Intrauterine growth restriction can be caused by a number of conditions but pregnancy induced hypertension and vascular disorders of the placenta are among the most common etiologies responsible for about 25-30% of IUGR [1]. Although the incidence of IUGR is about 8% in the Western world [2], the prevalence in the developing world is much higher at ~35% [3].

Parents of 238 very low birth weight (VLBW) infants (<1500 gm birth weight) and gestation <35 weeks born consecutively between the periods January 2007 to December 2008 at our referral perinatal center were prospectively approached for informed consent for enrolment at admission into the NICU. Infants with major congenital malformations were excluded. Gestational age was determined by a first trimester ultrasound scan, or by the mother’s last menstrual period. Antenatal umbilical artery Doppler flows (Voluson, Philips and Logic Q machines) were measured in pregnant women less than 35 weeks of gestation and reported as forward, absent or reversal of flow during diastole. The indications for Doppler studies were (a) evidence of growth restriction on serial scans (based on Mediscan charts, Chennai [15]), (b) pregnancy induced hypertension, and (c) history of intrauterine death in a previous pregnancy. The umbilical artery Doppler velocimetries reported in the study were those obtained closest to delivery. The study population was divided into two cohorts viz., AREDF group comprising VLBW infants with absent or reversed end-diastolic flow velocities in the umbilical artery; and FEDF group with VLBW infants with forward Doppler flow velocity in umbilical artery and those in whom antenatal Doppler studies were not indicated.

The primary outcomes included: Composite outcome of death or major neuro-morbidity at 12-18 months of corrected age, defined as presence of cerebral palsy or visual or hearing impairment. The secondary outcomes included morbidities common in preterm infants. The diagnosis of cerebral palsy was made by clinical examination by experienced physicians blinded to the antenatal Doppler studies. Hearing impairment was defined as any degree of hearing loss requiring the need for hearing aids.

The antenatal details of study infants were collected retrospectively from a computerized database and patient medical records. All enrolled infants were followed up weekly/biweekly till they were 40 weeks of corrected postmenstrual age, and then at 3,6,9,12 and 18 months of corrected age for growth and neurological assessment in the high-risk neurodevelopmental follow-up clinic. At 40 weeks of corrected postmenstrual age, each infant had a cranial ultrasound and a brain stem evoked response audiometry. Growth was evaluated by measuring the weight, head circumference and length by a trained nurse and plotted on the Indian Academy of Pediatrics growth charts. Neurological assessment was done by experienced physicians using the Amiel-Tison method [16]. All measurements were performed by investigators blinded to antenatal studies.

Statistical analysis: Outcome variables were compared between the study and the control groups. Statistical analyses were performed by using SPSS (Version 16.0 for Windows, SPSS Inc., Chicago, IL) followed by the R package (Version 13.2.1). Fisher’s exact test was used for categorical variables and for continuous variables the student t-tests (normally distributed data) or Mann-Whitney U tests (data not distributed normally) were used. Significance was accepted at P<0.05. For multivariate analyses, initial exploration of associations were performed using classification tree and random forest methodology (not reported). Based on the initial exploratory analysis, several responses were modeled as predictors of outcome of interest. The odds ratio of a predictor adjusted for the presence of the other predictors along with 95% confidence interval is reported.

We estimated that a sample size of 88 patients in each group would provide 80% power at 95% confidence level to detect a 4-fold difference in risk of the primary outcome (death or major neuromorbidity) between the groups.

238 VLBW infants fulfilled the eligibility criteria. Of these, 220 infants were analyzed for short-term outcomes. Long-term outcomes were evaluated in 181 infants for growth and neurological outcomes (Fig. 1). Compared to the AREDF group, more infants in the FEDF group were lost to follow up (3.3% vs 18.6%, P=0.001).

Fig. 1 Study flow chart.

Although the degree of prematurity did not differ, the infants in the AREDF group were smaller compared with FEDF group. Expectedly, more infants in the AREDF group were growth restricted at birth. Delivery by Caesarean section, and oligohydramnios was significantly higher in the AREDF group compared with the FEDF group. (Table I).

TABLE I Baseline Characteristics of Study Infants

Short-term outcomes: More infants had hospital deaths in the AREDF group compared to the FEDF group (Table II). Need for resuscitation at birth was similar between the groups, but the incidence of respiratory distress syndrome (RDS) was higher in the AREDF vs FEDF group. There was a tendency to need more respiratory support in the AREDF vs FEDF group. However both the groups were comparable for morbidities such as patent ductus arteriosus, neonatal jaundice, chronic lung disease, and retinopathy of prematurity.

TABLE II Short-term Outcome of Study Infants

Of the 17 infants with abnormal cranial ultrasounds in the AREDF group, leucomalacia and the others had grade III-IV intraventricular hemorrhage (Table II).

Long term outcomes: The odds for the combined outcome of death or cerebral palsy (n=18,17% vs n=4, 3%, OR 5.9, 95% CI 1.9 to 25) was 5.9 times higher in the AREDF group compared to the FEDF. Also AREDF infants showed a trend toward higher risk for developing cerebral palsy compared to the FEDF infants (n=6,7% vs n=1,1%: P=0.06). None of the infants in either group were blind or had deafness. There were also no differences between the groups in the incidence of microcephaly, short stature or poor weight gain.

On logistic regression analysis for the short-term outcomes after adjusting for ELBW (birth weight<1000g) and IUGR status, AREDF continued to have an independent association with neonatal mortality (OR 9.8, 95% CI 2.1- 46.4) and RDS (OR 2.4, 95% CI,1.1-5.0). For the long-term outcomes, AREDF had an independent association with the composite outcome of death or cerebral palsy (OR 8.4, 95% CI 2.3- 30.5) but not cerebral palsy or microcephaly alone.

To better capture the contribution of AREDF in neonatal outcomes, we examined all predictors of bad outcome in the NICU. Since there were very few cases of chronic lung disease in this population, bad outcome was defined as death or cystic periventricular leukomalacia, or culture positive sepsis or necrotizing enterocolitis. The only predictors that were significant were birthweight (P=0.01) and Doppler flow status (P=0.05). To better model the relationship between the predictors and bad outcome as a response, a logistic regression curve of the probability of bad outcome as a function of birth weight adjusted for AREDF or FEDF was fitted (Fig. 2). The preterm infants in the AREDF group had a consistently higher probability of a bad outcome compared to the FEDF group with the disadvantage being more pronounced at lower birth weights.

Fig. 2 Relationship between birth-weight, umbilical Doppler flow patterns and outcome. Bad outcome (defined as death or periventricular leukomalacia, or culture positive sepsis or necrotizing enterocolitis); AREDF: Absent/reversed end-diastolic unbilical artery doppler flow; FEDF: Forward end-diastolic flow.

In this cohort of moderately preterm infants with a history of fetal growth restriction or exposure to pre-eclampsia, demonstration of antenatal absent or reversed end-diastolic flow in the umbilical artery was shown to increase the risk for neonatal death. This study was specifically designed to prospectively compare outcomes after AREDF vs FEDF, the gestational ages between the groups were comparable, and the numbers of infants were relatively large permitting meaningful comparisons. We evaluated both short-term and long-term outcomes comprehensively with follow-up rates in excess of 90%, all infants were enrolled in a 2-year time-span from a single-perinatal center minimizing the confounding of changing or differing management practices on the outcomes, and the groups were relatively homogenous in that the underlying diagnosis was PIH in a great majority. To our knowledge, the present study is the largest and the most comprehensive report on the contribution of abnormal Doppler flow patterns, and IUGR to outcomes in Indian preterm infants.

The higher neonatal mortality and morbidity in infants with history of AREDF noted in this study is similar to previous studies [17-21]. In comparison with these older studies, we had higher numbers of infants with absent or reversed end-diastolic flow and the gestational ages in both the groups were comparable. Consistent with the reported literature, findings from the present study confirm that birthweight and gestational age are more potent predictors of short-term adverse neonatal outcomes in infants with IUGR, compared to Doppler flow patterns. Interestingly, our data clearly demonstrated that despite birth weight being a potent predictor of poor neonatal outcomes, the diagnosis of AREDF had an independent adverse impact at all birth weights with a more pronounced effect at lower birth weights.

The variables of birthweight, gestation, IUGR and Doppler flow patterns are inevitably interlinked. In this regard a randomized trial (GRIT trial) evaluated trade-offs between immediate vs. delayed delivery in the management of preterm infants ~28 weeks gestation with fetal growth restriction [29]. The immediate delivery group had higher neonatal deaths but the stillbirth rate was higher in the delayed group. Adverse neurological outcome at 2 years was more common in the earlier delivery group, but these handicaps did not persist at school age [23,24]. The prevalent practice at our study site is to give maternal glucocorticoids and deliver infants within 48 hours after demonstration of absent/reversed end-diastolic flow, similar to the early delivery arm of the GRIT trial. Despite the immediate delivery, fetuses with AREDF had an increased mortality and morbidity in our study, suggesting that the umbilical Doppler changes may be a late finding in the pathophysiology of fetal compromise in IUGR and pre-eclampsia [27]. Alternatively, the fetuses in our study may have been sicker than previously reported. Regardless, the findings are informative for clinicians managing these high risk pregnancies .

Despite several strengths of our study, some weaknesses were apparent. The study population was entirely from a large referral perinatal center with a higher rate of IUGR and pre-eclampsia than the general population. Lost to follow up was significantly higher in the forward flow group. The study was not randomized. Therefore the findings of the study may not be generalizable. We did not evaluate multiple different ultrasound measurements of fetal well-being, because umbilical artery doppler studies are the most commonly used modality at most perinatal centers dealing with high risk pregnancies.

In a cohort of moderate preterm delivery with IUGR or maternal pre-eclampsia, absent or reversed end diastolic umbilical arterial blood flow independently increased the risk for neonatal mortality, and had a trend towards increased incidence of cerebral palsy at 12-18 months corrected age.

Acknowledgements: Professors Alan H. Jobe (Cincinnati) and John P. Newnham (Perth) for review of the manuscript and helpful suggestions.

Contributors: All the authors have written, designed and approved the study.

Funding: NIH HD-57869 to SGK;

Competing interests: None stated.

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