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doi:10.1111/j.1447-0756.2012.02010.x
631, March 2013

J. Obstet. Gynaecol. Res. Vol. 39, No. 3: 627

Risk factors of early and late onset pre-eclampsia

Adisorn Aksornphusitaphong and Vorapong Phupong
Department of Obstetrics and Gynecology, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand

Abstract
Aims: The aim of this study was to identify the differences in risk factors between early and late onset
pre-eclampsia.
Material and Methods: A casecontrol study was carried out involving pregnancies with pre-eclampsia (152
early onset and 297 late onset) and 449 controls at King Chulalongkorn Memorial Hospital, Bangkok, Thailand
between 1 January 2005 and 31 December 2010. The data were reviewed from antenatal and delivery records.
eclampsia were family history of diabetes mellitus, high pre-pregnancy body mass index 25 kg/m and
Results: Factors which were signicantly associated with increased risk for both early and late onset pre2

weight gain 0.5 kg per week. History of chronic hypertension (odds ratio 4.4; 95% condence interval
2.19.3) was signicantly associated with increased risk for only early onset pre-eclampsia, while family history
of chronic hypertension (odds ratio 18; 95% condence interval 654) was signicantly associated with
increased risk for only late onset pre-eclampsia.
body mass index 25 kg/m and weight gain 0.5 kg per week were risk factors of both early and late onset
Conclusions: The risk factors that differ between early and late onset of pre-eclampsia were history of chronic
hypertension and family history of chronic hypertension. Family history of diabetes mellitus, pre-pregnancy
2

pre-eclampsia. These risk factors are of value to obstetricians in identifying patients at risk for pre-eclampsia
and in implementing primary prevention.
Key words: early onset, late onset, pre-eclampsia, risk factor, Thai.
ing. Some studies demonstrated higher morbidity and
mortality from pre-eclampsia at an early gestational
Introduction
age than from that at a late stage.
The early onset offactors
the world. In severe cases, it causes multiple organthis disorder causes
a
severe morbidity in mothers and are prote
ctive; one of these is cigarette smokhigher preterm birth rate in fetuses.
The aim of this study is to nd the difference in
risk factors between early onset and late onset prerestriction (IUGR), which result from this disorder.
eclampsia in the Thai population.
5

MethodsPreeclampsia is a common obstetric complication. It is

impaired placentation is one possible cause.

one of three common causes of maternal mortality in

2,68

failures, which leads to maternal death. A high fetal

morbidity and mortality rate is associated with prematurity, placental insufciency and intrauterine growth

7,9

2,3

The exact cause of pre-eclampsia is still unknown. The

4

There are many studies that aim to evaluate risk

factors of pre-eclampsia. Primigravida, previous
pregnancy-induced hypertension, obesity, diabetes,
hypertension and multiplicity are risk factors. Some

This was a casecontrol study conducted at the Department of Obstetrics and Gynecology, King Chulalongkorn Memorial Hospital, Faculty of Medicine,

Received: February 1 2012.

Accepted: July 20 2012.
Reprint request to: Dr Vorapong Phupong, Department of Obstetrics and Gynecology, Faculty of Medicine, Chulalongkorn
University, Rama IV Road, Pathumwan, Bangkok 10330, Thailand. Email: vorapong.p@chula.ac.th

 2012 The Authors

Journal of Obstetrics and Gynaecology Research 2012 Japan Society of Obstetrics and Gynecology

627

A. Aksornphusitaphong and V. Phupong

Chulalongkorn University, Bangkok, Thailand. The

from the time elapsed since the rst day of the last
study was approved by the Institutional Review Board
menstrual period, or calculated from rst-trimester
of the Faculty of Medicine, Chulalongkorn University.
ultrasonography if the last menstrual period was
The antenatal and delivery records of all pregnant
uncertain.
women with gestational age of 20 weeks or more and
Sample size calculation was based on the risk factors
11

live birth or stillbirth) at King Chulalongkorn Memo-

risk factor that gave the largest sample size in the early

estimate fetal weight of 500 g delivered (regardless of

based on a previous study. Body mass index was the
rial Hospital from 1 January 2005 to 31 December 2010
onset group: 152 women. Multifetal pregnancy was the
were reviewed. Exclusion criteria included abortion,
risk factor that gave the largest sample size in the late
hydatidiform mole, pregnancies complicated with
onset group: 297 women. The samples in the control
chromosomal or structural anomalies and birth before
group were equal to all women in both case groups:
arrival.
449 women. These samples were enough to detect a
Data were divided into three groups (two case
statistical difference (a = 0.05 and b = 0.1).
groups and one control group). Cases were diagnosed
The following risk factors were evaluated: age, parity,
as mild pre-eclampsia, severe pre-eclampsia, eclampgestational age, multifetal pregnancies, blood pressure
sia, or superimposed pre-eclampsia. Cases were
at rst visit, height, pre-pregnancy weight, body mass
divided into two subgroups, early onset and late onset.
index (underweight: body mass index [BMI] 20 kg/
2

Controls were normotensive pregnant women who

delivered consecutively after pre-eclamptic pregnant

m ; normal: BMI 2024.9 kg/m ; overweight: BMI 25.0

29.9 kg/m ; obese: BMI 30 kg/m ), weight gain per
2

women.
week (calculated by bodyweight at last visit minus
Data were collected regarding general information,
pregestational weight and divided by gestational week
pregnancy information, antenatal care, medical history,
at last visit), medical illness and family history (hyperand pregnancy outcome.
tension, diabetes, and renal disease), drug allergy,
Mild pre-eclampsia was dened as a blood pressure
medication, previous history of pre-eclampsia, history
of at least 140/90 mmHg, measured on two occasions
of gestational hypertension, infants sex, Apgar scores,
at least 6 h apart, with proteinuria of at least 300 mg/
maternal and fetal complications.
24 h or at least 1+ on urine dipstick test. Both elevateStatistical analysisd
time after gestational age of 20 weeks. Severe preblood pressure and proteinuria occurred for the rst

Data were presented as mean standard deviation

10

least 160/110 mmHg, proteinuria of at least 5 g/24 h or

eclampsia was dened on the basis of pre-eclampsia
with one or more of the following: blood pressure of at

used for continuous variables. The c -test and Fishers

and percentage. anova with post-hoc analysis (Fishers
least-signicant difference) and KruskalWallis were
2

at least 3+ on urine dipstick test, serum creatinine

1.2 mg/dL, platelet count 100 000/mL, microangiopathic hemolysis (increased lactate dehydrogenase),
elevated serum transaminase level (aspartate ami-

exact test were used for categorical variables.

Risk factors were compared between each preeclampsia group and the controls in univariate analysis. Then, multivariate logistic regression analysis was

ine growth restriction. Eclampsia was dened as

notransferase or alanine aminotransferase), persistent

tivariate regression analysis. Adjusted odds ratio (OR)

used to evaluate the association of risk factors with each

women with pre-eclampsia.

Superimposed preP-value 0.05 was considered statistically signicant.
headache or other cerebral or visual disturbance, perpre-eclampsia group. The risk factors that were signisistent epigastric pain, pulmonary edema, or intrauter
cant on the univariate analysis were entered into a m Resultsul10

seizures that cannot be attributed to other causes in

10

gestation. The onset of pre-eclampsia was divided

eclampsia was dened as a new onset of proteinuria of
at least 300 mg/24 h in hypertensive women but no
proteinuria prior to 20 weeks gestation, or a sudden
increase in proteinuria or blood pressure in women
with hypertension and proteinuria before 20 weeks

with 95% condence interval (CI) was calculated. A

early onset pre-eclampsia and 297 women in late onset

There were a total of 449 consecutive cases with

pre-eclampsia. They were divided into 152 women in

10

into early and late onset; early onset was gestational age
less than 34 weeks, and late onset was gestational age of
7,9

pre-eclampsia and 449 controls.

Demographic characteristics are shown in Table 1.

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2012 The Authors

Journal of Obstetrics and Gynaecology Research 2012 Japan Society of Obstetrics and Gynecolog
y

34 weeks or more.

Gestational age was calculated

Mean maternal age and proportion of multiparity were

Early and late onset pre-eclampsia

Table 1 Demographic characteristics of study population

Characteristic

Control
(n = 449)

Early onset
(n = 152)

P-value

Age (years)
Nulliparity
Previous abortion
Previous preterm delivery
Pregestational bodyweight (kg)
Total weight gain (kg)
Weight gain per week (kg)

28.5 6.6
206 (45.9%)
101 (22.5%)
13 (2.9%)
54.9 10.9
14.0 5.5
0.37 0.14

31.6 6.4
52 (34.2%)
44 (28.9%)
0
57.9 14.0
13.7 5.3
0.45 0.19

0.001
0.012
0.108
0.046
0.012
0.6
0.001

Late onset
(n = 297)
29.4 6.8
146 (49.2%)
64 (21.5%)
0
59.2 14.0
16.1 5.9
0.44 0.16

P-value
0.076
0.380
0.760
0.002
0.001
0.001
0.001

Table 2 Perinatal characteristics

Characteristic
Gestational age at delivery (weeks)
Preterm delivery
Birthweight (g)
Birthweight 2500 gram
Cesarean delivery
Apgar scores at 1 min 7
Apgar scores at 5 min 7

Control
(n = 449)

Early onset
(n = 152)

P-value

30.5 3.3
152 (100%)
1472.6 547.3
147 (96.7%)
144 (94.7%)
56 (36.8%)
17 (11.2%)

0.001
0.001
0.001
0.001
0.001
0.001
0.001

37.0 3.7
129 (28.7%)
2791.2 782.1
164 (36.5%)
78 (17.4%)
14 (3.1%)
1 (0.2%)

signicantly higher in the early onset pre-eclampsia

group than in controls. The pregestational weight and
weight gain per week were signicantly higher in both
the early and late onset pre-eclampsia groups than in
controls. The total weight gain was signicantly higher
in the late onset pre-eclampsia group than in controls.
Perinatal characteristics are shown in Table 2. The
proportion of preterm deliveries and cesarean sections
were signicantly higher in both the early and late
onset pre-eclampsia groups than in controls. The
control group did not represent a normal population in

Late onset
(n = 297)
36.8 2.2
155 (52.2%)
2690.3 617.3
98 (33%)
147 (49.5%)
17 (5.7%)
3 (1%)

P-value
0.313
0.001
0.052
0.323
0.001
0.080
0.306

history of hypertension were signicantly associated

with increased risk of both early and late onset preeclampsia. Multiparity, chronic hypertension, pregestational DM or gestational DM, history of pre-eclampsia
in previous pregnancy, history of hemolysis, and
elevated liver enzyme and low platelet (HELLP) in
previous pregnancy were signicantly associated
with increased risk of early onset pre-eclampsia only.
There was no risk factor signicantly associated with
increased risk of late onset pre-eclampsia only. Gestational age at rst antenatal care 27 weeks and
2

high in the controls. The reasons for this may be as

our institution. The preterm birth rate appeared to be
follows: (i) our institution is a tertiary care hospital,
and thus, there were a high number of complicated
cases that needed preterm delivery; and (ii) coincidentally, controls were recruited from normotensive
pregnant women who delivered consecutively after
pre-eclamptic pregnant women. The proportion of
Apgar scores below 7 at 1 and 5 min were signicantly
higher in the early onset pre-eclampsia group than in

associated with decreased risk of both early and late

pre-pregnancy BMI 20 kg/m were signicantly
onset pre-eclampsia. Gestational age at rst antenatal
care 1426 weeks and maternal weight gain 0.2 kg
per week were signicantly associated with decreased
risk of late onset pre-eclampsia only.
Table 3 shows the results of multivariate logistic
regression analysis. Risk factors which were signicantly associated with increased risk of both early and
late onset pre-eclampsia were family history of DM,
2

controls. Neonatal birthweight in the early onset preeclampsia group was signicantly less than in controls.
pre-pregnancy
BMI
2529.9
kg/m ,
weight
From univariate analysis, maternal age 35 years,

pre-pregnancy BMI 2529.9 kg/m , pre-pregnancy

BMI 30 kg/m and weight gain 0.5 kg per week.
2

9.3) was signicantly associated with increased risk

History of chronic hypertension (OR 4.4; 95% CI 2.1

gain 0.5 kg per week, female infant, calcium intake,

family history of diabetes mellitus (DM), and family

of early onset pre-eclampsia only. Family history

of chronic hypertension (OR 18; 95% CI 654) was

2012 The Authors

Journal of Obstetrics and Gynaecology Research 2012 Japan Society of Obstetrics and Gynecology

629

A. Aksornphusitaphong and V. Phupong

Table 3 Results of multivariate logistic regression analysis

Risk factors

Early onset
Adjusted
OR (95% CI)

History of chronic hypertension

Family history of hypertension
Family history of diabetes

4.4 (2.1, 9.3)

2.5 (1.1, 5.6)

Late onset
Adjusted
OR (95% CI)

18 (6, 54)
2.7 (1.6, 4.4)

2
2

Pre-pregnancy body mass index 2529.9 kg/m

3.5 (1.3, 8.9)
2.1 (1.2, 3.7)
Pre-pregnancy body mass index 30 kg/m
16.2 (4.5, 58.3) 5.8 (2.8, 11.9)
Pre-pregnancy body mass index 20 kg/m

0.5 (0.3, 0.8)

Weight gain 0.2 kg/week
0.3 (0.1, 0.9)

Weight gain 0.5 kg/week

2.1 (1.2, 3.7)
1.9 (1.3, 2.8)
CI, condence interval; OR, odds ratio.

signicantly associated with increased risk of late onset

pre-eclampsia only. Pre-pregnancy BMI 20 kg/m

gestational hypertension. There were 37 cases with

early pre-eclampsia, 128 with late pre-eclampsia,

was a signicant protective factor for both early and

and 140 with gestational hypertension. They found
late onset pre-eclampsia. Maternal weight gain 0.2 kg
that predictors of early pre-eclampsia were African
per week was a signicant protective factor for early
race, chronic hypertension, prior pre-eclampsia and
onset pre-eclampsia only.
use of ovulation drugs. Predictors of late onset
pre-eclampsia and gestational hypertension were
Discussion
increased maternal age and BMI, and family history
or history of pre-eclampsia. The detection rates of
This study shows that risk factors that differ between
early pre-eclampsia, late pre-eclampsia and gestaearly and late onset pre-eclampsia were a history of
tional hypertension in screening by maternal factors
chronic hypertension and family history of chronic
were only 37.0, 28.9 and 20.7%, respectively, for a 5%
hypertension. History of chronic hypertension was
false positive rate.
onset pre-eclampsia only, while family history of
signicantly associated with increased risk of early

severe pre-eclampsia and eclampsia. They found that

Nanjundan et al. evaluated risk factors for early onset
14

chronic hypertension was signicantly associated with

history of pre-eclampsia or eclampsia in a previous

factors of early and late onset of pre-eclampsia.

increased risk of late onset pre-eclampsia only.

one or more rst-degree relatives, living in a joint

pregnancy, exposure to passive smoking, inadequate

Fang

early and late onset pre-eclampsia. This may be due to

There has been only one study evaluating the risk

status were associated with increased risk of early

antenatal supervision, family history of hypertension in

12

et al. did not nd any difference in risk factors between

family, being overweight and lower socioeconomic

index 30 kg/m and failure to use prenatal care

services were associated with increased risk of preeclampsia. The difference between this study and that

The results of the present study were similar to previous studies.

Overweight and obesity increased
the risk of pre-eclampsia, which was explained by

12

the small sample size of their study. There were only 29

cases of early onset and 121 cases of late onset preeclampsia. They found that pre-pregnancy body mass
pre-eclampsia by subgroup analysis.
Poon et al. developed prediction algorithms for
2

of factors from the maternal history and compared the

onset pre-eclampsia and eclampsia. The difference in

these studies may be due to difference in the study
population.

stress. This can lead to endothelial cell damage.

Maternal weight gain 0.2 kg per week was a signiPre-pregnancy
6,7,11

BMI 20 kg/m

was

signicant

12

of Fang et al. may be due to the difference of methodology. This study recruited cases as early and late onset
pre-eclampsia at the beginning of the study, while
Fang et al. divided cases into early and late onset

increase in triglyceride and free fatty acid levels. These

lipid alterations can produce major factors leading to
endothelial cell dysfunction in pre-eclampsia with
increased circulating levels of lipid peroxides oxidative
1517

13

hypertensive disorders based on multivariate analysis

cant protective factor for early onset pre-eclampsia.

2

estimated performance of such algorithms in the pre-

protective factor for late onset pre-eclampsia. This is

11,18

630

2012 The Authors

Journal of Obstetrics and Gynaecology Research 2012 Japan Society of Obstetrics and Gynecolog
y

diction of early pre-eclampsia, late pre-eclampsia and

similar to the previous studies.

Early and late onset pre-eclampsia

History of chronic hypertension was a signicant

2. Assis TR, Viana FP, Rassi S. Study on the major maternal risk
factors in hypertensive syndromes. Arq Bras Cardiol 2008; 91:
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risk factor for early onset pre-eclampsia in the present
8,18

study. This is in agreement with previous studies that

sion was a signicant risk factor for late onset
showed that chronic hypertension was a risk factor for
p
pre-eclampsia.
Family history of chronic hyperten4. Phupong V, Dejthevaporn T. Predicting risks of preeclampsia
reand small for gestational age infant by uterine artery Doppler.
Hypertens Pregnancy 2008; 27: 387395.

eclampsia in the present study. This is in agreement

19,20
with previous studies.
5. Bainbridge SA, Sidle EH, Smith GN. Direct placental effects
2,6,8
of cigarette smoke protect women from pre-eclampsia: The
In contrast to previous studies,
cigarette smoking
and high calcium intake were not protective factors in
the placenta. Med Hypotheses 2005; 64: 1727.

specic roles of carbon monoxide and antioxidant systems in

of cigarette smokers in the groups and because people

in Thailand generally take a sufcient amount of
calcium. However, we did not exactly evaluate the
calcium intake in their food. We did not identify mater-

our study. This may due to the relatively small nu

mber
6. Duckitt K, Harrington D. Risk factors for

pre-eclampsia at
cohort study. BMJ 2009; 338: b2255.
antenatal booking: Systematic review of controlled studies.
BMJ 2005; 330: 565571.
onset pre-eclampsia. This is consistent with previous 7. Hernandez-Diaz S, Toh S, Cnattingius S. Risk of prestudies.
eclampsia in rst and subsequent pregnancies: Prospective

Chronic hypertension can cause end-organ damage

and vascular complications. This may be the reason
nal age as a signicant risk factor for early and late

10. ACOG. Diagnosis and management of preeclampsia and

8. Conde-Agudelo A, Belizan JM. Risk factors for pre-eclampsia
in a large cohort of Latin American and Caribbean women.

onset pre-eclampsia; however, family history of

14,21
chronic hypertension is associated with late onset preBJOG 2000; 107: 7583.
eclampsia. This may be explained by a genetic predis- 9. Mattar F, Sibai BM. Eclampsia. VIII. Risk factors for maternal
position. Vascular complications still do not occur in
12. Fang R, Dawson A, Lohsoonthorn V, Williams MA. Risk
morbidity. Am J Obstet Gynecol 2000; 182: 307312.

The strength of the present study was the large

number of cases in early and late onset pre-eclampsia.
Thus, we could compare and indentify the difference in
the risk factors between these groups. The limitation of

why chronic hypertension is associated with ea

rly
eclampsia. ACOG practical bulletin. Clinical

management
14. Nanjundan P, Bagga R, Kalra JK, Thakur JS, Raveendran A.
guidelines for obstetrician-gynecologists Number 33, January
2002. Obstet Gynecol 2002; 99: 159166.
small number of pregnant women who used calcium 11. Luealon P, Phupong V. Risk factors of preeclampsia in Thai
medication during pregnancy. Thus we could not
women. J Med Assoc Thai 2010; 93: 661666.

assess the effect of these factors.

In conclusion, the risk factors differing between
e

preeclampsia activate NF-kappaB and upregulate ICAM-1 inthes

chronic hypertension and family history of chronic

hypertension. Family history of DM, pre-pregnancy
BMI 25 kg/m 2and weight gain 0.5 kg per week
were risk factors of both early and late onset pre-

es.

cas

fa
ctors of early and late onset preeclampsia among Tha
i
women. Asian Biomed (Res Rev News) 2009; 3: 477486.

pathophysiology of preeclampsia. Expert Rev Mol Diagn 2009;

13. Poon LC, Kametas NA, Chelemen T, Leal A, Nicolaides KH.
Maternal risk factors for hypertensive disorders in pregnancy:
cians for identifying patients at risk for pre-eclampsia A multivariate approach. J Hum Hypertens 2010; 24: 104110.

and for implementing primary prevention.

this study was the small number of smokers and the

Disclosure

Risk factors for early onset severe pre-eclampsia and eclampSevere preeclampsia is associated with a positive family
sia among north Indian women. J Obstet Gynaecol 2011; 31:
384389.
15. Takacs P, Kauma SW, Sholley MM, Walsh SW, Dinsmoor MJ,
Green K. Increased circulating lipid peroxides in severe

early and late onset pre-eclampsia were history of

vascular endothelial cells. FASEB J 2001; 15: 279281.

16. OBrien TE, Ray JG, Chan WS. Maternal body mass index and
the risk of preeclampsia: A systematic overview. Epidemiology
2003; 14: 368374.
17. Cheng MH, Wang PH. Placentation abnormalities in the

eclampsia. These risk factors are valuable to obstetri-

9: 3749.
18. Lee CJ, Hsieh TT, Chiu TH, Chen KC, Lo LM, Hung TH. Risk
factors for pre-eclampsia in an Asian population. Int J Gynaecol Obstet 2000; 70: 327333.
19. Roes EM, Sieben R, Raijmakers MT, Peters WH, Steegers EA.
history of hypertension and hypercholesterolemia. Hypertens

No author has any potential conict of interest.

Pregnancy 2005; 24: 259271.

20. Qiu C, Williams MA, Leisenring WM et al. Family history of
hypertension and type 2 diabetes in relation to preeclampsia
risk. Hypertension 2003; 41: 408413.
1. World Health Organization. Maternal mortality fact sheet.
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2012 The Authors

Journal of Obstetrics and Gynaecology Research 2012 Japan Society of Obstetrics and Gynecology

References

631