In chorioamnionitis, IL-1β abundance was shown to be increased in maternal and fetal tissues (Figure 1 and Table 1), particularly in the amniotic fluid, placenta, maternal blood as well as cord blood in some instances.

It is well-documented that chorioamnionitis, possibly due to the infiltration of leukocytes into the chorion and amnion (1, 64), is associated with an increased abundance of IL-1 in amniotic fluid (5, 46, 64–70), in addition to preterm labor (46, 70) and preterm pre-labor rupture of membranes (PPROM) (5). Additionally, placental tissues from chorioamnionitis-affected deliveries presented with a seventeen-fold increase in IL-1 abundance compared to healthy pregnancies, with a predisposition towards greater placental IL-1β compared to IL-1α (6). In maternal serum, IL-1β was elevated in preterm histological chorioamnionitis (71), term clinical chorioamnionitis (72) and PPROM complicated by chorioamnionitis (73). IL1B mRNA in maternal blood was elevated in women with chorioamnionitis complicated by PPROM (74). There is therefore a strong clinical association between chorioamnionitis and increased abundance of IL-1, which might be related to an increased incidence of PPROM and preterm labor.

This relationship between chorioamnionitis and IL-1 abundance in cord blood is less clear. Increased IL-1β was associated with chorioamnionitis in a select number of studies (75–77), however other studies reported no difference (78–81). This discrepancy may be explained by the concurrent presence of funisitis, an indicator of the fetal inflammatory response, marked by focal aggregation of polymorphonuclear leukocytes at the umbilical cord surface (77).

Additionally, there is now ample evidence from amniotic fluid, cervical secretions, and cord blood (82–85) that IL-1Ra, the natural IL-1 inhibitor, also positively correlates with chorioamnionitis. At first glance, elevations of anti-inflammatory mediators seem counterintuitive in this context; however, increases in the abundance of anti-inflammatory/regulatory mediators are well-recognized as part of the immune system's attempt at regaining homeostasis. Examples include increased IL-1Ra in autoimmune diseases such as rheumatoid arthritis (126) or systemic lupus erythematosus (127). Moreover, as IL-1Ra concentrations increased in maternal serum at 22–24 weeks gestation, so did the risk of preterm birth (56). Polymorphisms in the gene encoding IL-1Ra (IL1RN) have been associated with acute deciduitis (86). These findings are consistent with an involvement of IL-1 in chorioamnionitis and preterm labor.

Animal studies support the key role of IL-1 during chorioamnionitis (Figure 1 and Table 1). Intraperitoneal (i.p.) injection of lipopolysaccharide (LPS; an endotoxin of Gram-negative bacteria) to pregnant dams increased expression of the gene for IL-1β in both sheep chorion (IL1B) (58) and rat placenta (Il1b) (57), and additionally increased IL-6 and IL-1β in the maternal serum and amniotic fluid of guinea pigs (60). Moreover, pregnant rhesus macaques injected with live Group B Streptococcus (GBS) into the amniotic cavity or choriodecidual space demonstrated increased abundance of IL-1β and TNF from 13 h post-injection, and concurrently reduced the abundance of prolactin (7). Very high levels of prolactin in amniotic fluid suggest an important role in fetal development, and has been speculated to be involved in the balance of water and electrolytes, yet there is no consensus on the function of prolactin during pregnancy (128).

In addition to chorioamnionitis triggering IL-1 production, i.a. injection of IL-1 was shown to induce sterile chorioamnionitis similar to endotoxins such as LPS: Rhesus macaques were injected with either IL-1β or saline 24 or 72 h before preterm delivery via cesarean section at 80% gestation, i.e., equivalent to 32 weeks GA for a human (8). Monkeys exposed to IL-1β 24 h before cesarean exhibited infiltration of predominantly neutrophils into the decidua parietalis, and these decidual neutrophils produced increased pro-inflammatory cytokines such as TNF and IL-8, and more frequently expressed anti-inflammatory IDO (indoleamine 2, 3-dioxygenase) mRNA, than vehicle-treated controls (8). These effects were short-lasting however and by 72-hours post-dose the neutrophil infiltration and cytokine production was lower than at 24 h (8). Data on IL-1 blockade in chorioamnionitis are described in Section 7.

FGR is intimately related to issues in the cardiopulmonary transition to postnatal life, as placental insufficiency results in chronic deprivation of oxygen and nutrients, which the fetus responds to with adaptations in circulation. These adaptations can be conceptualized as “brain-sparing”, whereby blood flow is increased to the brain, as measured by middle cerebral artery Doppler studies (129, 130), whereas flow to the lower body is reduced. Due to placental vascular bed resistance, the fetal heart is subject to increased afterload, resulting in bilateral ventricular hypertrophy and reduced compliance (131, 132). Moreover, greater coronary artery blood flow, a local response seen in FGR infants, was not associated with improved cardiac function (133). As the severity of FGR increases, fetal cardiac dysfunction and myocardial cell damage increase, and perinatal morbidity worsens (134–136). Dysmorphic pulmonary vascular growth increases right to left ductal shunting, further contributing to cardiac dysfunction (137). Despite extensive research into FGR and the transitional circulation, little is known of the role of inflammation and IL-1 in this relationship.

Knowledge on the clinical association between FGR and IL-1 in maternal and infantile samples is limited (Figure 1 and Table 1). Maternal serum abundance of IL-1β was elevated in third trimester pregnancies affected by placental insufficiency and FGR, compared to uncomplicated pregnancies (96, 97). Moreover, on day 14 of neonatal life, IL-1β was increased in peripheral blood from growth-restricted or -limited infants (98), and placentas from growth-restricted pregnancies exhibited higher IL1A mRNA when compared to healthy pregnancies (99). Polymorphisms in IL1A, namely −889C/T and +4,845G/T alleles, were associated with altered transcriptional activity and aberrant production of IL-1α. Females carrying these alleles had an elevated risk of preterm birth, and bearing of low birthweight infants, however no significant difference in the risk of FGR was confirmed (100). These findings suggest that aberrant production of IL-1α may increase the risk of preterm birth, and thus low birthweight, but were not directly associated with FGR. No associations between polymorphisms in IL1B and the risk of preterm birth, low birthweight, nor FGR were found (100). When examining amniotic fluid and cord blood, no differences in IL-1 abundance were detected between growth-restricted and appropriately grown infants (101–103).

FGR has been linked to dysregulated IL-1 and related pathways in vivo (Figure 1 and Table 1). Many animal models of FGR have been used to investigate IL-1, including calorie-restriction (89), uteroplacental ligation (90), maternal ethanol exposure (87), bariatric surgery (10) and administration of uric acid (93). These studies demonstrated increased maternal and fetal protein production and gene expression of IL-1α and IL-1β in FGR-affected pregnancies compared to uncomplicated pregnancies.

In FGR piglets, cellular immune responses were compromised and contributed to an increased incidence of sepsis in the postnatal period (88). Piglets born FGR were associated with a lower serum immunoglobulin A and IL-1 when compared to control offspring (91, 92), potentially via increased expression of HSP70 (heat shock protein 70) (91, 138). HSP70 is a stress-response protein which can be induced by hypoxia-ischaemia (139), and thus may be increased in FGR, as found in one study examining piglet intestines at birth (140). HSP70 is also a danger signal to the innate immune system (141), and if overexpressed, can inhibit cytokine expression (142). Thus, HSP70 overproduction secondary to FGR may compromise cellular immune responses, including IL-1 expression (91).

Exposure to IL-1β has been linked to cardiac depression. IL-1β depressed rat cardiac myocyte contractile function in vitro (143, 144), and isolated hearts from IL-1 receptor associated kinase-1 (IRAK1) deficient mice were resistant to LPS-induced contractile dysfunction ex vivo (104).

Whilst a causal relationship between IL-1 in the transitional circulation and cardiac dysfunction has not yet been established, excessive inflammation in utero, to which IL-1 signaling contributes, induced cardiac dysfunction in neonatal rodents and sheep. The intracervical injection of LPS to pregnant rats on embryonic day (E)15 and subsequent serial transabdominal echocardiogram performed on fetuses in utero revealed a blunted increase in gestation related aortic blood flow velocity (BFC), and a decreased middle cerebral artery BFC compared to the vehicle controls (105). Another study administered LPS i.p. to pregnant mice on E14-15 and after 6 h investigated fetal cardiac dysfunction and inflammatory changes in the placenta. LPS exposed animals revealed increased fetal cardiac afterload, reduced fetal cardiac output, and increased placental expression of Il1a, Il6 and Tnf (106).

An association between intrauterine inflammation and long-term vulnerability to cardiac disease is beginning to be explored. Lambs exposed to i.a. injection of LPS 48 h before delivery exhibited impaired cardiomyocyte growth, increased collagen deposition and remodeling of the left ventricular myocardium, when compared to saline-treated controls. Affected lambs also demonstrated increased expression of genes related to cardiac metabolism and calcium handling, however expression of IL1B was not significantly increased (107). In non-human primates, cardiac tissue exposed to intrauterine infection identified reduced gene expression of pathways involved in cardiac morphogenesis and vasculogenesis (108). Abundance of IL-6 and IL-8 in cardiac tissue was increased in intrauterine infection, however IL-1 and TNF abundance was not significantly different between groups (108). These studies highlight the long-term implications of intrauterine inflammation on heart disease, beyond the transition to extrauterine life.

In humans with sepsis, circulating depressing factors, such as IL-1β, are speculated to induce myocardial dysfunction (145), and cardiac dysfunction after inflammation is further evidenced in human fetuses exposed to pre-labor rupture of membranes (PROM) or i.a. infections. Affected infants had increased ventricular compliance and reduced contractile function (109, 110). Cardiotocography during PROM also showed that fetuses exposed to histological chorioamnionitis exhibited a higher baseline heart rate and increased periods of low variability (111). Histological chorioamnionitis has been correlated with increased cord blood IL-1β and IL-6, increased heart rate and decreased blood pressure in the first week after birth (76).

Therefore, inflammation in the transitional circulation, as occurring in chorioamnionitis, precipitates cardiac dysfunction, and is speculated to be mediated in part by IL-1 (Table 1), however this needs to be confirmed in future studies.

In addition to cardiac complications, chorioamnionitis and increased IL-1 were associated with pulmonary complications (Table 1). Early life inflammation had an initial maturing effect which increased surfactant production from type-2 alveolar epithelial cells. This increased surfactant production increased lung compliance and improved lung functionality, in experimentally-induced chorioamnionitis (112, 113) or i.a. IL-1α injection (114). Clinically, there is little research on the relationship between chorioamnionitis and surfactant production. However, it was reported that infants with respiratory distress from pregnancies complicated by chorioamnionitis presented with an altered lung surfactant lipidome compared to those without chorioamnionitis (119).

Despite the initial maturing effect of chorioamnionitis on the immature lung, the longer-term outcomes are often poor. Chronic pulmonary inflammation in mice, induced with antenatal inflammation and postnatal hyperoxia, disrupted alveolarization and vasculogenesis, manifesting a lung disease known as bronchopulmonary dysplasia (BPD). This BPD phenotype was precipitated by a rise in pulmonary inflammation, to which IL-1β was established as a key pathogenic factor (115–118, 146). In humans, infants from pregnancies complicated by chorioamnionitis have elevated IL-1β in bronchoalveolar lavage fluid (120, 121) and serum (122). Thus, somewhat paradoxically, chorioamnionitis was associated with a reduced incidence of early respiratory distress (147), but an increased incidence of BPD (148).

PDA describes a persistent opening between the aorta and pulmonary artery after birth, affecting up to 55% of infants ≤28 weeks' GA (149) and 31% of infants <1,500 g (150). Patency and closure of the ductus arteriosus (DA) is a complex area of study [as reviewed in (151)]. During early fetal development nitric oxide (NO) is the primary mediator responsible for maintaining patency (152, 153). Closer to term, this role is filled by prostaglandin E₂ (PGE₂) (152, 153). Importantly IL-1β is a potent inducer of PGE₂ expression (154), yet the relationship between IL-1 and PDA remains understudied (Table 1). Infection and inflammation increase the risk of PDA, and is associated with increased cyclooxygenase-1 (155) and 6-keoprostaglandin F1α (156).

After birth, multiple factors contribute to the closure of the DA, a process that is ultimately achieved by smooth muscle constriction (157). Key triggers for this muscular contraction likely include a drop in circulating PGE₂ (158, 159), and increased calcium activity after acute oxygenation (as is seen in preterm infants with ventilation) (160–162).

Systematic review and meta-analysis of 23 studies, including over 17,708 infants, revealed that chorioamnionitis predisposed infants to PDA (123). Further, another clinical study found that late-onset sepsis (i.e., sepsis occurring later than ∼72 h of life) was associated with a higher rate of unsuccessful closure after treatment with concomitant diuretic and oral paracetamol treatment (124). Accordingly, inflammation is likely to play an important role in persistence of the DA. There is very little research on the relationship between IL-1 and PDA. However, echocardiography and plasma samples taken on day 3 of life in 53 infants, with a GA at birth below 28 completed weeks, revealed an association between large PDA (>1.5 mm) and increased pro-inflammatory (IL-1β, IL-8) and anti-inflammatory (IL-1Ra, IL-10) cytokines (125).