http://informahealthcare.

com/jmf
ISSN: 1476-7058 (print), 1476-4954 (electronic)
J Matern Fetal Neonatal Med, 2013; 26(13): 12991302
! 2013 Informa UK Ltd. DOI: 10.3109/14767058.2013.783807

ORIGINAL ARTICLE

Influencing factors for late-onset preeclampsia*

Sara Ornaghi, Anastasia Tyurmorezova, Paola Algeri, Valentina Giardini, Patriza Ceruti, Emanuela Vertemati, and
Patrizia Vergani
Department of Obstetrics and Gynecology, San Gerardo Hospital, University of Milan-Bicocca, Monza, Italy

Abstract

Keywords

Objective: Different etiologies for early- (534.0 weeks) and late (34.0 weeks)-onset
preeclampsia (EOLO PE) are reported. The aim of our study is to identify influencing factors
for the LO form.
Methods: Retrospective study of 284 consecutive women diagnosed as preeclamptic at
22.441.5 weeks, from 3/2005 to 10/2011, evaluated in relation to EO versus LO PE.
Results: LO PE was identified in 151 cases. Gestational Diabetes Mellitus (11% versus 4%,
p 0.04), body mass index (BMI) 35 kg/m2 (9% versus 2%, p 0.03), pathological weight
gain for BMI class (30% versus 13%, p 0.001), 5 (58% versus 23%, p50.001) and 7 kg/m2
BMI increase (19% versus 9%, p 0.04) were more common in LO than in EO PE. At Estimation
Regression analysis weighted for Gestational Age (GA) at delivery BMI 35 and 5 kg/m2 BMI
increase resulted related to LO PE (OR 3.76, CI(95%) 1.9717.04; OR 4.28, CI(95%) 2.44
7.54).
Conclusions: BMI 35 and 5 kg/m2 increase appeared as influencing factors for LO PE, thus
supporting the role of systemic inflammation in its pathogenesis.

Body mass index, hypertensive disorder,

metabolic syndrome, obesity, weight gain

Preeclampsia (PE) is a multisystem disorder that affects about

23% of all pregnancies. It is an important cause of maternal
death worldwide, the first cause of iatrogenic prematurity and
a leading cause of fetal growth restriction [1]. The incidence
of PE has risen in the United States in the last decades;
this finding might be related to an increased prevalence of
predisposing disorders, such as maternal age, chronic hypertension (CH), diabetes, pre-pregnancy obesity and multiple
births [2,3].
PE has been characterized by some investigators into two
different disease entities: early-onset (EO) PE and late-onset
(LO) PE. EO PE is usually defined as a disease that develops
before 34 weeks of gestation, whereas LO PE develops at or
after 34 weeks of gestation. Although the presenting features
overlap, they are associated with different maternal and fetal
outcomes, biochemical markers, heritability and clinical
features [4].
This concept of EO and LO PE is quite modern, and it is
widely accepted that these two entities have different etiologies

*Presented as poster presentation at the 32nd Annual Meeting of the

Society of Maternal-Fetal Medicine, 611 February 2012, Dallas, Texas.
Address for correspondence: Sara Ornaghi, MD, Department of
Obstetrics and Gynecology, San Gerardo Hospital, University of
Milan-Bicocca, Monza, Italy. Tel: +39 0392333109/+39 3381693586.
Fax: +39 0392333131. E-mail: sara.ornaghi@virgilio.it

Received 21 April 2012

Accepted 27 February 2013
Published online 12 April 2013

and should be regarded as different forms of the disease [57].

Specifically, placentation anomalies are reported as main
etiopathogenetic mechanism in EO PE, whereas predisposing
cardiovascular or metabolic risks for endothelial dysfunction,
as part of an exaggerated systemic inflammatory response,
might dominate in the origins of LO PE [8]. In addition, this
contention is supported by both pathological findings and
circulating factors analysis [1,911].
Normal pregnancy evokes a systemic inflammatory
response, especially toward the end of the third trimester,
and it is associated with evidence of increasing systemic
oxidative stress as gestation advances. These changes appear
to be more intense in PE; thus, the inflammatory response
of this disease cannot be considered as a different condition
but a more extreme part of the spectrum common to all
pregnancies, and PE develops when the systemic inflammatory process causes maternal systems to decompensate [12].
The metabolic, endothelial, vascular and inflammatory
changes of PE are similar to those of the metabolic syndrome;
and its components, including obesity, diabetes and CH, are
well known to predispose to PE [1315].
Obesity is becoming an increasingly common problem
for obstetricians, thus increasing the risk of maternal and
perinatal complications. In 1990, the Institute of Medicine in
the United States recommended that weight gain (WG) during
pregnancy be based on pre-pregnancy BMI. More recent
studies analyzing the correlation between the risk of obstetric
complications and gestational WG found a reduced risk for
lower than expected for BMI class WGs [16,17].

20
13

Introduction

History

1300

S. Ornaghi et al.

J Matern Fetal Neonatal Med, 2013; 26(13): 12991302

Pre-pregnancy BMI has been recognized as an important

predictor of severe PE [1821], and a doubled risk of PE for
each 57 kg/m2 increase in BMI during pregnancy is reported
in the literature [22].
The aim of our study is to analyze general characteristics of women affected by either EO or LO PE in order
to identify specific influencing factors for the LO form of
disease.

Table 1. General characteristics of study population.

Methods

The values are in N(%) or mean  SD.

Previous APO: cumulative previous Adverse Pregnancy Outcome, as
preeclampsia, eclampsia, HELLP syndrome, abruptio placentae, and
Small for Gestational Age neonates.
RPL: recurrent pregnancy losses (42 miscarriages before 20 weeks of
gestation).

This is a retrospective cohort study of 284 consecutive

singleton women diagnosed as preeclamptic at 22.441.5
weeks of gestation, managed and delivered at our Institution
from March 2005 to October 2011, evaluating demographic,
clinical, and sonographic variables on hospital admission, in
relation to EO versus LO PE. Twin pregnancies, HELLP
syndrome and stillbirth cases diagnosed on admission and
patients with fetal congenital or chromosomal anomalies were
excluded from the analysis. All variables considered in the
analysis were prospectively collected at time of patients
hospital admission and registered in a dedicated logbook,
which is periodically audited.
CH was defined as previously diagnosed pre-pregnancy
hypertension or systolic blood pressure of 140 mmHg
and/or diastolic blood pressure of 90 mmHg before the
20th week of gestation. PE and superimposed PE were
defined according to the guidelines of the International
Society for the Study of Hypertension in Pregnancy. With
the use of these guidelines, PE was defined as the development of new-onset hypertension and proteinuria (excretion
of 300 mg of protein over 24 h) occurring after week 20
of gestation; whereas the diagnosis of superimposed PE in
women with CH was based on the development of new-onset
proteinuria or, in case of pre-existing proteinuria, the
worsening of blood pressure and the identification of clinical
symptoms (headache, vision changes and upper abdominal
pain) [23,24]. Gestational Diabetes Mellitus (GDM) was
defined as the presence of 1 pathological value at 75 g
Oral Glucose Tolerance Test, performed in women at
high risk (GDM in a previous pregnancy) between 16 and
18 weeks of gestation and in patients with intermediate
risk between 24 and 28 weeks, according to the protocol
implemented at our institution [25].
Pre-pregnancy and pregnancy BMI was based on selfreported height and weight before beginning of gestation and
at the time of diagnosis of PE, respectively. A pre-pregnancy
BMI  30 kg/m2 defined obesity, whereas a pre-pregnancy
BMI  35 kg/m2 recognized morbidly obese women. WG
during pregnancy was obtained by the difference between
maternal weight at hospital admission and pre-pregnancy
weight; in the same way was defined the increase of BMI
throughout gestation. Pathological gestational WG according
to pre-pregnancy BMI class was based on those described
by Crane et al. Specifically, the authors reported that the
appropriate WG during pregnancy, associated with a reduction in the risk of obstetric adverse outcome, was 11.516 kg
for women with a normal pre-pregnancy BMI (BMI
between 18.50 and 24.99 kg/m2), 7.011.5 kg for overweight
(BMI between 25.00 and 29.99 kg/m2) and obese women

Variables
Maternal age (years)
Nulliparity
Chronic hypertension
Diabetes mellitus
Kidney disease
Previous APO
RPL

EO PE (n 133)

LO PE (n 151)

p Value

33.7  4.8
69 (52%)
16 (12%)
0
2 (2%)
30 (23%)
6 (5%)

31.8  5.0
84 (56%)
16 (11%)
5 (3%)
2 (1%)
21 (14%)
4 (3%)

0.001
0.55
0.70
0.06
1.00
0.06
0.52

(BMI between 30.00 and 34.99 kg/m2), and less than 7.0 kg
for morbidly obese women (BMI  35.00 kg/m2) [17].
The study was approved on 13 April 2006 (protocol no. 236)
by the Institutional Review Board.
Statistical analysis
Demographic, clinical and sonographic variables were
compared between EO and LO PE groups using Chi-Square
test for categorical variables and one-way ANOVA for
continuous variables; Estimation Regression weighed for
GA at delivery was used for performing regression analysis.
A value of p50.05 was considered significant (SPSS version
15, Chicago, IL).

Results
A total of 19 433 women delivered during the study period,
284 of whom fulfilled the inclusion criteria of the study
(1.5%). Fifty-three percent (151) of preeclamptic patients
were in LO PE group. No cases of PE managed and delivered
at our Hospital were lost at data collection.
Table 1 shows general characteristics of study population.
EO PE women were older than LO PE ones; no differences
were found at the analysis for incidence of nulliparity, chronic
diseases, such as CH, diabetes mellitus and kidney disease
and previous Adverse Pregnancy Outcome or Recurrent
Pregnancy Losses. In particular, there were four cases of
nephropathy superimposed PE: two with polycystic kidney
disease, one with nephrotic syndrome and the last one with
glomerulonephritis.
LO PE patients were more likely to be morbidly obese
and to have a pathological gestational WG according to prepregnancy BMI class [17]. Moreover, a BMI increase during
pregnancy 5 and 7 kg/m2 was more common in this group
than in EO PE (Table 2).
Table 3 displays current pregnancy complications and
outcome. The incidence of vascular drawbacks, as
Intrauterine Growth Restricted (IUGR) fetuses and Small
for Gestational Age (SGA) babies, was higher in EO PE
women, whereas the frequency of GDM was more common in
the LO PE group.
Considering the obviously different GA at delivery of the
two study groups, depending to the GA at diagnosis of PE and
subsequently to the type of obstetric management carried out,

Influencing factors for late-onset preeclampsia

DOI: 10.3109/14767058.2013.783807

Table 2. Phenotypical characteristics of study population.

Variables
Pre-pregnancy weight (kg)
End-pregnancy weight (kg)
Pathological WG
Pre-pregnancy BMI (kg/m2)
Obesity
Morbidly obesity
End-pregnancy BMI (kg/m2)
5 kg/m2 BMI increase
7 kg/m2 BMI increase

EO PE
(n 133)

LO PE
(n 151)

p Value

63.1  13.8
73.9  13.2
16 (12%)
23.8  4.9
14 (11%)
3 (2%)
27.9  4.8
30 (23%)
12 (9%)

65.6  15.5
80.1  14.9
45 (30%)
24.6  5.6
19 (13%)
13 (9%)
30.0  5.2
88 (58%)
29 (19%)

0.17
0.01
0.01
0.25
0.85
0.03
0.01
50.001
0.04

The values are in N(%) or mean  SD.

Pathological WG: defined according to pre-pregnancy BMI class (data
reported by Crane et al).

Table 3. Current pregnancy complications and outcome.

Variables
IUGR
GDM
GA at delivery (weeks)
Birth weight (grams)
SGA neonates

EO PE (n 133) LO PE (n 151) p Value

60 (45%)
5 (4%)
30.8  3.0
1196.7  512.6
66 (50%)

16 (11%)
16 (11%)
37.6  1.7
2723.9  623.3
47 (31%)

50.001
0.04
50.001
50.001
0.01

The values are in N(%) or mean  SD.

IUGR: AC510th percentile regardless UA Doppler flow.
SGA: birth weight 510th percentile according to the national growth
curves.
Table 4. GA at delivery-weighed estimation regression.
Variables
Pathological WG for BMI class
Morbidly obesity
5 kg/m2 BMI increase
7 kg/m2 BMI increase
GDM

p Value
0.58
0.04
0.01
0.44
0.20

OR

CI (95%)

3.76
4.28

1.9717.04
2.447.54

a GA at delivery weighed Estimation Regression was

performed to identify independent influencing factors for
LO form of disease (Table 4).

Discussion
The results of our study recognize pre-pregnancy morbidly
obesity and 5 kg/m2 BMI increase during gestation as
independent risk factors for the LO form of PE, thus
confirming data of previous studies about relation among
obesity, pathological gestational WG and development of the
disease.
Obese and morbidly obese pregnant women are already
known to be at higher risk for obstetric adverse outcome,
including hypertensive disorders as PE; thats why they are
intensively monitored during pregnancy. However, it is also
evident that this relationship is not limited to obese and
overweight women because an excessive increase in BMI,
although in the normal range, is also associated with an
increased risk of PE [26]. Moreover, the metabolic, endothelial, vascular and inflammatory changes of PE are similar
to those of the metabolic syndrome; and its components,
including obesity, diabetes and CH, are well known to

1301

predispose to this hypertensive disorder. All these conditions

are characterized by mild systemic inflammation, thus
increasing the baseline of inflammation on which the
changes of pregnancy are superimposed, and consequently
the decompensation from excessive systemic inflammation
would happen at a lower threshold, accounting for the
predisposition of affected women to PE [1315].
Systemic inflammation and oxidative stress have been
suggested to be the potential mechanisms by which obesity
and pathological WG increase PE risk. In fact, highly
pathological pre-pregnancy BMI and gestational increase in
BMI are phenotypical conditions characterized by abnormal
systemic inflammatory response activation and oxidative
stress and by their augmentation throughout pregnancy,
thus leading maternal system to decompensate quickly and,
consequently, to the clinically evident disease [1215].
Pathological WG according to BMI class did not result
significant risk factor at the GA at delivery weighed
Estimation Regression analysis, thus maybe supporting the
theory reported in literature about the superiority of BMI
on weight evaluation in defining phenotypical human constitution and, consequently, in identifying the abnormal phenotypes at risk for obstetric complications, and, specifically,
for PE [1719,22].
This was a single tertiary-care-center retrospective study
and therefore influenced by some intrinsic limitations, related
to the design of the study itself. Moreover, we took into
account BMI increase during pregnancy without evaluating
maternal body composition, thus limiting the reliability of
this measure to express the actual gestational fat accrual of
preeclamptic women. In fact, Roberts et al. reported that
the impact of WG in women who subsequently develop PE
is as likely related to fluid retention as it is to fat accrual
and that the answer to understand the actual role of WG
in developing PE would be represented by direct assessment
of percent body fat [26].
In conclusion, our results recognize a potential influencing
role of morbidly obesity and pathological gestational BMI
increase for the severe obstetric complication of PE, maybe
through the inflammation and oxidative stress typical of these
conditions. Consequently, we could underline the need of
applying new strategies of action throughout pregnancy for
these patients, such as anti-oxidant components intake, and
the importance of developing new researches in this fruitful
area, in order to discover new potential therapeutic molecular
targets.

Declaration of interest
The authors report no declarations of interest.
References
1. Redman CWG, Sargent IL. Latest advances in understanding
preeclampsia. Science 2005;308:15924.
2. Berg CJ, MacKay AP, Qin C, Allaghan WM. Overview of maternal
morbidity during hospitalization for labor and delivery in the united
states: 19931997 and 20012005. Obstet Gynecol 2009;113:
107581.
3. Shamshirsaz AA, Paidas M, Krikun G. Preeclampsia, hypoxia,
thrombosis, and inflammation. J Pregnancy 2012;2012:374047.
doi: 10.1155/2012/374047.

1302

S. Ornaghi et al.

4. Raymond D, Peterson E. A critical review of early-onset and

late-onset preeclampsia. Obstet Gynecol Surv 2011;66:497506.
5. Valensise H, Vasapollo B, Gagliardi G, Novelli GP. Early and late
preeclampsia: two different maternal hemodynamic states in the
latent phase of the disease. Hypertension 2008;52:87380.
6. Von Dadelszen P, Magee LA, Roberts JM. Subclassification
of preeclampsia. Hypertens Pregnancy 2003;22:1438.
7. Huppertz B. Placental origins of preeclampsia: challenging the
current hypothesis. Hypertension 2008;51:9705.
8. Steegers EAP, von Dadelszen P, Duvekot J, Pijnenborg R.
Pre-eclampsia. Lancet 2010;376:63144.
9. Van der Merwe JL, Hall DR, Wright C, et al. Are early and late
preeclampsia distinct subclasses of the disease what does the
placenta reveal? Hypertens Pregnancy 2010;29:45767.
10. Wikstrom AK, Larsson A, Akerud H, Olovsson M. Increased
circulating levels of the antiangiogenic factor endostatin in
early-onset but not late-onset preeclampsia. Reprod Sci 2009;16:
9951000.
11. Wikstrom AK, Larsson A, Eriksson UJ, et al. Placental growth
factor and soluble FMS-like tyrosine kinase-1 in early-onset and
late-onset preeclampsia. Obstet Gynecol 2007;109:136874.
12. Redman CWG, Sacks GP, Sargent IL. Preeclampsia: an excessive
maternal inflammatory response to pregnancy. Am J Obstet
Gynecol 1999;180:499506.
13. Redman CWG, Sargent IL. Preeclampsia and the systemic inflammatory response. Semin Nephrol 2004;24:56570.
14. Borzychowski AM, Sargent IL, Redman CWG. Inflammation and
preeclampsia. Semin Fetal Neonat Med 2006;11:30916.
15. Zavalza-Gomez AB. Obesity and oxidative stress: a direct link to
preeclampsia? Arch Gynecol Obstet 2011;283:41522.
16. Cedergren MI. Optimal gestational weight gain for body mass
index categories. Obstet Gynecol 2007;110:75964.

J Matern Fetal Neonatal Med, 2013; 26(13): 12991302

17. Crane JMG, White J, Murphy P, et al. The effect of gestational

weight gain by body mass index on maternal and neonatal
outcomes. J Obstet Gynaecol Can 2009;31:2835.
18. Bodnar LM, Ness RB, Markovic N, Roberts JM. The risk of
preeclampsia rises with increasing prepregnancy body mass index.
Ann Epidemiol 2005;15:47582.
19. Bodnar LM, Catov JM, Klebanoff MA, et al. Prepregnancy body
mass index and the occurrence of severe hypertensive disorders of
pregnancy. Epidemiology 2007;18:2349.
20. Cedergren MI. Maternal morbid obesity and the risk of adverse
pregnancy outcome. Obstet Gynecol 2004;103:21924.
21. Fortner RT, Pekow P, Solomon CG, et al. Prepregnancy body
mass index, gestational weight gain, and risk of hypertensive
pregnancy among Latina women. Am J Obstet Gynecol 2009;200:
167.e17.
22. OBrien TE, Ray JG, Chan WS. Maternal body mass index and the
risk of preeclampsia: a systematic overview. Epidemiol 2003;14:
36874.
23. Gifford Jr RW, August PA, Cunningham G, et al. Report of the
National High Blood Pressure Education Program Working Group
on high blood pressure in pregnancy. Am J Obstet Gynecol 2000;
183:S122.
24. Brown MA, Lindheimer MD, de Swiet M, et al. The classification
and diagnosis of the hypertensive disorders of pregnancy: statement
from the International Society for the Study of Hypertension in
Pregnancy (ISSHP). Hypertens Pregnancy 2001;20:IXXIV.
25. IADPSG Consensus Panel. International Association of Diabetes
and Pregnancy Study Group recommendations on the diagnosis and
classification of hyperglycemia in pregnancy. Diabetes Care 2010;
33:67682.
26. Roberts JM, Bodnar LM, Patrick TE, et al. The role of obesity
in preeclampsia. Pregnancy Hypertens 2011;1:616.

Copyright of Journal of Maternal-Fetal & Neonatal Medicine is the property of Taylor &
Francis Ltd and its content may not be copied or emailed to multiple sites or posted to a
listserv without the copyright holder's express written permission. However, users may print,
download, or email articles for individual use.

Copyright of Journal of Maternal-Fetal & Neonatal Medicine is the property of Taylor &
Francis Ltd and its content may not be copied or emailed to multiple sites or posted to a
listserv without the copyright holder's express written permission. However, users may print,
download, or email articles for individual use.