Preterm parturition is a syndrome that may result from many underlying mechanisms. Infection and inflammation are the prominent ones. Intrauterine infection and inflammation have an effect akin to sepsis, and that is similar to systemic inflammatory response in adults. Indeed, there is evidence to support the association of a fetal inflammatory response syndrome (FIRS) to systemic infection and inflammation. The utilization of invasive procedures for the prenatal diagnosis of FIRS is associated with a risk for complications resulting from the invasive method. The progress in the imaging quality of obstetrical ultrasound and the development of novel methods for functional anatomical assessment of the fetal organs may help to identify, noninvasively, fetuses at risk for FIRS in patients presenting with preterm labor. We review the studies describing advanced sonographic modalities and the imaging findings in the heart, thymus, kidney, adrenal glands, and spleen of these fetuses.
FIRS and spontaneous preterm parturition
Preterm parturition is a syndrome that may result from many underlying mechanisms. Infection and inflammation are the most prominent ones. Intrauterine infection and inflammation have an effect akin to sepsis, and that is similar to systemic inflammatory response observed in adults. Indeed, there is evidence to support the association of a fetal inflammatory response syndrome (FIRS) to systemic infection and inflammation.
The “fetal inflammatory response syndrome” describes a condition characterized by systemic activation of the fetal immune system accompanied by multiorgan involvement. FIRS was originally reported among patients with preterm labor (PTL) and intact membranes and in those with preterm prelabor rupture of the membranes (PROM). The rate of FIRS in pregnancies complicated by preterm parturition is about 39% and increases to 49.3% in fetuses delivered within 1 week from cordocentesis. Of interest, FIRS is present in nearly 50% of fetuses with preterm PROM.
This syndrome is associated with a microbial invasion of the amniotic cavity (MIAC) and histological chorioamnionitis (among patients with MIAC alone, 17% have FIRS, whereas in those who have MIAC and histological chorioamnionitis, 68% have FIRS). Nevertheless, some fetuses of patients with preterm parturition will have FIRS without the presence of MIAC, whereas, in women with MIAC, not all the fetuses will develop FIRS.
FIRS can be considered the fetal counterpart of the systemic inflammatory response syndrome (SIRS), described in adults. Table 1 compares criteria for the diagnosis of SIRS and FIRS. Since it is not possible to measure fetal vital signs and inflammatory mediators aside the heart rate in utero, the definition of SIRS cannot be applied on the fetus and other diagnostic criteria are needed. Invasive methods such as amniocentesis and cordocentesis were used to establish cutoff values of interleukin-6 (IL-6) to achieve a prenatal diagnosis of fetuses affected by FIRS (a cutoff value of 11 pg/mL was reported). In addition, evidence of umbilical cord inflammation, named funisitis, as well as chorionic vasculitis, is regarded as the histologic counterparts and histopathologic hallmarks of FIRS, allowing a postnatal diagnosis.
| SIRS 1,2 | Two or more of the following:
|
| FIRS 3,4 | At least one of the following:
|
1 American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference: Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. Crit Care Med 1992;20:864-74
2 Muckart DJ, Bhagwanjee S. American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference definitions of the systemic inflammatory response syndrome and allied disorders in relation to critically injured patients. Crit Care Med 1997;25:1789-95
3 Gomez R, Romero R, Ghezzi F, Yoon BH, Mazor M, Berry SM. The fetal inflammatory response syndrome. Am J Obstet Gynecol 1998;179:194-202
4 Romero R, Gomez R, Ghezzi F, et al. A fetal systemic inflammatory response is followed by the spontaneous onset of preterm parturition. Am J Obstet Gynecol 1998;179:186-93.
Funisitis is associated with endothelial activation, and this is a key mechanism in the development of organ damage. The utilization of invasive procedures for the prenatal diagnosis of FIRS is associated with a risk for complications resulting from the invasiveness of the method. The advances in the imaging quality of obstetrical ultrasound and the development of novel methods for functional anatomical assessment of the fetal organs may help today to identify, noninvasively, fetuses at risk for FIRS, in patients presenting with preterm parturition or preterm PROM. In this review, we describe the available sonographic diagnostic modalities for the study of the heart, thymus, kidney, adrenal glands, and spleen in these fetuses.
What are the consequences of FIRS?
FIRS is associated with a higher risk for short-term perinatal morbidity (respiratory distress syndrome, neonatal sepsis, pneumonia, bronchopulmonary dysplasia, intraventricular hemorrhage, periventricular leukomalacia, necrotizing enterocolitis) and mortality after adjustment for gestational age at delivery, as well as for the development of long-term sequelae such as bronchopulmonary dysplasia and cerebral palsy.
The involvement of FIRS in the pathophysiology of cerebral palsy in preterm neonates was reported by Yoon et al. This group followed a number of 123 children who were delivered preterm (≤35 weeks of gestation from mothers who underwent amniocentesis) until the age of 3 years. The authors found that, after adjustment for gestational age at delivery, the risk of developing cerebral palsy was higher in cases of increased amniotic fluid IL-6 concentrations (odds ratio [OR], 6.4; 95% confidence interval [CI], 1.3-33.0), increased amniotic fluid IL-8 concentrations (OR, 5.9; 95% CI, 1.1-30.7), and funisitis (OR, 5.5; 95% CI, 1.2-24.5). Collectively, these findings suggest that there is a direct link between intrauterine fetal insults such as infection and inflammation, leading to FIRS, and subsequent adverse neonatal outcome and long term sequelae of prematurity.
What are the consequences of FIRS?
FIRS is associated with a higher risk for short-term perinatal morbidity (respiratory distress syndrome, neonatal sepsis, pneumonia, bronchopulmonary dysplasia, intraventricular hemorrhage, periventricular leukomalacia, necrotizing enterocolitis) and mortality after adjustment for gestational age at delivery, as well as for the development of long-term sequelae such as bronchopulmonary dysplasia and cerebral palsy.
The involvement of FIRS in the pathophysiology of cerebral palsy in preterm neonates was reported by Yoon et al. This group followed a number of 123 children who were delivered preterm (≤35 weeks of gestation from mothers who underwent amniocentesis) until the age of 3 years. The authors found that, after adjustment for gestational age at delivery, the risk of developing cerebral palsy was higher in cases of increased amniotic fluid IL-6 concentrations (odds ratio [OR], 6.4; 95% confidence interval [CI], 1.3-33.0), increased amniotic fluid IL-8 concentrations (OR, 5.9; 95% CI, 1.1-30.7), and funisitis (OR, 5.5; 95% CI, 1.2-24.5). Collectively, these findings suggest that there is a direct link between intrauterine fetal insults such as infection and inflammation, leading to FIRS, and subsequent adverse neonatal outcome and long term sequelae of prematurity.
How do we diagnose FIRS today?
The diagnosis of FIRS can be achieved antenatally or postnatally. In the first case, the gold standard is represented by invasive procedures such as amniocentesis and cordocentesis, whereas the postnatal diagnosis of FIRS is established through histology.
Amniocentesis and cordocentesis allow prenatal diagnosis of intraamniotic infection/inflammation through the measurement of intraamniotic or cord concentrations of cytokines and matrix metalloproteinases (MMPs). Indeed, Kim et al used a rapid bedside test that can be performed in 15 minutes to examine whether the MMP-8 PTD Check (SK Pharma Co, Ltd, Kyunggi-do, Korea) could be valid in the identification of intraamniotic infection and/or inflammation and in the assessment of the likelihood of adverse pregnancy outcomes including short latency such as chorioamnionitis, and significant neonatal morbidity in patients with preterm PROM. They found that patients with a positive MMP-8 PTD Check test result had a significantly higher rate of intraamniotic infection/inflammation (77% [54/70 women] vs 9% [6/71 women]; P < .001), proven amniotic fluid infection (33% [23/70 women] vs 3% [2/71 women]; P < .001), and adverse outcome than those with a negative MMP-8 PTD Check test result. A positive MMP-8 PTD Check test result had a sensitivity of 90%, a specificity of 80%, a positive predictive value of 77%, and a negative predictive value of 92% in the identification of intraamniotic infection/inflammation, and was an independent predictor of interval to delivery (hazards ratio, 3.7; 95% CI, 2.4-5.9) and significant neonatal morbidity (OR, 3.1; 95% CI, 1.2-7.9).
In an attempt to avoid the complications arising from direct procedures, currently, there is an effort to seek for an indirect approach for those patients who should be considered at risk for the development of FIRS (patients with preterm labor and intact membranes or with preterm prelabor rupture of membranes). To achieve this goal, the approach of monitoring fetal heart rate patterns with non-stress test, fetal well-being with the biophysical profile (BPP), and the evaluation of cervical length is being attempted. Laboratory exams and fetal well-being assessment with BPP are used to diagnose subclinical intraamniotic infection. BPP test scores of 6 or less have been demonstrated to correlate with perinatal infection, with high sensitivity and specificity according to some authors. However, evidence supporting the BPP as a predictor of infections is lacking and has led to questions about its clinical use for predicting chorioamnionitis and FIRS, especially in cases of PROM. In their study, Muller et al showed that although neonatal sepsis was present in 73.3% of the preterm PROM group, there was an abnormal BPP score in only 26.7% of these cases.
In light of these results, a more specific and targeted sonographic examination may represent a tool to study those fetuses at risk for the development of FIRS and to identify, noninvasively, this pathologic entity.
What are the utilities for ultrasound in the diagnosis of FIRS?
In addition to the anatomical evaluation of fetal organs, sonographic functional assessment is gaining interest in obstetrics. Mediators of infection and inflammation can hamper the function and growth of the affected fetal organs, and recent evidence suggests that these changes can be detected/assessed by ultrasound. Indeed, a multiorgan fetal involvement is reported in FIRS. Our review is focused on the sonographic identification of functional and anatomical changes associated with FIRS that were reported in the fetal heart, thymus, spleen, adrenal glands, and kidneys. Table 2 summarizes the sonographic approach to the diagnosis of the multiorgan alterations in fetuses at high risk for the development of FIRS, compared with normal fetuses.
| Fetal organ | Parameter evaluated | Type of alteration | Physiopathological hypothesis |
|---|---|---|---|
| Heart | E/A ratio Velocity time integral | Higher E/A Higher velocity time integral | Increase in left ventricular compliance as a protective effect to avoid brain ischemia in utero, when ventricular stroke volume and cardiac output cannot be maintained. Unclear mechanism regarding the altered compliance in the right ventricle |
| Tei index | Increased Tei index | Left ventricular dysfunction due to altered (increased) cerebral artery resistance to impede the arrival of oxygen and protect against endotoxin, leading to flow decrease and decreased ejection time | |
| Strain imaging | Inverted and positive peak systolic strain and strain rate | Increased ventricular relaxation associated with microbial invasion of the amniotic cavity, leading to paradoxical myocardial movements with longitudinal expansion in systole | |
| Thymus | Thymus volume | Decreased volume | Corticomedullary decreased ratio accompanied by a shift to a proinflammatory microenvironment and lymphocyte migration toward affected organs, or a mechanism of thymocyte apoptosis |
| Spleen | Splenic vein flow pattern | Pulsatile flow pattern | Fetal venous system changes transmitted through the main portal vein/changes in vessel compliance |
| Adrenal gland | Gland volume | Increased volume | Increased hormonal production in the central zone of the fetal adrenal gland (fetal zone) |
| Kidney | Amniotic fluid volume | Oligohydramnios | Decreased fetal urine production due to redistribution of blood flow away from kidneys as part of the host response to microbial products |
The technical description of the cited parameters is beyond the scope of this review, but the interested reader is referred to the attached references.
Heart
Several parameters have been proposed in the literature to study cardiac function in normal and affected fetuses: 1) E/A ratio, a widely used parameter to examine diastolic ventricular function. It is calculated by dividing the peak velocity of the E wave by the peak velocity of the A wave and reflects changes in blood velocity during atrial contraction; 2) velocity time integral (VTI), which is a measurement of the area under the curve of the E and A wave and is used to study the blood flow during each component of diastole (early ventricular filling and atrial systole) ; 3) Tei index, a noninvasive method for the assessment of global cardiac function. It is defined as the sum of the isovolumetric contraction time (ICT) and the isovolumetric relaxation time (IRT), divided by the ventricular ejection time (ET): (ICT+IRT)/ET ( Figures 1 and 2 ); and 4) Strain imaging of myocardial tissue and tissue Doppler imaging, which measure myocardial wall motion velocity and the magnitude of tissue deformation, and strain rate (SR), which provides information on the rate at which this deformation occurs.
E/A ratio and E/A VTI have been shown to undergo significant changes in patients with preterm PROM, especially if associated with MIAC. Fetuses with preterm PROM have a higher delta E/A ratio in both ventricles and a higher delta E/A VTI in the left ventricle than normal fetuses. Moreover, fetuses with documented intraamniotic infection had similar findings in the left but not the right ventricle. The changes in the Doppler waveform characteristics suggest an increase in left ventricular compliance in fetuses with preterm PROM, particularly those with proven intraamniotic infection.
It is possible that fetuses with FIRS are unable to change cardiac compliance (as in adults with SIRS ). Consequently, they may not be able to maintain ventricular stroke volume and cardiac output and hence, may not perfuse the brain adequately, predisposing to hypotension and brain ischemia in utero, which could create conditions for the development of periventricular leukomalacia. Indeed, a linear association has been described in normal fetuses between the mitral E/A peak velocity ratio and cardiac output and the changes in diastolic function may, therefore, have a protective value.
Tei index also studies the left heart in cases with preterm PROM and gestational age between 24 and 33 weeks. The left ventricular Tei index was significantly higher in fetuses with preterm PROM compared with controls (0.63 ± 0.13 vs. 0.51 ± 0.96, P = .007). Although there was no difference in isovolumetric times, the left ventricular ejection time was significantly shorter in the preterm PROM group (164 ± 17 ms vs. 184 ± 16 ms, P = .003).
The Tei index is considered a useful predictor of cardiac function, independent of both heart rate and ventricular geometry, and is not significantly affected by blood pressure or ventricular loading conditions. Therefore, its increase, associated with the shortening of the ET in patients with preterm PROM, has been suggested to indicate a ventricular dysfunction in fetuses with FIRS. This may be deriving from the fact that in the presence of chorioamnionitis, the fetal cerebral blood flow reaction is different from that produced by other kinds of fetal distress, with the cerebral artery resistance increasing (rather than decreasing) to impede the arrival of oxygen and protect against endotoxin. This results in flow decrease and a decrease in the left ventricular ET.
In addition, Di Naro et al used strain imaging to assess right ventricular function in patients with a diagnosis of preterm PROM between 24 and 34 weeks and documented intrauterine infection/inflammation by amniocentesis ( n = 12) that was compared with women with uncomplicated pregnancies ( n = 27). This is a novel tool providing information on myocardial properties and mechanics by mean of myocardial strain and SR. In this study, an impairment of both systolic and diastolic performance was found. SR analysis showed that fetuses with preterm PROM had a significantly higher peak SR in early diastole than did control subjects (5.7 ± 4.0 sec –1 vs 3.4 ± 2.4 sec –1 ; P = .038). When considering systolic function, systolic lengthening of the right ventricle was observed in 5 fetuses (5/12, 41.7%) with preterm PROM, compared with no cases in the comparison group ( P = .001). Fetuses with funisitis exhibited paradoxical myocardial movements with longitudinal expansion in systole (inverted and positive peak systolic strain and SR), suggesting dyskinesia of the free wall of the right ventricle ( Figure 3 ).
These authors studied right ventricular function because it is anatomically and functionally dominant in utero, contributing to 60% of total cardiac output. The reported results of diastolic SR measurements, indicating higher values in preterm PROM fetuses than in control fetuses, support the concept of an increased ventricular relaxation in the presence of MIAC.
The finding of more compliant myocardial walls (a so-called “floppy heart”) is consistent with an abnormal ventricular compliance that has been described in the affected fetus, although not only in the left ventricle, and in adults with sepsis or septic shock.
Thymus
The thymus is one of the main organs involved in the development of the fetal immune system. This organ is known to be reduced in size in IUGR fetuses, pregnancies complicated by preeclampsia, and in fetuses with trisomy 21.
There is evidence arising from both human and animal studies that the size of this organ is also affected by infection and inflammation.
The thymic involution associated with such conditions has been attributed both to a corticomedullary decreased ratio accompanied by a shift to a proinflammatory microenvironment and a lymphocyte migration towards affected organs or a mechanism of apoptotic thymocytes, leading to gland involution. This results from an activation of the hypothalamic–pituitary–adrenal axis by the fetal acute phase response to infection, accompanied by increased concentrations of IL-1 (a powerful stimulator of this axis), IL-6, tumor necrosis factor (TNF)-α, and glucocorticoids.
As a consequence of these recognized changes in the fetal thymus related to infection/inflammation, the sonographic evaluation of this organ might add information in the assessment of the fetus at risk for complications arising from infection/inflammation. Prenatal sonographic measurement of the fetal thymus was described initially in the late 1980s with a detection rate of 74%. As a result of the interest developed toward this organ, sonographer expertise has increased over the years, leading to a detection of the fetal thymus in >99% of fetuses, during early and late second trimester anatomy scans ( Figure 4 ) and to the definition of nomograms for its measurement in singleton and twin gestations.
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