International gestational age-specific centiles for umbilical artery Doppler indices: a longitudinal prospective cohort study of the INTERGROWTH-21st Project.
Drukker L., Staines-Urias E., Villar J., Barros FC., Carvalho M., Munim S., McGready R., Nosten F., Berkley JA., Norris SA., Uauy R., Kennedy SH., Papageorghiou AT.
BACKGROUND: Reference values for umbilical artery Doppler indices are used clinically to assess fetal wellbeing. However, many studies that have produced reference charts have important methodological limitations, and these result in significant heterogeneity of reported reference ranges. OBJECTIVES: To produce international gestational age-specific centiles for umbilical artery Doppler indices based on longitudinal data and the same rigorous methodology used in the original Fetal Growth Longitudinal Study (FGLS) of the INTERGROWTH-21st Project. STUDY DESIGN: In Phase II of the INTERGROWTH-21st Project (the INTERBIO-21st Study), we prospectively continued enrolling pregnant women according to the same protocol from three of the original populations in Pelotas (Brazil), Nairobi (Kenya) and Oxford (UK) that had participated in FGLS. Women with a singleton pregnancy were recruited at <14 weeks' gestation, confirmed by ultrasound measurement of crown-rump length, and then underwent standardized ultrasound every 5±1 weeks until delivery. From 22 weeks of gestation umbilical artery indices (Pulsatility Index, Resistance Index and Systolic/Diastolic Ratio) were measured in a blinded fashion, using identical equipment and a rigorously standardized protocol. Newborn size at birth was assessed using the international INTERGROWTH-21st Standards and infants had detailed assessment of growth, nutrition, morbidity and motor development at 1 and 2 years of age. The appropriateness of pooling data from the three study sites was assessed using variance component analysis and standardized site differences. Umbilical artery indices were modeled as functions of the gestational age using an exponential, normal distribution with second-degree fractional polynomial smoothing; goodness of fit for the overall models was assessed. RESULTS: Of the women enrolled at the three sites 1629 were eligible for this study, 431 (27%) met the entry criteria for the construction of normative centiles, similar to the proportion seen in the original fetal growth longitudinal study. They contributed a total of 1243 Doppler measures to the analysis; 74% had three measures or more. The healthy low-risk status of the population was confirmed by the low rates of preterm birth (4.9%), and pre-eclampsia (0.7%). There were no neonatal deaths and satisfactory growth, health and motor development of the infants at 1 and 2 years of age were documented. The only a very small proportion (2.8-6.5%) of the variance of Doppler indices was due to between site differences; in addition standardized site difference estimates were marginally outside this threshold in only one of xx comparisons, and this supported the decision to pool data from the three study sites. All three Doppler indices decreased with advancing gestational age. The 3rd, 5th 10th, 50th, 90th, 95th and 97th centiles according to gestational age for each of the three indices are provided, as well as equations to allow calculation of any value as a centile and z-scores. The mean Pulsatility Index (PI) according to gestational age (GA) = 1.02944 + 77.7456*GA-2 - 0.000004455*GA3. CONCLUSIONS: We present here international gestational age-specific normative centiles for umbilical artery Doppler indices produced by studying healthy, low-risk pregnant women living in environments with minimal constraints on fetal growth. The centiles complement the existing INTERGROWTH-21st Standards for assessment of fetal wellbeing.