Funisitis

Funisitis is an inflammatory process involving the umbilical cord (umbilical vein, umbilical artery, and the Wharton’s jelly) ¹. Wharton’s jelly is the gelatinous extracellular matrix contained within the umbilical cord that serves to protect the umbilical vessels ². It is accepted that funisitis is a hallmark of fetal inflammatory response syndrome (FIRS), a condition characterized by an elevation in fetal plasma concentrations of interleukin-6, associated with the impending onset of preterm labor, a higher rate of neonatal morbidity (after adjustment for gestational age), and multi-organ fetal involvement ³. The fetal inflammatory response syndrome (FIRS) is the counterpart of the systemic inflammatory response syndrome (SIRS) in adults; however, in fetuses, it is a risk factor for short- and long-term complications (i.e. neonatal sepsis, bronchopulmonary dysplasia, periventricular leukomalacia, and cerebral palsy) ⁴.

The placenta is composed of three major structures: the placental disc, the chorioamniotic membranes, and the umbilical cord (Figure 1) ⁴. Acute inflammatory lesions of the placenta are characterized by the infiltration of neutrophils in each of these structures ⁵. Specifically, when the inflammatory process affects the chorion and amnion, this is termed acute chorioamnionitis ⁵; if it affects the villous tree, this represents acute villitis ⁵. If the inflammatory process involves the umbilical cord (umbilical vein, umbilical artery, and the Wharton’s jelly), this is referred to as funisitis, the histological counterpart of the fetal inflammatory response syndrome ⁶.

Funisitis is diagnosed by the marked presence of neutrophils in the wall of umbilical vessels with or without Wharton jelly infiltration ⁷. Inflammation in the umbilical vein (phlebitis) can be seen separately from the umbilical arteries (arteritis). Established or long standing infections can cause tissue necrosis and accumulation of cellular debris is called necrotizing funisitis. Inflammation located at the periphery or surface of the umbilical cord may be the primary pattern seen is called peripheral funisitis. Necrotizing funisitis is a very severe form of funisitis that occurs when the funisitis has been present for a long time. Debris from inflammatory cells accumulate and the umbilical cord becomes calcified. Treatment with IV antibiotics is necessary for necrotizing funisitis, with a minimum of 7 days. This can occur in healthy born infants; the infection can also occurs in the days and weeks following birth. With IV antibiotic treatment and early management, outcomes are good ⁸.

Systematic studies of the umbilical cord suggest that acute funisitis begins as multiple, discrete foci, along the umbilical cord, which then merge with the progression of the inflammatory process ⁹. Figure 2 illustrates the topography of the inflammatory process in several umbilical cords serially sectioned at 1 mm intervals. The chemotactic gradient attracting neutrophils from the lumen of the umbilical vessels into the Wharton’s jelly is thought to be dependent on elevated concentrations of chemokines in the amniotic fluid. The severity of funisitis correlates with fetal plasma IL-6 concentrations (an indicator of the severity of the systemic fetal inflammatory response) and amniotic fluid IL-6 – the latter reflects the intensity of the intra-amniotic inflammatory response ¹⁰.

Typically, acute funisitis begins as inflammation of the umbilical vein (umbilical phlebitis), followed by umbilical arteritis involving theumbilical arteries (Figure 2). Progression of inflammation along the length of the umbilical cord. The initial phase is multifocal, as demonstrated by the yellow/orange rings in the second umbilical cord from left to right (Figure 2). Subsequently,the areas of inflammation coalesce, and funisitis affects the entire umbilical cord.

In an attempt to define the stages of the spectrum of umbilical cord infection, some experts have separated the infection into distinct categories: category 1, funisitis and umbilical discharge (shaggy unhealthy umbilical stump, malodorous or purulent discharge); category 2, omphalitis with abdominal wall cellulitis (periumbilical erythema and superficial tenderness in addition to findings in category 1); category 3, omphalitis with systemic sepsis; and category 4, omphalitis with fasciitis (umbilical necrosis with extensive local disease, periumbilical ecchymosis, crepitus bullae, and evidence of involvement of superficial and deep fascia)

The presence of funisitis is significantly associated with interventional delivery and other adverse outcomes including an Apgar score <7 at 1 min, clinical evidence of sepsis and admission to the neonatal intensive care unit ¹¹.

Figure 1. Anatomy of the pregnant uterus with an emphasis on the placenta

Footnote: The upper part of the figure illustrates the fetus, umbilical cord and placenta. The chorioamniotic membranes include the amnion and chorion. Decidua is of maternal origin (secretory endometrium) and is adjacent to the myometrium. The lower part of the figure represents a cross-section of the human placenta, including the chorionic plate, chorioamniotic membranes, umbilical cord, and the intervillous space. The basal plate of the placenta is formed of decidua, and is traversed by the spiral arteries, which bring maternal blood into the intervillous space. The villous circulation (fetal) is illustrated in a cross-section of the stem villi. The fetal vessels on the surface of the chorionic plate include arteries and veins, which coalesce to form the umbilical vein and umbilical arteries.

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Figure 2. Inflammatory process in the umbilical cord

Footnote: Topography of the inflammatory process in the umbilical cord. (A) Typically, acute funisitis begins as inflammation of the umbilical vein (umbilical phlebitis; the blue vessel represents the umbilical vein), followed by umbilical arteritis involving the umbilical arteries (red). (B) Progression of inflammation along the length of the umbilical cord. The initial phase is multi-focal, as demonstrated by the yellow/orange rings in the second umbilical cord from left to right in figure 3B. Subsequently, the areas of inflammation coalesce, and funisitis affects the entire umbilical cord.

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Figure 3. Pathways of intra-amniotic infection

Footnote: (A) Most cases of microbial invasion of the amniotic cavity are the result of ascending infection from the vagina and cervix. (B) Extensive microbial invasion of the amniotic cavity can result in fetal infection (bacteria are located in the fetal lung) and damaged chorioamniotic membranes (i.e. necrotizing chorioamnionitis). The destruction of the amnion epithelium is a cardinal feature of necrotizing chorioamnionitis.

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Funisitis causes

Funisitis is the migration of fetal neutrophils out of the bloodstream and into the umbilical cord. This process of migration initiates with the release of neutrophil chemokines, such as interleukin-8 and granulocyte chemotactic protein. Funisitis is most commonly present in the setting of intraamniotic infection, specifically chorioamnionitis, and is part of the fetal inflammatory response syndrome (FIRS), which indicates a high risk of preterm labor and increased neonatal morbidity. This process is identified microscopically after delivery, but due to the need for mature neutrophils within fetal blood, it is not typically present before 20 weeks of gestation ¹².

Under normal conditions, the amniotic cavity is sterile for microorganisms using cultivation ¹³ and molecular microbiologic techniques, based on the detection of the 16S rRNA gene (present in all bacteria, but not in mammalian cells). Four pathways have been proposed whereby microorganisms reach the amniotic cavity ¹⁴:

1. Ascending from the lower genital tract ¹⁵;
2. Hematogenous ¹⁶;
3. Accidental introduction at the time of amniocentesis, percutaneous umbilical cord blood sampling, fetoscopy, or another invasive procedure ¹⁷;
4. Retrograde seeding from the peritoneal cavity from the fallopian tubes ¹⁸. However, there is limited evidence in support of the latter pathway.

Ascending microbial invasion from the lower genital tract appears to be the most frequent pathway for intra-amniotic infection ¹⁹. While all pregnant women have microorganisms in the lower genital tract, most do not have intra-amniotic infection. The mucus plug represents an anatomical and functional barrier to ascending infection during pregnancy ²⁰. In the non-pregnant state, the endometrial cavity is not sterile ²¹, but the decidua is thought to be sterile during pregnancy.

A hematogenous pathway can operate during the course of blood-born maternal infections ¹⁶. Microorganisms such as Listeria monocytogenes ²², Treponema pallidum, Yersinia pestis, Cytomegalovirus, Plasmodium species, and others can gain access through the maternal circulation to the intervillous space, from where they invade the villi and the fetal circulation ¹⁹. Bacteria involved in periodontal disease may use this pathway to reach the amniotic cavity ²³.

Intra-amniotic infection has been documented in patients with preterm labor with intact membranes ²⁴, prelabor rupture of membranes ²⁵, cervical insufficiency ²⁶, an asymptomatic short cervix ²⁷, idiopathic vaginal bleeding ²⁸, placenta previa ²⁹ and clinical chorioamnionitis at term ³⁰. Rupture of membranes is not necessary for bacteria to reach the amniotic cavity – indeed, there is experimental evidence that bacteria can cross intact membranes ³¹. Most of these infections are subclinical in nature, and therefore, they occur in the absence of clinical chorioamnionitis ³². Hence, most of these infections are undetected unless the amniotic fluid is analyzed. The most frequent microorganisms found in the amniotic cavity are genital mycoplasmas ³³ and in particular, Ureaplasma species ³⁴, Gardnerella vaginalis ³⁵, Fusobacteria species, etc. ³⁶. Fungi can also be found – women who became pregnant with intrauterine contraceptive devices are at high risk for intra-amniotic infection with Candida albicans ³⁷. Polymicrobial invasion of the amniotic cavity is present in approximately 30% of cases ³⁸. Table 1 describes the frequency of microbial invasion of the amniotic cavity in different obstetrical syndromes. Table 2 demonstrates the microorganisms detected in amniotic cavity in patients with preterm labor with intact membranes ³⁹ and clinical chorioamnionitis at term ³⁰.

The frequency of microbial invasion of the amniotic cavity is similar in patients with spontaneous labor at term and those with preterm labor and intact membranes who subsequently deliver a preterm neonate (17% vs. 22%, respectively) ⁴⁰. Yet, preterm neonates born to mothers with microbial invasion of the amniotic cavity have a higher frequency of neonatal sepsis, a systemic inflammatory response (defined as an elevated umbilical cord IL-6 concentration), and funisitis than those born to mothers at term with microbial invasion of the amniotic cavity. Why? Microbial invasion of the amniotic cavity in women in spontaneous labor at term is of shorter duration and can occur after the initiation of parturition ⁴¹. For example, bacteria can be introduced when the chorioamniotic membranes are exposed to the vaginal microbiota during the course of digital examinations performed during labor to determine cervical dilatation and effacement. Such microbial invasion typically has a low inoculum size which elicits a mild intra-amniotic inflammatory response and rarely leads to fetal microbial invasion (hence, the low frequency of funisitis and neonatal sepsis).

On the other hand, in preterm labor with intact membranes or preterm PROM, microbial invasion is established before the initiation of preterm labor. Such infections have a higher microbial burden than those observed in most women in spontaneous labor at term, have probably lasted longer, and therefore, result in a more intensive intra-amniotic inflammatory response ⁴¹. Given the longer duration of infection, the likelihood of a fetal attack is higher, and thus, not surprisingly, the rate of congenital neonatal sepsis is greater in preterm than in term neonates (2.27-5.14/1000 in preterm neonates versus 0.04-0.89/1000 term neonates) ⁴².

Recently, scientists reported a new type of intra-amniotic inflammation termed “sterile inflammation”, which is more frequent than intra-amniotic infection (microbial-associated intra-amniotic inflammation) in patients with preterm labor with intact membranes ⁴³, preterm PROM ⁴⁴ and an asymptomatic short cervix ⁴⁵. Interestingly, sterile intra-amniotic inflammation is associated with acute histologic chorioamnionitis (40-60% of cases) ³⁰. Moreover, acute inflammatory lesions of the placenta are present in a small subset of patients without intraamniotic inflammation in the context of preterm labor ⁴⁶, preterm PROM ⁴⁴, short cervix ⁴⁷ and clinical chorioamnionitis ³⁰. Potential explanations are: 1) inflammation of chorioamniotic membranes is a non-specific mechanism of host defense against “danger signals” of non-microbial origin; 2) extra-amniotic infection, which is probably rare; 3) non-viable microorganisms which may release chemotactic factors leading to inflammation ¹⁵. These organisms may have invaded the amniotic cavity and been cleared by the immune system.

The observation that acute histologic chorioamnionitis is present without demonstrable intra-amniotic infection is now well-established ³⁰. Roberts et al ⁴⁸ reported, using both cultivation and molecular microbiologic techniques, that only 4% of patients with acute histologic chorioamnionitis at term have microorganisms in the placenta. Therefore, acute histologic chorioamnionitis should not be considered synonymous with amniotic fluid infection. The characterization of any biological fluid as “sterile” is dependent on the sensitivity of the assays used to detect microorganisms. Cultivation can be very sensitive, and even one microorganism can grow into a colony under optimal conditions; however, such conditions are rarely provided in clinical laboratories. Molecular microbiologic techniques are considered more sensitive; yet, sufficient microbial DNA must be present for this methodology to provide a positive result. PCR assays with specific primers for a microorganism are considered superior to broad range PCR assays based on conserved regions of the bacterial genome (e.g. 16S gene). The use of deep sequencing can change what is known about the microbiologic landscape of biological fluids. Extreme caution must be used when interpreting the results of sequencing studies, as contamination during metagenomics can occur.

Table 1. Frequency of chorioamnionitis according to gestational age at delivery

Weeks of gestation	Chorioamnionitis (n)	Total number of patients	Percent (%)
21–24	17	18	94.4
25–28	19	48	39.6
29–32	34	96	35.4
33–36	53	497	10.7
37–40	233	6139	3.8
41–44	36	707	5.1
Total	392	7505	5.2

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Table 2. Microorganisms detected in the amniotic fluid of patients with spontaneous preterm labor with intact membranes and patients with clinical chorioamnionitis at term using cultivation and molecular microbiologic technique

Patients with spontaneous preterm labor with intact membranes 39	Patients with clinical chorioamnionitis at term 30
Fusobacterium nucleatum	Ureaplasma species
Sneathia sanguinegens	Gardnerella vaginalis
Ureaplasma species	Mycoplasma hominis
Streptococcus mitis	Streptococcus agalactiae
Gardnerella vaginalis	Lactobacillus species
Peptostreptococcus species	Bacteroides species
Leptotrichia amnionii	Acinetobacter species
Mycoplasma hominis	Sneathia
Streptococcus agalactiae	Streptococcus viridans
Lactobacillus species	Porphyromonas species
Bacillus species	Veillonella species
Coagulase-negative Staphylococcus species	Peptostreptococcus species
Prevotella species	Escherichia coli
Others: Uncultivated Bacteroidetes, Delftia acidovorans, Neisseria cinerea	Pseudomonas aeruginosa
	Staphylococcus aureus
	Eubacterium species
	Gram (–) bacilli
	Enterococcus species
	Others: Fusobacterium species, Candida species, Abiotrophia defective, Micrococcus luteus, Staphylococcus epidermidis, Firmicute, Propionibacterium acnes

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Funisitis diagnosis

Presence of any neutrophilic infiltrate involving the umbilical vein, umbilical arteries, cord substance (Wharton jelly) or peripheral umbilical cord. Qualifying the location and degree of inflammation is encouraged over the generic use of the term “funisitis,” historically used to inadequately describe the presence of any inflammation in any location.

Funisitis treatment

The primary management of funisitis is antibiotic therapy, particularly if accompanying symptoms of choriamnionitis are present. The most common antibiotics used are ampicillin and gentamicin. Alternative antibiotics include clindamycin, cefazolin, and vancomycin in women allergic to penicillin. After delivery, the current recommendation is to administer one additional dose with a cesarean section but no additional antibiotics for vaginal deliveries. Additional broad-spectrum antibiotics may be required, depending on the clinical status ⁵⁰.

Funisitis prognosis

Severe inflammation has been linked to periventricular leukomalacia ⁵¹. More severe inflammatory response seen when funisitis is present in preterm infants, possibly accounting for some differences in gestational age related morbidity ⁵²

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