Fetal inflammatory response syndrome predicts early-onset sepsis and cystic periventricular leukomalacia in preterm neonates: A retrospective study

Abstract

BACKGROUND:

Fetal inflammatory response syndrome (FIRS), the fetal equivalent of chorioamnionitis, is associated with poorer neonatal outcomes. FIRS is diagnosed through placental histology, namely by the identification of funisitis (inflammation of the umbilical cord) and chorionic vasculitis (inflammation of fetal vessels within the chorionic plate). The aim of this study was to identify and evaluate associations between FIRS and neonatal outcomes in preterm neonates.

METHODS:

We performed a retrospective cohort study at a level III neonatal intensive care unit (NICU), from January 1^st 2008 to December 31^st 2022, involving all inborn neonates with a gestational age below 30 weeks. We compared preterm neonates based on whether their placental histology described funisitis with chorionic vasculitis (FCV) or not.

RESULTS:

The study included 113 preterms, 27 (23.9%) of those had FCV and 86 (76.1%) did not. After adjusting to gestational age, prolonged rupture of membranes and preeclampsia, FCV was independently associated with the development of early-onset sepsis (OR = 7.3, p = 0.021) and cystic periventricular leukomalacia (OR = 4.6, p = 0.004).

CONCLUSION:

The authors identified an association between FIRS and the development of early-onset sepsis and cystic periventricular leukomalacia, highlighting the importance of early detection and management of this condition in order to improve long-term neonatal outcomes.

Keywords

Chorioamnionitis chorionic vasculitis cystic periventricular leukomalacia early onset sepsis funisitis

1 Introduction

Morbidity and mortality among very preterm neonates remain high, despite the advances in neonatal care [1 –4]. On the maternal side, intra-uterine inflammation/infection, previously known as chorioamnionitis, is responsible for up to 40% of premature deliveries [4, 5], as well as for a fetal syndrome with clinical and histological features [4, 6] and is a primary risk factor for the high morbidity associated with prematurity [1 , 7]. Regarding chorioamnionitis, its incidence is inversely correlated with gestational age [6 –9] and its histological diagnosis lies on placental inflammation/infection with maternal neutrophil recruitment in response to stimuli. Clinically, chorioamnionitis, more recently known as “intra-amniotic infection”, has been described by maternal fever (≥38°C), maternal leukocytosis (≥15,000 leukocytes/mm³), fetal tachycardia (≥160/min) and foul-smelling amniotic fluid [3 , 10–12]. On the fetal side, an exposure to an inflammatory/infectious stimulus, a fetal immune reaction involving the umbilical cord and the chorionic vessels of the placenta is elicited; neutrophils are recruited from fetal circulation to the umbilical cord and there is an increased production of pro-inflammatory cytokine. Histologically, this effect is characterized as inflammation of the umbilical cord (funisitis) and inflammation of fetal vessels within the chorionic plate (chorionic vasculitis): funisitis with chorionic vasculitis (FCV) [6, 13]. The clinical counterpart of FCV is named Fetal Inflammatory Response Syndrome (FIRS) [6 , 12–14], therefore being related to one another.

Both intra-amniotic infection and FIRS (diagnosed through the identification of FCV) have been shown to be related to adverse neonatal outcomes, such as spontaneous preterm birth [1 , 11], sepsis, necrotizing enterocolitis (NEC), bronchopulmonary dysplasia (BDP), retinopathy of prematurity (ROP), neonatal brain injury and even death [4 , 12–19].

The aim of this study was to assess the association between FCV and neonatal outcomes in preterm neonates.

2 Methods

A retrospective cohort study was performed at a level III neonatal intensive care unit (NICU), including all inborn neonates with a gestational age below 30 weeks, admitted from January 1st, 2008, to December 31st, 2022. Exclusion criteria were: Outborn neonates; preterm affected by a TORCH infection, a major congenital anomaly, a chromosomopathy, an inborn error of metabolism or a neuromuscular disease; preterm neonates transferred to another center before seven days of age; and those who died before seven days of age.

We grouped and compared our cohort of preterm neonates based on whether their placental histological examination identified funisitis with chorionic vasculitis (FCV) or not.

The study was approved by the Ethics Committee for Research of our Hospital (reference number 50/2023).

2.1 Subjects and data

The data were collected directly from patients’ electronic files in accordance with a previously established protocol for this purpose.

Mother’s data included: Age, chronic diseases and social history (drugs, alcohol and smoking), and number of prior deliveries. Data on gestation and delivery included: order, multiplicity, fetal growth restriction, complications of pregnancy, use of antenatal steroids, prolonged rupture of membranes, clinical chorioamnionitis and type of delivery. Placentas were blindly analyzed by certified pathologists from our hospital. Neonatal data included: demographics, delivery room management, evolution in NICU including morbidity and mortality.

2.2 Definitions

Funisitis is histologically defined by inflammation affecting the umbilical cord (umbilical vein, umbilical artery and the Wharton’s jelly), and chorionic vasculitis is defined as the inflammatory process of the fetal vessels within the chorionic plate [6].

All preterms had a cranial ultrasound examination in the first 72 hours of life (preferably on day 1) and then weekly. To classify intraventricular hemorrhage (IHV), we used the classification of Volpe JJ et al [20] and to classify cystic periventricular leukomalacia (cPVL) we used the classification of Rennie JM et al [21].

Ophthalmologic examination and ROP screening are performed as recommended by the Portuguese Society of Neonatology [22]; briefly, the first ophthalmological examination should be performed at 31-33 weeks of gestational age or 4-6 weeks of life, which occurs later. ROP severity was classified according to the revised International Classification of Retinopathy of Prematurity [22].

At our NICU, all preterms below 30 weeks of gestational age are submitted to echocardiographic screening of hemodynamically significant Patent Ductus Arteriosus (HS-PDA) between 48 and 72 hours of life. The first line of medical treatment, when indicated, is intravenous ibuprofen.

The ventilation strategy used at our NICU along all the study period was preferably non-invasive with nasal NCPAP, with or without assisted pressure and, if it failed, conventional ventilation (CV) in synchronized intermittent positive pressure (SIPPV) mode with volume guarantee. High frequency oscillatory ventilation (HFOV) was used as rescue ventilation. Peripheral saturation (SpO2) target range was 90 to 95%. All preterm started caffeine citrate on the first day of life, independently of apneas, which was continued until approximately 34 weeks.

Neonates with respiratory distress syndrome (RDS) were given early-rescue surfactant (poractant-α 200 mg/Kg initial dose; occasionally a 2nd dose of 100 mg/Kg was given if there was ongoing evidence of RDS), when inspired oxygen fraction (FiO2) above 0.30 was required to maintain the SpO2 in the target range. Bronchopulmonary dysplasia (BPD) was defined according to the National Institute of Health [23]. The analysis carried out in this study considered BPD as the dependency on administered oxygen until 36 weeks of postmenstrual age.

Total parenteral nutrition (TPN) is started as soon as there is clinical stability, preferably starting at day one of life with an initial volume of 70-80 mL/kg/day, and incremented daily by 10-20 mL/Kg up to a total of 150 mL/kg/day (around day 7 of life).

Placenta histological examination was performed by one pathologist, and histological FCV was defined as an histopathological inflammatory process involving the umbilical cord (the connective tissue of Wharton’s jelly and the umbilical vessels), and fetal chorionic vessels (at least one of them) [6].

Sepsis was defined as: proven sepsis if any systemic infection was proved by blood culture; and clinical sepsis, i.e. without microbiological identification, was considered in the presence of clinical signs (fever, hypothermia, lethargy, tachypnea, apnea/bradycardia, cyanosis or hypoglycemia not explained by other diagnosis) associated with at least one laboratory marker (thrombocytopenia, leukopenia, C-reactive protein elevation). Early and late onset sepsis were distinguished whether the diagnosis was established before or after the 72-hour of life mark, respectively. Meningitis was diagnosed based upon an elevation of polymorphonuclear cell counts and biochemical changes in the cerebrospinal fluid, with or without isolation of microbiological agent. Necrotizing enterocolitis (NEC) was diagnosed and classified by Modified Bell Staging Criteria [24].

2.3 Statistical analysis

Statistical analysis was performed using SPSS statistical software (SPSS for Windows, version 28, IBM SPSS statistics, Inc., Chicago, IL, USA). Categorical variables were described as absolute and relative frequencies, continuous variables with symmetric distribution by mean (±standard deviation) and with asymmetric distribution by median (minimum–maximum). Chi-square or Fisher’s exact test was applied to compare categorical variables and the independent t-test and Mann–Whitney U test were used for symmetric and asymmetric continuous variables, respectively. A multivariate analysis by logistic regression was performed to evaluate predictors of neonatal morbidities. A p-value<0.05 was considered statistically significant.

3 Results

From a total of 195 preterms, 113 were included in the study. This cohort was grouped according to whether FCV was described (27 cases; 23.9%) or not in the placental histopathological study.

Data regarding mother, pregnancy and delivery are summarized in Table 1, while data regarding neonatal birth and delivery room management are summarized in Table 2. Mean gestational age was higher in the FCV group compared to the no-FCV group (28.0±1.1 weeks vs 27.5±1.4 weeks; p = 0.036), more preterms had longer rupture of membranes compared to the no-FCV group (40.7% vs 12.8%; p = 0.002) and the presence of preeclampsia/eclampsia was more frequent in the no-FCV group (0.0% vs 25.6%; p = 0.004).

Table 1
Data on mother, gestation and delivery for the subgroups of neonates with funisitis with chorionic vasculitis and no funisitis with chorionic vasculitis

Total (n = 113) Funisitis with Chorionic Vasculitis (n = 27) No Funisitis with Chorionic Vasculitis (n = 86) p-value

Mother’s age, mean (SD) 32.7 (±5.7) 32.4 (±6.2) 32.7 (±5.6) 0.757^c

1st pregnancy, n (%) 51 (45.1) 10 (37.0) 41 (47.7) 0.333^a

Multiple gestation, n (%) 24 (21.2) 7 (25.9) 17 (19.8) 0.495^a

Antenatal steroids, n (%) 103 (91.2) 23 (85.2) 80 (93.0) 0.247^b

- Full cycle, n (%) 68 (60.2) 15 (55.6) 53 (61.6) 0.574^a

Chronic diseases n (%) 20 (17.7) 3 (11.1) 17 (19.8) 0.395_b

Autoimmune disease n (%) 3 (2.7) 2 (7.4) 1 (1.2) 0.141_b

Chronic arterial hypertension, n (%) 8 (7.1) 1 (3.7) 7 (8.1) 0.678^b

Smoking, n (%) 10 (8.8) 2 (7.4) 8 (9.3) 0.980^b

Alcohol, n (%) 1 (0.9) 0 (0.0) 1 (1.2) 0.990^b

Drugs, n (%) 5 (4.4) 1 (3.7) 4 (4.7) 0.890^b

Gestational hypertension, n (%) 4 (3.5) 0 (0.0) 4 (4.7) 0.571^b

Gestational diabetes, n (%) 9 (8.0) 3 (11.1) 6 (7.0) 0.444^b

Preeclampsia / Eclampsia, n (%) 22 (19.5) 0 (0.0) 22 (25.6) 0.004^a

Cervical insufficiency, n (%) 14 (12.4) 7 (25.9) 7 (8.1) 0.015^a

Fetal growth restriction, n (%) 22 (19.5) 5 (18.5) 17 (19.8) 0.886^a

Rupture of membranes > 18 h, n (%) 22 (19.5) 11 (40.7) 11 (12.8) 0.002^a

C-section, n (%) 83 (73.5) 17 (63.0) 66 (76.7) 0.157^a

Placental histopathological analysis, n (%)

– Chorioamnionitis, n (%) 55 (48.7) 21 (77.8) 34 (39.5) 0.001^a

– Preeclampsia-related abnormalities, n (%) 20 (17.7) 0 (0) 20 (23.3) 0.003^b

	Total (n = 113)	Funisitis with Chorionic Vasculitis (n = 27)	No Funisitis with Chorionic Vasculitis (n = 86)	p-value
Mother’s age, mean (SD)	32.7 (±5.7)	32.4 (±6.2)	32.7 (±5.6)	0.757^c
1st pregnancy, n (%)	51 (45.1)	10 (37.0)	41 (47.7)	0.333^a
Multiple gestation, n (%)	24 (21.2)	7 (25.9)	17 (19.8)	0.495^a
Antenatal steroids, n (%)	103 (91.2)	23 (85.2)	80 (93.0)	0.247^b
- Full cycle, n (%)	68 (60.2)	15 (55.6)	53 (61.6)	0.574^a
Chronic diseases n (%)	20 (17.7)	3 (11.1)	17 (19.8)	0.395_b
Autoimmune disease n (%)	3 (2.7)	2 (7.4)	1 (1.2)	0.141_b
Chronic arterial hypertension, n (%)	8 (7.1)	1 (3.7)	7 (8.1)	0.678^b
Smoking, n (%)	10 (8.8)	2 (7.4)	8 (9.3)	0.980^b
Alcohol, n (%)	1 (0.9)	0 (0.0)	1 (1.2)	0.990^b
Drugs, n (%)	5 (4.4)	1 (3.7)	4 (4.7)	0.890^b
Gestational hypertension, n (%)	4 (3.5)	0 (0.0)	4 (4.7)	0.571^b
Gestational diabetes, n (%)	9 (8.0)	3 (11.1)	6 (7.0)	0.444^b
Preeclampsia / Eclampsia, n (%)	22 (19.5)	0 (0.0)	22 (25.6)	0.004^a
Cervical insufficiency, n (%)	14 (12.4)	7 (25.9)	7 (8.1)	0.015^a
Fetal growth restriction, n (%)	22 (19.5)	5 (18.5)	17 (19.8)	0.886^a
Rupture of membranes > 18 h, n (%)	22 (19.5)	11 (40.7)	11 (12.8)	0.002^a
C-section, n (%)	83 (73.5)	17 (63.0)	66 (76.7)	0.157^a
Placental histopathological analysis, n (%)
– Chorioamnionitis, n (%)	55 (48.7)	21 (77.8)	34 (39.5)	0.001^a
– Preeclampsia-related abnormalities, n (%)	20 (17.7)	0 (0)	20 (23.3)	0.003^b

^a Chi-square test | ^bFisher test | ^c Independent T test.

Table 2

Data on neonatal demographics and delivery room management

	Total (n = 113)	Funisitis / Chorionic Vasculitis (n = 27)	No Funisitis / Chorionic Vasculitis (n = 86)	p-value
Male, n (%)	54 (47.8)	13 (48.1)	41 (47.7)	0.966a
Gestational age, mean (±SD)	27.6 (1.4)	28.0 (1.1)	27.5 (1.4)	0.036^c
Birthweight, mean (±SD)	1 005.4 (255)	1 026 (260)	990.9 (249)	0.521 ^c
Small for gestational age, n (%)	24 (21.2)	5 (18.5)	16 (18.6)	0.992 ^a
Positive pressure ventilation, n (%)	106 (93.4)	25 (92.6)	81 (94.2)	0.671^b
Invasive mechanical ventilation n (%)	69 (61.1)	16 (59.3)	53 (61.6)	0.826^a
NCPAP, n (%)	57 (50.4)	16 (59.3)	41 (48.8)	0.345^a
Oxygen, n (%)*	91 (80.5)	22 (81.5)	69 (60.2)	0.886^a
Adrenaline, n (%)	1 (0.9)	0 (0)	1 (1.2)	0.986^b
Apgar score
≤5 at 1st minute, n (%)	26 (23.0)	6 (22.2)	20 (23.3)	0.911^a
>5 at 5th minute, n (%)	6 (5.3)	2 (7.4)	4 (4.7)	0.628^b

*FiO2 up to 0.30. ^a Chi-square test | ^b Fisher test | ^c Mann-Whitney test.

Neonatal morbidity and mortality are described in Table 3. The bivariate analysis showed higher incidence of early-onset sepsis (18.5% vs 4.7%; p = 0.020) and cPVL (63.0% vs 36.0%; p = 0.014) in the FCV group, however the incidence of HS-PDA (37.0% vs 60.5; p = 0.033) was lower in this group.

Table 3

Data on neonatal morbidities and mortality

	Total (n = 113)	Funisitis / Chorionic Vasculitis (n = 27)	No Funisitis / Chorionic Vasculitis (n = 86)	p- value
RDS, n (%)	91 (80.5)	21 (77.8)	70 (81.4)	0.514 ^a
Surfactant, n (%)	85 (75.2)	19 (70.4)	66 (76.7)	0.503 ^a
BPD, n (%)	46 (40.7)	7 (25.9)	39 (45.3)	0.073 ^a
Number of patients with MV, n (%)	104 (92.0)	23 (85.2)	81 (94.2)	0.132 ^b
Total days of MV, median (min-max)	41 (4-143)	41 (10-143)	41 (4-101)	0.456 ^c
Days with O₂ supplementation, median (min-max)	50 (1-191)	39 (1-191)	50 (1-148)	0.544 ^c
Need of O₂ at discharge, n (%)	11 (9.7)	5 (18.5)	6 (7.0)	0.089 ^a
Days with PTN, median (min-max)	26 (8-210)	24 (8-67)	28 (8-210)	0.230 ^c
HS-PDA, n (%)	62 (54.9)	10 (37.0)	52 (60.5)	0.033 ^a
PDA surgical closure	12 (10.6)	2 (7.4)	10 (11.6)	0.535 ^b
NEC stage≥2, n (%)	9 (8.0)	3 (11.1)	6 (7.0)	0.489 ^b
IHV, n (%)	17 (15.0)	4 (14.8)	13 (15.1)	0.995 ^a
PVI, n (%)	3 (2.7)	0 (0.0)	3 (3.5)	0.325 ^b
cPVL, n (%)	48 (42.5)	17 (63.0)	31 (36.0)	0.014 ^a
Total of ROP, n (%)	64 (56.6)	14 (51.9)	50 (58.1)	0.565 ^a
ROP stage > 2, n (%)	26 (23.0)	3 (11.1)	23 (26.7)	0.108 ^a
Early-onset sepsis, n (%)	9 (8.0)	5 (18.5)	4 (4.7)	0.020 ^b
Late-onset sepsis, n (%)	62 (54.9)	15 (55.6)	47 (54.7)	0.934 ^a
Pneumonia, n (%)	7 (6.2)	1 (3.7)	6 (7.0)	0.538 ^b
Meningitis, n (%)	2 (1.8)	0 (0.0)	2 (2.3)	0.424 ^b
Days in NICU, median (min-max)	70 (15-255)	65 (48-191)	70 (15-255)	0.630 ^c
Death, n (%)	2 (1.8)	0 (0.0)	2 (2.3)	0.424 ^b

A multivariate analysis, described in Table 4, was then performed, adjusted to risk factors with a significant p-value, such as gestational age, rupture of membranes over 18 hours and preeclampsia. This last analysis revealed that FCV was independently associated with the development of early-onset sepsis (OR = 7.3, 95% _CI: 1.4 – 38.9; p = 0.021) and development of cPVL (OR = 4.6; 95% _CI: 1.6 – 13.1; p = 0.004), but not with HS-PDA (OR = 0,6; 95% _CI: 0,2–1,6; p = 0.264).

Table 4

Multivariate analysis by logistic regression of relationship between funisitis with chorionic vasculitis and previously identified outcomes, adjusted for gestational age, rupture of membranes > 18 hours and preeclampsia

	OR	Confidence Interval (95%)	p-value
Early-onset sepsis	7.3	1.4 – 38.9	0.021
cPVL	4.6	1.6 – 13.1	0.004
HS-PDA	0.6	0,2 – 1,6	0.264

cPVL – cystic periventricular leukomalacia.

4 Discussion

This study focuses on identifying consequences of FIRS in preterm neonates, and its results support that there is a higher risk for early-onset sepsis and hypoxic ischemic brain injury in term newborns that are subjected to an inflammatory stimulus during pregnancy and/or childbirth. Funisitis is an histological finding that occurs when the umbilical cord is infiltrated by neutrophils, mediated by the release of cytokines and chemokines, among other substances that are released when a fetus is exposed to an inflammatory/infectious stimulus [25]. Some authors claim that funisitis develops as a consequence to chorioamnionitis, and that the latter must be present in order for microorganisms to reach the amniotic fluid and the umbilical cord for FIRS to develop [3 , 10]. Following this line of thought, some authors suggest that early-onset sepsis begins in utero after a maternal infection, later spreading to the fetus [3 , 11]. In our study, most preterms with FCV had mothers with histological chorioamnionitis, and some preterm neonates were identified as having FCV despite no histological chorioamnionitis; this suggests that factors beyond infection may be involved in the development of FIRS, as proposed by some authors [13]. The inflammatory response that the fetus is exposed may lead to several adverse neonatal outcomes such as prematurity, sepsis, NEC, BPD, ROP, neonatal brain injury and even death [1 , 14]. According to some authors, organ injury appears to be mainly due to hypoxic-ischemic events along with an inflammatory status and increased cytokine production that leads to unstable blood pressure, all of which are detrimental to the fetal normal development [25 –27].

“Chorioamnionitis” is a result of maternal immune response to a possible intraamniotic infection, and such an infection can be the starting point for FIRS [6 , 29], with consequent preterm premature rupture of membranes (PPROM) and a preterm birth [29 –31]. While our study did not find a significant difference in gestational age between the two groups, several studies have reported that mothers with chorioamnionitis give birth to neonates with lower gestational ages compared to those without it [10 , 18]. It is noteworthy that not only infection can lead to chorioamnionitis, as there are other inflammatory states (e.g. exposure to tobacco or pollutants) that can cause fetal distress, leading to prematurity [32].

4.1 Sepsis

The analysis conducted in this study revealed two significant associations with funisitis: early-onset sepsis and cPVL, both of which are important adverse outcomes in preterm neonates. It is of note that the association with early-onset sepsis was still present after a multivariate regression analysis. Evidence suggest that early-onset sepsis develops after a microorganism infecting the fetus/neonate and some authors claim that, for many neonates, this infection begins in utero [2 , 10]. Our study found that the group of preterm neonates with FCV had a higher incidence of histological chorioamnionitis, supporting the idea that intraamniotic infection is a potential mechanism for early-onset sepsis [6]. Usually, bacteria ascend from the lower genital tract [29], and prolonged rupture of membranes (ROM) is a known risk factor for bacterial infection, as presented in other studies [6 , 34]. Consistent with this, our study revealed that neonates in the FCV group had a significantly longer ROM than the control group, which is a risk for morbidity and mortality in preterm neonates.

4.2 Cystic periventricular leukomalacia

The state of FIRS affects many organs and systems, and the brain is one of the them [8 , 35]. Our study showed a significant association between FCV and cPVL, which is a type of brain injury commonly found in very preterm neonates, that characterizes itself by the death of small areas of brain tissue around the ventricles [21]. The most commonly type of brain injury described, as a consequence of chorioamnionitis/funisitis is IVH, but periventricular leukomalacia (PVL) is also mentioned frequently [1 , 34–36]. PVL is a type of white matter injury due to oxygen and nutrients deprivation, more commonly in the premature, and more fragile, neonatal brain. It is believed that brain injury is dependent on both hypoxic-ischemic events and the inflammatory status that occur during FIRS [25 –27]. The inflammation present in FIRS increases cytokine production and neutrophil recruitment which, in turn, damages the blood-brain barrier directly and indirectly by also affecting uteroplacental blood flow and placental function; the former allows the influx of cytotoxic proteins and cell into the brain, and the latter has an impact on gas and metabolic exchanges between the fetus and the mother, leading to hemodynamic instability and deprives the fetus from vital nutrients that will further increase the inflammatory status and brain lesion [1 , 31]. As a result, oligodendrocytes and microglial cells are injured and induce apoptosis, cell differentiation is disrupted, myelination is impaired and brain development is affected at a cellular level; at a macroscopic level, there is inadequate blood flow leading to damage to the white-matter that may evolve to PVL and cerebral palsy [18 , 31]. The spectrum of PVL has two main forms: a cystic (with larger macroscopic focal necrotic areas, that evolve to cysts) and a non-cystic (with smaller, microscopic, necrotic areas and focal gliosis) [37]. cPVL, the cystic form, is becoming less common due to improvements in intensive neonatal care, however it represents a severe lesion that results from a grade 3 IVH or from a periventricular hemorrhagic infarction (previously called grave 4 IVH), depending on the extent of the lesion [37, 38].

Some authors claim that such damage could be induced not only by an infectious stimulus, but also by the inflammatory status itself, as it is a cause for unstable blood pressure and potentially to IVH [4 , 35], a known risk factor for cPVL and white matter-disease [1 , 34]. The grade of cPVL has a linear relationship with prognosis [27] and, despite advances in neonatal care practices in recent years, only a small reduction in cPVL has been reported [27]. Since preterm neonates are already at-risk for brain injury, this inflammatory response only increases the risk and likelihood of poorer neurologic outcomes [2 , 39]. Therefore, chorioamnionitis, FIRS and other factors such as PROM, particularly at younger gestational ages, are risk factors for cPVL [27].

Early brain injury is related to poorer developmental outcomes, which helped to coin the term “encephalopathy of the prematurity” [3 , 26]. This poses a problem for society as survival among extreme premature neonates increases: the higher number of survivals, represent higher number of neonates that grow with a higher likelihood of neurodevelopment impairment that need to be addressed [3, 26]. Therefore, closely monitoring preterm neonates whose placenta had funisitis and chorionic vasculitis, for early signs of infection or ultrasound evidence of IVH, is essential due to the risk of developing early-onset sepsis and cPVL, particularly if such histopathological results could be accessed earlier than usual.

Some authors suggest that antenatal corticosteroid therapy could reduce the incidence of cPVL and other neonatal comorbidities [34]. Although we did not observe a statistically significant difference in our population, many other reports have demonstrated that since the common use of antenatal corticoids, the prevalence of chorioamnionitis and some neonatal adverse outcomes have decreased [27, 34]. Regarding prematurity and exposure to ante- or perinatal infection, there is an association with adverse neonatal outcomes that further exacerbate the vulnerability of the preterm neonates [4 , 10]. Despite this known association, in our study, the FCV group had a higher mean gestational age, when compared to the non-FCV (mean 28.0±1.1 weeks vs 27.5±1.4 weeks, respectively).

4.3 Limitations

The retrospective nature and the lack of follow-up to evaluate long term neurodevelopmental outcomes are the major limitations of this study.

The clinical utility of the relationship between FCV and sepsis is limited due to how long it takes to have histopathological results ready [5].

5 Conclusion

In conclusion, this study contributes to the body of evidence supporting the association between FCV and adverse neonatal outcomes in preterm neonates. Clinicians should be aware of the increased possibility of adverse neonatal outcomes and the need for a careful surveillance and management of neonates whose umbilical cord histology shows funisitis and chorionic vasculitis. This would allow to anticipate some of neonatal care, such as laboratory assessment of inflammatory surrogate markers, early antibiotics, and more careful respiratory and hemodynamic support, to improve neonatal outcomes, particularly those related to neurodevelopmental. However, the histological analysis of the placenta may not be performed rapidly enough to be of help in clarifying the risk of early-onset neonatal sepsis and the need for antibiotics. Therefore, in cases of suspected or presumed chorioamnionitis, it is imperative to start antibiotics to protect the fetus and reduce the risk of adverse neonatal outcomes.

Further studies are needed to better understand the association between FCV and long-term neonatal outcomes.

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Conflicts of interest

None declared.

References

Bersani

, Thomas

, Speer

. Chorioamnionitis the good or the evil for neonatal outcome? J Matern Neonatal Med. 2012;25:12–6.

Hofer

, Kothari

, Morris

, Müller

, Resch

. The fetal inflammatory response syndrome is a risk factor for morbidity in preterm neonates. Am J Obstet Gynecol. 2013;209:542.e1–542.e11.

Xiao

, Zhu

, Qu

, Gou

, Huang

, Li

, et al. Maternal chorioamnionitis and neurodevelopmental outcomes in preterm and very preterm neonates: A meta-analysis. PLoS One. 2018;13:e0208302.

Huang

, Meng

, Choonara

, Xiong

, Wang

, et al. Antenatal infection and intraventricular hemorrhage in preterm infants. Medicine (Baltimore). 2019;98:e16665.

Beck

, Gallagher

, Taylor

, Goldstein

, Mithal

, Gernand

. Chorioamnionitis and risk for maternal and neonatal sepsis. Obstet Gynecol. 2021;137:1007–22.

Kim

, Romero

, Chaemsaithong

, Chaiyasit

, Yoon

, Kim

. Acute chorioamnionitis and funisitis: Definition, pathologic features, and clinical significance. Am J Obstet Gynecol. 2015;213:S29.

Soraisham

, Trevenen

, Wood

, Singhal

, Sauve

. Histological chorioamnionitis and neurodevelopmental outcome in preterm infants. J Perinatol. 2013;33:70–5.

Pugni

, Pietrasanta

, Acaia

, Merlo

, Ronchi

, Ossola

, et al. Chorioamnionitis and neonatal outcome in preterm infants: A clinical overview. J Matern Fetal Neonatal Med. 2016;29(9):1525–9.

Tsiartas

, Kacerovsky

, Musilova

, Hornychova

, Cobo

, Sävman

, et al. The association between histologicalchorioamnionitis, funisitis and neonatal outcome in women withpreterm prelabor rupture of membranes. J Matern Fetal Neonatal Med. 2013;26(13):1332–6.

10.

Villamor-Martinez

, Lubach

, Rahim

, Degraeuwe

, Zimmermann

, Kramer

, et al. Association of histological and clinical chorioamnionitis with neonatal sepsis among preterm infants: A systematic review, meta-analysis, and meta-regression. Front Immunol. 2020;11.

11.

Fowler

, Simon

L V

. Chorioamnionitis. Chorioamnionitis. 2022:1–156.

12.

Jessop

, Lees

, Pathak

, Hook

, Sebire

. Funisitis is associated with adverse neonatal outcome in low-risk unselected deliveries at or near term. Virchows Arch. 2016;468:503.

13.

Pacora

, Chaiworapongsa

, Maymon

, Kim

, Gomez

, Yoon

, et al. Funisitis and chorionic vasculitis: The histological counterpart of the fetal inflammatory response syndrome. J Matern Fetal Neonatal Med. 2002;11(1):18–25.

14.

Ozalkaya

, Karatekin

, Topcuoğlu

, Gürsoy

, Ovalı

. Morbidity in preterm infants with fetal inflammatory response syndrome. Pediatr Int. 2016;58:850–4.

15.

Leviton

, Hecht

, Allred

, Yamamoto

, Fichorova

, Dammann

. Persistence after birth of systemic inflammation associated with umbilical cord inflammation. J Reprod Immunol. 2011;90:235–43.

16.

Tang

, Zhang

, Li

, Shao

. The fetal inflammation response syndrome and adverse neonatal outcomes: a meta-analysis. J Matern Neonatal Med. 2021;34:3902–14.

17.

Thomas

, Speer

. Chorioamnionitis: Important risk factor or innocent bystander for neonatal outcome? Neonatology. 2011;99:177–87.

18.

RRocha

, Proença

, Quintas

, Rodrigues

, Guimarães

. Chorioamnionitis and brain damage in the preterm newborn. J MaternFetal Neonatal Med. 2007;20(10):745–9.

19.

Yoon

, Park

, Chaiworapongsa

. Intrauterine infection and the development of cerebral palsy. BJOG An Int J Obstet Gynaecol. 2003;110:124–7.

20.

Volpe

, Inder

, Darras

, de Vries

L de

, du Plessis

, Neil

, et al. Volpe’s Neurology of the Newborn. 6th Editio. Elsevier; 2017.

21.

Rennie

, Roberton

. Textbok of Neonatology. 5th editio. London: Churchill Livingstone; 2012.

22.

Henriques

, Brito

, Teixeira

, Breda

, Bettencourt

, Flor-de-Lima

. Retinopatia da Prematuridade. Soc Port Neonatol. 2014.

23.

Jobe

, Bancalari

. Bronchopulmonary Dysplasia. Am J Respir Crit Care Med. 2001;163:1723–9.

24.

Neu

. Necrotizing enterocolitis: The search for a unifying pathogenic theory leading to prevention. Pediatr Clin North Am. 1996;43:409–32.

25.

Muraskas

, Astrug

, Amin

. FIRS: Neonatal considerations. Semin Fetal Neonatal Med. 2020;25:101142.

26.

Humberg

, Fortmann

, Siller

, Kopp

, Herting

, Göpel

, et al. Preterm birth and sustained inflammation: Consequences for theneonate. Semin Immunopathol. 2020;42:451–68.

27.

Abiramalatha

, Bandyopadhyay

, Ramaswamy

, Shaik

, Thanigainathan

, Pullattayil

, et al. Risk Factors for Periventricular Leukomalacia in Preterm Infants: A Systematic Review, Meta-analysis, and GRADE-Based Assessment of Certainty of Evidence. Pediatr Neurol. 2021;124:51–71.

28.

Hall

, Hutter

, Suff

, Avena Zampieri

, Tribe

, Shennan

, et al. Antenatal diagnosis of chorioamnionitis: A review of the potential role of fetal and placental imaging. Prenat Diagn. 2022;42:1049–58.

29.

Peng

C-C

, Chang

J-H

, Lin

H-Y

, Cheng

P-J

, Su

B-H

. Intrauterine inflammation, infection, or both (Triple I): A new concept for chorioamnionitis. Pediatr Neonatol. 2018;59:231–7.

30.

Miao

, Ren

, Rao

, Xia

, Wang

, Xu

, et al. Pathological staging of chorioamnionitis contributes to complications in preterm infants. Ital J Pediatr. 2020;46:127.

31.

Yap

, Perlman

. Mechanisms of brain injury in newborn infants associated with the fetal inflammatory response syndrome. Semin Fetal Neonatal Med. 2020;25:101110.

32.

Jain

, Willis

, Jobe

, Ambalavanan

. Chorioamnionitis and neonatal outcomes. Pediatr Res. 2022;91:289–96.

33.

Venturelli

, Zeis

, De Beritto

, Hageman

. Ureasplasma and its role in adverse perinatal outcomes: A review. Neoreviews. 2021;22:e574–84.

34.

Nasef

, Shabaan

, Schurr

, Iaboni

, Choudhury

, Church

, et al. Effect of clinical and histological chorioamnionitis on the outcome of preterm infants. Am J Perinatol. 2013;30:59–68.

35.

Villamor-Martinez

, Fumagalli

, Alomar

, Passera

, Cavallaro

, Mosca

, et al. Cerebellar hemorrhage in preterm infants: A meta-analysis on risk factors and neurodevelopmental outcome. Front Physiol. 2019;10.

36.

Naccasha

, Hinson

, Montag

, Ismail

, Bentz

, Mittendorf

. Association between funisitis and elevated interleukin-6 in cord blood. Obstet Gynecol. 2001;97:220–4.

37.

Adle-Biassette

, Golden

, Harding

. Developmental and perinatal brain diseases. Handb Clin Neurol. 2018;145:51–78.

38.

Van Camp

, Steyaert

. Cystic periventricular leukomalacia: A Condition that became uncommon in the premature neonate, diagnosed on transcranial ultrasound. J Belgian Soc Radiol. 2016;100.

39.

Francis

, Bhat

, Mondal

, Adhisivam

, Jacob

, Dorairajan

, Harish

. Fetal inflammatory response syndrome (FIRS) and outcome of preterm neonates – a prospective analytical study. J Matern Fetal Neonatal Med. 2019;32(3):488–492.