Postnatal Growth in a Cohort of Sardinian Intrauterine Growth-Restricted Infants

Recent studies have shown that infants with intrauterine growth restriction (IUGR) undergo catch-up growth during infancy. The aim of our study was to evaluate the postnatal growth in a cohort of IUGR infants born in a tertiary-level Obstetric University Hospital of Northern Sardinia. An observational retrospective study was conducted on 12 IUGR (group A) and 12 control infants (group B) by measuring the anthropometric parameters of weight (W), length (L) and head circumference (HC) from birth to the 3rd postnatal year. At birth, significant differences were found between group A and group B with regard to all the auxological parameters (W, mean 1846.6 versus 3170.8 g, p < 0.0001; HC, 30.1 versus 34.4 cm, p < 0.0001; L, mean 43.4 versus 49.4 cm, p < 0.0001). During the 1st year, 8 of 12 (70%) IUGR infants exhibited a significant catch-up growth in the 3 anthropometric parameters and a regular growth until the 3rd year of follow-up. The majority but not all infants born with IUGR in our series showed significant postnatal catch-up growth essentially during the first 12 months of life. An improved knowledge of the causes of IUGR will help to develop measures for its prevention and individualized treatment.


Introduction
A combination of environmental, genetic, and epigenetic factors, still partially unknown, can be responsible for a condition in which a fetus is unable to reach its genetically determined growth potential: this condition is defined as intrauterine growth restriction (IUGR) [1,2]. The IUGR fetus begins to lose its growth potential during the first trimester of pregnancy, mainly as a result of uterine hypoperfusion often associated with thin umbilical cord [1,2]. The causes can be maternal, fetal, or placental. Preeclampsia, pathologic conditions of the umbilical arteries, maternal smoking, and unbalanced diet are known risk factors of IUGR [3][4][5][6]. It is essential to diagnose IUGR by ultrasound scan before the 28th week of gestation and to monitor its evolution throughout pregnancy. In this regard, Doppler flow measurement of the fetal vessels (namely, umbilical artery, ductus venosus, and middle cerebral artery) has been found to be particularly helpful [7]. The circulatory status of the fetus is assessed especially in the middle cerebral artery, to determine the appropriate timing of delivery, that needs to be neither too early nor too late for a better outcome and prognosis [7,8].
Clinical studies have shown that IUGR is a condition associated not only with an increased perinatal mortality, but also with significant morbidity later in life, including short stature, metabolic syndrome, and neurocognitive impairment [9][10][11]. The "symmetric" form of IUGR, defined by significant reduction of all anthropometric parameters including a small head circumference for gestational age, is associated with a worst prognosis compared to the "asymmetric" form of IUGR, in which the head circumference is within the normal range, and a favorable, complication-free postnatal course is generally observed [12,13]. Among term infants, morbidity and mortality are 5-30-fold higher in low 2 BioMed Research International birth weight infants (LBWI) compared to infants with birth weight within the normal range (10th-90th centile) [12,13]. The postnatal catch-up growth begins as soon as infants move to a more favorable environment and becomes evident during the first months of life. However, not all IUGR infants exhibit a postnatal catch-up growth, likely depending on the underlying causative factor/s and genetic diversity [14].
The present study reports results from a 3-year follow-up of a cohort of Sardinian IUGR infants with special emphasis on the postnatal catch-up growth.

Study Population.
In the year 2013, a total 27 IUGR diagnoses were made among infants born in the Gynecologic and Obstetric Clinic of the University of Sassari, Italy. Gestational age (GA) was defined on the basis of ultrasonographic estimation (Voluson E8 ultrasound system, GE Healthcare, Fairfield CT, USA) performed at the time of the first scan, as recommended (SIEOG Italian guidelines), and at about 20, 28, and 36 weeks' gestation [15]. Distributions of all measurements were similar to previously reported reference cohorts (data not reported). At the 20-week scan, details about medical history and demographic characteristics of the pregnant women were collected retrospectively. At this time, women were also informed about fetal anatomy and biometric measurements, as well as uterine and umbilical artery Doppler flow velocimetry data [15]. Ultrasonographic measurements of fetal biparietal diameter, head circumference, abdominal circumference, and femur length were performed according to standard techniques. The Hadlock equations and reference standard were used to calculate the fetal weight (EFW) centile, and EFW values less than the 10th centile defined the IUGR [15]. At the 36 week scan, pregnant women were informed about previously undiagnosed placenta praevia, severe oligohydramnios, a previously undiagnosed fetal abnormality, or noncephalic presentation [15]. Women were selected for additional, clinically indicated scans in the third trimester of pregnancy as per routine clinical care, using local and national guidelines (e.g., SIEOG guidelines). The indications for cesarean section (CS) included a not reassuring cardiotocography (85%) and a reversed end diastolic flow of umbilical artery at ultrasound evaluation (15%).
As 13 families moved out of the Sassari province and 2 newborns unfortunately deceased, the access to postnatal data was available for 12 IUGR infants (F : M = 8 : 4), enrolled as group A. Twelve term infants with a birth weight greater than 2,500 g (F : M = 8 : 4) were enrolled as a control group (group B). The parents of all the infants enrolled in this study provided informed consent.

2.2.
Methods. This is an observational study conducted by retrospective collection of the measures of weight ( ), length ( ), and head circumference (HC), at birth and at 3-month intervals during the first year, then annually in the second and third years of follow-up ( and ). All values were plotted and recorded in the growth charts as follows: (1) weight to age, (2) length to age, and (3) head circumference to age (Center for Disease Controls, Atlanta, GA, USA).

Statistical Analysis.
Student's -test was used to compare groups, considering significant a value of p < 0.05.

Results
At birth, significant differences were found between group A and group B infants with regard to all anthropometric parameters considered in this study ( , mean 1846.  (Figure 1). However, analysis of data from individual patients revealed that 4 of 12 (30%) IUGR infants (Table 1, A2, A6, A8, and A10) did not exhibit catch-up growth during the first postnatal year with minimal improvement during the second and third years of follow-up ( Figure 1). Categories of centiles for weight, length, and head circumference of IUGR infants at 12 months of life are reported in Tables 2, 3, and 4.
It deserves a note that among those who did not show postnatal catch-up growth, the only IUGR infant born at term (A10, Table 1) was discovered to be affected by the rare Pallister-Killian syndrome, caused by tetrasomy of chromosome 12p which is characterized by facial dysmorphism, rhizomelic limb shortness, and small hands and feet, along with corpus callosum hypoplasia. Moreover, during the postnatal years of follow-up, one of the IUGR preterm infants (A2; GA = 32 + 4; Table 1) showed failure to thrive, and it is currently under pediatric endocrinology evaluation.

Discussion
The majority of IUGR infants in our series showed significant postnatal catch-up growth during the first 12 months of life, and regular growth until 3 years of age.
Several studies in literature have reported on the postnatal catch-up growth in preterm IUGR and SGA infants, but only a few studies exist on term IUGR infants [1,[10][11][12].
One study conducted in North America (USA) on 42 IUGR infants has calculated growth velocity, which was significantly higher in IUGR infants compared to the control group (3.58 kg/m 2 versus 2.36 kg/m 2 ) during the first 12 months of life [13].
Another study, conducted in North Europe on 73 IUGR newborns, found catch-up growth in up to 90% of cases during the first year of life; 7% of infants among those who did not have significant catch-up growth exhibited neurological and cognitive impairment [3].
This study was not a clinical trial and was also limited by both its retrospective, observational design and the small sample size. Even with these limitations of the study, our results further confirm those reported by others. All the term IUGR infants but the one affected by Pallister-Killian syndrome exhibit a catch-up growth. More than half of the preterms IUGR did show also a significant catch-up growth, and it was significantly greater during the first 12 months of life [9].
It was not possible for us to determine for each single case whether maternal or fetal factors played a role in the development of IUGR, as well as the role played by genetic, epigenetic, and environmental factors, or likely the complex combination of multiple factors on the catch-up growth and outcome during the postnatal life.
Interesting, the recent personalized medicine approach through the Newborn Individualized Developmental Care and Assessment Program (NIDCAP) has been the focus of a study conducted on preterm infants born with severe IUGR by a multidisciplinary research working group of Harvard University [16,17]. The NIDCAP was shown to be effective in ameliorating the neurobehavior, electrophysiology and brain structure outcomes compared to IUGR controls [16,17]. At least 2/3 of our IUGR infants required special assistance at the Newborn Intensive Care Unit (NICU). We can therefore speculate that also our infants compromised by severe IUGR who showed postnatal catch-up growth might have had significant benefit from an individualized developmental care approach during NICU stay. Moreover, methods of infant feeding (breast-feeding versus formula feeding) and other nutritional factors (including iron, zinc, and vitamins) might play a critical role in the catchup growth during the first months of life [18,19] and would deserve further, more extensive, investigation.

CS:
Cesarean section EFW: Estimated fetal weight GA: Gestational age HC: Head circumference IUGR: Intrauterine growth restriction : Length LBWI: Low birth weight infants NIDCAP: Newborn Individualized Developmental Care and Assessment Program NICU: Newborn Intensive Care Unit PROM: Premature rupture of the membrane SGA: Small for gestational age VD: Vaginal delivery VLBW: Very low birth weight : W e i g h t .

Conflicts of Interest
The authors declare that there are no conflicts of interest regarding the publication of this paper.