal 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 sig-
nificantly 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 4.3–75.1,
P < 0.001). Chronic hypertension (OR 5.7, 95% CI 1.8–18.1,
P = 0.003) and abnormal MCA velocimetry (OR 8.7, 95%CI
1.6–46.1, P = 0.011) were also associated with an increased
risk of a preterm birth  < 34+0 weeks. Placental hypotro-
phy (weight  < 10th percentile) did not increase the risk of
preterm birth (OR 1.4, 95% CI 0.5–3.8, P = 0.550). Therefore,
low 5-min Apgar values mainly resulted from premature
parturition and the remaining risk factors were predomi-
nantly predictors of preterm birth with the highest OR for
abnormal UtADV.
All significant risk factors for the delivery of SGA new-
borns 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 7 Crude odds ratios for perinatal outcome parameters.

Outcome parameter   Explanatory variable   Crude OR  95% CI  P-value

5-min Apgar score   ≤  7   Chronic hypertension   3.5  1.1–11.6  0.037

  General anesthesia   3.5  1.1–11.7  0.038
  Abnormal UtADV   8.0  1.6–40.3  0.012
  Abnormal ACM velocimetry   3.7  0.9–15.6  0.076
  Abnormal UA velocimetry   3.1  0.9–11.1  0.081
  Delivery  < 34+0 weeks   12.3  3.1–49.5   < 0.001
  Placenta weight  < 10th percentile   4.1  1.1–14.4  0.030
  Oligohydramnion (AFI  < 8)   1.6  0.4–6.2  0.487
SGA   Chronic hypertension   0.8  0.2–2.5  0.655
  General anesthesia   0.6  0.2–1.8  0.364
  Abnormal UtADV   2.4  0.7–8.3  0.155
  Abnormal ACM velocimetry   2.0  0.5–8.1  0.309
  Abnormal UA velocimetry   4.9  1.5–16.6  0.010
  Delivery  < 34+0 weeks   1.2  0.4–3.6  0.679
  Placenta weight  < 10th percentile   4.6  1.3–16.3  0.018
  Oligohydramnion (AFI  < 8)   5.0  1.3–18.7  0.016
Neonatal acidosis (UApH  < 7.20)  Chronic hypertension   16.4  1.8–142.9  0.014
  General anesthesia   1.1  0.2–5.7  0.936
  Abnormal UtADV   3.8  0.4–37.0  0.243
  Abnormal ACM velocimetry   4.0  0.5–32.3  0.194
  Abnormal UA velocimetry   2.1  0.3–16.4  0.472
  Delivery  < 34+0 weeks   8.5  0.9–76.9  0.058
  Placenta weight  < 10th percentile   0.4  0.1–2.4  0.317
  Oligohydramnion (AFI  < 8)   2.6  0.4–15.9  0.315

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

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624      Stubert et al., 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 preec-
lampsia. 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 predis-
posing 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 preec-
lampsias 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 uteropla-
cental perfusion and of fetal growth. This known corre-
lation and the observation of abnormal UtADV and also
of the histopathological correlate – a shallow tropho-
blast invasion – in cases of fetal growth restriction
without hypertensive disorders [3] led to the hypothesis
that abnormal uteroplacental perfusion is predomi-
nantly responsible for impaired fetal growth and is not
exclusive for the development of the preeclampsia syn-
drome [13]. The observation that in our study only about
half of all severe preeclampsias showed an abnormal
UtADV partially supported this hypothesis. But in con-
trast, 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 abnor-
mal UtADV. Therefore, in severe preeclampsia, other
factors seemed to be more important for the develop-
ment of SGA, although insufficient transformation of
spiral arteries may impair placental development even
in a minor grade that cannot be visualized by an abnor-
mal UtADV.
The strong associations with abnormal UA veloci-
metry as well as low placental weight suggest that a
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concomitant intraplacental dysfunction may be arbitra-
tive for fetal malnutrition in preeclampsia. The develop-
ment of growth restriction in preeclampsia may also be
triggered by inherent changes in the villus structure with
subsequent increase in umbilical impedance and nutri-
tive impairment. In accordance, we found differences
between EO and LO diseases in respect of the develop-
ment 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 normoten-
sive SGA newborns were compared, showing no differ-
ences 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 decen-
tile of placental weight [7]. The OR for preeclamptic SGA
newborns with a placenta weight   ≥  90th percentile was
1.36 (95% CI 0.66–2.79) 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 microcircula-
tion 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 con-
tained many newborns with appropriate birth weights
that showed a placental weight  < 10th percentile, illustrat-
ing the compensatory capability of the placental nutri-
tive 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 pla-
centas showed a more common infiltration with inflam-
matory cells [22]. These findings further emphasize the
differences between both entities of preeclampsia. Fur-
thermore, 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 preg-
nancy 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 et al., Differences between early- and late-onset severe preeclampsia      625
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 develop-
ment of EO preeclampsia.
Recent studies showed that the presence of an abnor-
mal UtADV was predictive for an impaired perinatal
outcome in cases of manifest EO as well as LO preeclamp-
sias [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 multivari-
ate 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 dura-
tion 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.
References
[1] ACOG practice bulletin. Diagnosis and management of
preeclampsia and eclampsia. Obstet Gynecol. 2002;99:
159–67.
[2] Bhide A, Acharya G, Bilardo CM, Brezinka C, Cafici D,
Hernandez-Andrade E, et al. ISUOG practice guidelines: use
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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. More-
over, Doppler measurements were not available for all
patients. However, our data represented the current clini-
cal practice out of study conditions.
In conclusion, patients with EO and LO preeclamp-
sia showed differences even if only severe manifesta-
tions 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 unfa-
vorable 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 preeclamp-
sia 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 preeclamp-
tic mothers including the assessment of cardiovascular
diseases.
Author contributions: Johannes Stubert: Study concep-
tion, manuscript writing and statistical analysis. Ste-
fanie 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.
of Doppler ultrasonography in obstetrics. Ultrasound Obstet
Gynecol. 2013;41:233–9.
[3] Brosens I, Kong TY. Defective spiral artery remodeling.
In: Pijnenborg R, Brosens I, Romero R, editors. Placental
bed disorders: basic science and its translation to
626      Stubert et al., Differences between early- and late-onset severe preeclampsia
obstetrics. Cambridge: Cambridge University Press; 2010.
p. 11–21.
[4] Churchill D, Duley L, Thornton JG, Jones L. Interventionist
versus expectant care for severe pre-eclampsia between
24 and 34 weeks’ gestation. Cochrane Database Syst Rev.
2013;7:CD003106.
[5] Cnossen JS, Morris RK, ter RG, Mol BW, van der Post JA,
Coomarasamy A, et al. Use of uterine artery Doppler
ultrasonography to predict pre-eclampsia and intrauterine
growth restriction: a systematic review and bivariable
meta-analysis. Can Med Assoc J. 2008;178:701–11.
[6] Dolea C, AbouZahr C. Global burden of hypertensive disorders
of pregnancy in the year 2000. Evidence and Information for
Policy (EIP). Geneva: World Health Organization; July 2003.
http://www.who.int/evidence/bod.
[7] Eskild A, Vatten LJ. Do pregnancies with pre-eclampsia have
smaller placentas? A population study of 317 688 pregnancies
with and without growth restriction in the offspring. Br J Obstet
Gynaecol. 2010;117:1521–6.
[8] Espinoza J, Kusanovic JP, Bahado-Singh R, Gervasi MT,
Romero R, Lee W, et al. Should bilateral uterine artery
notching be used in the risk assessment for preeclampsia,
small-for-gestational-age, and gestational hypertension?
J Ultrasound Med. 2010;29:1103–15.
[9] Frusca T, Soregaroli M, Platto C, Enterri L, Lojacono A,
Valcamonico A. Uterine artery velocimetry in patients with
gestational hypertension. Obstet Gynecol. 2003;102:
136–40.
[10] Gaillard R, Arends LR, Steegers EA, Hofman A, Jaddoe VW.
Second- and third-trimester placental hemodynamics and the
risks of pregnancy complications: the Generation R Study. Am J
Epidemiol. 2013;177:743–54.
[11] Ganzevoort W, Rep A, de Vries JI, Bonsel GJ, Wolf H. Prediction
of maternal complications and adverse infant outcome at
admission for temporizing management of early-onset severe
hypertensive disorders of pregnancy. Am J Obstet Gynecol.
2006;195:495–503.
[12] Ghi T, Youssef A, Piva M, Contro E, Segata M, Guasina F,
et al. The prognostic role of uterine artery Doppler studies in
patients with late-onset preeclampsia. Am J Obstet Gynecol.
2009;201:36–5.
[13] Huppertz B. Placental origins of preeclampsia: challenging the
current hypothesis. Hypertension. 2008;51:970–5.
[14] Iams JD. Small for gestational age (SGA) and fetal growth
restriction (FGR). Am J Obstet Gynecol. 2010;202:513.
[15] Kucukgoz GU, Ozgunen FT, Buyukkurt S, Guzel AB, Urunsak IF,
Demir SC, et al. Comparison of clinical and laboratory findings
in early- and late-onset preeclampsia. J Matern Fetal Neonatal
Med. 2013;26:1228–33.
[16] Li H, Gudnason H, Olofsson P, Dubiel M, Gudmundsson S.
Increased uterine artery vascular impedance is related to
adverse outcome of pregnancy but is present in only one-third
of late third-trimester pre-eclamptic women. Ultrasound Obstet
Gynecol. 2005;25:459–63.
[17] Lisonkova S, Joseph KS. Incidence of preeclampsia: risk
factors and outcomes associated with early- versus late-onset
disease. Am J Obstet Gynecol. 2013;209:544e1–e12.
[18] MacKay AP, Berg CJ, Atrash HK. Pregnancy-related mortality
from preeclampsia and eclampsia. Obstet Gynecol.
2001;97:533–8.
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[19] Meler E, Figueras F, Bennasar M, Gomez O, Crispi F, Gratacos E.
The prognostic role of uterine artery Doppler investigation in
patients with severe early-onset preeclampsia. Am J Obstet
Gynecol. 2010;202:559–4.
[20] Meler E, Figueras F, Mula R, Crispi F, Benassar M, Gomez O,
et al. Prognostic role of uterine artery Doppler in patients with
preeclampsia. Fetal Diagn Ther. 2010;27:8–13.
[21] Muntefering H, Wysocki M, Rastorguev E, Gerein V. Placenta in
gestational hypertension. Pathologe. 2004;25:262–8.
[22] Nelson DB, Ziadie MS, McIntire DD, Rogers BB, Leveno KJ.
Placental pathology suggesting that preeclampsia is more
than one disease. Am J Obstet Gynecol. 2013;210:66e1–7.
[23] Ness RB, Sibai BM. Shared and disparate components
of the pathophysiologies of fetal growth restriction and
preeclampsia. Am J Obstet Gynecol. 2006;195:40–9.
[24] Newman MG, Robichaux AG, Stedman CM, Jaekle RK,
Fontenot MT, Dotson T, et al. Perinatal outcomes in
preeclampsia that is complicated by massive proteinuria.
Am J Obstet Gynecol. 2003;188:264–8.
[25] Odegard RA, Vatten LJ, Nilsen ST, Salvesen KA, Austgulen R.
Preeclampsia and fetal growth. Obstet Gynecol. 2000;96:
950–5.
[26] Odegard RA, Vatten LJ, Nilsen ST, Salvesen KA, Austgulen R.
Risk factors and clinical manifestations of pre-eclampsia. Br J
Obstet Gynaecol. 2000;107:1410–6.
[27] Rana S, Powe CE, Salahuddin S, Verlohren S, Perschel FH,
Levine RJ, et al. Angiogenic factors and the risk of adverse
outcomes in women with suspected preeclampsia. Circulation.
2012;125:911–9.
[28] Rempen A, Chaoui R, Kozlowski P, Häusler M, Terinde R,
Wisser J. Standards zur Ultraschalluntersuchung in der
Frühschwangerschaft AWMF 015/32 Leitlinie (S1). 2010;
http://www.awmf.org/uploads/tx_szleitlinien/015-032_
S1_Ultraschalluntersuchung_in_der_Fruehschwange
rschaft_07-2008_09-2012.pdf.
[29] Report of the National High Blood Pressure Education Program
Working Group on High Blood Pressure in Pregnancy. Am J
Obstet Gynecol. 2000;183:S1–22.
[30] Schaffer H. Doppler-Referenzkurven. In: Steiner H, Schneider
KTM, editors. Dopplersonographie in Geburtshilfe und
Gynäkologie. Berlin, Heidelberg: Springer Verlag; 2000.
p. 292–3.
[31] Sibai BM. Evaluation and management of severe preeclampsia
before 34 weeks’ gestation. Am J Obstet Gynecol.
2011;205:191–8.
[32] Steegers EA, von DP, Duvekot JJ, Pijnenborg R. Pre-eclampsia.
Lancet. 2010;376:631–44.
[33] Thompson JM, Irgens LM, Skjaerven R, Rasmussen S. Placenta
weight percentile curves for singleton deliveries. Br J Obstset
Gynaecol. 2007;114:715–20.
[34] Trogstad L, Magnus P, Moffett A, Stoltenberg C. The effect
of recurrent miscarriage and infertility on the risk of
pre-eclampsia. Br J Obstet Gynaecol. 2009;116:108–13.
[35] Villar J, Carroli G, Wojdyla D, Abalos E, Giordano D, Ba’aqeel H,
et al. Preeclampsia, gestational hypertension and intrauterine
growth restriction, related or independent conditions? Am J
Obstet Gynecol. 2006;194:921–31.
[36] Voigt M, Rochow N, Hesse V, Olbertz D, Schneider KT, Jorch G.
Short communication about percentile values of body measures
of newborn babies. Z Geburtshilfe Neonatol. 2010;214:24–9.
 Stubert et al., Differences between early- and late-onset severe preeclampsia      627

[37] von Dadelszen P, Magee LA, Roberts JM. Subclassification of
preeclampsia. Hypertens Pregnancy. 2003;22:143–8.
[38] Zhang WH, Alexander S, Bouvier-Colle MH, Macfarlane A.
Incidence of severe pre-eclampsia, postpartum haemorrhage
and sepsis as a surrogate marker for severe maternal
morbidity in a European population-based study: the MOMS-B
survey. Br J Obstet Gynaecol. 2005;112:89–96.
[39] Zhang J, Merialdi M, Platt LD, Kramer MS. Defining normal and
abnormal fetal growth: promises and challenges. Am J Obstet
Gynecol. 2010;202:522–8.
The authors stated that there are no conflicts of interest regarding
the publication of this article.

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