Klinisk institutt 2

Midtveisevaluering - Siw Helen Westby Eger



The significance of intrauterine growth and fetoplacental circulatory abnormalities for neonatal and long-term outcome in preterm infants

Kandidat: SH Westby Eger1,2, Hovedveileder: K Sommerfelt1,2

1Department of Clinical Science, University of Bergen, Norway

2Department of Pediatrics, Haukeland University Hospital, Norway

Fetuses with low birth weight (BW) caused by prematurity and/or intrauterine growth retardation (IUGR) are at increased risk of perinatal and neonatal mortality. Furthermore, they also have an increased risk of later brain related dysfunctions such as cerebral palsy (CP) and abnormalities in psycho-motordevelopment. Previously it has been difficult to estimate with sufficient precision fetal growth in order to identify IUGR. More recently, high resolution ultrasound and Doppler examinations of fetuses/ placenta in pregnancies with increased risk of IUGR, has made it possible to determine both fetal growth and different measures concerning fetoplacental circulation, with high accuracy. Fetal development and growth depends on sufficient fetoplacental circulation, something that can be assessed by measuring blood flow in, for instance the umbilical artery, middle cerebral artery, or ductus venosus using Doppler. Compromised fetoplacental circulation, assessed by such methods, have, in several studies been associated with increased neonatal mortality and morbidity. A major problem in management of pregnancies complicated by preeclampsia and IUGR is timing of delivery. Too early delivery increases neonatal mortality and morbidity due to immaturity. Too late delivery may harm the fetus through longer time in a non-optimal fetal environment. Information about fetoplacental circulation using Doppler evaluation may provide useful supplementary information when determining the optimal time of delivery. There is, however, still uncertainty concerning which of several Doppler measurements of the fetal circulation that best predicts optimal delivery timing. The main motivation for the present study was to further understanding of the predictive value of such Doppler evaluations for neonatal and long term outcome in at risk pregnancies with preterm delivery or birth.

The aims of the study were; 1. To assess if growth restricted (small for gestational age SGA) extremely preterm infants have excess neonatal mortality and morbidity, and 2. To determine the significance of fetoplacental Doppler parameters for survival, growth and development of premature infants with IUGR or maternal preeclampsia.

The first part of the study was a cohort study of all infants born alive at 22-27 weeks’ post menstrual age in Norway during 1999-2000. Outcomes were compared between those who were SGA, defined as a birth weight <5th percentile for post menstrual age and those who had weights ≥5th percentile. Of 365 infants with post menstrual age <28 weeks, 31 (8%) were SGA. Among infants with post menstrual age <28 weeks, only chronic lung disease (CLD) was associated with SGA status (OR 2.7, 95% CI 1.0 to 7.2). Small for gestational age (GA) infants with post menstrual age 26-27 weeks had excess neonatal mortality (OR 3.8, 95% CI 1.3 to 11), CLD and significantly higher mean number of days (age) before tolerating full enteral nutrition. SGA infants with post menstrual age 22-25 weeks had an excess risk of necrotizing enterocolitis (NEC).

From the same cohort study, prenatal Doppler data were retrospectively collected for liveborn infants with GA <28 weeks or BW <1000 g, born SGA (SGA- BW <5th percentile for GA) or of mothers with preeclampsia but only from the four largest university hospitals in Norway during 1999-2000. Neonatal mortality and morbidities, CP and IQ at 5 years of age were compared for infants with or without absent or reversed end-diastolic flow in the umbilical artery (AREDF).  Of 260 infants, 84 were eligible and 71 of them had sufficient Doppler data. Of these, 38 (54%) had AREDF. Of 33 infants born <28 weeks, 7/19 (37%) with AREDF and none of 14 without AREDF had severe cerebral haemorrhage (SCH) (p=0.01). AREDF was not significantly associated with mortality, other NICU morbidities, CP or reduced IQ. For the 38 infants with GA ≥28 weeks AREDF (19/38) was not associated with adverse outcomes.

The third part of the study was a population based cohort study of all infants of 22^0 - 33^6 weeks’ GA with BW below the 10th percentile for GA and/or maternal preeclampsia born alive in Hordaland County, Norway, during 2003-2007. Fetal circulation was assessed by pulsed Doppler of the umbilical artery (UA), middle cerebral artery (MCA) and ductus venosus (DV). Circulatory compromise was defined in terms of AREDF, MCA pulsatility index (PI) <2.5 percentile for GA (brain sparing) and DV pulsatility index for veins (PIV)  >97.5 percentile. Of 172 eligible infants, 15 were stillborn and two died immediately after birth. Of the remaining 155 infants, Doppler assessments in UA, MCA and DV were available in 127, 125 and 95, respectively. Thirty-six of 127 infants (28%) had AREDF which was associated with increased frequencies of neonatal sepsis and NEC after adjusting for GA (p<0.05), but not neonatal mortality. Brain sparing was not associated with adverse outcome. Abnormal DV PIV was associated with increased risk of neonatal sepsis (p<0.05), but only in combination with AREDF. In stratified analyses these associations were only present when GA was <28 weeks.

The study’s overall conclusions are that extremely preterm SGA infants had excess neonatal mortality and morbidity in terms of NEC and CLD. Furthermore, AREDF was associated with increased morbidity in premature infants born SGA or after preeclampsia, but the risk related to AREDF was low. The findings underscore the importance of gathering more information on associations between fetal circulatory patterns and outcome, especially when elective delivery before 28 weeks’ GA is considered.