A C TA Obstetricia et Gynecologica
AOGS M A I N R E SE A RC H A R TI C LE
Amniotic fluid erythropoietin and neonatal outcome in pregnancies complicated by intrauterine growth restriction before 34 gestational weeks 2 € AL € AINEN € LAURA SEIKKU1, LEENA RAHKONEN1, MINNA TIKKANEN1, ESA HAM , PETRI RAHKONEN3, 3 1 1 STURE ANDERSSON , KARI TERAMO , JORMA PAAVONEN & VEDRAN STEFANOVIC1 1
Department of Obstetrics and Gynecology, Helsinki University Central Hospital, Helsinki, 2Department of Clinical Chemistry, University of Helsinki, Helsinki, and 3Children0 s Hospital, Helsinki University Central Hospital, Helsinki, Finland
Key words Intrauterine growth restriction, amniotic fluid, erythropoietin, timing of delivery, amniocentesis, intrauterine hypoxia, antenatal diagnosis Correspondence Laura Seikku, Department of Obstetrics and Gynecology, University Central Hospital, Haartmaninkatu 2, 00029 HUS, Helsinki, Finland. E-mail: [email protected] Conflict of interest The authors have stated explicitly that there are no conflicts of interest in connection with this article. Please cite this article as: Seikku L, Rahkonen L, Tikkanen M, H€ am€ al€ ainen E, Rahkonen P, Andersson S, et al. Amniotic fluid erythropoietin and neonatal outcome in pregnancies complicated by intrauterine growth restriction before 34 gestational weeks. Acta Obstet Gynecol Scand 2015; 94: 288–294. Received: 13 June 2014 Accepted: 24 November 2014 DOI: 10.1111/aogs.12553
Abstract Objective. High amniotic fluid erythropoietin concentration reflects chronic fetal hypoxia. Our aim was to study amniotic fluid erythropoietin concentration in relation to neonatal outcome in pregnancies complicated by intrauterine growth restriction. Design. Retrospective case series. Setting. Helsinki University Hospital, Finland. Sample. A total of 66 singleton pregnancies complicated by intrauterine growth restriction. Methods. Amniocentesis or amniotic fluid sampling at cesarean section was performed between 24 and 34 gestational weeks. Values of amniotic fluid erythropoietin were quantitated with immunochemiluminometric assay. Normal amniotic fluid erythropoietin was defined as 27 IU/L. Main outcome measures. Adverse neonatal outcome. Results. Abnormal biophysical profile and reversed end-diastolic flow in umbilical artery were associated with abnormal amniotic fluid erythropoietin (p < 0.001 and p = 0.042, respectively). Abnormal amniotic fluid erythropoietin was not associated with absent end-diastolic flow in umbilical artery or with oligohydramnios (p = 0.404 and p = 0.080, respectively). Decreased umbilical artery pH and base excess values were associated with abnormal amniotic fluid erythropoietin (p = 0.027 and p = 0.007, respectively). Composite adverse neonatal outcome defined as intraventricular hemorrhage, periventricular leukomalacia, cerebral infarction and/or necrotizing enterocolitis was associated with abnormal amniotic fluid erythropoietin (p < 0.001). Conclusions. High amniotic fluid erythropoietin concentrations are associated with decreased umbilical artery pH and base excess and with adverse neonatal outcome in pregnancies complicated by intrauterine growth restriction before 34 gestational weeks. In selected pregnancies complicated by intrauterine growth restriction, determining amniotic fluid erythropoietin could be a useful additional tool in fetal surveillance and possibly in optimizing timing of delivery. aEPO, amniotic fluid erythropoietin; BMI, body mass index; EPO, erythropoietin; IUGR, intrauterine growth restriction.
Abbreviations:
Key Message Introduction Intrauterine growth restriction (IUGR) affects up to 10% of pregnancies (1). IUGR is associated with stillbirth, prematurity, intrauterine hypoxia, meconium aspiration
288
Amniotic fluid erythropoietin is a biomarker of fetal hypoxia. In preterm pregnancies complicated by intrauterine growth restriction, increased amniotic fluid erythropoietin concentration may predict adverse neonatal outcome.
ª 2014 Nordic Federation of Societies of Obstetrics and Gynecology, Acta Obstetricia et Gynecologica Scandinavica 94 (2015) 288–294
L. Seikku et al.
and long-term adverse outcome such as cognitive dysfunction and cerebral palsy (1–3). Timing of delivery in preterm pregnancy with severe IUGR is challenging. Many methods are used in surveillance, including biophysical profile and Doppler velocimetry. One of the biomarkers of chronic fetal hypoxia is erythropoietin (EPO) (4). EPO is the primary regulator of erythropoiesis in adults, newborns and fetuses (5). Hypoxia strongly stimulates EPO synthesis, and the EPO concentration in the amniotic fluid correlates well with the fetal plasma EPO concentration (6). During fetal hypoxia the EPO concentration in amniotic fluid increases somewhat more slowly compared with the EPO concentration in fetal plasma (4). Hence even a moderate increase in amniotic fluid EPO (aEPO) concentration may be an early sign of fetal hypoxia (4). High EPO concentration in fetal plasma or amniotic fluid predicts fetal distress in pregnancies complicated by Rh-immunization, diabetes and hypertension with or without IUGR (6–9). The aim of this study was to evaluate aEPO concentrations in relation to neonatal outcome in IUGR pregnancies of 0.3 g/24 h) or severe symptoms in a woman with previously normal blood pressure (12). Ultrasound examinations were carried out by perinatologists. Blood flow characteristics were analysed using the flow velocity waveform of the umbilical artery. The findings of absent or reverse end-diastolic flow were noted if recorded repeatedly. Abnormal biophysical profile was defined as decreased or absent fetal movements and tone in ultrasound examination for the duration of 30 min, oligohydramnios and/or non-reassuring fetal heart rate pattern. Oligohydramnios was defined as amniotic fluid index ≤4 cm. Non-reassuring fetal heart rate was defined as the presence of decelerations or prolonged decrease in short- and long-time variability. Because aEPO concentrations were not normally distributed, unpaired comparisons were performed using the Mann–Whitney U-test. Comparisons of categorical data were made by the chi-squared test and Fisher’s exact test when appropriate. Pearson’s test was used to assess correlations between aEPO and umbilical artery pH and base excess. The receiver operating characteristics (ROC) curves were constructed and areas under the curves (AUC) were determined to evaluate the accuracy of aEPO in predicting adverse neonatal outcome. Probability (p) values
AOGS M A I N R E SE A RC H A R TI C LE
Amniotic fluid erythropoietin and neonatal outcome in pregnancies complicated by intrauterine growth restriction before 34 gestational weeks 2 € AL € AINEN € LAURA SEIKKU1, LEENA RAHKONEN1, MINNA TIKKANEN1, ESA HAM , PETRI RAHKONEN3, 3 1 1 STURE ANDERSSON , KARI TERAMO , JORMA PAAVONEN & VEDRAN STEFANOVIC1 1
Department of Obstetrics and Gynecology, Helsinki University Central Hospital, Helsinki, 2Department of Clinical Chemistry, University of Helsinki, Helsinki, and 3Children0 s Hospital, Helsinki University Central Hospital, Helsinki, Finland
Key words Intrauterine growth restriction, amniotic fluid, erythropoietin, timing of delivery, amniocentesis, intrauterine hypoxia, antenatal diagnosis Correspondence Laura Seikku, Department of Obstetrics and Gynecology, University Central Hospital, Haartmaninkatu 2, 00029 HUS, Helsinki, Finland. E-mail: [email protected] Conflict of interest The authors have stated explicitly that there are no conflicts of interest in connection with this article. Please cite this article as: Seikku L, Rahkonen L, Tikkanen M, H€ am€ al€ ainen E, Rahkonen P, Andersson S, et al. Amniotic fluid erythropoietin and neonatal outcome in pregnancies complicated by intrauterine growth restriction before 34 gestational weeks. Acta Obstet Gynecol Scand 2015; 94: 288–294. Received: 13 June 2014 Accepted: 24 November 2014 DOI: 10.1111/aogs.12553
Abstract Objective. High amniotic fluid erythropoietin concentration reflects chronic fetal hypoxia. Our aim was to study amniotic fluid erythropoietin concentration in relation to neonatal outcome in pregnancies complicated by intrauterine growth restriction. Design. Retrospective case series. Setting. Helsinki University Hospital, Finland. Sample. A total of 66 singleton pregnancies complicated by intrauterine growth restriction. Methods. Amniocentesis or amniotic fluid sampling at cesarean section was performed between 24 and 34 gestational weeks. Values of amniotic fluid erythropoietin were quantitated with immunochemiluminometric assay. Normal amniotic fluid erythropoietin was defined as 27 IU/L. Main outcome measures. Adverse neonatal outcome. Results. Abnormal biophysical profile and reversed end-diastolic flow in umbilical artery were associated with abnormal amniotic fluid erythropoietin (p < 0.001 and p = 0.042, respectively). Abnormal amniotic fluid erythropoietin was not associated with absent end-diastolic flow in umbilical artery or with oligohydramnios (p = 0.404 and p = 0.080, respectively). Decreased umbilical artery pH and base excess values were associated with abnormal amniotic fluid erythropoietin (p = 0.027 and p = 0.007, respectively). Composite adverse neonatal outcome defined as intraventricular hemorrhage, periventricular leukomalacia, cerebral infarction and/or necrotizing enterocolitis was associated with abnormal amniotic fluid erythropoietin (p < 0.001). Conclusions. High amniotic fluid erythropoietin concentrations are associated with decreased umbilical artery pH and base excess and with adverse neonatal outcome in pregnancies complicated by intrauterine growth restriction before 34 gestational weeks. In selected pregnancies complicated by intrauterine growth restriction, determining amniotic fluid erythropoietin could be a useful additional tool in fetal surveillance and possibly in optimizing timing of delivery. aEPO, amniotic fluid erythropoietin; BMI, body mass index; EPO, erythropoietin; IUGR, intrauterine growth restriction.
Abbreviations:
Key Message Introduction Intrauterine growth restriction (IUGR) affects up to 10% of pregnancies (1). IUGR is associated with stillbirth, prematurity, intrauterine hypoxia, meconium aspiration
288
Amniotic fluid erythropoietin is a biomarker of fetal hypoxia. In preterm pregnancies complicated by intrauterine growth restriction, increased amniotic fluid erythropoietin concentration may predict adverse neonatal outcome.
ª 2014 Nordic Federation of Societies of Obstetrics and Gynecology, Acta Obstetricia et Gynecologica Scandinavica 94 (2015) 288–294
L. Seikku et al.
and long-term adverse outcome such as cognitive dysfunction and cerebral palsy (1–3). Timing of delivery in preterm pregnancy with severe IUGR is challenging. Many methods are used in surveillance, including biophysical profile and Doppler velocimetry. One of the biomarkers of chronic fetal hypoxia is erythropoietin (EPO) (4). EPO is the primary regulator of erythropoiesis in adults, newborns and fetuses (5). Hypoxia strongly stimulates EPO synthesis, and the EPO concentration in the amniotic fluid correlates well with the fetal plasma EPO concentration (6). During fetal hypoxia the EPO concentration in amniotic fluid increases somewhat more slowly compared with the EPO concentration in fetal plasma (4). Hence even a moderate increase in amniotic fluid EPO (aEPO) concentration may be an early sign of fetal hypoxia (4). High EPO concentration in fetal plasma or amniotic fluid predicts fetal distress in pregnancies complicated by Rh-immunization, diabetes and hypertension with or without IUGR (6–9). The aim of this study was to evaluate aEPO concentrations in relation to neonatal outcome in IUGR pregnancies of 0.3 g/24 h) or severe symptoms in a woman with previously normal blood pressure (12). Ultrasound examinations were carried out by perinatologists. Blood flow characteristics were analysed using the flow velocity waveform of the umbilical artery. The findings of absent or reverse end-diastolic flow were noted if recorded repeatedly. Abnormal biophysical profile was defined as decreased or absent fetal movements and tone in ultrasound examination for the duration of 30 min, oligohydramnios and/or non-reassuring fetal heart rate pattern. Oligohydramnios was defined as amniotic fluid index ≤4 cm. Non-reassuring fetal heart rate was defined as the presence of decelerations or prolonged decrease in short- and long-time variability. Because aEPO concentrations were not normally distributed, unpaired comparisons were performed using the Mann–Whitney U-test. Comparisons of categorical data were made by the chi-squared test and Fisher’s exact test when appropriate. Pearson’s test was used to assess correlations between aEPO and umbilical artery pH and base excess. The receiver operating characteristics (ROC) curves were constructed and areas under the curves (AUC) were determined to evaluate the accuracy of aEPO in predicting adverse neonatal outcome. Probability (p) values
