Feng et al. BMC Pediatrics(2024) 24:546
https://doi.org/10.1186/s12887-024-05006-4

BMC Pediatrics

CASE REPORTOpen AccessTwo cases of Leukemoid reactionin premature infants caused by fetal
inflammatory response syndrome
Meng-Ting Feng1, Qiong Ji1, Dan-Dan Liu1 and Wei Xu1*
Abstract
Background Fetal inflammatory response syndrome (FIRS) is a systemic inflammatory response caused by theactivation of the fetal immune system. The serological diagnostic criterion for fetal inflammatory response syndrome
is a cord blood interleukin-6 concentration that exceeds 11 pg/mL, while pathologic evidence indicates the presenceof funisitis or chorionic vasculitis. It can affect all systems of the fetus. Alterations in patients’ hematopoietic system areprimarily reflected by changes in peripheral blood leukocyte and neutrophil counts.
Case presentation We performed placental pathology to identify FIRS and showed two cases of neonatal leukemoid
reaction caused by FIRS. These two babies’ alterations in hematopoietic system resolves spontaneously with the
inflammation relief, without specific interventions. During the 16‑month and14- month follow‑up period, their motorand intellectual development was normal.
Conclusions . Neonatal leukemoid reaction is a reactive disease characterized by abnormal blood parameters similar
to those of leukemia, but not leukemia. It is an aberrant hematopoietic response that typically resolves spontaneouslywith cause relief without requiring specific interventions.
Keywords Fetal inflammatory response syndrome, Neonatal leukemoid reaction, Premature infants, Hematopoietic
systemBackgroundFetal inflammatory response syndrome (FIRS) refers to asystemic inflammatory response caused by the activationof fetal immune system and the release of a large numberof proinflammatory cytokines. 1 FIRS is characterized
by an increase in pro-inflammatory cytokines and multisystemic involvement in utero or in the immediate neonatal period [1-2]. Some studies have demonstrated that

*Correspondence:
Wei Xuxwei@jlu.edu.cn
1
Department of Neonatology, Children’s Medical Center, The First Hospitalof Jilin University, NO.1 Xinmin Street, Changchun 130012, China

FIRS might increase the risk of perinatal multisystemic
disorders such as intraventricular hemorrhage, hydrocephalus, periventricular leukoencephalopathy, earlyonset sepsis and neonatal respiratory distress syndrome,bronchopulmonary dysplasia, and neonatal death. However, few studies on the hematopoietic system have beenreported. Neonatal leukemoid reaction refers to a peripheral blood WBC count exceeding 50 × 109/L, a neutrophil
count > 30 × 109/L, or a neutrophil count that is greaterthan two standard deviations from the mean for the corresponding gestational age and the presence of immature
cells. We present two cases of neonatal leukemoid reaction caused by FIRS affecting the hematopoietic system
in premature infants admitted to our hospital, aimed at© The Author(s) 2024. Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0
International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you
give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified thelicensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images orother third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to thematerial. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation
or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://
creativecommons.org/licenses/by-nc-nd/4.0/.

Feng et al. BMC Pediatrics(2024) 24:546

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improving clinicians’ understanding of abnormal hematopoietic reactions induced by FIRS and providing a reference for diagnosis and treatment.

cell morphology examination at the postnatal day six
revealed that precursor neutrophils constitute 14% of thetotal WBC count. The WBC count gradually decreased(Table 1). No immature blood cells were observed undera microscope on day 20. Maternal placental pathology
revealed necrotizing histological chorioamnionitis (stage
3, grade 2; Fig 1) with abscess formation, chorionic vasculitis, and umbilical vasculitis (stage 2, grade 1; Fig 1).
On day 29, the baby was still inseparable from respiratory
support therapy and was diagnosed with bronchopulmonary dysplasia. On day 33, the baby was diagnosed withretinopathy of prematurity. The patient improved andwas discharged from the hospital on day 65. At the corrected gestational age of 16 months, her body length was
81 cm (P80), her weight was 12 kg (P80), and her motorand intellectual development was normal.

Case presentation
Case 1

The female infant was born at 28 + 6 weeks of gestation by
spontaneous vaginal delivery (gravida 5 para 2), weighing
1370 g (50–75th percentile). No anomalies were detectedin the umbilical cord, amniotic fluid or placenta. Apgar
scores of six at 1 and 5 min. The mother received four
doses of antenatal dexamethasone, 6 mg, q12h, im. The
fetal heart rate increased one day before delivery, and themother’s temperature peak reached 37.5 ˚C. The mother’s laboratory tests revealed leukocytosis: white blood
cell (WBC) count 16.17 × 109/L, neutrophilic granulocyte
percentage (NE%) 75%, and an increase in highly sensitive c-reaction protein (hs-CRP) 46.42 mg/L (normal
range: 0-1 mg/L) 16 h before delivery. Physical examination on admission revealed no rash on the whole body,the liver was 2.0 cm under the rib, and the spleen was
not palpated. The infant was administered cefepime andampicillin intravenously, and symptomatic support, suchas alveolar surfactant supplementation and mechanicalventilation, was provided. The infant’s postnatal complete
blood count (CBC) was as follows: WBC 64.31 × 109/L,
NE% 72%, NE 46.09 × 109/L, lymphocyte percentage(LY%) 22%, and monocyte percentage (MO%) 6%. At
11 h, the baby’s temperature peak reached 39.1 ˚C. The
blood cell morphology examination on day 2 revealed
that precursor neutrophils accounted for 31% of thetotal WBC count and six nucleated red blood cells per
100 classified WBCs. Procalcitonin (PCT) was 25 ng/ml(normal range: 0.00-0.01ng/ml); hs-CRP was 12.41 mg/L.
Cranial ultrasound revealed a Grade II intraventricularhemorrhage. On day 3, the infant’s CBC was as follows:
WBC 88.10 × 109/L, NE% 85%, NE 74.87 × 109/L, LY%
11%, and MO%, 4%. Blood cell morphology examination revealed that precursor neutrophils constitute 26%of the total WBC count. The infant had a fever again at
the age of three days, with a peak temperature of 38.3 ˚C.
We discontinued antibiotics after the blood culture andmetagenomic next-generation sequencing results were
negative at five days postnatal age. The infant’s blood

Case 2

The female neonate was delivered via cesarean section(gravida 1 para 1) at 30 + 3 weeks of gestation with a birthweight of 1380 g (50th percentile) due to a prematurerupture of membranes lasting 45 h and fetal tachycardia
with no uterine contraction. No anomalies were detectedin the umbilical cord, amniotic fluid or placenta. The
Apgar score were seven at 1 min and eight at 5 min. The
mother received four doses of antenatal dexamethasone,
6 mg, q12h, im. The mother’s laboratory tests revealed
leukocytosis (WBC: 17.10 × 109/L and NE% 88%) andhs-CRP elevation (52.8 mg/L) 6 h before delivery. At the
10 h after delivery, the mother presented with a postpartum fever of 39.0 ˚C. Physical examination on admission
revealed no rash on the whole body, the liver was 2.0 cm
under the rib, and the spleen was not palpated. The infant
was administered cefepime and ampicillin intravenously
and received symptomatic support such as alveolar surfactant supplement and respiratory support. The baby’s
postnatal CBC was as follows: WBC 50.84 × 109/L, NE%
77%, NE 39.17 × 109/L, LY% 13%, MO% 4%. Blood cellmorphology examination on the second day revealed
that precursor neutrophils constitute 21% of the total
WBCs. PCT was 25 ng/mL, and hs-CRP 12.41 was mg/L.
On day three, the infant’s CBC was as follows: WBC
80.35 × 109/L, NE% 82%, NE 66.23 × 109/L, LY% 11%,and MO% 11%. Cranial ultrasound revealed a grade II

Table 1 CBC of the infant in case 1
Day-age
D1
D3
D7
D14
D19
D25

WBC
(×109/L)
64.31
88.10
65.97
20.61
16.43
14.39

NE
(×109/L)
46.09
74.87
52.81
9.13
8.21
2.70

NE
(%)
72
85
80
44
50
19

LY
(%)
22
11
13
35
36
69

MO
(%)
6
4
5
12
11
9

RBC
(×1012/L)
4.47
4.42
4.89
4.79
4.24
3.88

HGB
(g/dl)
16.8
15.3
16.6
15.9
13.8
12.3

PLT
(×109/L)
300
357
307
271
259
378

Feng et al. BMC Pediatrics(2024) 24:546

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Table 2 CBC of the infant in case 2
Day-age
D1
D3
D8
D10
D14
D20

WBC
(×109/L)
50.84
80.35
52.29
38.53
18.80
12.82

NE
(×109/L)
39.17
66.23
40.75
38.53
8.12
4.12

NE
(%)
77
82
78
68
43
32

LY
(%)
11
13
17
24
42
53

MO
(%)
11
4
5
6
7
11

RBC
(×1012/L)
3.58
3.65
3.25
3.26
3.09
2.83

HGB
(g/dl)
13.1
13.7
11.8
11.5
10.6
9.7

PLT
(×109/L)
229
282
257
378
418
401

Fig. 1 The maternal placental pathology of the infant in case 1. a. Chorioamnionitis (yellow arrow), subchorionitis (green arrow). b. Microabscess formation (green arrow) and necrosis (yellow arrow) within the chorionic plate. c. Chorionic vasculitis (yellow arrow). d. Umbilical phlebitis (yellow arrow). e.
Umbilical arteritis (yellow arrow)intraventricular hemorrhage. The infant presented with a
postpartum fever three days after delivery, with a temperature of 38.2 ˚C. We stopped antibiotics after the blood
culture and metagenomic next-generation sequencing
were negative on day 6. The infant had a fever on day 10
with a temperature of 38.1 ˚C. The WBC count gradually
decreased (Table 2). On day 13, the infant’s CBC was asfollows: WBC 18.18 × 109/L, NE% 43%, NE 8.12 × 109/L,
and no immature blood cells were observed during blood
cell morphology examination. Maternal placental pathology revealed necrotizing histological chorioamnionitis(stage 3, grade 2) with abscess formation, chorionic vasculitis, and umbilical vasculitis (stage 2, grade 2). On day
23, the baby did not need respiratory support therapy,
improved and was discharged from hospital on day 38.
At the corrected gestational age of 14 months, her bodylength was 78 cm (P75), weight was 9kg (P10), and her
motor and intellectual development is normal.

Discussion and conclusions
FIRS is characterized by the elevation of fetal proinflammatory cytokines. The serological diagnostic criteria for
FIRS is a cord blood interleukin-6 (IL-6) concentrationthat exceed 11 pg/mL, while pathologic evidence indicates the presence of funisitis or chorionic vasculitis [3].
FIRS is primarily caused by intrauterine infection withmicroorganisms such as bacteria, viruses, and protozoa.
It is a special type of systemic inflammatory response
syndrome occurs during the fetal period. Cord blood IL-6
levels were not detected in either patient. Similarly, noamniotic fluid microbiological examination and cytokine
detection was performed in either patient. On placental
pathology examination, both patients exhibited funisitis
and chorionic vasculitis, leading to the diagnosis of FIRS.

The impact of FIRS on the hematopoietic system is primarily characterized by an increase in peripheral blood
leukocyte and neutrophil counts [4]. Neonatal leukemoid
reaction is a reactive disease characterized by abnormal blood parameters similar to those of leukemia, but
not leukemia. It is an aberrant hematopoietic responsethat typically resolves spontaneously with cause relief
without requiring specific interventions. It is associatedwith various clinical conditions, such as premature birth,
infection, chromosomal anomalies, histologic chorioamnionitis, and exposure to antenatal corticosteroids[5]. The incidence of neonatal leukemoid reactions interm and preterm infants ranges from 1.3 to 15%, andapproximately one-quarter of patients are diagnosed with
culture-proven infections [6]. Both cases in the reportwere premature infants, had necrotizing histologicalchorioamnionitis, were exposed to antenatal corticosteroids, and the mothers had signs of systemic infection, allthese may impact the occurrence of neonatal leukemoid
reactions to some extent. Because the blood culture andmetagenomic next-generation sequencing were negative,neither patient had sepsis.
One study revealed that neonatal leukemoid reaction
were significantly associated with sepsis, intraventricular hemorrhage, bronchopulmonary dysplasia and higher
mortality rates in low birth weight neonates [7]. For
example, case 1 was diagnosed with bronchopulmonary
dysplasia. Therefore, neonatal leukemoid reaction may be
a potential predictor of severe complications in certain
pediatric FIRS patients.
The predominant cell types observed in the bonemarrow with neonatal leukemoid reactions were metaphase and late-stage immature granulocytes, with rarepromyelocytes. Toxic granular and vacuolar degeneration of neutrophils is common, but anemia andFeng et al. BMC Pediatrics(2024) 24:546

thrombocytopenia are usually absent. There was no evidence of extramedullary hematopoiesis or organ infiltration, distinguishing neonatal leukemoid reaction fromleukemia. The hyperactivity of granulocyte proliferation was accompanied by a conspicuous leftward shift innuclear morphology, whereas erythrocytes and megakaryocytes remained unchanged. The primary purposeof a bone marrow examination is to rule out the possibility of leukemia. Routine blood examination is crucial
for diagnosing neonatal leukemoid reaction. Peripheral
blood cell morphology is the primary diagnostic basis for
identifying the underlying disease.
There has been little research on the effects of FIRS on
the fetal and neonatal hematopoietic systems. The available literature suggests that alterations in this system
are primarily reflected by changes in peripheral blood
leukocyte and neutrophil counts. Romero [4] demonstrated that leukocytosis was present in approximately
two-thirds of preterm infants with FIRS while the nucleated red blood cell count increased. However, there wasno significant association between FIRS and hemoglobin concentration, platelet count, lymphocyte count,monocyte count, basophil count or eosinophil count.
It has been reported that preterm infants with funisitis
have an increase in total monocyte count [8]. Although
the mechanism of FIRS-induced neonatal leukemoid
reaction is unknown, some researchers believe that anincrease in leukocytes and neutrophils may be related
to increased serum IL-6 and serum granulocyte colonystimulating factor in FIRS [9, 10]. Studies have demonstrated an increase in the expression of CD14, CD64, andCD66b on granulocytes and monocytes in the cord bloodof children with FIRS and an increase in WBC metabolic
activity [11], which may contribute to neonatal leukemoid reaction.
Abbreviations
FIRS	Fetal inflammatory response syndromeWBC	White blood cellNE	Neutrophilic granulocyte
hs-CRP	Highly sensitive c-reaction proteinCBC	Complete blood count
LY	Lymphocyte percentage
MO	Monocyte percentage
PCT	Procalcitonin
Acknowledgements
We would appreciate the editors and reviewers for their precious suggestions.
We thank Home for Researchers editorial team (www.home-for-researchers.
com) for language editing service.
Author contributions
Meng-Ting Feng: conceptualization, writing original draft, conception
and design of study, acquisition of data, analysis of data, final approvalof manuscript.Qiong Ji: conceptualization, writing original draft, draftingof article and critical revision, final approval of manuscript.Dan-Dan Liu:
formal analysis, analysis of data, final approval of manuscript.Wei Xu:
conceptualization, funding acquisition, formal analysis, conception and designof study, analysis of data, drafting of article and critical revision, final approvalof manuscript.

Page 4 of 4

Funding
None.
Data availability
The datasets used and/or analyzed during the current study are available fromthe corresponding author on reasonable request.

Declarations
Ethics approval and consent to participate
Ethical approval was obtained from the ethical committee of The First Hospitalof Jilin University. The committee’s reference number was: 2024-070. Informed
Consent from patients’ parents was obtainedConsent for publication
The patient’s guardian provided written informed consent for the publicationof the data. Informed consent for the publication of identifiable information/
images in open-access journals was obtained from parents.
Competing interests
The authors declare no competing interests.
Received: 27 August 2023 / Accepted: 12 August 2024

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