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

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.Raskauden aikana sikiö elää verrattain vähähappisessa ympäristössä. Normaalin raskauden aikana lukuisat kompensaatiomekanismit varmistavat sikiön riittävän hapensaannin ja hyvinvoinnin. Sen sijaan komplisoituneissa raskauksissa sikiön kroonisen hapenpuutteen riski on suurentunut lisäten sikiökuoleman, kasvuhidastuman, neurologisten kehityshäiriöiden ja pitkäaikaisten terveysongelmien todennäköisyyttä. Näissä raskauksissa optimaalisen synnytysajankohdan määrittely on usein haastavaa, koska tällöin on huomioitava kohdunsisäisen hapenpuutteen, ennenaikaisen synnytyksen, sekä obstetristen toimenpiteiden aiheuttamat mahdolliset haitat. Sikiön hengityskaasujen vaihdon ongelmat raskauden tai synnytyksen aikana johtavat kudosten hapenpuutteeseen ja hiilidioksidin kertymiseen eli asfyksiaan, mikä pitkittyessään väistämättä johtaa aineenvaihdunnalliseen happamuuteen. Maailmanlaajuisesti perinataalinen asfyksia aiheuttaa vuosittain jopa miljoonan vastasyntyneen kuoleman. Asfyksian aiheuttama hypoksis-iskeeminen enkefalopatia voi myös johtaa pysyvään vammautumiseen ja vakaviin neurologisiin kehityshäiriöihin. Keskushermoston suojaamiseen tähtäävät hoitotoimenpiteet - kuten vastasyntyneen viilennyshoito - ovat olennaisesti parantaneet vastasyntyneen vaikean enkefalopatian ennustetta. Sikiön hyvinvoinnin ja istukan toiminnan seurannassa käytetään lukuisia menetelmiä, kuten sikiön sydänäänten monitorointia ja Doppler-ultraäänitutkimuksia. Käytössä olevilla menetelmillä ei kuitenkaan aina pystytä yksiselitteisesti ennustamaan vastasyntyneen epäsuotuisaa lopputulemaa riskiraskauksissa. Vastasyntyneen asfyksiadiagnoosin asetuksen ja keskushermostoa suojaavien hoitojen käynnistämisen aikaikkuna on kapea, eikä kaikkia intensiivistä tehohoitoa tarvitsevia vastasyntyneitä löydetä nykymenetelmien avulla ajoissa. Uusia menetelmiä kaivataan sekä hapenpuutteen riskissä olevien sikiöiden, että intensiivisestä tehohoidosta hyötyvien vastasyntyneiden tunnistamiseen ja ennusteen arviointiin. Erytropoietiini (EPO) on punasolujen muodostumista lisäävä hormoni, jota käytetään myös hapenpuutteen merkkiaineena. Napaplasman ja lapsiveden kohonneet EPO-pitoisuudet liittyvät vastasyntyneen huonoon lopputulemaan. S100B-proteiini on aivokudoksen soluvaurion merkkiaine, jonka pitoisuudet nousevat myös asfyksiaan liittyvien vaurioiden ilmaantuessa. Vasopressiini on elimistön nestetasapainoa ylläpitävä hormoni, jonka eritys lisääntyy monentyyppisissä stressitilanteissa. Kopeptiini on vasopressiini-erityksen sivutuote, jota pidetään potentiaalisena perinataalisen asfyksian ja hypoksis-iskeemisen aivovaurion merkkiaineena. Tutkimuksessamme selvitimme näiden valikoitujen biomerkkiaineiden käyttöä hapenpuutteen riskissä olevien sikiöiden tunnistamisessa, sekä näiden merkkiaineiden käytettävyyttä perinataalisen asfyksian diagnostiikassa ja vastasyntyneen ennusteen arvioinnissa. Lisäksi selvitimme raskauden keston vaikutuksia perinataalisen asfyksian ja pitkäaikaisen neurologisen sairastavuuden esiintyvyyteen täysiaikaisissa ja yliaikaisissa raskauksissa. Sikiön kasvuhidastumaa ennenaikaisissa raskauksissa käsittelevässä tutkimuksessamme (n=66) totesimme kohonneiden lapsiveden EPO-pitoisuuksien liittyvän napavaltimon vakava-asteisiin virtausmuutoksiin, sekä vastasyntyneen alentuneisiin napavaltimon pH- ja BE-arvoihin. Lisäksi kohonneet EPO-pitoisuudet liittyivät vastasyntyneen vakavaan sairastavuuteen, mukaan lukien vaikea-asteiset aivokammioverenvuodot, aivoinfarktit, periventrikulaarinen leukomalasia, sekä nekrotisoiva enterokoliitti (p < 0.001). Matalan riskin täysiaikaisissa ja lasketun ajan ohittaneissa raskauksissa (≥41 raskausviikkoa) (n=93) EPO-pitoisuudet korreloivat raskauden keston kanssa. Näissä raskauksissa emme todenneet yhteyttä lapsiveden EPO-pitoisuuden ja vastasyntyneen huonon lopputuleman välillä. Asfyktisilla vastasyntyneillä (n=140) totesimme selvästi korkeammat kopeptiinipitoisuudet kuin hyväkuntoisilla vastasyntyneillä. Kopeptiinipitoisuudet myös nousivat synnytyksen keston myötä. Rekisteritutkimuksemme asfyksiasta ja neurologisesta sairastavuudesta kattoi 1 138 109 raskautta vuosina 1989 – 2008. Totesimme varhaiseen täysiaikaiseen syntymään (raskausviikoilla 37+0-38+6) liittyvän matalien Apgarin pisteiden, CP-vamman, älyllisen kehitysvammaisuuden, aistitoimintojen vammojen, sekä perinataalikuolleisuuden suurentuneen riskin. Yliaikainen raskaus (≥42 raskausviikkoa) lisäsi matalan syntymä-pH:n, matalien Apgarin pisteiden, sekä älyllisen kehitysvammaisuuden riskiä, mutta ei liittynyt yleiseen neurologiseen sairastavuuteen eikä lisännyt perinataalikuolleisuutta. Johtopäätöksenä totesimme, että tietyissä riskiraskauksissa lapsiveden EPO-pitoisuuden määrittäminen saattaa olla hyödyllinen lisämenetelmä sikiön voinnin ja synnytyksen ajankohdan arvioinnissa. Toisaalta matalan riskin raskauksissa EPO-pitoisuuden määrityksestä ei vaikuttaisi olevan hyötyä edes lasketun ajan ylittämisen jälkeen. Kopeptiini vaikuttaa erittäin lupaavalta vastasyntyneen asfyksian ja hypoksis-iskeemisen enkefalopatian biomerkkiaineelta, joskin kopeptiinin käytettävyys pitkäaikaisennusteen arvioinnissa edellyttää jatkotutkimuksia. Kohorttitutkimuksessamme totesimme varhaiseen täysiaikaisuuteen liittyvän suurentuneen riskin vastasyntyneen sairastavuuteen ja kuolleisuuteen, sekä pitkäaikaiseen neurologiseen sairastavuuteen. Löydös tukee nykyistä hoitosuositusta synnytyksen ajoittamisesta mahdollisuuksien mukaan lasketun ajan tuntumaan. Toisaalta laajassa kotimaisessa kohortissamme yliaikaisuuden vaikutukset lapsen pitkäaikaiseen neurologiseen terveyteen olivat oletettua vähäisemmät

Impact of fetal presentation on neurodevelopmental outcome in a trial of preterm vaginal delivery : a nationwide, population-based record linkage study

Publisher Copyright: © 2021, The Author(s).Purpose: To assess the risk of adverse neurodevelopmental outcomes at the age of four after an attempted vaginal delivery according to the fetal presentation in birth. Methods: This retrospective record linkage study evaluated the risks of cerebral palsy, epilepsy, intellectual disability, autism spectrum disorder, attention-deficit/hyperactivity disorder, and speech, visual, and auditory disabilities among preterm children born after an attempted vaginal breech delivery. The control group comprised children born in a cephalic presentation at the same gestational age. This study included 23 803 singleton deliveries at gestational weeks 24 + 0–36 + 6 between 2004 and 2014. Results: From 1629 women that underwent a trial of vaginal breech delivery, 1122 (66.3%) were converted to emergency cesarean sections. At extremely preterm and very preterm gestations (weeks 24 + 0—31 + 6), no association between a trial of vaginal breech delivery and neurodevelopmental delay occurred. At gestational weeks 32 + 0—36 + 6, the risks of visual disability (aOR 1.67, CI 1.07—2.60) and autism spectrum disorders (aOR 2.28, CI 1.14—4.56) were increased after an attempted vaginal breech delivery as compared to vaginal cephalic delivery. Conclusion: A trial of vaginal breech delivery at extremely preterm and very preterm gestations appears not to increase the risk of adverse neurodevelopmental outcomes at the age of four. In moderate to late preterm births, a trial of vaginal breech delivery was associated with an increased risk of visual impairment and autism spectrum disorders compared to children born in cephalic presentation. A trial of vaginal preterm breech delivery requires distinctive consideration and careful patient selection.Peer reviewe

Congenital anomalies in breech presentation : A nationwide record linkage study

Our study aimed to determine if congenital anomalies are associated with breech presentation at delivery. We conducted a nationwide, retrospective population-based record linkage study and analyzed all singleton births in Finland from 1996 to 2016 using the mandatory health register data collected by the Finnish Institute for Health and Welfare. We compared all major congenital anomalies detected during pregnancy, birth, or the first year of life according to the fetus's presentation at the time of delivery using X-2-square statistic and Student's t test. We adjusted the results for known risk factors for congenital anomalies to estimate adjusted odds ratios and 95% confidence intervals. Fetuses in breech presentation at delivery had an increased risk for congenital anomalies (6.5%) compared with fetuses in cephalic presentation (3.6%), P <.001. Breech presentation was associated with nearly all types of examined congenital anomalies. The strongest associations were observed with congenital deformities of the hip, the central nervous system, the respiratory system, and the musculoskeletal system. Our study supports the theory that breech presentation is, in many cases, a symptom of a fundamental problem in fetal morphogenesis or function. Neonates born in the breech presentation have a higher risk of congenital anomalies and should undergo a postnatal screening.Peer reviewe

Fetofetaalisen transfuusio-oireyhtymän laserhoito

Teema : sikiölääketiede. English summaryPeer reviewe

Amniotic fluid and umbilical cord serum erythropoietin in term and prolonged pregnancies

Objective: Erythropoietin - a hormone regulating erythropoiesis - is a biomarker of chronic fetal hypoxia. High erythropoietin levels in fetal plasma and amniotic fluid are associated with increased risk of adverse neonatal outcome. Since the risk of perinatal morbidity and mortality is increased in pregnancies beyond 41 gestational weeks, we evaluated erythropoietin levels in amniotic fluid and umbilical cord serum in apparently low-risk term (>= 37 gestational weeks) and prolonged pregnancies (>= 41 gestational weeks) with labor induction. Study design: This prospective cohort study comprised 93 singleton pregnancies at 37(+0)-42(+1) gestational weeks, of which prolonged pregnancies numbered 63 (67.7%). Amniotic fluid samples were collected at time of labor induction by amniotomy. Umbilical cord blood samples for evaluation of pH, base excess, and umbilical cord serum erythropoietin were collected at birth. Erythropoietin levels were measured by immunochemiluminometric assay. Normal value of amniotic fluid erythropoietin level was defined as = 27 IU/L. Normal umbilical cord serum erythropoietin was defined as <40 IU/L. Data on maternal pregnancy and delivery characteristics and short-term neonatal outcomes such as Apgar score were obtained from the hospital charts. Associations were calculated using Spearman's rank correlation coefficient. The Chi-square test, Fisher's exact test and the Mann-Whitney U test were utilized to determine differences in the study groups. Results: Amniotic fluid erythropoietin levels correlated with gestational age (r = 0.261, p = 0.012) and were higher among prolonged pregnancies as compared to term pregnancies (p = 0.005). There were 78 (83.9%) vaginal deliveries, and among these erythropoietin levels in amniotic fluid correlated with the levels in umbilical cord serum (r = 0.513, p <0.000). Umbilical cord serum erythropoietin levels correlated with gestational age among vaginal deliveries (r = 0.250, p = 0.027). Erythropoietin levels in amniotic fluid and umbilical cord serum did not correlate with umbilical artery pH or base excess, or other adverse pregnancy outcome. Conclusions: In vaginal deliveries erythropoietin levels in amniotic fluid correlated with the levels in umbilical cord serum. Erythropoietin levels correlated with gestational age, probably due to weakening placental function and relative hypoxemia occurring in advanced gestation. However, in this relatively low-risk study population erythropoietin was not related to adverse delivery outcome. (C) 2018 Elsevier B.V. All rights reserved.Peer reviewe

Comparison of Umbilical Serum Copeptin Relative to Erythropoietin and S100B as Asphyxia Biomarkers at Birth

Background: Birth asphyxia, estimated to account for a million neonatal deaths annually, can cause a wide variety of neurodevelopmental impairments. There is a need to develop new, swift methods to identify those neonates who would benefit from neuroprotective treatments such as hypothermia. Objectives: To examine the utility of cord serum copeptin, a stable byproduct of arginine vasopressin release, as a biomarker of birth asphyxia based on a comparison with 2 biomarkers of hypoxia and brain trauma: erythropoietin and S100B. Methods: The study population consisted of 140 singleton, term neonates: 113 controls and 27 with birth asphyxia (2/3 criteria met: umbilical artery pHPeer reviewe