Medico-legal implications of the fetal inflammatory response syndrome

Babies who sustain long term neurologic injury and disability are frequent subjects in medical malpractice litigation. In the United States, the tort system enables adjudication of claims through a proscribed system. This paper will review salient elements of the tort system-duty, breach, causation, and damages- and how they apply to encephalopathic infants whose injuries are believed to be the result of fetal inflammatory response syndrome (FIRS) and/or hypoxic-ischemic damage. FIRS may confound the diagnosis of neonatal encephalopathy but may be a credible explanation for it as well. The ways in which FIRS may impact malpractice lawsuits are presented.     

FIRS: Neonatal considerations

Fetal Inflammatory Response Syndrome (FIRS) is the fetal counterpart of systemic inflammatory response syndrome (SIRS) described in adults. When the fetus is directly exposed to inflammation of the fetal membranes or the placental-fetal circulation, and organs are adversely affected, the disorder is known as FIRS. This syndrome can significantly affect multiple organs with significant short and long term implications for the newborn. In cases of neonatal encephalopathy when no obvious etiology is identified, FIRS needs to be considered. Based on the significant incidence of chorioamnionitis and its potential effects on the newborn, any evidence of maternal, fetal, or neonatal infection should mandate further evaluation of the placenta and membrane histopathology.     

Mechanisms of brain injury in newborn infants associated with the fetal inflammatory response syndrome

The fetal inflammatory response syndrome (FIRS) is characterized by umbilical cord inflammation and elevated fetal pro-inflammatory cytokines. Surviving neonates, especially very preterm infants, have increased rates of neonatal morbidity including neurodevelopmental impairment. The mechanism of brain injury in FIRS is complex and may involve “multiple hits.” Exposure to in utero inflammation initiates a cascade of the fetal immune response, where pro-inflammatory cytokines can cause direct injury to oligodendrocytes and neurons. Activation of microglia results in further injury to vulnerable pre-myelinating oligodendrocytes and influences the integrity of the fetal and newborn's blood-brain barrier, resulting in further exposure of the brain to developmental insults. Newborns exposed to FIRS are frequently exposed to additional perinatal and postnatal insults that can result in further brain injury. Future directions should include evaluations for new therapeutic interventions aimed at reducing brain injury by dampening FIRS, inhibition of microglial activation, and regeneration of immature oligodendrocytes.     

Evaluation for the etiology of neonatal encephalopathy and the diagnosis of FIRS

A common disorder managed in the neonatal intensive care unit (NICU) is neonatal encephalopathy (NE). There are multiple causes of NE, including hypoxic-ischemic encephalopathy (HIE) and the fetal inflammatory response syndrome (FIRS). It is important to ascertain the specific cause of NE in an affected child, as it may affect the clinical management and will assist in prognostication. This paper discusses the background of inflammatory damage to the fetal brain, the history of FIRS as a clinical diagnosis, the characteristics of infants with FIRS, and methods to evaluate the etiology of NE.     

The fetal inflammatory response syndrome: the origins of a concept,pathophysiology, diagnosis,and obstetrical implications

The fetus can deploy a local or systemic inflammatory response when exposed to microorganisms or, alternatively, to non-infection-related stimuli (e.g., danger signals or alarmins). The term “Fetal Inflammatory Response Syndrome” (FIRS) was coined to describe a condition characterized by evidence of a systemic inflammatory response, frequently a result of the activation of the innate limb of the immune response. FIRS can be diagnosed by an increased concentration of umbilical cord plasma or serum acute phase reactants such as C-reactive protein or cytokines (e.g., interleukin-6). Pathologic evidence of a systemic fetal inflammatory response indicates the presence of funisitis or chorionic vasculitis. FIRS was first described in patients at risk for intraamniotic infection who presented preterm labor with intact membranes or preterm prelabor rupture of the membranes. However, FIRS can also be observed in patients with sterile intra-amniotic inflammation, alloimmunization (e.g., Rh disease), and active autoimmune disorders. Neonates born with FIRS have a higher rate of complications, such as early-onset neonatal sepsis, intraventricular hemorrhage, periventricular leukomalacia, and death, than those born without FIRS. Survivors are at risk for long-term sequelae that may include bronchopulmonary dysplasia, neurodevelopmental disorders, such as cerebral palsy, retinopathy of prematurity, and sensorineuronal hearing loss. Experimental FIRS can be induced by intra-amniotic administration of bacteria, microbial products (such as endotoxin), or inflammatory cytokines (such as interleukin-1), and animal models have provided important insights about the mechanisms responsible for multiple organ involvement and dysfunction. A systemic fetal inflammatory response is thought to be adaptive, but, on occasion, may become dysregulated whereby a fetal cytokine storm ensues and can lead to multiple organ dysfunction and even fetal death if delivery does not occur (“rescued by birth”). Thus, the onset of preterm labor in this context can be considered to have survival value. The evidence so far suggests that FIRS may compound the effects of immaturity and neonatal inflammation, thus increasing the risk of neonatal complications and long-term morbidity. Modulation of a dysregulated fetal inflammatory response by the administration of antimicrobial agents, anti-inflammatory agents, or cell-based therapy holds promise to reduce infant morbidity and mortality.     

Parenting skills and family support programs for drug-abusing mothers

Children born to drug-using mothers can suffer from fetal alcohol or drug syndrome (FAS/FDS) or fetal alcohol or drug effect (FAE/FDE). Such children have a greater likelihood of developing acute or chronic physical, cognitive and behavioral problems. In-utero exposure to tobacco, alcohol or drugs impact on the developing fetus and, after birth, the family environment and family system exert effects on the infants and children of substance-abusing parents. Evidence-based prevention and maternal drug treatment programs focus on enhancing parental childcaring abilities, supporting parent-child attachment and encouraging family support systems to improve children's health and cognitive outcomes. FAS/FDS prevention programs, as well as selective and indicated prenatal and postnatal interventions, can improve the support given both to mother and to child, and evidence-based, in-home parenting and family-skills-training approaches are particularly useful.     

Therapeutic interventions for fetal inflammatory response syndrome (FIRS)

Fetal inflammatory response syndrome (FIRS) is a condition defined by systemic inflammation in the fetus, a rapid increase of pro-inflammatory cytokines into the fetal circulation (including interleukin-1 and interleukin-6), as well as a cellular response (such as increased neutrophils, monocyte/macrophages, and T cells) and the presence of funisitis. FIRS can lead to death and multisystem organ damage in the fetus and newborn. Brain injuries and subsequent risk of cerebral palsy and cognitive impairments are the most threatening long-term complications. This paper reviews the definition of FIRS, summarizes its associated complications, briefly describes the available methods to study FIRS, and discusses in more detail the potential therapeutic candidates that have been so far studied to protect the fetus/newborn from FIRS and to alleviate its associated complications and sequelae.     

Histopathology of the fetal inflammatory response to intra-amniotic pathogens

Obstetric endorsement of the utility of placental histologic examination remains infrequent, especially from obstetricians who do not have a placental pathologist as part of their own local clinical care team. Placental pathologic examinations are viewed as useless if they do not provide answers to urgent clinical questions. Increasingly, however, it is appreciated that while placental analysis should be considered with regard to its longer term value; results can assess lifelong risks of a wide range of diseases that have been tied to prenatal exposures (e.g., [1]), including distinguishing sex-specific differences in those risks. (e.g., [2]) This review will focus solely on acute fetal (?) inflammation, more specifically, the fetal neutrophil responses in umbilical cord, chorionic plate vessels and to some degree, the fetal system as a whole. This histologic fetal inflammatory response is often the most readily accessible aspect of “FIR” piece of FIRS (the fetal inflammatory response syndrome). Some researchers have defined FIRS by a combination of both cytokine (especially IL-6) levels and the histopathologic FIR (Musilova et al., 2018) [3]. As we and others have noted, many histology based FIR cases, even those associated with neurodevelopmental outcomes such as cerebral palsy, are clinically silent.(e.g., [4]) Current clinical diagnostic criteria may have high specificity as they are very good at identifying non-FIR cases. However, that high specificity is coupled with very low specificity, identifying only 10% of FIR (Doty et al., 2018 Jul) [5]. Our aim is to provide a conceptual framework for the readers of the journal to better understand how to answer the following questions: What is a neutrophil and how is it important in FIR? What is the differential diagnosis for histologic FIR? How long has there been FIR? What secondary processes may have been recruited (and when) to contribute to the final pathology and pathophysiology of the given pregnancy?     

The epidemiology of FIRS in term and late preterm births

The definition of FIRS requires systemic inflammation and elevated levels of IL-6 in fetal plasma. That definition does not specify how systemic inflammation is to be recognized, and perinatal measurement of IL-6 is not a standard procedure. FIRS has not been examined in a population-based study that included post-neonatal outcome so its incidence and natural history are not known. The overlap, and similarities and differences, of FIRS as compared with other causes of neonatal encephalopathy, and how these relate to findings in the placenta, have not been jointly examined in a generalizable sample. FIRS has chiefly been discussed in the obstetric literature because of the need for decisions about management of delivery and antibiotic use. If the term “FIRS” is to be employed in other contexts, consensus should be sought as to which clinical, placental, and laboratory findings are most appropriate for identification of perinatal inflammatory processes, infectious or sterile.     

Neuroimaging findings associated with the fetal inflammatory response syndrome

The fetal inflammatory response syndrome (FIRS) is a condition whereby the fetus mounts an inflammatory response to intrauterine infection/inflammation. Clinical consequences include preterm premature rupture of membranes (PPROM), spontaneous preterm delivery, neonatal sepsis, bronchopulmonary dysplasia, and brain and other organ injury. Mechanisms leading to brain injury in FIRS have been investigated in animal and human studies. We review the neuroimaging findings of brain injury in FIRS, which overlap those of hypoxic-ischemic injury, and clinical correlation is necessary for a correct diagnosis. FIRS should be considered the primary diagnosis when neuroimaging findings such as periventricular leukomalacia are identified in preterm children born as a consequence of PPROM and spontaneous preterm labor. Additionally, FIRS should be considered in term infants who do not have the most common features of HIE (e.g. a sentinel event). Systematic histopathologic examination of the placenta and umbilical cord and/or detection of characteristic inflammatory markers in such cases are needed to establish the correct diagnosis.     

Fetal growth and postnatal growth failure in very-low-birthweight infants

Aim: To determine in a cohort of very-low-birthweight (VLBW) infants the incidence of postnatal growth failure and the influence of intrauterine growth and neonatal morbidities on the risk for severe postnatal growth failure (PNGF). Methods: The study was based on analysis of data from the Israel Neonatal Network database on VLBW infants born between 1995 and 2001. Z-score was determined for weight at birth and discharge, and severe PNGF was defined as a decline in z-score of greater than 2. Univariate analysis and multi-linear regression determined the effect of fetal growth and neonatal morbidities on the risk for severe PNGF. Results: Severe PNGF occurred in 10.6% of the cohort. The mean±SD birthweight (BW) z-score was -0.59±0.74, decreasing to -1.67±0.77 at discharge. The incidence of severe PNGF increased significantly with decreasing BW and gestational age. Each 1-unit increase in z-score BW was associated with a 2.37-fold increased risk for severe PNGF. Severe respiratory distress syndrome, patent ductus arteriosus, sepsis, necrotizing enterocolitis, and bronchopulmonary dysplasia were associated with severe PNGF.

Conclusion: Severe PNGF among VLBW infants was markedly influenced by intrauterine growth as well as major morbidities. In the assessment of postnatal growth among VLBW infants, growth status at birth should be considered.     

Delivery room emergencies in critical congenital heart diseases

Transition from fetal to postnatal life is a complex process. Even in the absence of congenital heart disease, about 4–10% of newborns require some form of assistance in the delivery room. Neonates with complex congenital heart disease should be expected to require significant intervention and thus the resuscitation team must be well prepared for such a delivery. Prenatal assessment including fetal and maternal health in general and detailed information on fetal heart structure, function and hemodynamics in particular are crucial for planning the delivery and resuscitation. In addition, understanding the impact of cardiac structural anomaly and associated altered blood flow on early postnatal transition is essential for success of resuscitation in the delivery room. In this article, we will briefly review transitional circulation focusing on altered hemodynamics of the complex congenital heart diseases and then discuss the process of preparing for these high-risk deliveries. Finally, we will review the pathophysiology resulting from the cardiac structural anomaly with resultant altered fetal circulation and discuss delivery room management of specific critical congenital heart diseases.     

Obstetric aspects of hypoxic ischemic encephalopathy

Hypoxic ischemic encephalopathy (HIE) describes neonatal encephalopathy that is caused by intrapartum asphyxia and it can result in the long term sequelae of cerebral palsy which is a major cause of disability. The incidence of cerebral palsy has not changed over the last few decades and the challenge to obstetricians remains how best to recognise those babies at risk of this intrapartum insult both before and during labour. Many associations and risk factors are unavoidable or unrecognisable, and others are fairly common and associated with poor predictive value. Intrapartum fetal heart monitoring remains the main focus of attention but how this is best achieved is still the subject of research. Computerised decision support systems built into fetal heart rate monitoring and non-invasive fetal ECG signal pick-up are currently being explored.     

White matter injury following fetal inflammatory response syndrome induced by chorioamnionitis and fetal sepsis: Lessons from experimental ovine models

Chorioamnionitis and fetal sepsis can induce a fetal inflammatory response syndrome (FIRS) which is closely related to the development of white matter injury in the fetal brain. Large epidemiological studies support the link between FIRS and fetal brain injury with a clear association between the presence of in utero inflammation and neurodevelopmental complications such as cerebral palsy, autism and cognitive impairments later in life.     

Cardiac Arrhythmias in the Human Fetus

Fetal cardiac arrhythmias have been recognized with increasing frequency during the past several years. Most fetal arrythmias are intermittent extrasystoles, often presenting as irregular pauses of rhythm. These are significant only when they occur with appropriate timing to initiate sustained tachycardia, mediated by anatomic bypass pathways. The most common important fetal arrhythmias are: 1) supraventricular tachycardias, and 2) severe bradyarrhythmias, associated with complete heart block. Symptomatic fetal tachycardias are usually supraventricular in origin, and may be associated with the developmet of hydrops fetalis. These patients may respond to antiarrhythmic drug therapy, administered via maternal ingestion or via direct fetal injection. Such therapy should be offered with careful fetal and maternal monitoring, and must be based on a logical, sequential analysis of the electrical mechanism underlying the arrhythmia, and an appreciation of the pharmacology and pharmacokinetics of the maternal, placental fetal system. Bradycardia from complete heart block may either be associated with complex congential heart malformations involving the atrioventricular junction of the heart, or may present in fetuses with normal cardiac structure, in mothers with autoimmune conditions associated with high titres of anti-SS-A or anti-SS-B antibody, which cross the placenta to cause immune-related inflammatory damage to the fetal atroventricular node. This paper reviews experience with the analysis of fetal caridac rhythm, a detailed discussion of the pathophysiology of arrhythmias and their effect on the fetal circulatory system, and offers a logical framework for the construction of treatment algorithms for fetuses at risk for circulatory compromise from fetal arrhythmias.     

Progression of outflow tract obstruction in the fetus

Fetal ventricular outflow tract obstruction (OTO) is congenital heart disease with significant potential for progression before birth as a consequence of the unique nature of the fetal circulation. The pattern of evolution depends upon the timing of development, severity of obstruction and the influence of the OTO on the fetal atrioventricular valve and myocardial function. Critical aortic (AS) or pulmonary (PS) valve stenosis, the two most common forms of fetal OTO, may be associated with progressive ventricular and great artery hypoplasia if presenting early in gestation or with normal ventricular and great artery growth if evolving later in gestation. In some affected fetuses, AS or PS may lead to the evolution of fetal heart failure. This article will review our current understanding of the natural history of fetal AS and PS, experience with fetal intervention and future directions of research.     

肾盂前后径对胎儿肾积水出生后行肾盂成形术的预测价值分析

目的分析出生前后肾盂前后径(anteroposterior diameter of renal pelvis,APD)预测胎儿肾积水患儿在随访期间行肾盂成形术的临床价值。方法回顾性分析2017年6月至2019年3月湖南省儿童医院、湖南省妇幼保健院通过产前超声检出孕中期APD≥4 mm或孕晚期APD≥7 mm胎儿肾积水患者的临床资料。在随访过程中,胎儿肾积水患者出生后结局分为手术和非手术,在手术组与非手术组间分别比较孕中期、孕晚期及出生后1个月的APD值。结果本研究共纳入98例患儿(161肾),36例患儿(40肾)因出现临床手术指征而行肾盂成形术。多因素Logistic回归分析发现,孕中期、孕晚期及出生后1个月的APD值均是肾积水患儿行肾盂成形术的危险因素。孕中期、孕晚期及出生后1个月APD值分辨肾积水患儿出生后行肾盂成形术的最佳临界值分别为7.5 mm、16.4 mm和15.5 mm,灵敏度分别为75.7%、70.3%和83.8%,特异度分别为79.0%、90.0%和87.0%。当孕中期APD值为7.5 mm、孕晚期APD值为16.4 mm或出生后1个月APD值为15.5 mm时对预测行肾盂成形术的临床价值最佳(灵敏度为91.9%,特异度为85.0%)。结论孕中期、孕晚期及出生后1个月的APD值均能在一定程度上预测患儿出生后行肾盂成形术的概率。孕晚期及出生后1个月可以更好地预测UPJO患儿出生后行肾盂成形术的最佳临界值,但在妊娠中期就可以对手术风险较高的患儿进行筛查。结合胎儿期及出生后APD值,可以提高预测UPJO患儿行肾盂成形术的准确性。     

The contribution of fetal drug exposure to temperament: potential teratogenic effects on neuropsychiatric risk

BACKGROUND: Preliminary evidence indicates that fetal drug exposure may be associated with alterations in temperament. However, studies often do not dissociate the potential effects of drug exposure from other perinatal or environmental factors that could influence temperament phenotypes. METHODS: High risk children (n = 120) were followed from birth to 6 months of age to determine the effects of fetal drug exposure on temperament, after controlling for the child's gender, gestational age, medical morbidity, ethnicity, and maltreatment as well as the mother's stress, income adequacy, and quality of caregiving. Methods included medical chart review, questionnaires, and videotapes of mother-child interaction. RESULTS: Preliminary analyses indicated that fetal drug exposure was associated with both distractibility and intensity of children's responses to the environment at 6 months of age. After adjusting for potentially confounding variables, drug exposure accounted for 12% of the variance in distractibility but was not a significant predictor in the regression model for intensity. CONCLUSIONS: Findings suggest that drug-exposed children may experience difficulty sustaining their focus of attention and be more easily distracted by environmental stimuli than non-drug-exposed children. Results converge with previous research to implicate cortical hyperarousal, stemming from teratogenic effects on the dopaminergic system during fetal development.     

Controversies of fetal cardiac intervention

Remarkable advances in ultrasound imaging technology have made it possible to diagnose fetal cardiovascular lesions as early as 12-14 weeks of gestation and to assess their physiological relevance by echocardiography. Moreover, invasive techniques have been developed and refined to relieve significant congenital heart disease (CHD), such as critical aortic and pulmonary stenoses in the pediatric population including neonates. Recognition of the fact that certain CHDs can evolve in utero, and early intervention may improve the outcome by altering the natural history of such conditions has led to the evolution of a new fetal therapy, i.e. fetal cardiac intervention. Two entities, pulmonary valvar atresia and intact ventricular septum (PA/IVS) and hypoplastic left heart syndrome (HLHS), are associated with significant morbidity and mortality even with postnatal surgical therapy. These cases are believed to occur due to restricted blood flow, leading to impaired growth and function of the right or left ventricle. Therefore, several centers started the approach of antenatal intervention with the primary goal of improving the blood flow through the stenotic/atretic valve orifices to allow growth of cardiac structures. Even though centers with a reasonable number of cases seem to have improved the technique and the immediate outcome of fetal interventions, the field is challenged by ethical issues as the intervention puts both the mother and the fetus at risk. Moreover, the perceived benefits of prenatal treatment have to be weighed against steadily improving postnatal surgical and hybrid procedures, which have been shown to reduce morbidity and mortality for these complex heart defects. This review is an attempt to provide a balanced opinion and an update on fetal cardiac intervention.     

The Impact of Fetal Echocardiography

Fetal echocardiography has impacted the fetus with congenital heart disease in many important ways. Advances in fetal echocardiography have allowed for more accurate and earlier detection of cardiac abnormalities. In turn, the prenatal diagnosis of cardiac abnormalities has improved the care and outcome of selected fetuses with severe cardiac malformations or arrhythmias. Fetal echocardiography has improved the understanding of the development and evolution of congenital heart disease in utero, and it may serve a role in identifying candidates for prenatal intervention. The prenatal diagnosis of congenital heart disease has allowed for better counseling and preparation of families regarding the anticipated prenatal development of the fetus as well as the expected postnatal management plans and prognosis. This article reviews the impact of fetal echocardiography in these and other areas.