Early Human Development 90 (2014) 131–135
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Early Human Development journal homepage: www.elsevier.com/locate/earlhumdev
Umbilical arterial pH in patients with cerebral palsy Yoshio Matsuda a,b,⁎, Hikaru Umezaki a, Masaki Ogawa b, Michitaka Ohwada a, Shoji Satoh c, Akihito Nakai d a
Department of Obstetrics and Gynecology, International University of Health and Welfare Hospital, 537-3 Iguchi, Nasushiobara, Tochigi 329-2763, Japan Department of Obstetrics and Gynecology, Tokyo Women's Medical University, Kawada-cho, 8-1, Shinjuku-ku, Tokyo 162-8666, Japan c Maternal and Perinatal Care Center, Oita Prefectural Hospital, Bunyo 476, Oita 870-8511, Japan d Tama-Nagayama Hospital, Nippon Medical School, 1-7-1 Nagayama, Tama-City, Tokyo 206-8512, Japan b
a r t i c l e
i n f o
Article history: Received 22 November 2013 Received in revised form 27 December 2013 Accepted 3 January 2014 Keywords: Cerebral palsy Chorioamnionitis Intraparum hypoxic event Placental abruption Umbilical arterial pH
a b s t r a c t Background: Umbilical arterial pH (UApH) in severe cerebral palsy (CP) is not fully understood. Aims: This work aims to determine the relationship between fetal acidemia and clinical features of severe CP. Study design: A retrospective study design is used. Subjects: A review was conducted unti1 April 2013 among 218 infants with CP diagnosed to be caused by antenatal and/or intrapartum conditions determined by the Japan Council for Quality Health Care. After excluding patients in whom the causes of CP were thought to be due to events after delivery, 168 infants born at over 34 weeks of gestation that both Apgar score and UApH were measured were selected. Outcome measures: Severe fetal acidemia was defined as a pH of less than 7.0. Results: Six major factors were found to be associated with CP: placental abruption (A, n = 42), traumatic delivery with an abnormal FHR pattern (B, n = 29), an abnormal FHR pattern during labor (C, n = 27), chorioamnionitis with an abnormal FHR pattern (D, n = 17), an abnormal FHR pattern before labor (E, n = 14), and cord prolapse (F, n = 10). The UApH was less than 7.0 in 114 cases (67.9%) and more than 7.20 in 20 cases (11.9%). The UApH values were lowest in group A (median 6.7, 6.43–6.99) and highest in group E (7.18, 6.92–7.45). The distribution of the UApH values was significantly different in these groups. Conclusion: Placental abruption was a factor most associated with low pH. Even among the infants with severe CP, over 10% of patients exhibited a non-acidemic status at birth. © 2014 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Although birth asphyxia can be a cause of cerebral palsy (CP), it has been demonstrated in controlled population-based studies that birth asphyxia does not account for most cases of CP [1]. Among term-born children evaluated in a well-planned study of a regional cohort, only one-third had recognized intrapartum asphyxia events that appeared to account for the observed clinical sequence [2]. In the remaining affected infants, despite similarities in clinical features, the causes of CP were not apparent. Pathological acidemia is defined as a pH of less than 7.0. It is an objective measurement of intrapartum hypoxia–ischemia and is correlated with the occurrence of hypoxic ischemic encephalopathy [3]. However, few papers have investigated the relationship between the incidence of CP and the value of umbilical arterial pH (UApH). The Japan obstetric compensation system for CP was established by the Japan Council for Quality Health Care (JCQHC) to compensate for CP
⁎ Corresponding author at: Department of Obstetrics and Gynecology, International University of Health and Welfare Hospital, 537-3 Iguchi Nasushiobara, Tochigi 329-2763 Japan. Tel.: +81 287 39 3060; fax: +81 287 39 3001. E-mail address: [email protected] (Y. Matsuda). 0378-3782/$ – see front matter © 2014 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.earlhumdev.2014.01.001
derived in principle from intrapartum events and improve perinatal care. The present study was performed to determine the associated factors for CP and to evaluate the relationship between fetal acidemia and severe CP among antepartum and/or intrapartum factors using this compensation system for CP. 2. Methods This study was approved by the Ethics Committee of International University of Health and Welfare Hospital, Tochigi, Japan. The Japan obstetric compensation system for CP was launched on January 1st, 2009 to provide rapid monetary compensation for CP [4] certified as first or second degree in severity according to the criteria of the Japanese Social Welfare System [5] in infants with a birth weight of over 2000 g and/or a pregnancy length of over 33 weeks. This system, however, does not cover infants with disabilities apparently due to congenital anomalies in metabolism, chromosomal aberrations, brain malformation, or postnatal factors [4]. Once the parent of a patient with CP applies for compensation, the obstetric facility that treated the applicant must disclose the corresponding medical charts and relevant information at the request of the JCQHC. The decision to provide compensation in each case is made by the JCQHC after a preliminary investigation.
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Y. Matsuda et al. / Early Human Development 90 (2014) 131–135
Table 1 Clinical characteristics in the 168 cases with severe cerebral palsy.
n
Gestational age (weeks)
Birth weight (g)
median
range
median
range
C/S
Antenatal An abnormal FHR pattern before labor
14
37
(34–40)
2610
(1754–3510)
12
Intrapartum An abnormal FHR pattern during labor Traumatic delivery with an abnormal FHR pattern Placental abruption (before labor) Placental abruption (during labor) Umbilical cord prolapse Ruptured uterus Feto-maternal transfusion Maternal factors Chorioamnionitis with an abnormal FHR pattern during labor
27 29 42 6 10 7 4 4 17
39 40 37 39 40 39 37.5 36.5 39
(35–41) (36–41) (34–41) (37–40) (37–40) (38–41) (36–41) (34–41) (36–41)
2758 3110 2476 2897 3117 3078 2603 3103 3015
(1498–4032) (2012–4110) (1486–3306) (2488–3148) (2543–3582) (2586–3828) (2292–2578) (2350–3962) (2158–3860)
12 6 41 0 9 7 4 3 7
4 4 168
39.5 38 38
(36–40) (35–39) (34–41)
3170 2808 2819
(2190–3990) (2300–3315) (1486–4110)
1 0 102
Perinatal Perinatal infection Uneventful (Unknown cause) Total
complete expulsion of the baby, and perinatal; the timing of the associated factor was uncertain. Second, possible perinatal factors were chosen according to the timing of onset. Sentinel hypoxic event occurring immediately before or during labor were as follows: a ruptured uterus, cord prolapse, placental abruption, amniotic fluid embolism, and fetal exsanguinations due to vasa previa or feto-maternal hemorrhage. Other factors suggesting that CP was caused by an event other than acute intrapartum hypoxia were also listed, as follows: an umbilical arterial base deficit less than 12 mmol/l or pH greater than 7.00, central nervous system or systemic infection, minimal or absent fetal heart rate variability from the onset of labor, major antenatal placental abruption, and extensive chorioamnionitis. The FHR patterns were defined as abnormal when one of the following patterns was detected: persistent late decelerations, minimal or absent variability, severe variable deceleration, prolonged deceleration, or bradycardia [10,11]. These patterns were also used for the assessment of preterm fetuses. Bradycardia was defined as a baseline FHR of less than 100 bpm (N3 min) [10]. Fetal pathological/severe acidemia was defined as a pH of less than 7.0 [11]. The distribution of UApH was graded as follows: less than 7.0
Subsequently, a professional committee of the JCQHC consisting of physicians, midwives, lawyers and citizens carefully investigates the causative factors for CP in each case and publishes a brief summary of the case together with the cause of CP in a form with privacy protection on their website [6]. Researchers can gain access to a more detailed report provided by the committee after receiving approval from the JCQHC [7]. A review was conducted unti1 April 2013 among 218 infants with CP diagnosed to be caused by antenatal and/or intrapartum conditions determined by the JCQHC. All 218 infants were born in or after January 2009, as the compensation system was started on January 2009. In the reports, personal information regarding the date of birth, including year and month, place of birth, and maternal age, was masked for privacy protection. The reports were retrospectively reviewed focusing on clinical backgrounds and causes of CP. The possible factors for CP were classified according to the report by MacLennan (International Consensus Criteria) with modifications [8,9]. First, the timing of the factor was determined as follows: antenatal; if the factor occurred before the onset of labor, intrapartum; if the factor occurred or recurred between the onset of labor and
Table 2 The associated factors and their pH in the 168 cases with severe cerebral palsy. pH n
Grade of pH
Median
Range
Less than 7
7.0–7.19
Over 7.20
Antenatal An abnormal FHR pattern before labor
14
7.18
(6.92–7.45)
3
4
7
Intrapartum An abnormal FHR pattern during labor Traumatic delivery with an abnormal FHR pattern Placental abruption (before labor) Placental abruption (during labor) Umbilical cord prolapse Ruptured uterus Fetomaternal transfusion Maternal factors Chorioamnionitis with an abnormal FHR pattern during labor
27 29 42 6 10 7 4 4 17
6.94 6.78 6.7 6.97 7.05 6.76 6.9 6.66 7.07
(6.57–7.34) (6.55–7.08) (6.43–6.99) (6.69–7.14) (6.56–7.29) (6.48–7.18) (6.83–6.97) (6.51–6.8) (6.8–7.19)
17a 25a 42 4a 4a 5a 4a 4a 6
7 4 0 2 4 2 0 0 11
3 0 0 0 2 0 0 0 0
4 4 168
7.35 7.34 6.9
(7.27–7.42) (7.2–7.39) (6.43–7.45)
0 0 34
4 4 20
Perinatal Perinatal infection Uneventful (unknown cause) total a
Acute intrapartum hypoxic event.
0 0 114
Y. Matsuda et al. / Early Human Development 90 (2014) 131–135
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Table 3 Comparison of statistical differences in UApH among six major factors. Continuous variables Placental abruption before labor Continuous variables Placental abruption before labor Traumatic delivery with an abnormal FHR pattern An abnormal FHR patterns during labor Chorioamnionitis with an abnormal FHR pattern An abnormal FHR pattern before labor Cord prolapse Analysis of variance confirmed by Tukey's test Nominal variables Placental abruption before labor Traumatic delivery with an abnormal FHR pattern An abnormal FHR pattern during labor Chorioamnionitis with an abnormal FHR pattern An abnormal FHR pattern before labor Cord prolapse
Traumatic delivery with an abnormal FHR pattern
An abnormal FHR pattern Chorioamnionitis with an during labor abnormal FHR pattern
1
0.0006
b0.0001
b0.0001
0.0067
0.2081
0.0114
b0.0001
0.254
1
An abnormal FHR pattern Cord before labor prolapse
0.1432
1
1
1 1
0.922
0.011
0.0001
b0.0001
0.003
0.008
b0.0001
0.0434
0.672
0.029
0.786
0.668
1 0.809
Kruscal–Wallis test confirmed by Tukey's test.
(pathological/severe acidemia), between 7.0 and 7.20 (mild to moderate acidemia) and more than 7.20 (normal pΗ). Analysis of variance confirmed by Tukey's test and Kruscal–Wallis test confirmed by Tukey's test were used for statistical analysis, and significant difference was set to at less than 0.05.
3. Results 3.1. Clinical backgrounds of CP in the present study After excluding patients in whom the cause was thought to be events after delivery, 168 infants born at over 34 weeks of gestation [8] that both Apgar score and UApH were measured were selected. The clinical background data of the 168 patients are shown in Table 1. The timing of onset was considered to be antenatal (14 cases, 8.3%), intrapartum (146 cases, 86.9%), or perinatal (8 cases, 4.8%). Cesarean section was performed in 102 cases (60.7%). Six major factors were responsible for CP infants as follows: placental abruption before labor (A, n = 42), traumatic delivery with an abnormal FHR pattern (B, n = 29), an abnormal FHR pattern during labor (C, n = 27), chorioamnionitis with an abnormal FHR pattern during labor (D, n = 17), an abnormal FHR pattern before labor (E, n = 14), and cord prolapse (F, n = 10). Six cases were considered to involve placental abruption during labor. Other maternal sentinel hypoxic events occurring during labor were as follows: a ruptured uterus (seven cases), and fetal exsanguinations due to feto-maternal hemorrhage (four cases). Maternal factors were detected in four cases: two cases of amniotic fluid embolism, one case of maternal cardiac failure and one case of maternal cardiac arrest during endotracheal intubation. Perinatal infection was also detected in four cases: two cases of group B streptococcus, one case of pneumonia, and one case of Coxsackie virus. The remaining four cases were coded as ‘uneventful (unknown cause)’, because no associated factor was identified in the report (Table 1).
3.2. Relationship between UApH and the associated factors in CP The UApH was less than 7.0 in 114 cases (67.9%). Of these cases, 103 (90.4%) were equivalent to acute intrapartum hypoxic events, including maternal sentinel hypoxic event occurring during labor, such as a ruptured uterus, cord prolapse, placental abruption, amniotic fluid embolism, and fetal exsanguinations due to fetal-maternal hemorrhage (Table 2). On the other hand, the pH was more than 7.20 in 20 cases (11.9%). These cases involved an abnormal FHR pattern before labor (seven cases), an abnormal FHR pattern during labor (three cases), umbilical cord prolapse (two cases), perinatal infection (four cases) and an uneventful clinical course (four cases). Statistical differences in UApH among six major factors are shown in Table 3. For continuous variables, analysis of variance confirmed by Tukey's test was used, whereas for nominal variables, Kruscal–Wallis test confirmed by Tukey's test was used. The distribution of UApH was significantly different in these groups (Tables 2, 3) (p b 0.0001). In summary, the UApH values were lowest in group A (median 6.7, range 6.43– 6.99) and highest in group E (7.18, 6.92–7.45). In addition, the UApH in group D (7.07, 6.8–7.19) was significantly higher than that observed in group A (6.7, 6.43–6.99) and in group B (6.78, 6.55–7.08) (Tables 2, 3). 3.3. Relationship between FHR monitoring and UApH in CP FHR monitoring was recorded in 156 cases. An abnormal FHR pattern was observed in 148 cases (94.9%). Prolonged deceleration was observed in 124 cases (95 cases in the severe pH group, 24 cases in the mild to moderate pH group and five cases in the normal pH group), minimal or absent variability was observed in 19 cases (six cases in the severe pH group, seven cases in the mild to moderate pH group and six cases in the normal pH group), recurrent late deceleration was observed in three cases (two cases in the severe pH group and one case in the mild to moderate pH group) and severe variable deceleration were observed in two cases (one case in the severe pH group and one case in the normal pH group).
Y. Matsuda et al. / Early Human Development 90 (2014) 131–135
0 9 (34.6%) 8 (29.6%) 3 (17.6%) 0 2 (25%) 22 (16.8%)
Severe variable deceleration
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Among the acidemic fetuses, an abnormal FHR pattern was observed in all cases. On the other hand, in the normal pH group (n = 20), a reassuring FHR pattern was noted in eight cases (40%). Minimal or absent variability with a normal pH was observed in seven cases (50%) in group E. Table 4 shows abnormal FHR patterns in main causative factors of severe CP. Although minimal or absent variability was seen in all cases in the group of ‘an abnormal FHR pattern before labor’, prolonged deceleration was dominant in most cases.
39 26 27 17 14 8 131 Placental abruption (before labor) Traumatic delivery with an abnormal FHR pattern An abnormal FHR pattern during labor Chorioamnionitis with an abnormal FHR pattern during labor An abnormal FHR pattern before labor Umbilical cord prolapse* TOTAL
Table 4 Abnormal FHR patterns in six major factors of severe cerebral palsy.
n
37 (94.9%) 23 (88.5%) 25 (92.6%) 12 (70.6%) 3 (21.4%) 8 (100%) 108 (82.4%)
Prolonged deceleration
2 (5.1%) 5 (19.2%) 3 (11.1%) 3 (17.6%) 14 (100%) 0 27 (20.6%)
Minimal or absent variability
5 (12.8%) 9 (34.6%) 5 (18.5%) 2 (11.8%) 2 (14.3%) 0 23 (17.6%)
Recurrent late deceleration
4. Discussion The present study investigated the relationship between UApH and severe CP. The UApH values were lowest in the cases involving placental abruption among the associated factors. Moreover, among the severe CP cases, over 10% of patients exhibited a non-acidemic status at birth. MacLenann categorized three essential criteria linking acute intrapartum hypoxia as a possible cause of CP [8] and listed other factors suggesting that CP was caused by an event other than acute intrapartum hypoxia, as follows: umbilical arterial base deficit less than 12 mmol/l or pH greater than 7.00, central nervous system or systemic infection, minimal or absent fetal heart rate variability from the onset of labor, major antenatal placental abruption, and extensive chorioamnionitis. According to these criteria, the frequency of intrapartum hypoxic event was 37.5% (63/168) in this study, which was higher than previously reported rates [12,13]. The severity of CP in the present study may have been higher than that observed in other studies. Kodama et al. reported ten patients with CP who exhibited bradycardia with a nadir b80 bpm and a duration over 13 min, which was significantly elevated with respect to acidemia related CP [9]. We recently demonstrated a significant difference between acidemia and nonacidemia regarding the occurrence of neonatal adverse outcome in cases involving placental abruption [11]. Moreover, fetal acidemia was linked to bradycardia in patients with CP. Several mechanisms have been proposed to explain the association between chorioamnionitis and CP, including an inflammatory cytokine response, placental inflammation leading to impaired placental perfusion and gas exchange and intrauterine infection with bacteremia resulting in the direct involvement of the brain or fever associated with the infection itself, exacerbating the primary insult to the brain [14]. Whether the presence of infection/inflammation, such as that associated with chorioamnionitis, confers an additional risk for CP in term infants delivered in the presence of severe fetal acidosis has not been thoroughly studied. Shalak et al. showed that the presence of histological chorioamnionitis had a poor predictive value and did not confer an additional risk for the subsequent development of neonatal encephalopathy [15]. A single severe exposure, such as uterine rupture or massive abruption, can be sufficient to cause CP; however, much more often it is not a single cause, but rather multiple concurrent risk factors that precede CP. In addition, multiple risk factors markedly increase risk. In the present study, the UApH was 7.07 (6.8–7.19) in the cases involving chorioamnionitis with an abnormal FHR pattern, which was significantly higher than that observed in the cases involving a history of placental abruption or traumatic delivery with abnormal FHR pattern. This finding indicates that brain injury may occur following a lower level of hypoxic stress in the presence of chorioamnionitis. In the present study, even among the severe CP, over 10% of the patients exhibited a non-acidemic status at birth, including those in whom the causes of CP was derived from an abnormal FHR pattern before labor (seven cases), an abnormal FHR pattern during labor (three cases), umbilical cord prolapse (two cases), perinatal infection (four cases) and an uneventful clinical course (4 cases). Although it is very difficult to prove the occurrence of hypoxic event during pregnancy (before the onset of labor), such phenomena have been reproduced in experimental animal models. After the recovery
Y. Matsuda et al. / Early Human Development 90 (2014) 131–135
from the hypoxic insult in utero, cardiovascular parameters return to the same levels observed before the insult if the fetus is able to compensate adequately. We previously showed that induced prolonged sustained hypoxia in fetal lambs in the last third of gestation resulted predominantly in white matter damage with some adjacent cortical necrosis despite the normalization of cardiovascular and biophysical activities and biochemical parameters [16,17]. Ikeda et al. also demonstrated that asphyxia due to partial umbilical cord occlusion in near-term fetal lambs produced variable neuropathologic changes, although the fetuses showed a full recovery in all physiologic parameters [18]. After the normalization of cardiovascular and blood gas status, it has been reported that minimal or absent variability of the FHR represents the first recognized signs of chronic neurological compromise [8]. In the present study, minimal or absent variability was seen in all cases involving an abnormal FHR pattern before the onset of labor (group E) and half of them showed normal UApH. On the other hand, it is well known that abnormal FHR monitoring is often noted in fetuses with congenital malformations [19] or congenital cytomegaloviral infection [20]. In one case, the FHR patterns of 20 anencephalic fetuses showed varying degrees of decreased variability in correlation with the severity of brain defects [21]. These data show that an abnormal FHR pattern is the result of pre-existing CNS disorders; however, a causal relationship with CNS damage has not been established. Our data were not derived from a nationwide population-based cohort, because the essential information was masked for personal protection. Nevertheless, this peer review system in Japan is the best clinically available method. It may be argued that our results reflect bias due to the small sample size; however, we consider this to be unlikely given the low-frequency nature of the cohort. The causes of CP are multifactorial. In addition, it is possible that currently unidentified etiologies will be clarified in future, as diagnostic technology and gene analyses, including radiologic diagnosis, advance [12]. In cases lacking evidence from the fetal umbilical arterial cord, it is not possible to determine whether hypoxia or asphyxia caused CP or contributed to other clinical signs. Therefore, we would like to emphasize that it is essential to record the Apgar score and perform an umbilical cord artery blood gas analysis at the time of delivery when possible. In conclusion, placental abruption was a factor most associated with low pH. Even among the infants with severe CP, over 10% of patients exhibited a non-acidemic status at birth. Conflict of interest The authors report no conflict of interest. Funding sources The authors report no funding for this study.
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Acknowledgments We thank Mr. Sugimoto for his statistical help.
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Early Human Development journal homepage: www.elsevier.com/locate/earlhumdev
Umbilical arterial pH in patients with cerebral palsy Yoshio Matsuda a,b,⁎, Hikaru Umezaki a, Masaki Ogawa b, Michitaka Ohwada a, Shoji Satoh c, Akihito Nakai d a
Department of Obstetrics and Gynecology, International University of Health and Welfare Hospital, 537-3 Iguchi, Nasushiobara, Tochigi 329-2763, Japan Department of Obstetrics and Gynecology, Tokyo Women's Medical University, Kawada-cho, 8-1, Shinjuku-ku, Tokyo 162-8666, Japan c Maternal and Perinatal Care Center, Oita Prefectural Hospital, Bunyo 476, Oita 870-8511, Japan d Tama-Nagayama Hospital, Nippon Medical School, 1-7-1 Nagayama, Tama-City, Tokyo 206-8512, Japan b
a r t i c l e
i n f o
Article history: Received 22 November 2013 Received in revised form 27 December 2013 Accepted 3 January 2014 Keywords: Cerebral palsy Chorioamnionitis Intraparum hypoxic event Placental abruption Umbilical arterial pH
a b s t r a c t Background: Umbilical arterial pH (UApH) in severe cerebral palsy (CP) is not fully understood. Aims: This work aims to determine the relationship between fetal acidemia and clinical features of severe CP. Study design: A retrospective study design is used. Subjects: A review was conducted unti1 April 2013 among 218 infants with CP diagnosed to be caused by antenatal and/or intrapartum conditions determined by the Japan Council for Quality Health Care. After excluding patients in whom the causes of CP were thought to be due to events after delivery, 168 infants born at over 34 weeks of gestation that both Apgar score and UApH were measured were selected. Outcome measures: Severe fetal acidemia was defined as a pH of less than 7.0. Results: Six major factors were found to be associated with CP: placental abruption (A, n = 42), traumatic delivery with an abnormal FHR pattern (B, n = 29), an abnormal FHR pattern during labor (C, n = 27), chorioamnionitis with an abnormal FHR pattern (D, n = 17), an abnormal FHR pattern before labor (E, n = 14), and cord prolapse (F, n = 10). The UApH was less than 7.0 in 114 cases (67.9%) and more than 7.20 in 20 cases (11.9%). The UApH values were lowest in group A (median 6.7, 6.43–6.99) and highest in group E (7.18, 6.92–7.45). The distribution of the UApH values was significantly different in these groups. Conclusion: Placental abruption was a factor most associated with low pH. Even among the infants with severe CP, over 10% of patients exhibited a non-acidemic status at birth. © 2014 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Although birth asphyxia can be a cause of cerebral palsy (CP), it has been demonstrated in controlled population-based studies that birth asphyxia does not account for most cases of CP [1]. Among term-born children evaluated in a well-planned study of a regional cohort, only one-third had recognized intrapartum asphyxia events that appeared to account for the observed clinical sequence [2]. In the remaining affected infants, despite similarities in clinical features, the causes of CP were not apparent. Pathological acidemia is defined as a pH of less than 7.0. It is an objective measurement of intrapartum hypoxia–ischemia and is correlated with the occurrence of hypoxic ischemic encephalopathy [3]. However, few papers have investigated the relationship between the incidence of CP and the value of umbilical arterial pH (UApH). The Japan obstetric compensation system for CP was established by the Japan Council for Quality Health Care (JCQHC) to compensate for CP
⁎ Corresponding author at: Department of Obstetrics and Gynecology, International University of Health and Welfare Hospital, 537-3 Iguchi Nasushiobara, Tochigi 329-2763 Japan. Tel.: +81 287 39 3060; fax: +81 287 39 3001. E-mail address: [email protected] (Y. Matsuda). 0378-3782/$ – see front matter © 2014 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.earlhumdev.2014.01.001
derived in principle from intrapartum events and improve perinatal care. The present study was performed to determine the associated factors for CP and to evaluate the relationship between fetal acidemia and severe CP among antepartum and/or intrapartum factors using this compensation system for CP. 2. Methods This study was approved by the Ethics Committee of International University of Health and Welfare Hospital, Tochigi, Japan. The Japan obstetric compensation system for CP was launched on January 1st, 2009 to provide rapid monetary compensation for CP [4] certified as first or second degree in severity according to the criteria of the Japanese Social Welfare System [5] in infants with a birth weight of over 2000 g and/or a pregnancy length of over 33 weeks. This system, however, does not cover infants with disabilities apparently due to congenital anomalies in metabolism, chromosomal aberrations, brain malformation, or postnatal factors [4]. Once the parent of a patient with CP applies for compensation, the obstetric facility that treated the applicant must disclose the corresponding medical charts and relevant information at the request of the JCQHC. The decision to provide compensation in each case is made by the JCQHC after a preliminary investigation.
132
Y. Matsuda et al. / Early Human Development 90 (2014) 131–135
Table 1 Clinical characteristics in the 168 cases with severe cerebral palsy.
n
Gestational age (weeks)
Birth weight (g)
median
range
median
range
C/S
Antenatal An abnormal FHR pattern before labor
14
37
(34–40)
2610
(1754–3510)
12
Intrapartum An abnormal FHR pattern during labor Traumatic delivery with an abnormal FHR pattern Placental abruption (before labor) Placental abruption (during labor) Umbilical cord prolapse Ruptured uterus Feto-maternal transfusion Maternal factors Chorioamnionitis with an abnormal FHR pattern during labor
27 29 42 6 10 7 4 4 17
39 40 37 39 40 39 37.5 36.5 39
(35–41) (36–41) (34–41) (37–40) (37–40) (38–41) (36–41) (34–41) (36–41)
2758 3110 2476 2897 3117 3078 2603 3103 3015
(1498–4032) (2012–4110) (1486–3306) (2488–3148) (2543–3582) (2586–3828) (2292–2578) (2350–3962) (2158–3860)
12 6 41 0 9 7 4 3 7
4 4 168
39.5 38 38
(36–40) (35–39) (34–41)
3170 2808 2819
(2190–3990) (2300–3315) (1486–4110)
1 0 102
Perinatal Perinatal infection Uneventful (Unknown cause) Total
complete expulsion of the baby, and perinatal; the timing of the associated factor was uncertain. Second, possible perinatal factors were chosen according to the timing of onset. Sentinel hypoxic event occurring immediately before or during labor were as follows: a ruptured uterus, cord prolapse, placental abruption, amniotic fluid embolism, and fetal exsanguinations due to vasa previa or feto-maternal hemorrhage. Other factors suggesting that CP was caused by an event other than acute intrapartum hypoxia were also listed, as follows: an umbilical arterial base deficit less than 12 mmol/l or pH greater than 7.00, central nervous system or systemic infection, minimal or absent fetal heart rate variability from the onset of labor, major antenatal placental abruption, and extensive chorioamnionitis. The FHR patterns were defined as abnormal when one of the following patterns was detected: persistent late decelerations, minimal or absent variability, severe variable deceleration, prolonged deceleration, or bradycardia [10,11]. These patterns were also used for the assessment of preterm fetuses. Bradycardia was defined as a baseline FHR of less than 100 bpm (N3 min) [10]. Fetal pathological/severe acidemia was defined as a pH of less than 7.0 [11]. The distribution of UApH was graded as follows: less than 7.0
Subsequently, a professional committee of the JCQHC consisting of physicians, midwives, lawyers and citizens carefully investigates the causative factors for CP in each case and publishes a brief summary of the case together with the cause of CP in a form with privacy protection on their website [6]. Researchers can gain access to a more detailed report provided by the committee after receiving approval from the JCQHC [7]. A review was conducted unti1 April 2013 among 218 infants with CP diagnosed to be caused by antenatal and/or intrapartum conditions determined by the JCQHC. All 218 infants were born in or after January 2009, as the compensation system was started on January 2009. In the reports, personal information regarding the date of birth, including year and month, place of birth, and maternal age, was masked for privacy protection. The reports were retrospectively reviewed focusing on clinical backgrounds and causes of CP. The possible factors for CP were classified according to the report by MacLennan (International Consensus Criteria) with modifications [8,9]. First, the timing of the factor was determined as follows: antenatal; if the factor occurred before the onset of labor, intrapartum; if the factor occurred or recurred between the onset of labor and
Table 2 The associated factors and their pH in the 168 cases with severe cerebral palsy. pH n
Grade of pH
Median
Range
Less than 7
7.0–7.19
Over 7.20
Antenatal An abnormal FHR pattern before labor
14
7.18
(6.92–7.45)
3
4
7
Intrapartum An abnormal FHR pattern during labor Traumatic delivery with an abnormal FHR pattern Placental abruption (before labor) Placental abruption (during labor) Umbilical cord prolapse Ruptured uterus Fetomaternal transfusion Maternal factors Chorioamnionitis with an abnormal FHR pattern during labor
27 29 42 6 10 7 4 4 17
6.94 6.78 6.7 6.97 7.05 6.76 6.9 6.66 7.07
(6.57–7.34) (6.55–7.08) (6.43–6.99) (6.69–7.14) (6.56–7.29) (6.48–7.18) (6.83–6.97) (6.51–6.8) (6.8–7.19)
17a 25a 42 4a 4a 5a 4a 4a 6
7 4 0 2 4 2 0 0 11
3 0 0 0 2 0 0 0 0
4 4 168
7.35 7.34 6.9
(7.27–7.42) (7.2–7.39) (6.43–7.45)
0 0 34
4 4 20
Perinatal Perinatal infection Uneventful (unknown cause) total a
Acute intrapartum hypoxic event.
0 0 114
Y. Matsuda et al. / Early Human Development 90 (2014) 131–135
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Table 3 Comparison of statistical differences in UApH among six major factors. Continuous variables Placental abruption before labor Continuous variables Placental abruption before labor Traumatic delivery with an abnormal FHR pattern An abnormal FHR patterns during labor Chorioamnionitis with an abnormal FHR pattern An abnormal FHR pattern before labor Cord prolapse Analysis of variance confirmed by Tukey's test Nominal variables Placental abruption before labor Traumatic delivery with an abnormal FHR pattern An abnormal FHR pattern during labor Chorioamnionitis with an abnormal FHR pattern An abnormal FHR pattern before labor Cord prolapse
Traumatic delivery with an abnormal FHR pattern
An abnormal FHR pattern Chorioamnionitis with an during labor abnormal FHR pattern
1
0.0006
b0.0001
b0.0001
0.0067
0.2081
0.0114
b0.0001
0.254
1
An abnormal FHR pattern Cord before labor prolapse
0.1432
1
1
1 1
0.922
0.011
0.0001
b0.0001
0.003
0.008
b0.0001
0.0434
0.672
0.029
0.786
0.668
1 0.809
Kruscal–Wallis test confirmed by Tukey's test.
(pathological/severe acidemia), between 7.0 and 7.20 (mild to moderate acidemia) and more than 7.20 (normal pΗ). Analysis of variance confirmed by Tukey's test and Kruscal–Wallis test confirmed by Tukey's test were used for statistical analysis, and significant difference was set to at less than 0.05.
3. Results 3.1. Clinical backgrounds of CP in the present study After excluding patients in whom the cause was thought to be events after delivery, 168 infants born at over 34 weeks of gestation [8] that both Apgar score and UApH were measured were selected. The clinical background data of the 168 patients are shown in Table 1. The timing of onset was considered to be antenatal (14 cases, 8.3%), intrapartum (146 cases, 86.9%), or perinatal (8 cases, 4.8%). Cesarean section was performed in 102 cases (60.7%). Six major factors were responsible for CP infants as follows: placental abruption before labor (A, n = 42), traumatic delivery with an abnormal FHR pattern (B, n = 29), an abnormal FHR pattern during labor (C, n = 27), chorioamnionitis with an abnormal FHR pattern during labor (D, n = 17), an abnormal FHR pattern before labor (E, n = 14), and cord prolapse (F, n = 10). Six cases were considered to involve placental abruption during labor. Other maternal sentinel hypoxic events occurring during labor were as follows: a ruptured uterus (seven cases), and fetal exsanguinations due to feto-maternal hemorrhage (four cases). Maternal factors were detected in four cases: two cases of amniotic fluid embolism, one case of maternal cardiac failure and one case of maternal cardiac arrest during endotracheal intubation. Perinatal infection was also detected in four cases: two cases of group B streptococcus, one case of pneumonia, and one case of Coxsackie virus. The remaining four cases were coded as ‘uneventful (unknown cause)’, because no associated factor was identified in the report (Table 1).
3.2. Relationship between UApH and the associated factors in CP The UApH was less than 7.0 in 114 cases (67.9%). Of these cases, 103 (90.4%) were equivalent to acute intrapartum hypoxic events, including maternal sentinel hypoxic event occurring during labor, such as a ruptured uterus, cord prolapse, placental abruption, amniotic fluid embolism, and fetal exsanguinations due to fetal-maternal hemorrhage (Table 2). On the other hand, the pH was more than 7.20 in 20 cases (11.9%). These cases involved an abnormal FHR pattern before labor (seven cases), an abnormal FHR pattern during labor (three cases), umbilical cord prolapse (two cases), perinatal infection (four cases) and an uneventful clinical course (four cases). Statistical differences in UApH among six major factors are shown in Table 3. For continuous variables, analysis of variance confirmed by Tukey's test was used, whereas for nominal variables, Kruscal–Wallis test confirmed by Tukey's test was used. The distribution of UApH was significantly different in these groups (Tables 2, 3) (p b 0.0001). In summary, the UApH values were lowest in group A (median 6.7, range 6.43– 6.99) and highest in group E (7.18, 6.92–7.45). In addition, the UApH in group D (7.07, 6.8–7.19) was significantly higher than that observed in group A (6.7, 6.43–6.99) and in group B (6.78, 6.55–7.08) (Tables 2, 3). 3.3. Relationship between FHR monitoring and UApH in CP FHR monitoring was recorded in 156 cases. An abnormal FHR pattern was observed in 148 cases (94.9%). Prolonged deceleration was observed in 124 cases (95 cases in the severe pH group, 24 cases in the mild to moderate pH group and five cases in the normal pH group), minimal or absent variability was observed in 19 cases (six cases in the severe pH group, seven cases in the mild to moderate pH group and six cases in the normal pH group), recurrent late deceleration was observed in three cases (two cases in the severe pH group and one case in the mild to moderate pH group) and severe variable deceleration were observed in two cases (one case in the severe pH group and one case in the normal pH group).
Y. Matsuda et al. / Early Human Development 90 (2014) 131–135
0 9 (34.6%) 8 (29.6%) 3 (17.6%) 0 2 (25%) 22 (16.8%)
Severe variable deceleration
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Among the acidemic fetuses, an abnormal FHR pattern was observed in all cases. On the other hand, in the normal pH group (n = 20), a reassuring FHR pattern was noted in eight cases (40%). Minimal or absent variability with a normal pH was observed in seven cases (50%) in group E. Table 4 shows abnormal FHR patterns in main causative factors of severe CP. Although minimal or absent variability was seen in all cases in the group of ‘an abnormal FHR pattern before labor’, prolonged deceleration was dominant in most cases.
39 26 27 17 14 8 131 Placental abruption (before labor) Traumatic delivery with an abnormal FHR pattern An abnormal FHR pattern during labor Chorioamnionitis with an abnormal FHR pattern during labor An abnormal FHR pattern before labor Umbilical cord prolapse* TOTAL
Table 4 Abnormal FHR patterns in six major factors of severe cerebral palsy.
n
37 (94.9%) 23 (88.5%) 25 (92.6%) 12 (70.6%) 3 (21.4%) 8 (100%) 108 (82.4%)
Prolonged deceleration
2 (5.1%) 5 (19.2%) 3 (11.1%) 3 (17.6%) 14 (100%) 0 27 (20.6%)
Minimal or absent variability
5 (12.8%) 9 (34.6%) 5 (18.5%) 2 (11.8%) 2 (14.3%) 0 23 (17.6%)
Recurrent late deceleration
4. Discussion The present study investigated the relationship between UApH and severe CP. The UApH values were lowest in the cases involving placental abruption among the associated factors. Moreover, among the severe CP cases, over 10% of patients exhibited a non-acidemic status at birth. MacLenann categorized three essential criteria linking acute intrapartum hypoxia as a possible cause of CP [8] and listed other factors suggesting that CP was caused by an event other than acute intrapartum hypoxia, as follows: umbilical arterial base deficit less than 12 mmol/l or pH greater than 7.00, central nervous system or systemic infection, minimal or absent fetal heart rate variability from the onset of labor, major antenatal placental abruption, and extensive chorioamnionitis. According to these criteria, the frequency of intrapartum hypoxic event was 37.5% (63/168) in this study, which was higher than previously reported rates [12,13]. The severity of CP in the present study may have been higher than that observed in other studies. Kodama et al. reported ten patients with CP who exhibited bradycardia with a nadir b80 bpm and a duration over 13 min, which was significantly elevated with respect to acidemia related CP [9]. We recently demonstrated a significant difference between acidemia and nonacidemia regarding the occurrence of neonatal adverse outcome in cases involving placental abruption [11]. Moreover, fetal acidemia was linked to bradycardia in patients with CP. Several mechanisms have been proposed to explain the association between chorioamnionitis and CP, including an inflammatory cytokine response, placental inflammation leading to impaired placental perfusion and gas exchange and intrauterine infection with bacteremia resulting in the direct involvement of the brain or fever associated with the infection itself, exacerbating the primary insult to the brain [14]. Whether the presence of infection/inflammation, such as that associated with chorioamnionitis, confers an additional risk for CP in term infants delivered in the presence of severe fetal acidosis has not been thoroughly studied. Shalak et al. showed that the presence of histological chorioamnionitis had a poor predictive value and did not confer an additional risk for the subsequent development of neonatal encephalopathy [15]. A single severe exposure, such as uterine rupture or massive abruption, can be sufficient to cause CP; however, much more often it is not a single cause, but rather multiple concurrent risk factors that precede CP. In addition, multiple risk factors markedly increase risk. In the present study, the UApH was 7.07 (6.8–7.19) in the cases involving chorioamnionitis with an abnormal FHR pattern, which was significantly higher than that observed in the cases involving a history of placental abruption or traumatic delivery with abnormal FHR pattern. This finding indicates that brain injury may occur following a lower level of hypoxic stress in the presence of chorioamnionitis. In the present study, even among the severe CP, over 10% of the patients exhibited a non-acidemic status at birth, including those in whom the causes of CP was derived from an abnormal FHR pattern before labor (seven cases), an abnormal FHR pattern during labor (three cases), umbilical cord prolapse (two cases), perinatal infection (four cases) and an uneventful clinical course (4 cases). Although it is very difficult to prove the occurrence of hypoxic event during pregnancy (before the onset of labor), such phenomena have been reproduced in experimental animal models. After the recovery
Y. Matsuda et al. / Early Human Development 90 (2014) 131–135
from the hypoxic insult in utero, cardiovascular parameters return to the same levels observed before the insult if the fetus is able to compensate adequately. We previously showed that induced prolonged sustained hypoxia in fetal lambs in the last third of gestation resulted predominantly in white matter damage with some adjacent cortical necrosis despite the normalization of cardiovascular and biophysical activities and biochemical parameters [16,17]. Ikeda et al. also demonstrated that asphyxia due to partial umbilical cord occlusion in near-term fetal lambs produced variable neuropathologic changes, although the fetuses showed a full recovery in all physiologic parameters [18]. After the normalization of cardiovascular and blood gas status, it has been reported that minimal or absent variability of the FHR represents the first recognized signs of chronic neurological compromise [8]. In the present study, minimal or absent variability was seen in all cases involving an abnormal FHR pattern before the onset of labor (group E) and half of them showed normal UApH. On the other hand, it is well known that abnormal FHR monitoring is often noted in fetuses with congenital malformations [19] or congenital cytomegaloviral infection [20]. In one case, the FHR patterns of 20 anencephalic fetuses showed varying degrees of decreased variability in correlation with the severity of brain defects [21]. These data show that an abnormal FHR pattern is the result of pre-existing CNS disorders; however, a causal relationship with CNS damage has not been established. Our data were not derived from a nationwide population-based cohort, because the essential information was masked for personal protection. Nevertheless, this peer review system in Japan is the best clinically available method. It may be argued that our results reflect bias due to the small sample size; however, we consider this to be unlikely given the low-frequency nature of the cohort. The causes of CP are multifactorial. In addition, it is possible that currently unidentified etiologies will be clarified in future, as diagnostic technology and gene analyses, including radiologic diagnosis, advance [12]. In cases lacking evidence from the fetal umbilical arterial cord, it is not possible to determine whether hypoxia or asphyxia caused CP or contributed to other clinical signs. Therefore, we would like to emphasize that it is essential to record the Apgar score and perform an umbilical cord artery blood gas analysis at the time of delivery when possible. In conclusion, placental abruption was a factor most associated with low pH. Even among the infants with severe CP, over 10% of patients exhibited a non-acidemic status at birth. Conflict of interest The authors report no conflict of interest. Funding sources The authors report no funding for this study.
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Acknowledgments We thank Mr. Sugimoto for his statistical help.
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