. 2023 Mar 13;11:1130013. doi: 10.3389/fped.2023.1130013

Table 1.

Effects and associated studies of IL-1.

Preclinical evidence	Abundance in humans
Labor Onset
Mice deficient in IL-1β (39), caspase-1 (40), or IL-1R1 (41, 42) are fully fertile and deliver at term. Intra-amniotic IL-1β triggers uterine contractions and preterm labor in a pregnant rhesus macaque model (43). Increased IL-1β abundance correlates with leukocyte infiltration in the chorionic membrane (54) and placental tissue (50–52) preceding spontaneous labour.	IL-1β is elevated in myometrium, cervix and fetal membranes during labor (53). Elevated IL-1α and IL-1β, and reduced IL-1Ra is observed in cervicovaginal fluid 4–14 days prior to spontaneous labor onset (48). IL1B expression is increased in fetal and maternal tissues during labor (49). Elevated IL-1Ra in maternal serum correlates with increased risk of preterm birth (56).
Chorioamnionitis
Animal models of chorioamnionitis demonstrate: • Increases in IL1B mRNA in rat placenta (57), and sheep chorion-amnion (58, 59). • Increases in IL-1β in maternal serum and amniotic fluid of guinea pigs (60). • Increases in IL-1β in amniotic fluid of rhesus macaques (7). Intrauterine recombinant IL-1β induces sterile chorioamnionitis similar to LPS in a preterm pregnant rhesus macaque model (8). Anakinra (human recombinant IL-1Ra): • Protective against GBS-induced fetal inflammatory response syndrome and neurobehavioral impairment in a rat model of chorioamnionitis (9). • Attenuates lung inflammation in a fetal sheep model of chorioamnionitis (61). • Protective against neutrophil infiltration and increased IL-6 and PGE₂ abundance in amniotic fluid in a rhesus macaque model of chorioamnionitis (62). • Does not ameliorate LPS-induced inflammation in a sheep model of chorioamnionitis (59). • Does not prevent the increase of pro-inflammatory T cells in fetal spleen from a rhesus macaque model of chorioamnionitis (62). A non-competitive allosteric IL-1Ra (rytvela) reduces IL-1β and CCL2 abundance in amniotic fluid in a sheep model of chorioamnionitis (63).	IL-1β is elevated in amniotic fluid (5, 46, 64–70), placenta (6), and maternal serum (71–73) from chorioamnionitis-affected pregnancies. IL1B mRNA expression is increased in maternal serum (74) during chorioamnionitis. Conflicting evidence: reports of increased IL-1 in cord blood from chorioamnionitis-affected pregnancies (75–77) however not in all studies (78–81). May require concurrent funisitis (77). IL-1Ra is increased in amniotic fluid, cervical secretions and cord blood (82–85) from chorioamnionitis-affected pregnancies. Polymorphisms of IL1RN are associated with acute deciduitis (86).
Fetal growth restriction (FGR)
Animal models of FGR demonstrate: • Increased IL-1 abundance in murine embryo brain (87). • Increased Il1 mRNA expression in rat placenta (10), neonatal rat liver (89), and fetal rabbit kidney (90). Growth-restricted offspring in a FGR piglet model demonstrate reduced serum IL-1 (91, 92) and compromised cellular immune responses (88). Treatment of human term placental explants with uric acid crystals induces a pro-inflammatory profile including increased IL-1β abundance, and these effects are IL-1 dependent, and prevented by treatment with anakinra (93). Administration of these uric acid crystals to pregnant rats result in FGR (93). Anakinra ameliorates IL-1β- and TNF-induced suppression of fetal rat metatarsal bone growth (94). Anakinra restores fetal growth in malaria-induced FGR in mice (95).	IL-1β is elevated in maternal serum from third trimester pregnancies affected by placental insufficiency and FGR (96, 97), and in peripheral blood from growth-restricted or -limited infants (98). IL1A mRNA expression is increased in placentas from growth-restricted pregnancies (99). Polymorphisms in IL1A and IL1B are not significantly associated with FGR (100). No significant differences in IL-1 abundance are observed in amniotic fluid and cord blood between growth-restricted and appropriately grown infants (101–103).
Cardiac Dysfunction
IRAK1 deficient mice are resistant to LPS-induced contractile dysfunction (104). Animal models of intrauterine inflammation demonstrate: • Reduced neonatal descending aorta and middle cerebral artery blood flow velocities in rats (105). • Reduced fetal cardiac output with increased cardiac afterload in mice (106). • Impaired cardiac development in neonatal lambs and pigtail macaques (107, 108). • However, the link to IL-1 here is understudied.	Increased ventricular compliance and reduced contractile function are observed in infants exposed to chorioamnionitis (109, 110). Histological chorioamnionitis is associated with: • Higher baseline fetal heart rate and increased periods of low variability (111). • Increased abundance of IL-1β and IL-6 in cord blood, increased heart rate, and decreased blood pressure in the first week post birth (76).
Pulmonary Inflammation and Maturation
Increased lung compliance and improved lung functionality are seen in fetal rabbit and lamb models of chorioamnionitis (112, 113), as well as after intra-amniotic injection with IL-1α (114). In murine models, BPD is precipitated by a rise in pulmonary inflammation, and IL-1β plays a key role in its pathogenesis (115–118).	Chorioamnionitis-exposed infants with respiratory distress exhibit an altered lung surfactant lipidome compared to unexposed infants (119). Chorioamnionitis is associated with increased IL-1β in bronchoalveolar lavage fluid (120, 121) and serum (122) from affected infants.
Patent Ductus Arteriosus (PDA)
No studies identified.	Chorioamnionitis predisposes infants to PDA (123). Late-onset sepsis is associated with a higher rate of unsuccessful DA closure with treatment (124). Large PDA is associated with increased pro-inflammatory (IL-1β, IL-8) and anti-inflammatory (IL-1Ra, IL-10) cytokines (125).

PDA, patent ductus arteriosus; LPS, lipopolysaccharide; GBS, group B streptococcus; PGE₂, prostaglandin E₂; CCL2, chemokine (C-C motif) ligand 2; FGR, fetal growth restriction; BPD, bronchopulmonary dysplasia; IRAK1, IL-1 receptor associated kinase-1.