Extrauterine growth restriction (EUGR) represents inadequate growth in preterm babies, defined by anthropometric measurements falling below the standard for their postmenstrual age (gestational age plus days of hospitalization). It results from prenatal factors, suboptimal nutrition, and a range of complications, both mild and severe. This condition significantly impacts physical development and neurodevelopmental outcomes.

EUGR typically reflects severe nutritional deficits during the first weeks of life, and its definitions can be categorized as cross-sectional and longitudinal. The cross-sectional definition identifies babies whose weight falls below the 10^th percentile at a given time, irrespective of birth weight. The longitudinal definition, on the other hand, assesses weight loss greater than one standard deviation from birth until a specific time, typically when the baby reaches term postmenstrual age. Studies have shown that longitudinal EUGR is a stronger predictor of long-term neurodevelopmental outcomes compared to the cross-sectional approach. Severe EUGR, especially when assessed cross-sectionally, is linked to continued deficits in height, weight, and body mass index (BMI) throughout childhood.

Additionally, comparing studies on EUGR is complicated by the inconsistent use of growth charts and definitions. Cross-sectional charts, such as the commonly used Fenton chart, may not accurately capture the growth patterns of premature babies adapting to extrauterine life. In contrast, the Intergrowth-21^st charts, which are based on rigorous longitudinal studies, offer a more standardized and health-focused approach, reflecting optimal growth across different populations and ethnicities.

AIM AND OBJECTIVES

Aim of this study was to determine the prevalence of extrauterine growth restriction in preterm neonates and risk factors contributing to it.

Primary Objective

Estimation of the prevalence of extrauterine growth restriction in preterm newborns.

SECONDARY OBJECTIVE

To identify the various risk factors for extrauterine growth restriction.

The incidence of EUGR is significantly higher in very low birth weight (VLBW) and extremely low birth weight (ELBW) babies. Data from neonatal intensive care units (NICUs) globally shows that approximately 30-60% of preterm babies experience growth restriction by discharge, with variations depending on the region and resources available. Risk factors include not only the degree of prematurity but also related issues such as respiratory distress syndrome, infections, and prolonged use of parenteral nutrition. Additionally, socio-economic challenges can further complicate access to advanced neonatal care, affecting growth outcomes in certain populations. -EUGR’s prevalence underscores the need for targeted interventions and research focused on minimizing growth failure rates among vulnerable groups.

Preterm babies are thrust into an extrauterine world before their bodies are fully prepared to handle external sources of nutrition and the rapid growth seen in utero. During late gestation, fetal growth is marked by rapid weight gain and brain development, supported by a steady supply of nutrients through the placenta. Upon birth, however, preterm babies experience disruptions in this growth pattern due to immature digestive systems, limited fat and glycogen stores, and high metabolic demands. Feeding tolerance and gastrointestinal function are often limited, which affects the ability to achieve caloric intake necessary for growth. These physiological challenges are core contributors to the high prevalence of EUGR in this population.

Optimal nutrition is central to combating EUGR in preterm babies. Preterm babies have elevated requirements for protein, fat, calcium and phosphorus compared to full-term babies due to rapid growth demands. However, ensuring these babies receive adequate nutrition is challenging, especially in the early weeks after birth. Parenteral nutrition is often initiated, but achieving a balance in nutrient provision is difficult, as overloading certain nutrients can harm fragile systems.

The transition to enteral nutrition, typically through human milk or specialized formulas, introduces additional complexities. Feeding tolerance, delayed gastric emptying, and the risk of necrotizing enterocolitis (NEC) are prominent issues, making nutrient delivery both challenging and critical.

Parenteral nutrition is a crucial intervention in preventing EUGR in preterm babies in the NICU. By providing essential nutrients directly into the bloodstream, PN supports optimal growth during the critical early days of life when enteral feeding is not feasible. Early initiation of PN, adequate protein and energy provision, and careful tailoring of nutritional requirements are all key components of this strategy. Preventing EUGR through PN is not only important for short-term outcomes, such as growth and weight gain, but also for long-term neurodevelopmental outcomes and overall health. However, while PN is essential, it is equally important to transition to enteral nutrition as soon as possible to promote gut maturation and minimize the risks associated with prolonged parenteral feeding.

Breastfeeding from the first day of life should be encouraged, with human milk fortifiers introduced for very low birth weight babies who fail to gain adequate weight. Addressing the nutritional needs of these babies is essential to prevent EUGR and to support their overall growth and developmental outcomes.

EUGR in preterm babies is multifaceted, involving hormonal imbalances, metabolic stress, and inflammation. Factors such as insulin-like growth factor-1 (IGF-1) are reduced in preterm babies, affecting growth signaling pathways. IGF-1 plays a crucial role in fetal development, especially for tissues such as muscle and bone. Additionally, the preterm body often faces oxidative stress due to a relatively immature antioxidant system, which can inhibit cellular growth. Metabolic dysregulation, including altered glucose and lipid metabolism, further complicates energy storage and tissue formation. Understanding these processes helps clinicians target EUGR by addressing not just caloric deficits but also biochemical imbalances. The prevalence of EUGR and small-for-gestational-age (SGA) classifications varies significantly depending on which growth charts and definitions are used, underscoring the importance of standardized assessment methods. Despite advances in neonatal care, ensuring adequate growth in preterm babies remains a critical challenge for neonatologists. Factors like inadequate nutrition, feeding difficulties, and complications such as respiratory distress, patent ductus arteriosus, sepsis, and bronchopulmonary dysplasia all contribute to the development of EUGR.

Research indicates that babies with EUGR face an elevated risk for various long-term health challenges. Neurologically, inadequate early growth may impair brain development, affecting cognition, motor skills, and behavioral outcomes. There is also evidence linking EUGR to an increased risk of metabolic disorders, such as insulin resistance and obesity, later in life. Cardiovascular health can also be affected, with some studies suggesting a predisposition to hypertension. These findings highlight EUGR’s potential to impact not just immediate health but also lifelong wellness, underscoring the need for effective early management to support better long-term outcomes. Long-term developmental delays and adverse neurodevelopmental outcomes, makes optimal nutrition and growth a key priority in the Neonatal Intensive Care Unit (NICU).

This study aims to evaluate the prevalence of extrauterine growth restriction in preterm newborns, focusing on the need for improved nutritional strategies to enhance growth outcomes.

STUDY DESIGN: This study was a descriptive cohort study.

The study included all preterm newborns admitted to the Government Kilpauk Medical College and Hospital. Data collection for the study spans from December 2022 to June 2024, totalling one year and six months, respectively. This study was conducted at the Government of Kilpauk Medical College and Hospital.

Inclusion Criteria

All preterm newborns delivered at Kilpauk Medical College Hospital were included in the study.

Exclusion Criteria

Preterm newborns with syndromes or major congenital anomalies were excluded from this study.

Sample Size Calculations

Based on a previous study by Karthikeya Makker et al. [45], expected prevalence (p) of 21% and a z- value of 1.96 at a 95% confidence level, with an absolute precision of 5%, the sample size was calculated to be 254. Factoring in a 5% non- responder rate, the final sample size was 270.

This descriptive cohort study assessed all live preterm neonates born at the Government Kilpauk Medical College and Hospital from November 2022 to June 2024. Informed consent obtained from parents before enrolling babies who meet the inclusion criteria. Prior to initiation of the study, ethical clearance was obtained from the Institutional ethics committee.

A standardized proforma containing details of risk factors such as sex, gestational age at birth, small for gestational age (SGA), maternal age, birth order, day of life of achieving full enteral feeds, ventilation status, very low birth weight (VLBW) status, presence of major neonatal illnesses, and duration of hospital stay was filled.

Table 1: Association of EUGR with gestational age

Inference: There exists a statistical significance between EUGR and No with respect to Gestational Age

Table 2: Association of SGA with EUGR

Inference: There exists a statistical significance between EUGR and No with respect to SGA

Table 3: Association of enteral feeds with EUGR

Inference: There exists a statistical significance between EUGR and No with respect to Different classification of Enteral feeds.

Table 4: EUGR association with mechanical ventilation

Inference: There exists a statistical significance between EUGR and No with respect to Mechanical ventilation.

Table 5: EUGR association with placental insufficiency

Inference: There exists a statistical significance between EUGR and No with respect to Placental insufficiency.

Table 6: EUGR association with Pre-eclampsia

Inference: There exists a statistical significance between EUGR and No with respect to Gestational Hypertension/Pre-eclampsia.

EUGR represents a significant clinical challenge commonly observed in Very Low Birth Weight babies (VLBW) [3]. Although only 27.5% of the VLBW babies in this study were Small for Gestational Age (SGA) at birth, 67.2% eventually developed EUGR. This prevalence is consistent with the findings of previous investigations [6, 15]. Growth retardation among VLBW babies can stem from a range of factors, including digestive complications, hormonal irregularities, neurological impairments, and comorbidities affecting nutritional needs [16]. Inadequate nourishment, particularly during the initial weeks after birth, largely contributes to the onset of EUGR.

Our study included a cohort of 270 babies, of whom 85 (31.5%) were diagnosed with Extrauterine Growth Restriction (EUGR) and 185 (68.5%) were not. Our investigation highlighted a male predominance in our cohort, with 160 males and 110 females observed within the cohort.

Analysis of gestational age distribution revealed a significant association with EUGR (p < 0.0001). Among babies born at 28–31 weeks plus 6 days, 73.3% experienced EUGR, compared to 64.1% for those born at 32–33 weeks plus 6 days, and 22.7% for those born at 34–36 weeks plus 6 days. This was also confirmed by Zhao et al. in a retrospective study of 137 babies. Gestational age was a significant risk factor for EUGR (odds ratio [OR] = 0.573, p<0.01). [44] Shan et al. also reported similar findings in a multicenter study, where gestational age was postulated to be a significant risk factor for the development of EUGR. [4]

Regarding Small Gestational Age (SGA) status, there was a significant association with the EUGR (p < 0.0001). Among SGA babies, 88.4% experienced EUGR, whereas only 11.6% did not. Conversely, among non-SGA babies, 11.9% experienced EUGR and 88.1% did not. Multivariate analysis by Zhao et al. confirmed that SGA can act as an independent risk factor for EUGR (odds ratio [OR] = 3.887, p = 0.022).[44] This was also in parallel with the findings of Griffinet al. [3] and Shlomai et al. [2], where the incidence of EUGR was higher in SGA babies.

Maternal age was not significantly associated with EUGR (p = 0.236), with varying percentages across age groups. The order of birth was also not significantly associated with EUGR (p = 0.248). This is consistent with the findings of Clark [1] and Embleton et al. [13].

Adequate nutrition is essential for supporting growth and may play a pivotal role in enhancing postnatal development. The timing of achieving full enteral feeding was significantly associated with EUGR (p< 0.0001). Notably, 62.6% of babies achieving this milestone before the fifth day of life did not experience EUGR, in contrast to 94.4% of those achieving EUGR after more than eight days who did experience EUGR. Although early enteral feeding has been associated with a reduced risk of necrotizing enterocolitis (NEC), the occurrence of complications, including NEC, did not show a significant difference between the groups in this study, contradicting previous study results. Our study report findings similar to those of previous studies, where enteral feeding was promoted as a measure for EUGR reduction. [11, 13-18] [28]

Mechanical ventilation necessity was significantly associated with EUGR (p < 0.0001), as 93.8% of babies requiring ventilation experienced EUGR compared with 27.6% of those who did not require ventilation. Clark et al. reported that the use of assisted ventilation on the first day of life can result in an increased risk of EUGR. [1] [17] However, no other studies have reported such instances as risk factors for EUGR. [14-18]

The EUGR observed in certain critically ill babies could be attributed to feeding intolerance. However, another equally plausible explanation could be elevated metabolic rates due to the severity of illness associated with multiple comorbidities. [8, 11, 16, 30] Major illnesses also exhibited a significant association with EUGR (p < 0.0001), with 87.6% of babies with major illnesses experiencing EUGR, compared to 3.9% of those without major illnesses. The study conducted by Zhao et al. did not report a significant association between illness or comorbidities and the risk of EUGR. [44]

The duration of hospital stay was significantly associated with EUGR (p < 0.0001). Notably, no cases of EUGR were observed among babies with a 1–3-day hospital stay, whereas 92.9% of those with a hospital stay of more than 14 days experienced EUGR. A significant association between hospital stay and EUGR was also reported by Zhao et al., among 137 babies. [44] Clinical Implications:

Identifying significant associations between EUGR and factors such as gestational age, SGA status, timing of achieving full enteral feeds, mechanical ventilation, major illnesses, and duration of hospital stay can aid in risk stratification and targeted interventions for at-risk neonates. Clinicians should prioritise monitoring and nutritional management of preterm babies, especially those with identified risk factors for EUGR, to mitigate adverse outcomes and promote optimal growth and development

This study conducted in Government Kilpauk medical college shows a prevalence of 31.5% EUGR. This prevalence emphasizes the need for targeted intervention to prevent EUGR in preterm babies. EUGR in preterm babies was not only due to inadequate nutrition support but also due to various factors like SGA, timing of achieving full enteral feeds, presence of major illness, duration of mechanical ventilation, duration of hospital stay. Statistical analysis showed association of these factors with occurrence of EUGR, with more incidence in babies with lower gestational age. Babies born between 28 and 31 weeks had the highest EUGR rates (73.3%), followed by those born between 32 and 33 weeks (64.1%) and those born between 34 and 36 weeks (22.7%). Hence extreme preterm babies are more prone to EUGR.

The study emphasizes that optimal and timely nutrition support is required to prevent EUGR. The nutritional support should be individualised and initiated and escalated in a graded manner, taking into account, the feeding pattern, maturity of gut and calorie requirement of the baby.

These optimal approaches prevent feed intolerance and necrotising enterocolitis. In addition to the nutritional strategies these babies should be monitored for growth flattering. The use of human milk fortifiers has given better growth outcomes hence, preventing EUGR.

There has been lot of advancements in neonatal medical care and nutritional support, but still there are challenges in identifying and managing EUGR. One major problem is with the definition of EUGR, which varies across different clinical settings and also the use of various growth charts worldwide further makes the diagnosis of EUGR difficult. Due to lack of standardisation outcomes can’t be compared and standard feeding protocols can’t be followed globally. Another issue is the need for more advanced monitoring tools to assess the nutritional status and growth of preterm babies in real-time. These monitoring tools will make the clinician follow the growth trajectories and identify the changes in the growth parameters. Based on the monitored parameters, nutrition and treatment strategies could be modified. It is necessary to adopt individualized approaches to managing growth in preterm babies.

While the overall goal is to maintain appropriate growth rates, it is equally important to focus on the quality of growth. EUGR is not just an underweight status but also reflects concerns about brain maturation, metabolic regulation and immune regulation. Preterm babies face the risk of both undernutrition and overnutrition. Overnutrition in later life can lead to obesity and metabolic syndrome. A more individualised approach is needed to prevent undernutrition and overnutrition, and also maintaining long term health. Further research is needed to understand the impact of EUGR on long term health, neurodevelopmental outcome, behavioural issues and learning disabilities. Further insights regarding genetic, environmental and social factors that contribute to EUGR is needed. Targeted strategies are needed to prevent EUGR. Providing prenatal care the mother, maintaining proper nutritional status of the mother, defined protocols for feeding pattern in NICU, adequate nutritional support in NICU, early discharge and follow up growth monitoring should be done. Hence, a comprehensive, interdisciplinary approach is needed to manage EUGR. This integrated approach can reduce the prevalence of EUGR and increase the chance of healthy growth and development into adulthood.

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