Early Human Development 88 (2012) 893–898

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Early Human Development

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Maternal preeclampsia is associated with increased risk of necrotizing enterocolitis in

preterm infants
Merih Cetinkaya ⁎, Hilal Ozkan, Nilgun Koksal
Uludag University, Faculty of Medicine, Department of Pediatrics, Division of Neonatology, Bursa, Turkey

a r t i c l e i n f o a b s t r a c t

Article history: Background: Necrotizing enterocolitis (NEC) is an important cause of mortality and morbidity in preterm infants.
Received 9 June 2012 Aims: To evaluate the effect of maternal preeclampsia on the development and severity of NEC in premature infants.
Received in revised form 3 July 2012 Study design: Prospective observational study in a tertiary neonatal intensive care unit.
Accepted 5 July 2012 Subjects: The preterm infants of ≤37 gestational age who were consecutively hospitalized were enrolled. The study
group contained preterm infants born to a preeclamptic mother and the comparison group contained preterm
Keywords:
infants born to a normotensive mother.
Necrotizing enterocolitis
Preeclampsia
Outcome measures: The primary outcome was to determine the association between preeclampsia and NEC.
Preterm infant Results: A total of 88 infants had NEC diagnosis. The incidence of NEC in infants born to preeclamptic mothers
Risk factor (22.9%) was significantly higher compared with those born to normotensive mothers (14.6%). According to NEC
stages, NEC was more advanced in preeclamptic mother infants. NEC developed significantly earlier in infants
with NEC in the study group. The duration of NEC was also significantly longer in infants born to preeclamptic
mothers. In multiple logistic regression model, preeclampsia was found to be predictive of NEC with an odds
ratio of 1.74 (95% confidence interval 0.64–0.92).
Conclusions: Maternal preeclampsia may be an important risk factor for the development of NEC in premature
infants as NEC incidence and severity of NEC were found to be significantly higher in premature infants born to
preeclamptic mothers. The onset of NEC was significantly earlier and duration of NEC was longer in these infants.
© 2012 Elsevier Ireland Ltd. All rights reserved.

1. Introduction feeding, sepsis, intestinal ischemia reperfusion injury, polycythemia,

Necrotizing enterocolitis (NEC), the commonest neonatal gastroin-
testinal emergency in preterm infants, is an important cause of both
short and long term morbidity as well as mortality [1–3]. As the survival
of very low birth weight (VLBW) infants increased due to the advances
in perinatology including pre- and postnatal care, the incidence and
rates of associated morbidity and mortality have remained unchanged
[3]. According to the recent data, NEC occurs in about 5% of VLBW and
10% of extremely low birth weight (ELBW) infants [4]. The estimated
mortality rate of NEC ranges between 20 and 30%, with the highest
rates among infants requiring surgical intervention and also infants
with lower gestational age and birth weight [5,6].
Although the pathogenesis of NEC is poorly understood, prematu-
rity is the main and the most important risk factor. Asphyxia, formula
⁎ Corresponding author at: Uludağ Üniversitesi Tıp Fakültesi, Çocuk Sağlığı
ve Hastalıkları ABD, 16059 Görükle, Bursa, Turkey. Tel.:+90 224 2950447;
fax: + 90 224 4428143.
E-mail address: drmerih@yahoo.com (M. Cetinkaya).
intrauterine growth retardation (IUGR) and the presence of an umbil-
ical catheter are other risk factors for NEC development [7].
Preeclampsia that is characterized by hypertension, proteinuria
and edema, is a pregnancy-specific hypertensive syndrome and is
associated with significant maternal mortality and morbidities,
perinatal death, preterm birth and IUGR [8]. The effect of preeclampsia
on fetus is reduced placental perfusion, ischemia and prematurity. It is
well established that reduced uteroplacental blood flow leading to
fetoplacental hypoxia is an important subject in the pathogenesis of
IUGR in preeclampsia [9].
Although there may be an association between NEC and fetal growth
restriction and/or comprise, there is no in utero NEC case which suggests
a possible postnatal interaction between prematurity, ischemia and
infection [6]. IUGR secondary to suboptimal placental support was
suggested to be an important risk factor for NEC development and it
was also reported that this association might be stronger if there was ev-
idence of fetal compromise accompanying IUGR [6,10–13]. In addition,
limited number of studies reported conflicting data about the risk
of maternal preeclampsia on NEC development in premature in-
fants [14,15].

0378-3782/$ – see front matter © 2012 Elsevier Ireland Ltd. All rights reserved.
doi:10.1016/j.earlhumdev.2012.07.004
894 M. Cetinkaya et al. / Early Human Development 88 (2012) 893–898
However, to our knowledge, there is no prospective study which
investigated the effect of maternal preeclampsia on NEC development
in premature infants.
Therefore, the aim of this study was to determine the effect of
maternal preeclampsia on NEC development in preterm infants. We
also aimed to determine the possible association between maternal
preeclampsia and severity of NEC.
2. Material and methods
A total of 652 premature infants that were less than 37 weeks of
gestational age and admitted to Uludag University, School of Medicine,
Neonatal Intensive Care Unit between June 2006 and June 2010 were
included in this observational prospective study. To eliminate the
effects of maternal diseases; mothers with a history of maternal
chorioamnionitis, prolonged rupture of membranes, diabetes, or the
use of any medication during pregnancy were not included in the
study. The other exclusion criteria were refusal of parental consent,
major congenital malformation and chromosomal anomalies. The infants
with stage I NEC and/or infants who had diagnosis of spontaneous
intestinal perforation (SIP) were also excluded. Fig. 1 shows the flow
diagram of study population. The study protocol was approved by
652 preterm
infant enrolled
194 born to
preeclamptic mother
Excluded
16 had refused to participate
4 had congenital/chromosomal
abnormality
174 infants born to
preeclamptic mother
Total NEC=40
15 Stage 1 NEC excluded
1 SIN excluded
Final NEC group=24
Fig. 1. Flow diagram of study population. * indicates maternal co‐existing factors: diabetes, chorioamnionitis, premature rupture of membranes. Abbreviations: NEC: necrotizing
enterocolitis; SIN: spontaneous intestinal perforation.
the Ethics Committee of Uludag University, Faculty of Medicine.
Informed parental consent was obtained for all infants.
The study group included preterm infants (≤37 gestational age) born
to a preeclamptic mother with no co-existing medical condition whereas
the comparison group included preterm infants (≤37 gestational age)
born to a normotensive mother with no co-existing medical condition.
A detailed maternal history including age, gravidity, antenatal steroid
use, medications used in pregnancy, and route of delivery was recorded.
Also gestational history of infants including birth weight, gestational
age, gender, Apgar scores, small for gestational age (SGA), need for
resuscitation, prenatal and postnatal hypoxia, feeding properties,
presence of other neonatal morbidities such as respiratory distress
syndrome (RDS), patent ductus arteriosus (PDA), intraventricular
hemorrhage (IVH), bronchopulmonary dysplasia (BPD), and reti-
nopathy of prematurity (ROP) were also recorded. Duration of ven-
tilation, duration of hospitalization, total number of transfusions and
duration of hospital stay of infants were obtained and recorded.
A blood pressure of ≥140/90 mm Hg accompanied by albuminuria
of at least 300 mg/24 h after 20 weeks of gestation was defined as
preeclampsia [16]. RDS, BPD, IVH and ROP were diagnosed according
to the defined criteria in the literature [17–20]. PDA was visualized by
two-dimensional echocardiograms of the parasternal short-axis view
at the level of the aortic valve or higher and then a color Doppler flow
Exclusion due to
maternal co-existing
factors*
n=96
362 born to
normotensive
mother
Excluded
26 refused to participate
9 had congenital/chromosomal
abnormality
327 infants born to
normotensive mother
Total NEC=48
29 Stage 1 NEC excluded
1 SIN excluded
Final NEC group=18
 M. Cetinkaya et al. / Early Human Development 88 (2012) 893–898 895

of the ductus was imaged. Gestational age was evaluated by maternal Table 1
dates and confirmed by the modified Ballard examination [21]. The Demographic features of the study and control groups.

birth weight below 10th percentile of gestational age was defined as Infants born to Infants born to p value
SGA [22]. preeclamptic mothers without
NEC was diagnosed according to clinical and radiographic findings, mothers preeclampsia
(Study group) (Control group)
and it was classified according to modified Bell's criteria [23]. Abdom-
n = 174 n = 327
inal distention or tenderness, gastric residuals, bloody or bilious
Gestational 31.2 ± 3.1 31.8 ± 3.6 0.28
gastric aspirates, bloody stools, emesis, feeding intolerance, absent
age (week),
or decreased bowel sounds, and abdominal wall erythema were mean ± SD
considered as clinical signs of NEC. According to modified Bell's Birth weight 1464 ± 486 1584 ± 601 0.12
criteria, radiographic findings, including intestinal dilation or mild (gram), mean ± SD
ileus was defined as stage I NEC; intestinal dilation, ileus and Gender (male), 91 (52) 163 (50) 0.29
n (%)
pneumatosis intestinalis with or without ascites were defined as
Small for 57 (33) 65 (20) 0.08
stage II NEC and additional findings of pneumoperitoneum were gestational age,
defined as stage III NEC [23]. However, to increase the power of n (%)
the study, infants with stage I NEC and/or infants who had a diagno- Multiple gestation, 73 (42) 134 (41) 0.51
n (%)
sis of SIP were excluded from the study, therefore, only infants with
Cesarean delivery, 104 (60) 182 (55) 0.50
confirmed NEC (stage II and stage III NEC) were included into the n (%)
final statistical analysis. SIP was defined as an acute localized and Antenatal steroid 96 (55) 174 (53) 0.54
isolated gastrointestinal perforation diagnosed by x-ray without treatment,
classical clinical, laboratory and/or radio-graphic findings of NEC n (%)
Apgar minute 1, 4.6 ± 1.4 5.6 ± 1.3 0.06
or findings of NEC at surgery (lack of gross necrosis of the intes-
mean ± SD
tine). The abdominal radiographs were repeated every 6 h for the Apgar minute 5, 6.8 ± 1.6 7.6 ± 1.5 0.06
first 48 h, and then less frequently during follow up, until the cessa- mean ± SD
tion of NEC antimicrobial therapy in cases with NEC. The duration of Perinatal asphyxia, 9 (5) 14 (4) 0.31
n (%)
NEC was used to define the total days from the first day of NEC
suspicion and/or diagnosis until the onset of feeding. Premature
infants were also given appropriate therapies, such as mechanical
ventilation, antibiotic treatment, gastric decompression or volume
expansion with fluid or blood products. The antimicrobial therapy group). The incidence of NEC in infants born to preeclamptic
was stopped and enteral feeding was started when clinical and mothers (13.7%) was significantly higher than those born to
laboratory improvement has obtained and both of these usually normotensive mothers (5.5%) (p = 0.02). In the study group, 18
included 7 to 10 days and 10 to 14 days for stage II and stage III infants (10.3%) had stage 2 NEC and 6 infants (3.4%) had stage 3
NEC, respectively. All groups were compared with regard to demo- NEC. In the control group, stage 2 and 3 NEC were diagnosed in
graphic features, clinical and laboratory findings. 15 (4.6%) and 3 (0.09%) infants, respectively (for stage 2 and 3
SPSS 16.0 software (Chicago, IL, USA) was used for statistical NEC, p b 0.05). Table 2 and Fig. 2 show the number of infants with
analyses. Descriptive statistics were given as mean ± standard devi- NEC according to NEC stages in the study and control groups.
ation, and percentage. Shapiro–Wilk test was used to test the normal In the study group, although the mean gestational age and birth
distribution of the data. The categorical data were analyzed by weight of the infants with NEC was lower than those without NEC
chi-square test. Mann–Whitney test and student's t test were used (28.0 ± 2.1 weeks vs. 28.7 ± 1.7 weeks) (1194 ± 292 g vs. 1375 ±
for comparisons between groups as appropriate. Kruskall–Wallis 371 g), the differences between these groups were not statistically
test and one-way analysis of variance were used for comparison of different (p > 0.05). There were no significant differences between
more than 2 groups. In addition, logistic regression analysis was infants with NEC in the study and control groups with respect to formu-
performed and the adjusted odds ratio (OR) and their 95% confi- la feeding, perinatal asphyxia, and PDA diagnosis. The incidence of ROP
dence intervals (%95 CI) were obtained for the risk factors included was found to be significantly higher in infants with NEC in the study
in the model. Values of p b 0.05 were considered to be significant. group compared with the infants in the control group (Table 3). When
the infants were divided into two subgroups in terms of gestational age
3. Results (b 30 gestational week) and birth weight (b1250 g), although the
incidence of NEC was higher in smaller infants born to preeclamptic
The study population included a total of 501 premature infants. mothers compared with those born to normotensive mothers (16.1% vs.
The mean gestational age of the infants was 31.4 ± 3.3 weeks and 11.1% and 19.5% vs. 11.1%, respectively), this difference was not statisti-
mean birth weights of them were 1476 ± 682 g. The study group cally significant (p=0.35 and p=0.06, respectively).
consisted of 174 premature infants born to preeclamptic mothers NEC occurred significantly earlier in infants with NEC in the
and the control group consisted of 327 premature infants born to study group compared to those with NEC in the control group
normotensive mothers. Mean gestational age of the infants born to (6.1 ± 1.7 days vs. 12.5 ± 4.2 days) (p = 0.0001). The duration of
preeclamptic mothers and normotensive mothers was 31.2 ± NEC was also significantly longer in infants born to preeclamptic
3.1 weeks and 31.8 ± 3.6 weeks, respectively. Mean birth weights of
the study and the control groups were 1464 ± 486 g and 1584 ±
601 g, respectively. There were no significant differences between the
Table 2
two groups in terms of demographic features as shown in Table 1.
Distribution of study group according to NEC stages.
A total of 88 infants had NEC diagnosis (40 infants in the study group
and 48 infants in the control group). However, 34 infants with stage I NEC Study group Control group p value
n = 174 n = 327
(15 infants in the study group and 19 infants in the control group) and 2
infants with SIN (1 in both groups) were excluded from the final analysis. Stage 2 NEC, n (%) 18/174 (10.3) 15/327 (4.6) 0.01
Stage 3 NEC, n (%) 7/174 (4.0) 4/327 (1.2) 0.04
Therefore, confirmed NEC was diagnosed in a total of 42 infants
Total NEC, n (%) 25/174 (14.3) 19/327 (5.8) 0.001
(24 infants in the study group and 18 infants in the control
896 M. Cetinkaya et al. / Early Human Development 88 (2012) 893–898

Table 4
Multiple regression analysis of risk factors associated with NEC development.

Odds ratio 95% confidence interval

Gestational age 1.12 0.52 to 1.64

Birth weight 1.36 0.88 to 1.46
Preeclampsia 1.74 0.64 to 1.92
Formula feeding 1.02 0.59 to 1.28
Small for gestational age 0.74 0.44 to 0.98

addition, NEC occurred significantly earlier in premature infants born to

preeclamptic mothers and the duration of NEC was significantly higher
in these infants compared to those born to normotensive mothers.
Fig. 2. Figure showing the percentage of infants in both study and control groups.
The risk of NEC development is primarily and inversely associated
with birth weight and gestational age. The risk of mortality and
serious adverse morbidity was also reported to be increased with
lower birth weight and gestational age [6,24,25]. Our study was in
mothers compared to those born to normotensive mothers (11.0 ± agreement with this data as infants who developed NEC had smaller
5.6 days vs. 6.1 ± 2.4 days) (p = 0.0001). Although the number of birth weight and gestational age.
infants who went to surgery was higher in infants with NEC in the It was suggested that neonatal outcomes of infants born to
study group, the difference was not statistically significant (25% vs. preeclamptic mothers were primarily associated with severity of pre-
17%) (p > 0.05). maturity and SGA [26]. Although the pathogenesis of preeclampsia is
In multiple logistic regression model, preeclampsia (OR, 1.74; CI, not fully understood, the placenta is thought to play an important role
0.64 to 1.92), birth weight (OR, 1.36; Cl, 0.88 to 1.46), gestational age in the development of preeclampsia. Placental ischemia, generalized
(OR, 1.12; CI, 0.52 to 1.64), and formula feeding (OR, 1.02; CI, 0.59 to vasospasm, vascular endothelial dysfunction, abnormal nitric oxide
1.28) were associated with NEC development (Table 4). metabolism, abnormal hemostasis with activation of the coagulation
system, leukocyte activation, and changes in cytokines constitute the
main pathophysiologic abnormalities of preeclampsia [27]. The inade-
4. Discussion quate placental circulation leading to placental hypoxia and oxi-
dative stress may also be considered as important problems in
This prospective study showed that NEC incidence was significantly morbidities associated with preeclampsia [28]. Therefore, pre-
higher in premature infants that were born to preeclamptic mothers eclampsia results with reduced placental perfusion and prematu-
compared to premature infants born to normotensive mothers. In rity. It was suggested that reduced uteroplacental blood flow
leading to fetoplacental hypoxia might be an important factor in
the pathogenesis of IUGR in preeclampsia [9,28].
Although the pathophysiology of NEC is multifactorial, prematuri-
Table 3
Frequency of neonatal morbidities in each group.
ty, intestinal immaturity, hypoxia, formula feeding, colonization with
pathogenic bacteria and low perfusion states are the main risk factors
Confirmed Confirmed NEC in the p value [24]. IUGR secondary to suboptimal placental support was also reported
NEC in the control group
to be an important risk factor for NEC development and this association
study group n = 19
n = 25 was suggested to be stronger with the evidence of fetal compromise indi-
cated by abnormal umbilical arterial flow [6,10–13]. Some studies also
Demographic features
Mean gestational age, (week), 28.0 ± 2.1 28.7 ± 1.7 0.17 established that intrauterine fetal malnutrition might be associated with
mean ± SD gastrointestinal complications including NEC and/or feeding intolerance
Mean birth weight, grams, 1194 ± 292 1375 ± 371 0.7 [29,30]. There are limited number of studies that reported conflicting
mean ± SD data about association between maternal preeclampsia and NEC in pre-
Gender (male),n (%) 16 (64) 12 (63.2) 0.6
mature infants [14,15]. Therefore, we performed this study and showed
Cesarean delivery, n (%) 17 (68) 12 (63) 0.07
Antenatal steroid treatment, n (%) 16 (64) 10 (52.6) 0.46 that maternal preeclampsia might be an important risk factor for NEC in
Small for gestational age, n (%) 5 (20) 4 (21) 0.5 premature infants.
Apgar minute1, mean ± SD 4.6 ± 1.2 6.1 ± 1.1 0.2 In animal models, hypoxia was shown to reduce intestinal blood flow
Apgar minute5, mean ± SD 6.2 ± 1.1 7.2 ± 1.2 0.06
and oxygen delivery through adrenergic vasoconstriction [31]. Although
Formula feeding, n (%) 8 (32) 7 (36.8) 0.42
Start of enteral feeding (day), 2.3 ± 0.8 1.9 ± 0.6 0.54
increased oxygen extraction could compensate for a 30% reduction in
mean ± SD intestinal blood flow, enteral feeding was found to decrease this ability
[32]. The metabolic demands of enteral feeding also increased oxygen
Neonatal characteristics/morbidities consumption by the intestine [33]. Therefore, in a review, it was hypoth-
Respiratory distress syndrome, 16 (64) 12 (63.2) 0.9
esized that the combination of persisting ante- and postnatal distur-
n (%)
Patent ductus arteriosus, n (%) 9 (36) 6 (31.5) 0.52 bances in gut perfusion that were interacted with the metabolic
Bronchopulmonary dysplasia, n (%) 11 (44) 7 (36.8) 0.6 demands of enteral feeding might adversely affect intestinal tissue oxy-
Retinopathy of prematurity, n (%) 10 (40) 4 (21) 0.04 genation in combination with stasis and immunological factors and all
Intraventricular hemorrhage, n (%) 6 (24) 4 (21) 0.41
these factors might lead to NEC development [10].
Time of NEC diagnosis (day), 6.1 ± 1.7 12.5 ± 4.2 0.0001
mean ± SD
In the presence of maternal preeclampsia, a combination of fetal
Duration of NEC (day), mean ± SD 11.0 ± 5.6 6.1 ± 2.4 0.0001 hypoxia and increased mesenteric vascular resistance might produce
Number of transfusion, mean ± SD 3.9 ± 1.5 4.2 ± 1.7 0.08 hypoxic-ischemic state in the intestine and/or in its mucosa in the
Duration of hospitalization (day), 30 ± 17 29 ± 15 0.07 antenatal period. It was also suggested that in the absence of direct
mean ± SD
tissue injury in the intestine, prolonged exposure to hypoxia might
 M. Cetinkaya et al. / Early Human Development 88 (2012) 893–898
provide an intestine that is more susceptible to stasis, abnormal
colonization and bacterial overgrowth in the postnatal period [10].
Neutropenia that is seen in the infants born to preeclamptic mothers
might also affect susceptibility to infective factors and lead to sepsis
[34]. All these data might suggest an increased risk of NEC in prema-
ture infants that were born to preeclamptic mothers. Therefore, our
findings including the higher incidence and severity of NEC in pre-
eclamptic mother infants might be explained by these mechanisms.
However, these mechanisms must be highlighted by other experimen-
tal and clinical studies.
Limited number of studies which investigated the neonatal outcomes
of infants born to preeclamptic mothers has reported conflicting data
[26,27,35,36]. In our previous study including smaller number of infants,
although maternal preeclampsia was associated with increased incidence
of sepsis and the number of preeclamptic mother infants who developed
NEC was significantly higher compared to those born to normotensive
mothers, the difference was not found to be statistically significant [36].
Similarly, other studies which evaluated the neonatal outcomes of mater-
nal preeclampsia, NEC was reported to be not increased in infants born to
preeclamptic mothers [37–39]. These differences between studies might
probably be associated with the sample sizes and none of these studies
was designed to evaluate the effect of preeclampsia on NEC development.
However, Kamoji et al. [11] reported an increased NEC incidence in pre-
mature infants who exposed to antenatal gut ischemia. Their finding
also confirmed a meta-analysis which reported five to sevenfold increase
in the odds of NEC development in infants who had abnormal antenatal
Doppler studies [10]. Also, in this study, ROP incidence was found to be
significantly higher in infants with NEC in the study group compared
with those with NEC that were born to normotensive mothers. This find-
ing was also in agreement of our recent data in which we showed that
maternal preeclampsia was associated with increased risk of ROP [40].
Another important findings of this study were that earlier occurrence
and longer duration of NEC in premature infants that were born to pre-
eclamptic mothers. We suggest that this finding might be explained by
the data that NEC occurred earlier in full term infants with a mechanism
related to perinatal ischemic insult [41]. The altered endothelin (ET) and
nitric oxide balance leading to vasoconstriction due to disruption of
endothelial cell function by ischemia–reperfusion and sustained low
state perfusion might also be associated with the earlier occurrence of
NEC in preeclamptic mother infants as high ET levels were reported in
these infants [42,43]. Although there may be an association between
NEC and fetal growth restriction and/or compromise, there is no in
utero NEC case which may suggest a possible postnatal interaction
between prematurity, ischemia and infection [6]. It was also postulated
that additional stresses such as increased metabolic demands, alterations
in mucosal integrity and infections might trigger a cascade of events
which could lead to NEC in preterm infants who had immature gastroin-
testinal tract and precarious vascular supply. Therefore, due to all these
data, it can be proposed that such an antenatal intestinal tissue hypoxia
may possibly lead to mucosal injury and facilitate bacterial colonization
which results with earlier occurrence of NEC in infants born to pre-
eclamptic mothers. This might also lead to longer duration of NEC in
preeclamptic mother infants. As a result, we suggest that intestinal
tissue hypoxia due to maternal preeclampsia might provide a more
susceptible intestine which might lead to earlier injury. Therefore,
intestinal hypoxia due to maternal preeclampsia may lead to earlier
occurrence of NEC as it does in term infants with hypoxia and/or
cyanotic congenital heart defects. So, we think that this important find-
ing must be evaluated in future studies.
In conclusion, this is the first study which evaluated the effect of
maternal preeclampsia on NEC development in premature infants.
NEC incidence and severity of NEC were found to be significantly
higher in premature infants born to preeclamptic mothers. Also, NEC
developed significantly earlier in preeclamptic mother infants and du-
ration of NEC was also found to be significantly longer in these infants.
Therefore, we suggest that maternal preeclampsia may be an
897
important risk factor for the development of NEC in premature infants.
The role of maternal preeclampsia in the occurrence and severity of
NEC remains to be elucidated by future prospective studies.
Conflict of interest statement
The authors report no conflict of interest.
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