UOG Journal Club: October 2013Perinatal morbidity and mortality in early-onset fetal growth

restriction: cohort outcomes of the trial of randomized umbilical and fetal flow in Europe (TRUFFLE)

C. Lees, N. Marlow, B. Arabin et al. on behalf of the TRUFFLE group.

Volume 42, Issue 4, Date: October 2013, pages 400-408.

Journal Club slides prepared by Dr Katherine Goetzinger

(UOG Editor for Trainees)

Perinatal Morbidity and Mortality in Early-Onset Fetal Growth Restriction:Cohort Outcomes of TRUFFLE

Lees et al., UOG 2013

• There is little data available to guide decision-making for timing of delivery in the early preterm growth-restricted fetus (FGR)

• Currently, physicians must balance the risks of prematurity, intrauterine fetal death (IUD) and chronic fetal hypoxia to determine timing of delivery

• Cardiotocography (CTG) and umbilical artery Doppler studies are currently the most commonly used techniques to stratify fetal risk in cases of FGR

• However, changes in the ductus venosus (DV) Doppler waveform may have a stronger association with neonatal morbidity in early preterm FGR and therefore, impact clinical decision-making

Perinatal Morbidity and Mortality in Early-Onset Fetal Growth Restriction:Cohort Outcomes of TRUFFLE

Lees et al., UOG 2013

Trial of Randomized Umbilical and Fetal Flow in Europe (TRUFFLE)

• A European multicenter study designed to investigate the optimal timing of delivery in preterm FGR based on DV Doppler versus CTG-short term variability (STV)

• Primary outcome: infant development at the age of 2 years

• Long-term follow up is not yet complete; therefore randomization allocation remains unblinded and undisclosed

• Short-term perinatal outcome data from the study cohort is available and may be used to to guide counseling and clinical management of pregnancies complicated by preterm FGR

To explore the association between obstetric characteristics and short-term perinatal outcomes in

women with early-onset preterm fetal growth restriction

What is the length of time from diagnosis to delivery?Which factors are important in prolonging gestation?

What is the risk of severe neonatal morbidity?

Objective

Perinatal Morbidity and Mortality in Early-Onset Fetal Growth Restriction:Cohort Outcomes of TRUFFLE

Lees et al., UOG 2013

Inclusion Criteria •Singleton gestations between 26+0 to 31+6 weeks•FGR: Abdominal circumference <10th percentile + abnormal umbilical artery Doppler studies•Short-term variation on CTG & DV pulsatility index (PI) <95th percentile

Intervention Delivery of the fetus was based on one of three randomization arms•CTG criteria of reduced short-term variation•Early changes in DV waveform (PI >95th percentile)•Late changes in DV waveform (absent or negative A-wave)

MethodologyProspective randomized management trial

Perinatal Morbidity and Mortality in Early-Onset Fetal Growth Restriction:Cohort Outcomes of TRUFFLE

Lees et al., UOG 2013

Primary Outcome•Composite of fetal/postnatal death or any of the following:

• Bronchopulmonary dysplasia (BPD), grade 3/4 intraventricular hemorrhage (IVH), periventricular leukomalacia (PVL), proven neonatal sepsis, necrotizing enterocolitis

Analysis • Association between demographic, clinical, and diagnostic

parameters with the composite endpoint• Univariate and multivariate logistic regression analysis• Interval between inclusion and delivery• Kaplan-Meier analysis

Methodology

Perinatal Morbidity and Mortality in Early-Onset Fetal Growth Restriction:Cohort Outcomes of TRUFFLE

Lees et al., UOG 2013

Perinatal Morbidity and Mortality in Early-Onset Fetal Growth Restriction:Cohort Outcomes of TRUFFLE

Lees et al., UOG 2013

ResultsEligible for study inclusion

(n=542)

Study cohort(n=503)

Antenatal fetal death(n=12)

Not entered into study (n=31)

Incomplete follow up data (n=8)

Composite outcome of death or severe morbidity(n=157)

Neonatal death prior to discharge

(n=27)

Perinatal Morbidity and Mortality in Early-Onset Fetal Growth Restriction:Cohort Outcomes of TRUFFLE

Lees et al., UOG 2013

26-27 wks(n=133)

28-29 wks(n=204)

30-31 wks(n=166)

Total(n=503)

Neonatal Death 12% 5% 1% 6%BPD 27% 7% 1% 10%Proven Sepsis 21% 18% 15% 18%NEC with pneumatosis 3% 2% 0% 1%NEC with perforation 2% 3% 1% 2%IVH Grade 3/4 5% 3% 1% 2%PVL Grade 2/3 2% 1% 1% 1%Intact Survival 49% 71% 82% 69%

Perinatal morbidity & mortality bygestational age at study entry

Perinatal Morbidity and Mortality in Early-Onset Fetal Growth Restriction:Cohort Outcomes of TRUFFLE

Lees et al., UOG 2013

Perinatal morbidity & mortality by gestational age at the Time of Delivery

Babies with the composite outcome were more likely to:

• Be delivered earlier294/7 vs 312/7 weeks

• Have a lower birth weight867g vs 1079g

• Have an Apgar score <715% vs 8%

• Have a lower umbilical artery pH7.23 vs 7.25

Perinatal Morbidity and Mortality in Early-Onset Fetal Growth Restriction:Cohort Outcomes of TRUFFLE

Lees et al., UOG 2013

Determinants of the composite outcome of perinatal death or severe morbidity

Variable OR(95% CI)

Gestational hypertensive morbidity at study entry

1.70(1.11-2.62)

Gestational age at study entry(per week gestation)

0.80(0.65-0.99)

Estimated fetal weight at study entry(per 100 grams)

0.84(0.72-0.99)

Perinatal Morbidity and Mortality in Early-Onset Fetal Growth Restriction:Cohort Outcomes of TRUFFLE

Lees et al., UOG 2013

Interval from study entry to delivery

Women with gestational hypertensive morbidity at study entry had a significantly shorter

median interval from inclusion to delivery

5 days (0.5-49)vs.

13 days (0.5-88)

This duration was associated with the severity of the hypertensive condition

Conclusions

• Early-onset preterm FGR is associated with a low rate of perinatal mortality as well as a low rate of severe short-term morbidity in survivors

• These findings may reflect improvement in both neonatal care and antenatal monitoring in contemporary practice

• Maternal hypertension shortens the interval from diagnosis to delivery and is a major determinant of adverse neonatal outcome

• This highlights the importance of close monitoring of maternal blood pressure and proteinuria once an initial diagnosis of FGR is made

• Data from this study can be used for counseling on short-term outcomes both at the time of antenatal diagnosis of FGR and at the time of delivery

Perinatal Morbidity and Mortality in Early-Onset Fetal Growth Restriction:Cohort Outcomes of TRUFFLE

Lees et al., UOG 2013

• Prospective data collection from the time of diagnosis

• Low loss to follow up rate

• Standardized antenatal surveillance and delivery strategies

• Definition of “genuine” FGR incorporating both fetal size and evidence of feto-placental impairment

Strengths

Perinatal Morbidity and Mortality in Early-Onset Fetal Growth Restriction:Cohort Outcomes of TRUFFLE

Lees et al., UOG 2013

• Outcomes reported for the entire cohort rather than for each intervention arm

• Use of primary composite outcome

• Short-term outcomes only

• Extremely high rate of Cesarean delivery

• Generalizability

Limitations

Discussion Points

Perinatal Morbidity and Mortality in Early-Onset Fetal Growth Restriction:Cohort Outcomes of TRUFFLE

Lees et al., UOG 2013

• What is the appropriate antenatal surveillance strategy in early-onset preterm FGR?

• What is the optimal trigger for delivery in these patients?• How might have the results of this study changed if the reporting of short-

term outcomes was based on randomization arm rather than the entire cohort?

• Considering the extremely high Cesarean delivery rate in this study, what is the optimal mode of delivery in early-onset preterm FGR? Does gestational age alter mode of delivery?

• Can results from this study be generalized to FGR diagnosed at or after 32 weeks?

• Will results from this study change your counseling of patients affected by early-onset preterm FGR?