2013

http://informahealthcare.com/jmfISSN: 1476-7058 (print), 1476-4954 (electronic)

J Matern Fetal Neonatal Med, 2013; 26(13): 1299–1302! 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, andPatrizia Vergani

Department of Obstetrics and Gynecology, San Gerardo Hospital, University of Milan-Bicocca, Monza, Italy

Abstract

Objective: Different etiologies for early- (534.0 weeks) and late (�34.0 weeks)-onsetpreeclampsia (EO–LO PE) are reported. The aim of our study is to identify influencing factorsfor the LO form.Methods: Retrospective study of 284 consecutive women diagnosed as preeclamptic at22.4–41.5 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%,p¼ 0.04), body mass index (BMI) �35 kg/m2 (9% versus 2%, p¼ 0.03), pathological weightgain for BMI class (30% versus 13%, p¼ 0.001), �5 (58% versus 23%, p50.001) and �7 kg/m2

BMI increase (19% versus 9%, p¼ 0.04) were more common in LO than in EO PE. At EstimationRegression analysis weighted for Gestational Age (GA) at delivery BMI �35 and �5 kg/m2 BMIincrease resulted related to LO PE (OR¼ 3.76, CI(95%)¼ 1.97–17.04; OR¼ 4.28, CI(95%)¼ 2.44–7.54).Conclusions: BMI �35 and �5 kg/m2 increase appeared as influencing factors for LO PE, thussupporting the role of systemic inflammation in its pathogenesis.

Keywords

Body mass index, hypertensive disorder,metabolic syndrome, obesity, weight gain

History

Received 21 April 2012Accepted 27 February 2013Published online 12 April 2013

Introduction

Preeclampsia (PE) is a multisystem disorder that affects about

2–3% 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 hyper-

tension (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

and should be regarded as different forms of the disease [5–7].

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 [1,9–11].

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 inflamma-

tory 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 [13–15].

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].

Address for correspondence: Sara Ornaghi, MD, Department ofObstetrics and Gynecology, San Gerardo Hospital, University ofMilan-Bicocca, Monza, Italy. Tel: +39 0392333109/+39 3381693586.Fax: +39 0392333131. E-mail: sara.ornaghi@virgilio.it

*Presented as poster presentation at the 32nd Annual Meeting of theSociety of Maternal-Fetal Medicine, 6–11 February 2012, Dallas, Texas.

Pre-pregnancy BMI has been recognized as an important

predictor of severe PE [18–21], and a doubled risk of PE for

each 5–7 kg/m2 increase in BMI during pregnancy is reported

in the literature [22].

The aim of our study is to analyze general characteris-

tics of women affected by either EO or LO PE in order

to identify specific influencing factors for the LO form of

disease.

Methods

This is a retrospective cohort study of 284 consecutive

singleton women diagnosed as preeclamptic at 22.4–41.5

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 patient’s

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 develop-

ment 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 self-

reported 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 reduc-

tion in the risk of obstetric adverse outcome, was 11.5–16 kg

for women with a normal pre-pregnancy BMI (BMI

between 18.50 and 24.99 kg/m2), 7.0–11.5 kg for overweight

(BMI between 25.00 and 29.99 kg/m2) and obese women

(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 pre-

pregnancy 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,

Table 1. General characteristics of study population.

Variables EO PE (n¼ 133) LO PE (n¼ 151) p Value

Maternal age (years) 33.7� 4.8 31.8� 5.0 0.001Nulliparity 69 (52%) 84 (56%) 0.55Chronic hypertension 16 (12%) 16 (11%) 0.70Diabetes mellitus 0 5 (3%) 0.06Kidney disease 2 (2%) 2 (1%) 1.00Previous APO 30 (23%) 21 (14%) 0.06RPL 6 (5%) 4 (3%) 0.52

The values are in N(%) or mean� SD.Previous APO: cumulative previous Adverse Pregnancy Outcome, as

preeclampsia, eclampsia, HELLP syndrome, abruptio placentae, andSmall for Gestational Age neonates.

RPL: recurrent pregnancy losses (42 miscarriages before 20 weeks ofgestation).

1300 S. Ornaghi et al. J Matern Fetal Neonatal Med, 2013; 26(13): 1299–1302

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; that’s 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, endothe-

lial, 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 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 [13–15].

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 [12–15].

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 consti-

tution and, consequently, in identifying the abnormal pheno-

types at risk for obstetric complications, and, specifically,

for PE [17–19,22].

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.

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Table 2. Phenotypical characteristics of study population.

VariablesEO PE

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Pre-pregnancy weight (kg) 63.1� 13.8 65.6� 15.5 0.17End-pregnancy weight (kg) 73.9� 13.2 80.1� 14.9 0.01Pathological WG 16 (12%) 45 (30%) 0.01Pre-pregnancy BMI (kg/m2) 23.8� 4.9 24.6� 5.6 0.25

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1302 S. Ornaghi et al. J Matern Fetal Neonatal Med, 2013; 26(13): 1299–1302

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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 alistserv without the copyright holder's express written permission. However, users may print,download, or email articles for individual use.