Arch Gynecol Obstet DOI 10.1007/s00404-014-3208-6
Review
Pathology of perinatal brain damage: background and oxidative stress markers Gabriele Tonni · Silvia Leoncini · Cinzia Signorini · Lucia Ciccoli · Claudio De Felice
Received: 3 October 2013 / Accepted: 3 March 2014 © Springer-Verlag Berlin Heidelberg 2014
Abstract Purpose To review historical scientific background and new perspective on the pathology of perinatal brain damage. The relationship between birth asphyxia and subsequent cerebral palsy has been extensively investigated. The role of new and promising clinical markers of oxidative stress (OS) is presented. Methods Electronic search of PubMed-Medline/EMBASE database has been performed. Laboratory and clinical data involving case series from the research group are reported. Results The neuropathology of birth asphyxia and subsequent perinatal brain damage as well as the role of electronic fetal monitoring are reported following a review of the medical literature. Conclusions This review focuses on OS mechanisms underlying the neonatal brain damage and provides different perspective on the most reliable OS markers during the perinatal period. In particular, prior research work on neurodevelopmental diseases, such as Rett syndrome, suggests
G. Tonni (*) Prenatal Diagnostic Service, Guastalla Civil Hospital, AUSL Reggio Emilia, Via Donatori Sangue, 1, 42016 Guastalla, Reggio Emilia, Italy e-mail: [email protected] S. Leoncini · C. Signorini · L. Ciccoli Department of Molecular and Developmental Medicine, University of Siena, Siena, Italy S. Leoncini Child Neuropsychiatry Unit, University Hospital Azienda Ospedaliera Universitaria Senese (AOUS), Siena, Italy C. De Felice Neonatal Intensive Care Unit, University Hospital Azienda Ospedaliera Universitaria Senese AOUS, Siena, Italy
the measurement of oxidized fatty acid molecules (i.e., F4-Neuroprostanes and F2-Dihomo-Isoprostanes) closely related to brain white and gray matter oxidative damage. Keywords Birth asphyxia · Perinatal brain damage · Cerebral palsy · Electronic fetal monitoring · Oxidative stress
Introduction The idea that events surrounding labor and delivery may cause cerebral palsy (CP) first developed in the mid-nineteenth century, when Little [1] observed an association between labor events and fetal brain damage. We have encountered the predominant thought that labor asphyxia is usually the cause of cerebral palsy, and that the obstetrician may be able to recognize the asphyxial event and prevent the disorder. However, these observations had little impact on the frequency of litigation deriving from braindamaged children until the introduction of electronic fetal monitoring (EFM) in the mid-twentieth century. Since then, claims regarding the effectiveness of EFM in preventing fetal death or brain damage have initiated a flood of legal actions worldwide. In 1980, a committee of the British House of Commons boldly stated that 5,000 children in UK each year suffered a handicap that better obstetric care (primarily EFM) could have prevented [2]. These ideas were based on a now generally debunked theory described as “a continuum of reproductive casualty” [3], i.e., severe fetal asphyxia would lead to fetal/neonatal death, while less severe asphyxia would result in neonatal survival but with associated brain damage. It is now known that fetal/ neonatal death is generally preceded by epidemiologic factors that differ from those which precede brain damage.
13
CP can be defined as “a chronic disability characterized by aberrant control of movement or posture appearing early in life and not the result of recognized progressive disease” [4]. There is no specific brain pathology associated with the syndrome, and there are probably many causes, even though perinatal asphyxia is the cause of greatest interest to obstetricians and neonatologists. Of special interest to obstetricians is whether EFM can reduce the risk of developing cerebral palsy, and critical questions need to be answered. For example, is there evidence that the use of EFM has reduced the risk of CP? How often does a failure to react to perinatal asphyxia result in CP? What criteria lead to assuming a cause-and-effect relationship between perinatal asphyxia and cerebral palsy? What are the associated legal ramifications?
Does the use of EFM reduce the risk of cerebral palsy? As yet, there are no reliable studies that report a lower incidence of CP when EFM has been utilized in place of traditional auscultation. Quilligan and Paul [5] postulated in 1975 that EFM would reduce by 50 % the incidence of deficits caused by perinatal events. On the contrary, there are several studies that report the opposite; i.e., that EFM has not been shown to reduce the risk of CP [6]. In response to this report, Freeman [7] wrote, “Clearly, the hoped-for benefit from intrapartum EFM has not been realized” and suggested three possible explanations for such a “disappointing story”. First, the hypoxic damage occurred before labor, thus providing a correlation between EFM and hypoxia, but no benefit from intervention. Secondly, hypoxic damage may occur so rapidly that the warning provided by EFM may not be sufficiently prompt. Thirdly, a fetus destined to develop CP will have hypoxia secondary to the brain damage, which accounts for the correlation of brain damage to hypoxia, but negates the value of intervention. In a review, Perlman [8] reported that although EFM may be able to reduce the rate of neonatal seizures, long-term neurological and cognitive outcome has been unaffected. Painter et al. [9] also stated that evidence suggests that injury during the intrapartum period is uncommon, although fetal heart rate abnormalities are infrequently associated with long-term adverse outcomes. Fetuses may manifest many minutes of ominous fetal heart rate patterns with no evidence of irreversible central nervous system injury. Neurologically abnormal fetuses also may show abnormal fetal heart rate patterns that are due to the neural mechanisms controlling heart rate, rather than intrapartum hypoxic events. The relationship between FHR patterns in neonatal hypoxic-ischemic encephalopathy and neurological outcome at 24 months was investigated in a paper by Murray et al. [10], who concluded that no correlation could
13
Arch Gynecol Obstet
be demonstrated between duration of pathological EFM traces and degree of encephalopathy (R = 0.09, p = 0.63) or neurological outcome (p = 0.75). Moreover, they also concluded that an EFM tracing suggesting “possible fetal asphyxia” (late decelerations, severe variable decelerations, loss of beat-to-beat variability, bradycardia, tachycardia, sinusoidal pattern) may be due to an abnormality of the fetus or placenta rather than asphyxia, and that in a possibly large percentage, a fetal abnormality is the cause of “fetal distress” and/or EFM pattern consistent with “fetal distress” rather than being the result of birth asphyxia. Nelson et al. [11] reported on the doubtful value of EFM in predicting cerebral palsy after studying 78 of 95 children with CP and 300 of 378 controls who had undergone intrapartum fetal monitoring. The authors showed that multiple late decelerations in fetal heart rate (OR = 3.9; 95 % CI = 1.7–9.3) and decreased beat-to-beat variability of the heart rate (OR = 2.7; 95 % CI = 1.1–5.8) were independently associated. The 21 children with CP who had multiple late decelerations or decreased beat-to-beat variability represented only 0.19 % of singleton infants with birth weights of 2,500 g or more who had had these fetalmonitoring findings, which amounts to a false positive rate of 99.8 %. Nelson raised the concern that since Cesarean section is often performed when such EFM abnormalities are noted, and Cesarean section is associated with risk to the mother, many Cesarean sections are being performed without benefit and with the potential for harm. In the same year, Saling [12] stated that, “…the most urgent task when monitoring the fetus during labor is not so much to reduce the number of cases of CP, since these are seldom caused by intrapartum asphyxia, with the major objective to prevent early morbidity of the fetus and newborn”. The possibility of fetal asphyxia must be considered when, within a 1-h window of recording, there are two or more cycles of minimal baseline fetal heart rate variability and two or more cycles of late or prolonged decelerations, or both. Because approximately 9 of 10 predictive fetal heart rate patterns are false-positive, supplementary tests are essential for confirming the diagnosis and identifying false positives, so that unnecessary intervention is prevented [13].
What is birth asphyxia? Birth asphyxia is a condition of impaired placental gas exchange which, if it persists, leads to hypoxemia and hypercapnia [14]. The prevalence of fetal asphyxia at term is 25 per 1,000 live births, of which 15 % are moderate or severe cases. In the preterm, the prevalence is 73 per 1,000 live births, of which 50 % are moderate or severe cases. However, it remains to be determined how often asphyxia recognized at delivery may have been present
Arch Gynecol Obstet
before the onset of labor, since there is a growing body of indirect and direct evidence which supports the contention that antepartum fetal asphyxia is an important factor in the occurrence of perinatal brain damage [15]. Such postdelivery diagnosis must currently rely on acid–base assessment of the umbilical cord artery and vein and a comparison of the resulting parameters with the classic Apgar score. An umbilical artery pH
Review
Pathology of perinatal brain damage: background and oxidative stress markers Gabriele Tonni · Silvia Leoncini · Cinzia Signorini · Lucia Ciccoli · Claudio De Felice
Received: 3 October 2013 / Accepted: 3 March 2014 © Springer-Verlag Berlin Heidelberg 2014
Abstract Purpose To review historical scientific background and new perspective on the pathology of perinatal brain damage. The relationship between birth asphyxia and subsequent cerebral palsy has been extensively investigated. The role of new and promising clinical markers of oxidative stress (OS) is presented. Methods Electronic search of PubMed-Medline/EMBASE database has been performed. Laboratory and clinical data involving case series from the research group are reported. Results The neuropathology of birth asphyxia and subsequent perinatal brain damage as well as the role of electronic fetal monitoring are reported following a review of the medical literature. Conclusions This review focuses on OS mechanisms underlying the neonatal brain damage and provides different perspective on the most reliable OS markers during the perinatal period. In particular, prior research work on neurodevelopmental diseases, such as Rett syndrome, suggests
G. Tonni (*) Prenatal Diagnostic Service, Guastalla Civil Hospital, AUSL Reggio Emilia, Via Donatori Sangue, 1, 42016 Guastalla, Reggio Emilia, Italy e-mail: [email protected] S. Leoncini · C. Signorini · L. Ciccoli Department of Molecular and Developmental Medicine, University of Siena, Siena, Italy S. Leoncini Child Neuropsychiatry Unit, University Hospital Azienda Ospedaliera Universitaria Senese (AOUS), Siena, Italy C. De Felice Neonatal Intensive Care Unit, University Hospital Azienda Ospedaliera Universitaria Senese AOUS, Siena, Italy
the measurement of oxidized fatty acid molecules (i.e., F4-Neuroprostanes and F2-Dihomo-Isoprostanes) closely related to brain white and gray matter oxidative damage. Keywords Birth asphyxia · Perinatal brain damage · Cerebral palsy · Electronic fetal monitoring · Oxidative stress
Introduction The idea that events surrounding labor and delivery may cause cerebral palsy (CP) first developed in the mid-nineteenth century, when Little [1] observed an association between labor events and fetal brain damage. We have encountered the predominant thought that labor asphyxia is usually the cause of cerebral palsy, and that the obstetrician may be able to recognize the asphyxial event and prevent the disorder. However, these observations had little impact on the frequency of litigation deriving from braindamaged children until the introduction of electronic fetal monitoring (EFM) in the mid-twentieth century. Since then, claims regarding the effectiveness of EFM in preventing fetal death or brain damage have initiated a flood of legal actions worldwide. In 1980, a committee of the British House of Commons boldly stated that 5,000 children in UK each year suffered a handicap that better obstetric care (primarily EFM) could have prevented [2]. These ideas were based on a now generally debunked theory described as “a continuum of reproductive casualty” [3], i.e., severe fetal asphyxia would lead to fetal/neonatal death, while less severe asphyxia would result in neonatal survival but with associated brain damage. It is now known that fetal/ neonatal death is generally preceded by epidemiologic factors that differ from those which precede brain damage.
13
CP can be defined as “a chronic disability characterized by aberrant control of movement or posture appearing early in life and not the result of recognized progressive disease” [4]. There is no specific brain pathology associated with the syndrome, and there are probably many causes, even though perinatal asphyxia is the cause of greatest interest to obstetricians and neonatologists. Of special interest to obstetricians is whether EFM can reduce the risk of developing cerebral palsy, and critical questions need to be answered. For example, is there evidence that the use of EFM has reduced the risk of CP? How often does a failure to react to perinatal asphyxia result in CP? What criteria lead to assuming a cause-and-effect relationship between perinatal asphyxia and cerebral palsy? What are the associated legal ramifications?
Does the use of EFM reduce the risk of cerebral palsy? As yet, there are no reliable studies that report a lower incidence of CP when EFM has been utilized in place of traditional auscultation. Quilligan and Paul [5] postulated in 1975 that EFM would reduce by 50 % the incidence of deficits caused by perinatal events. On the contrary, there are several studies that report the opposite; i.e., that EFM has not been shown to reduce the risk of CP [6]. In response to this report, Freeman [7] wrote, “Clearly, the hoped-for benefit from intrapartum EFM has not been realized” and suggested three possible explanations for such a “disappointing story”. First, the hypoxic damage occurred before labor, thus providing a correlation between EFM and hypoxia, but no benefit from intervention. Secondly, hypoxic damage may occur so rapidly that the warning provided by EFM may not be sufficiently prompt. Thirdly, a fetus destined to develop CP will have hypoxia secondary to the brain damage, which accounts for the correlation of brain damage to hypoxia, but negates the value of intervention. In a review, Perlman [8] reported that although EFM may be able to reduce the rate of neonatal seizures, long-term neurological and cognitive outcome has been unaffected. Painter et al. [9] also stated that evidence suggests that injury during the intrapartum period is uncommon, although fetal heart rate abnormalities are infrequently associated with long-term adverse outcomes. Fetuses may manifest many minutes of ominous fetal heart rate patterns with no evidence of irreversible central nervous system injury. Neurologically abnormal fetuses also may show abnormal fetal heart rate patterns that are due to the neural mechanisms controlling heart rate, rather than intrapartum hypoxic events. The relationship between FHR patterns in neonatal hypoxic-ischemic encephalopathy and neurological outcome at 24 months was investigated in a paper by Murray et al. [10], who concluded that no correlation could
13
Arch Gynecol Obstet
be demonstrated between duration of pathological EFM traces and degree of encephalopathy (R = 0.09, p = 0.63) or neurological outcome (p = 0.75). Moreover, they also concluded that an EFM tracing suggesting “possible fetal asphyxia” (late decelerations, severe variable decelerations, loss of beat-to-beat variability, bradycardia, tachycardia, sinusoidal pattern) may be due to an abnormality of the fetus or placenta rather than asphyxia, and that in a possibly large percentage, a fetal abnormality is the cause of “fetal distress” and/or EFM pattern consistent with “fetal distress” rather than being the result of birth asphyxia. Nelson et al. [11] reported on the doubtful value of EFM in predicting cerebral palsy after studying 78 of 95 children with CP and 300 of 378 controls who had undergone intrapartum fetal monitoring. The authors showed that multiple late decelerations in fetal heart rate (OR = 3.9; 95 % CI = 1.7–9.3) and decreased beat-to-beat variability of the heart rate (OR = 2.7; 95 % CI = 1.1–5.8) were independently associated. The 21 children with CP who had multiple late decelerations or decreased beat-to-beat variability represented only 0.19 % of singleton infants with birth weights of 2,500 g or more who had had these fetalmonitoring findings, which amounts to a false positive rate of 99.8 %. Nelson raised the concern that since Cesarean section is often performed when such EFM abnormalities are noted, and Cesarean section is associated with risk to the mother, many Cesarean sections are being performed without benefit and with the potential for harm. In the same year, Saling [12] stated that, “…the most urgent task when monitoring the fetus during labor is not so much to reduce the number of cases of CP, since these are seldom caused by intrapartum asphyxia, with the major objective to prevent early morbidity of the fetus and newborn”. The possibility of fetal asphyxia must be considered when, within a 1-h window of recording, there are two or more cycles of minimal baseline fetal heart rate variability and two or more cycles of late or prolonged decelerations, or both. Because approximately 9 of 10 predictive fetal heart rate patterns are false-positive, supplementary tests are essential for confirming the diagnosis and identifying false positives, so that unnecessary intervention is prevented [13].
What is birth asphyxia? Birth asphyxia is a condition of impaired placental gas exchange which, if it persists, leads to hypoxemia and hypercapnia [14]. The prevalence of fetal asphyxia at term is 25 per 1,000 live births, of which 15 % are moderate or severe cases. In the preterm, the prevalence is 73 per 1,000 live births, of which 50 % are moderate or severe cases. However, it remains to be determined how often asphyxia recognized at delivery may have been present
Arch Gynecol Obstet
before the onset of labor, since there is a growing body of indirect and direct evidence which supports the contention that antepartum fetal asphyxia is an important factor in the occurrence of perinatal brain damage [15]. Such postdelivery diagnosis must currently rely on acid–base assessment of the umbilical cord artery and vein and a comparison of the resulting parameters with the classic Apgar score. An umbilical artery pH
