Biomarkers of intrauterine hypoxia and perinatal asphyxia, and gestational age as predictors of neonatal outcome

Research output: ThesisDoctoral ThesisCollection of Articles


Fetal life occurs in a relatively hypoxic environment. During normal pregnancy, several compensatory mechanisms secure fetal oxygenation and wellbeing. In complicated pregnancies, however, intrauterine hypoxia predisposes the fetus to growth restriction, stillbirth, neurodevelopmental sequelae such as cognitive dysfunction and cerebral palsy (CP), and adverse long-term health impacts. Impairment of respiratory gas exchange—during either pregnancy or delivery—leads to tissue hypoxia, and, if prolonged, to metabolic acidosis and asphyxia. Worldwide, such asphyxia, diagnosed at birth, annually accounts for a million neonatal deaths. Furthermore, neonatal hypoxic ischemic encephalopathy (HIE) originating from perinatal asphyxia may lead to a variety of neurodevelopmental impairments. Therapeutic neuroprotective interventions such as hypothermia have significantly improved the prognosis of severe neonatal encephalopathy. Increased risk for intrauterine fetal hypoxia and perinatal asphyxia occur in various circumstances and pregnancy complications—such as intrauterine growth restriction (IUGR), which affects up to 10% of pregnancies. Timing the delivery in preterm pregnancy with severe IUGR is challenging, owing to balancing between risks related to prematurity and to fetal hypoxia. Another obstetric challenge concerns timing of delivery as well: Neonatal outcomes vary by gestational age also among term pregnancies. In pregnancies beyond 41 gestational weeks, the risk for perinatal morbidity and mortality increases, probably due to the relative insufficiency of the aging placenta. Numerous methods such as fetal Doppler assessments and computerized cardiotocography help in monitoring placental function and fetal wellbeing. These methods, however, are not unequivocally efficient in predicting adverse neonatal outcomes in IUGR or in prolonged pregnancies. Furthermore, the time window for neuroprotective treatment in birth asphyxia is narrow, and additional methods for identifying those neonates who would benefit from neuroprotective actions are essential. We thus searched for biomarkers identifying those fetuses at risk for hypoxia-caused complications, and for predicting outcome after birth asphyxia. Erythropoietin (EPO) is a biomarker of chronic hypoxia, with high levels of EPO associating with increased risk for adverse outcome. S100B is a biomarker of brain- cell damage, and its levels rise in early phases of acute asphyxia. Copeptin, a by-product of arginine vasopressin (AVP) production, is a potential biomarker of birth asphyxia and HIE. Additionally, we aimed to evaluate the association of gestational age with perinatal asphyctic complications and long-term neurologic morbidity. The biomarker studies (I-III) were conducted in the University Hospital of Helsinki, Finland. Data on maternal pregnancy and delivery characteristics, and short-term neonatal outcomes such as Apgar score, originated from hospital charts. The study populations comprised 66 pregnancies complicated by preterm IUGR, 93 low-risk term and prolonged pregnancies, and 140 term neonates with birth asphyxia. Amniotic fluid samples for EPO evaluations we obtained by amniocentesis, at cesarean section, or vaginally at amniotomy. Umbilical serum plasma samples for EPO, copeptin, and S100B assessments we collected at birth. Biomarker levels in amniotic fluid and umbilical plasma samples we measured by immunoassays. Normal amniotic fluid EPO levels we defined as <3 IU/L, with abnormal levels exceeding 27 IU/L. We considered as normal umbilical plasma EPO levels below 40 IU/L. The register-based cohort study on asphyxia and neurologic morbidity (IV) comprised 1 138 109 women with singleton pregnancies and their newborns between 1989 and 2008 in Finland. The Finnish Medical Birth Register (MBR), maintained by the National Institute for Health and Welfare (THL), provided data for this study. Statistical analyses we performed with the Statistical Package for Social Sciences (SPSS, Chicago, IL, USA), GraphPad Prism 6 and SAS version 9.3 (SAS Institute, Inc, Cary, NC, USA). All tests were two-sided, with probability (p) values of <0.05 as statistically significant. In IUGR pregnancies, abnormal amniotic fluid EPO levels were associated with decreased umbilical artery pH and base excess (BE) values, abnormal biophysical profile, and reversed end-diastolic flow in the umbilical artery. Most importantly, such abnormal EPO levels were associated with composite adverse neonatal outcomes defined as intraventricular hemorrhage, periventricular leukomalacia, cerebral infarction, or necrotizing enterocolitis (p <0.001). In low-risk term and postterm pregnancies, EPO levels in amniotic fluid and in umbilical serum correlated with gestational age. Furthermore, EPO levels in amniotic fluid correlated with the levels in umbilical serum, even after vaginal delivery. Among low-risk pregnancies, however, EPO levels correlated with neither umbilical artery pH or BE, nor with other adverse pregnancy outcomes. In our study on biomarkers in birth asphyxia, only copeptin correlated with arterial pH. Its correlation with umbilical artery BE was significantly stronger than were the correlations of S100B or of EPO. Copeptin levels, significantly higher among neonates with birth asphyxia, we demonstrated to increase as a function of labor duration. In the cohort study, multivariate analysis demonstrated an increased risk for low (<4) one- and five-minute Apgar score, CP, intellectual disability, sensorineural defects, and perinatal mortality among early-term births. Postterm birth resulted in increased risk for low one- and five-minute Apgar scores (<4), low umbilical artery pH ≤ 7.10, and intellectual disability, whereas risks for CP, epilepsy, sensorineural defects, and perinatal mortality showed no increase. In conclusion, among preterm IUGR pregnancies, high amniotic fluid EPO levels were associated with decreased umbilical artery pH and BE, and with adverse neonatal outcomes. In selected risk-pregnancies, determining amniotic fluid EPO may thus be a useful additional tool in fetal surveillance and in optimizing delivery timing. In term pregnancies, EPO levels correlated with gestational age, probably explained by advancing gestation resulting in weakening placental function and relative hypoxemia. Among low-risk populations, however, EPO was not related to adverse delivery outcomes, and thus may not prove clinically useful in such populations. Furthermore, in cases of acute birth asphyxia, S100B and EPO as biomarkers may not prove valid. In contrast, copeptin has potential for routine use as a biomarker for acute birth asphyxia and neonatal distress. Future studies should determine the correlation of biomarker levels at birth with severity of HIE and with long-term neurological outcome following birth asphyxia. Concerning gestational age at birth, we found an increased risk for low Apgar score, increased neurologic morbidity, and perinatal mortality among early-term neonates. Among postterm births, the risk for birth asphyxia was increased. The long-term neurologic health impacts of postterm birth, however, were less important than previously expected, meaning that further studies on the optimal management of pregnancies beyond 41 gestational weeks are essential
Original languageEnglish
  • Stefanovic, Vedran, Supervisor
  • Rahkonen, Leena, Supervisor
Award date24 Jan 2020
Place of PublicationHelsinki
Print ISBNs978-951-51-5755-3
Electronic ISBNs978-951-51-5756-0
Publication statusPublished - 2020
MoE publication typeG5 Doctoral dissertation (article)

Bibliographical note

M1 - 119 s. + liitteet

Fields of Science

  • Asphyxia Neonatorum
  • +complications
  • +diagnosis
  • Fetal Hypoxia
  • Hypoxia-Ischemia, Brain
  • Infant Health
  • Acidosis
  • Amniotic Fluid
  • Biomarkers
  • Erythropoietin
  • Fetal Growth Retardation
  • Gestational Age
  • Glycopeptides
  • Morbidity
  • Perinatal Mortality
  • Pregnancy Outcome
  • Pregnancy, Prolonged
  • Premature Birth
  • Prenatal Exposure Delayed Effects
  • S100 Calcium Binding Protein beta Subunit
  • Vasopressins
  • 3123 Gynaecology and paediatrics

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