Homocysteine in pregnancies complicated by preeclampsia with and without IUGR: a comparison with normotensive pregnant women with isolated IUGR and healthy pregnant women

doi:10.4236/ojog.2011.14037

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Open Journal of Obstetrics and Gynecology, 2011, 1, 191-196

doi:10.4236/ojog.2011.14037 Published Online December 2011 (http://www.SciRP.org/journal/ojog/

OJOG

Published Online December 2011 in SciRes. http://www.scirp.org/journal/OJOG

Homocysteine in pregnancies complicated by preeclampsia

with and without IUGR: a comparison with normotensive

pregnant women with isolated IUGR and

healthy pregnant women

Marzena Laskowska*, Jan Oleszczuk

Chair and Department of Obstetrics and Perinatology, Medical University of Lublin, Lublin, Poland.

Email: *[email protected]

Received 8 October 2011; revised 18 November 2011; accepted 29 November 2011.

ABSTRACT

Objective: The aim of this study was to analyze ho-

mocysteine levels in maternal serum in women with

pregnancie s complic ated by preeclam psia and/or IUGR.

Patients and methods: The study was carried out on

49 pregnant patients with normotensive pregnancies

complicated by intrauterine fetal growth restriction

(group IUGR), 31 patients with preeclampsia com-

plicated by IUGR (group PRE-IUGR), and 35 pree-

clamptic patients with appropriate-for-gestational-age

weight fetuses (group PRE). The control group con-

sisted of 47 healthy normotensive pregnant patients

with singleton uncomplicated pregnancies and with

proper intrauterine fetal growth. Results: We revea-

led higher levels of maternal serum homocysteine in

the group of pregnant patients with isolated fetal in-

trauterine growth restriction in comparison with the

control subjects. The concentrations of homocysteine

were also higher in both groups of patients with pre-

gnancy complicated by preeclampsia with and with-

out IUGR. The highest levels of homocysteine were

observed in preeclamptic women with appropriate-

for-gestational-age fetal g rowth. The mean values we-

re 9.004 +/– 2.820 mol/L in the IUGR group, 10.815

+/– 3.785 mol/ L in the group PRE, 9.808 +/– 2.543

mol/L in the group PRE-IUGR and 7.639 +/– 2.728

mol/L in the control group. Conclusions: Increased

levels of homocysteine are involved in pathogenesis

IUGR and preeclampsia and may contribute to endo-

thelial cells activation or dysfunction observed in the-

se pregnancy disorders. Further studies are needed to

explain these aspects in order to improve the mana-

gement and therapeutic strategies for pregnancies co-

mplicated by IUGR and/or preeclampsia.

Keywords: Homocysteine; Intrauterine Fetal Growth

Restriction (IUGR); Preeclampsia

1. INTRODUCTION

Intrauterine fetal growth restriction (IUGR) complicates

8% of all pregnancies and is a major cause of perinatal

mortality and morbidity [1]. One of the most common

maternal conditions associated with fetal growth restrict-

tion is maternal hypertension and especially preeclamp-

sia, which complicates 5% - 10% of all pregnancies [2].

But it is important that in many cases of pregnancies

complicated by IUGR there are an idiopathic placental

failure with abnormal placental development and subop-

timal fetal nutrition and oxygenation without maternal

hypertension or preeclampsia [3,4].

Pathophysiological processes underlying intrauterine

fetal growth restriction and/or preeclampsia are compli-

cated, multifactorial and unclear [5]. The impaired inva-

sion of uteroplacental arteries causes changes in the pla-

cental and fetal circulatory system and may be the cause

of the pathological structure and function of the placenta,

resulting in the inadequate fetal oxygenation and nutria-

tion, and consequently leading to preeclampsia or intrau-

terine fetal growth restriction.[5-7].

Endothelial dysfunction has been hypotheses to play a

central role in the pathogenesis of preeclampsia [8-10].

Animal studies suggest that hyperhomocysteinemia affe-

cts the blood vessel wall and causes a change in the en-

dothelium and smooth muscle proliferation [11-13].

Hypehomocysteinemia is a risk factor of cardiovascu-

lar diseases and vasculopathy. It may be a cause of chan-

ges and lesions in endothelial cells due to vascular fibro-

sis and resulting in the activation of thrombogenesis.

Hyperhomocysteinemia promotes oxidation of LDL cho-

lesterol molecules and alterations in the coagulation sys-

tem and enhances platelet activation [11].

The aim of this study was to analyze homocysteine le-

M. Laskowska et al. / Open Journal of Obstetrics and Gynecology 1 (2011) 191-196

192

vels in maternal serum in pregnancies complicated by in-

trauterine fetal growth restriction with and without pree-

clampsia, and in preeclamptic pregnancies with the ap-

propriate fetal growth, and in the control group of heal-

thy pregnancies with normal fetal growth. The study was

accepted by the local Ethics Committee (KE-0254/51/

2010).

2. PATIENTS AND METHODS

The study was carried out on 49 pregnant women with

normotensive pregnancies complicated by intrauterine

growth restricted fetuses (IUGR group), and 66 patients

with pregnancy complicated by severe preeclampsia. In

the group of preeclamptic women were 31 patients with

preeclampsia complicated by intrauterine fetal growth

restriction (PRE-IUGR group) and 35 preeclamptic pa-

tients with appropriate-for-gestational-age fetuses (PRE

group).

Among preeclamptic women there were 6 patients wi-

th HELLP syndrome (all in the PRE-IUGR group) and 4

patients with eclampsia (3 in the PRE-IUGR group and 1

in the PRE group). One patient from the IUGR group

had fetal intrauterine death in the week 38th of gestation.

The weight of her stillborn infant was 2060 g.

The control group consisted of 47 healthy normoten-

sive pregnant patients with singleton uncomplicated pre-

gnancies without any renal, cardiac and vascular disea-

ses and with normal laboratory tests and with appropria-

te-for-gestational-age weight infants (CON group).

Fetal biometry was based on non-invasive ultrasound

method and comprised the estimation of gestational age

in early gestation and diagnosis of fetal intrauterine gro-

wth restriction by monitoring fetal growth later in the se-

cond or third trimester of pregnancy.

Intrauterine growth restricted fetuses (IUGR) were

classified as such according to ultrasonographic measu-

rement when the weight of the fetus was lower than ex-

pected in relation to the gestational age, as determined

by the standard curves characteristic of the Polish popu-

lation, when the fetus was below the 5th centile for gesta-

tional age and diagnosis was confirmed by the infant’s

weight at birth according to the Bretelle et al. [5].

The exclusion criteria for women whose pregnancies

were complicated by IUGR fetuses were the presence of

a congenital malformation or chromosomal abnormality

in the fetus, recent cytomegalovirus infection or drug or

alcohol abuse during pregnancy. Pregnant women with

multiple pregnancies were also excluded from this study.

Preeclampsia was diagnosed by the increased blood

pressure of >140 mmHg systolic and >90 mmHg diasto-

lic in women who were normotensive before 20 weeks

of gestation accompanied by proteinuria, defined as the

urinary excretion of >0.3 g protein in 24 h specimen.

Severe preeclampsia was defined as blood pressure

>160/110 mmHg on at least 2 occasions 6h apart with

proteinuria >2 g in a 24 hour urinary protein excretion,

and when hypertension and proteinuria were associated

with one or more of the following clinical manifestations:

renal abnormalities, hematological abnormalities (throm-

bocytopenia and microangiopathic hemolysis) or HELLP

syndrome (hemolysis, elevated liver enzymes, low pla-

telet count and right-upper quadrant pain), or neurology-

cal symptoms (headache, visual disturbances and seizu-

res). None of the pregnant patients with preeclampsia

were affected by chronic hypertension, renal disorders

and/or proteinuria before pregnancy and all were nor-

motensive before 20th week of pregnancy.

Preeclamptic patients were admitted to the Department

of Obstetrics and Perinatology in the Medical University

Hospital in Lublin because of the symptoms of the di-

sease and without signs of labour. All preeclamptic wo-

men were normotensive 3 months after delivery.

All arterial blood pressure measurements in the con-

trol group and in the group of patients with isolated fetal

intrauterine growth restriction were normal and did not

exceed 135/85 mmHg. None of the patients from any of

these groups suffered from proteinuria.

All patients in the study were non-smokers. An infor-

med consent from all studied patients was obtained for

peripheral blood sampling. Five milliliters of blood were

collected by venipuncture from each preeclamptic pa-

tient and from each woman from the control group and

placed in sterile tubes. They were centrifuged for 15 min

at 500 xg. The homocysteine concentrations were esti-

mated using an ELISA assay according to the manufac-

turer’s instructions (human sandwich ELISA kit Axis-

Shield Diagnostics Ltd, UK)).

In the statistical analysis results were expressed as

mean +/– SD or SEM or as median values and were sta-

tistically analyzed with the computer program “Statis-

tica” using the Shapiro-Wilk test for the normal distribu-

tion of data, and equality of variance by Levene test and,

subsequently two-tailed Student’s t-tests, or (in unequal

variance) the Cochran-Cox test.

The Analysis of Variance—ANOVA and Kruskal-Wa-

llis tests were used to test for differences among four

independent groups. A statistically significant effect in

ANOVA was followed up with follow-up post hoc Tu-

key’s test in order to assess which group is different

from which other groups. A p-value of less than 0.05 was

considered to be significant.

3. RESULTS

There were no statistically significant differences in gra-

vidity, parity, maternal age and height in patient’s pro-

files between groups. Maternal weight and BMI were

M. Laskowska et al. / Open Journal of Obstetrics and Gynecology 1 (2011) 191-196

193

OJOG

lower in the group of patients with pregnancy compli-

cated by isolated IUGR than in the control group and

also in comparison with both groups of preeclamptic

women.

Systolic and diastolic blood pressure were higher in

both study groups of preeclamptic pregnant women than

in the control group and than in pregnancies complicated

by isolated fetal growth restriction. These differences

were statistically significant (p < 0.000001).

There were no statistically significant differences in

age of gestation between both groups of preeclamptic

patients, but significantly lower birth weight of infants

was observed in preeclamptic patients with IUGR. The

age of gestation was lower in both preeclamptic groups

of pregnant patients also in comparison with normoten-

sive women with pregnancy complicated by intrauterine

fetal growth restriction. But birth weight of infants was

lowest in the group PRE-IUGR and was significantly

lower in comparison with group PRE, group IUGR and

than in the control subjects. Birth weight of infants in the

group of patients with pregnancy complicated by isola-

ted IUGR was also lower than in group PRE, but this di-

fference was not statistically significant in spite of sig-

nificantly higher age of pregnancy in group IUGR.

Results are presented in Table 1.

The pregnant normotensive patients with isolated fetal

growth restriction revealed higher levels of maternal

serum homocysteine in comparison with the control

subjects.

The concentrations of homocysteine in maternal se-

rum were also higher in both groups of women with pre-

gnancies complicated by preeclampsia. The highest le-

vels of maternal homocysteine were observed in preecla-

mptic patients with appropriate intrauterine fetal growth.

The mean values were 9.004 +/– 2.820 mol/L in the

IUGR group, 10.815 +/– 3.785 mol/ L in the group

PRE, 9.808 +/– 2.543 mol/L in the group PRE-IUGR

and 7.639 +/– 2.728 mol/L in the control group. These

differences were statistically significant in Figure 1.

4. DISCUSSION

We revealed higher levels of maternal serum homocys-

teine in the group of pregnant patients with isolated fetal

intrauterine growth restriction in comparison with the

control subjects. The concentrations of homocysteine were

also higher in both groups of patients with pregnancy

complicated by preeclampsia with and without IUGR.

The highest levels of homocysteine were observed in

preeclamptic women with appropriate-for-gestational-age

fetal growth.

Tab le 1 . Analysis of obtained results in studied groups of preeclamptic women with appropriate-for gestational-age fetuses and with

intrauterine fetal growth restriction and in pregnant women with isolated IUGR without preeclampsia.

Data CON group

Statistical

analysis

CON-IUGR

IUGR group

Statistical

analysis

CON-PRE

PRE group

Statistical

analysis

CON-PREIUGR

PRE-IUGR group

Gravidity 1.29 +/– 0.59 p = 0.268 1.46 +/– 0.76 p = 0.0601.72 +/– 1.10 p = 0.277 1.46 +/– 0.95

Parity 1.24 +/– 0.48 p = 0.183 1..40 +/– 0.63 p = 0.0671.56 +/– 0.87 p = 0.364 1.35 +/– 0.80

Maternal

age (years) 29.98 +/– 3.94 p = 0.132 28.54 +/– 4.40 p = 0.14328.04 +/– 6.29 p = 0.693 29.59 +/– 3.92

Maternal

height (cm) 165.35 +/– 5.89 p = 0.381 164.00 +/– 5.30 p = 0.438167.21 +/– 6.85 p = 0.273 163.53 +/– 4.29

Maternal

weight (kg) 76.48 +/– 11.37 p = 0.020156* 69.17 +/– 10.80 p = 0.003558*92.38 +/– 19.74 p = 0.176 81.74 +/– 13.24

Maternal

BMI(kg/m2) 30.29 +/– 12.40 p = 0.08047 25.85 +/– 4.271 p = 0.003511*33.31 +/– 5.30 p = 0.122418 30.38 +/– 4.75

Age of gestation

(weeks) 38.409 +/– 1.624 p = 0.000614* 36.931 +/– 1.990p = 0.000044*34.327 +/– 4.858 p < 0.000001* 33.286 +/– 3.990

Birth weight of

infant (g) 3390.789 +/– 545.196p < 0.000001* 2016.486 +/– 420.997p = 0.000004*2325.172 +/– 1176.240p < 0.000001* 1695.862 +/– 620.967

Homocysteine

levels (μmol/L) 7.639 +/– 2.728 p = 0.0022* 9.004 +/– 2.820 p < 0.0001*10.815 +/– 3.785 p < 0.0001* 9.808 +/– 2.543

Data presented as a mean +/– SD, *statistical significance (p < 0.05). Groups of studied women: CON—healthy normotensive pregnant women (controls);

IUGR normotensive women with pregnancy complicated by isolated intrauterine growth restriction; PRE—preeclamptic women with appropriate growth

fetuses; PRE-IUGR—women with IUGR in the course of preeclampsia.

M. Laskowska et al. / Open Journal of Obstetrics and Gynecology 1 (2011) 191-196

194

Homocysteine levels in maternal serum (



mol/L)

Mean

Mean +/- standard error

Mean +/- SD

CONIUGRPRE PRE-IUGR

groups

Maternal homocysteine (mol/L)

Figure 1. Homocysteine in maternal serum in studied group of women with pregnancies complicated

by preeclampsia and/or IUGR.

Also López-Quesada et al. [14] revealed significantly

higher homocysteine levels in the preeclamptic women.

Similar findings were observed by Wang et al. [15], who

demonstrated elevated levels of maternal plasma homo-

cysteine in preeclamptic pregnancies and in pregnancies

with suspected fetal compromise and umbilical or pla-

cental vascular disease. They concluded that elevated

plasma homocysteine plays a role in pathogenesis of the

vascular disease in the uteroplacental circulation in pla-

cental insufficiency these results are consistent with the

hypothesis for the vascular lesion in maternal uteropla-

cental bed in both preeclampsia and fetal growth restrict-

tion.

Also Mao et al. [16] observed elevated concentrations

of homocysteine in patients with severe preclampsia.

These authors observed a highly significant positive co-

rrelation between the plasma concentrations of homocy-

steine and asymmetric dimetylarginine (ADMA). They

concluded that homocysteine-ADMA-NO pathway may

be responsible for etiology in preeclampsia and could be

regarded as a marker for the severity of the disease.

According to De Falco et al. [17] hyperhomocystei-

nemia during pregnancy could be responsible for placen-

tal abnormalities, which may be the cause of these very

serious pregnancy complications. Also Steegers-Thenissen

et al. [18] presented that hyperhomocysteinemia was a-

ssociated with an approximately 2-fold to 3-fold in-

creased risk of pregnancy-induced hypertension, abrup-

tion of placenta and intrauterine growth restriction.

A significant finding in our study is higher levels of

maternal serum homocysteine in the group of normoten-

sive pregnant patients with isolated fetal intrauterine

growth restriction.

Similar results higher total homocysteine levels in wo-

men delivering IUGR infants were presented by Lind-

blad et al. [19].

But different results were presented by Claire Infan-

te-Rivard et al. [20] who observed in their studies that

mothers with small babies had lower homocysteine con-

centrations than mothers with large babies. Furthermore

according to these authors [20] higher maternal homo-

cysteine levels were associated with a statistically sig-

nificant reduction in risk for IUGR.

Different results in pregnancy complicated by IUGR,

but similar results in preeclamptic pregnancies were pre-

sented also by Hogg et al. [21]. They analyzed homocy-

steine levels in maternal plasma in second and third tri-

mester of pregnancies complicated by pregnancy-indu-

ced hypertension, preeclampsia and IUGR, respectively.

In their studies in these three groups of pregnant women

the homocysteine levels in the second trimester of preg-

nancy did not differ from women with uncomplicated pre-

gnancies in any groups, but at 37th weeks of gestation,

the women with pregnancy-induced hypertension or pree-

clampsia had higher homocysteine concentrations than

controls.

M. Laskowska et al. / Open Journal of Obstetrics and Gynecology 1 (2011) 191-196 195

However Hogg et al. [21] did not find such differen-

ces in pregnancies with IUGR. They concluded that pla-

sma homocysteine concentrations in the second trimester

do not predict the subsequent complications of preg-

nancy-induced hypertension, preeclampsia and intraute-

rine growth restriction.

Contrary to our findings also D’Anna et al. [22] didn’t

find any association between homocysteine levels in pre-

gnancy and IUGR.

Our findings about higher levels of maternal serum

homocysteine in pregnancies complicated by IUGR are

inconsistent with some earlier reports about the rela-

tionship between higher levels of homocysteine in preg-

nancy with intrauterine fetal growth restriction. This may

be due to the fact that we included into a group of wo-

men with pregnancy complicated by IUGR only patients

with fetal weight estimated below the 5th percentile for

gestational age. Furthermore we divided all pregnant

patients with fetal growth restriction into two groups,

one with IUGR in the course of preeclampsia and the se-

cond group with isolated IUGR and normotensive preg-

nancy, without any maternal or fetal condition response-

ble for this pregnancy complication. The aim of this was

to select the patients with the IUGR due to placental

dysfunction.

5. CONCLUSIONS

In conclusion, our findings seem to suggest that homo-

cysteine is a mediator of endothelial activation or dys-

function observed in pregnancies complicated by pree-

clampsia, but also in normotensive pregnancies compli-

cated by isolated IUGR.

It seems that the pathomechanism underlying the de-

velopment of preeclampsia and/or intrauterine fetal grow-

th restriction is similar, but highest levels of homocys-

teine observed in preeclamptic pregnancies may suggest

that its beginning and intensity may be more enhanced in

pregnancy complicated by hypertension and preeclamp-

sia.

Thanks to our better understanding of its physiology

and pathophysiology, homocysteine may develop towa-

rds a novel target for pharmacological intervention for

patients with these pregnancy complications.

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