REVIEW ARTICLE

https://doi.org/10.5005/jp-journals-11002-0019
Newborn
Volume 1 | Issue 1 | Year 2022

Extra-uterine Growth Restriction in Preterm Infants

Nitasha Bagga1, Nalinikant Panigrahay2, Akhil Maheshwari3

1,2Rainbow Children’s Hospital and Birthright, Hyderabad, Telangana, India

3Global Newborn Society, Clarksville, Maryland, United States of America

Corresponding Author: Nitasha Bagga, Rainbow Children’s Hospital and Birthright, Hyderabad, Telangana, India, e-mail: nitashabagga@gmail.com

How to cite this article: Bagga N, Panigrahay N, Maheshwari A. Extra-uterine Growth Restriction in Preterm Infants. Newborn 2022;1(1):67–73.

Source of support: Nil

Conflict of interest: None

ABSTRACT

Extra-uterine growth restriction (EUGR) is frequently seen in premature and critically ill infants. Even though advancements in neonatal intensive care have improved the survival of these high-risk infants, many new questions have emerged about the relationship between postnatal growth and neurodevelopmental outcome of these infants. EUGR has traditionally been ascribed to caloric restriction during postnatal periods of critical illness. Nutritional compromise, particularly during the first few weeks of life, may affect the overall growth and could also cause long-term neurodevelopmental impairment. The accidental and premature interruptions of pregnancy could also alter the normal mobilization and utilization of major nutrients from the ways that would have otherwise occurred during the last trimester of pregnancy, which is normally a period of maximal in utero growth. In this article, we review our current understanding of defining EUGR, various risk factors for EUGR, its pathophysiology, and possible ways with which our current healthcare protocols could prevent EUGR.

Keywords: Development, Growth restriction, IUGR, Premature, Skeletal.

KEY POINTS

  1. Premature and critically ill infants often develop extra-uterine growth restriction (EUGR). In this article, we reviewed the risk factors, definitions, assessment of severity, and management of EUGR, and the likelihood of its association with altered neurodevelopmental outcome.

  2. We have briefly reviewed the association between changes in weight and skeletal parameters (skull growth, length).

  3. Chronic illnesses such as bronchopulmonary dysplasia, necrotizing enterocolitis, chronic liver disease, and cardiac conditions such as patent ductus arteriosus can alter postnatal growth.

  4. EUGR is usually secondary to chronic neonatal illnesses, but it may be a primary condition needing nutritional, medical, and genetic evaluation in some infants.

INTRODUCTION

Extra-uterine growth restriction (EUGR) is a “Nutritional Emergency” in preterm and critically ill term infants, which can arise from multiple clinical pathways and remains a challenge (Fig. 1). This term was first used in literature in 1982 by Hack et al. where weight <−2 Z scores at term gestation was used to define EUGR.1 Subsequently, a few more groups were defined to have EUGR if their postnatal weight was <2 SD or <10th centile at 36 weeks or at discharge.2,3

Fig. 1: Possible risk factors of EUGR (Extra-uterine Growth Restriction)

Poor weight gain and EUGR have been associated with adverse medium- and long-term clinical outcomes. For instance, many studies have identified an association of poor in-hospital growth, whether it be in terms of weight gain,4–6 length,7,8 or head circumference,4–6,9,10 with developmental delay. Even though causality remains unclear, these associations need study. The EUGR in some of the sicker infants could be rooted in feeding intolerance or in iatrogenic ultra-cautious provision of calories, but an alternative, equally valid explanation could also be in increased metabolic rates due to high severity of illness related to multiple comorbidities.4,11–13 There are questions on whether education and course correction in nutrition could fully restore growth and prevent EUGR in the first scenario. We also do not know whether hyperalimentation in critically ill infants can, at least partially, mitigate the effects of increased metabolic rates and enable both weight gain and skeletal growth. Further study is needed before we can confidently tailor the nutritional strategies without adverse metabolic changes. We also need information to identify infants who are likely to respond to hyperalimentation.14–16

We need better definitions of EUGR. A recent review questioned the concept of defining EUGR based on only weight <10th centile at 36–40 weeks or at discharge.17 In this article, we have extended this discussion and have included weight, skeletal, and cranial growth; modifiable and non-modifiable clinical associations; and the determinants of intrauterine growth. We also describe potential remedies to improve EUGR and the growth potential of these infants.

DEFINING EUGR

An accurate definition of EUGR is needed. As evident in literature, most of the studies defined EUGR based on weight at one point of time. It is important to appreciate that there is always biological variation in size of preterm infants; genetic determinants; social determinants; ante-, peri-, and postnatal morbidities; and inadequate nutritional support affecting the growth.17 With the evident literature, EUGR can be classified on the basis of consensus statement18 and also described by Fenton et al. in their recent review17 as “Identifying malnutrition in preterm and neonatal population-recommended indicators ” of defining malnutrition in preterm infants. These classifications are shown in Table 1.

Table 1: Classification of EUGR
Criteria Mild EUGR Moderate EUGR Severe EUGR When to apply
1. Weight-for-age Z scoresa Decline of 0.8–1.2 SD Decline of >1.2–2 SD Decline >2 SD Not appropriate for first 2 weeks of life
2. Weight gain velocityb <75% of expected weight gain for that particular age <50% of expected weight gain for that particular age <25% of expected weight gain for that particular age Not appropriate for first 2 weeks of life
3. ≥2 of the following:        
• Length-for-age Z scoresa Decline of 0.8–1.2 SD Decline of >1.2–2 SD Decline >2 SD Not appropriate for first 2 weeks, after that can be used in conjunction with other parameters if accurate length measurement is available Preferred for first 2 weeks of life
• Length gain velocityb <75% of expected weight gain for that particular age 15–18 days <50% of expected weight gain for that particular age 19–21 days <25% of expected weight gain for that particular age >21 days
• Days to regain birth weight (in conjugation with nutrient intake) (>3–5 consecutive days of <75% intakes of estimated protein/calorie) (>5–7 consecutive days of < 75% intakes of estimated protein/calorie) (>7 consecutive days of <75% intakes of estimated protein/calorie)
aExpected Z score for weight for age, length for age;
bWeight gain velocity and linear growth velocity were estimated using online calculator (www.peditools.org). In this calculator, weight gain velocity is estimated by using the World Health Organization methods; Weight increments are classified by birth-weight category presented in 1- and 2-week intervals from birth to 60 days

EXTRA-UTERINE HEAD GROWTH RESTRICTION (EUHGR)

EUHGR is another important parameter to follow up in infants with faltering postnatal growth. It is defined as decreased head circumference-for age-Z scores to <2 SD, and has been associated with suboptimal neurodevelopmental outcomes.4–6,10 The growth of the head circumference may be spared in some preterm infants with relatively recent onset of EUGR,13,19 but other chronically undernourished infants may show restricted growth of all parameters, including head circumference, weight, and length. If there is a restriction in only the growth of head circumference but not in weight and length, there may be a need to evaluate for antenatal or postnatal neurological morbidities.18 In preterm infants, post-discharge head growth may be more important as an indicator of cognitive outcome than in-hospital head growth.

PATHOPHYSIOLOGY OF EUGR

EUGR has been associated with multiple factors,20 where one of the most critical ones is inadequate nutrition.15 Despite consistent advancements to improvise preterm nutrition over decades, 28–97% of preterm infants develop EUGR as reported in various neonatal units.21–23 Most of the nutritional determinants of postnatal growth are modifiable if followed rigorously.

  1. Modifiable risk factors of EUGR (Fig. 1):

    1. Failing to meet required energy and protein needs during immediate postnatal period: Premature birth is the most critical period (third trimester) for nutritional accretion and rapid growth of fetus.24 There is a considerable discrepancy in recommended daily intake (RDI) (to match the intrauterine growth) to the actual intake that builds up a cumulative mean energy and protein deficits within few weeks after birth.15,25 Embelton et al. explained the cumulative energy and protein loss at the end of 5th week is around 813 ± 542 kcal/kg/day and 23 ± 12 g/kg respectively.25 The nutritional goals during the initial days should seek to prevent the catabolism typically seen during the postnatal transition following preterm birth.

    2. Variable nutritional practices: There is lack of consensus among individual neonatologists working in the same neonatal intensive care unit (NICU) and adhering to same nutrition protocol.26 Variability in the time of initiation and amount of parenteral and enteral nutrition leads to poor accretion in these infants, cumulative energy and protein loss, and is the iatrogenic cause of EUGR.27,28

    3. Overcautious increase of feeding volumes and frequent disruption of feeds: Neonatologists across the globe consider that delayed introduction, slow and cautious increase in feeding volumes may reduce the risk of necrotizing enterocolitis (NEC) in neonates.29 This overcautiousness often leads to energy deficit and hence growth faltering. Likewise, the feedings are often interrupted in many infants with non-specific abdominal signs that are perceived as feeding intolerance. In many instances, the feeds are not re-initiated in a timely fashion.

    4. Unintentional administration of low calories: In many premature infants born with lower-than-average birth weight, the nutritional goals may need to be carefully adjusted and if possible, aimed for the 50th percentile for that gestation.30 Apart from this, many times the daily feedings may be below the RDI, as no changes in the amount of nutrients administered are made with respect to the increasing birth weight, which if continued for long periods causes cumulative energy and protein deficits.24 Significant cumulative nutiritional deficit lies “in wait” in NICU as the clinicians hesitate about resumption of feedings.

    5. Insufficient standard fortification: Breast milk is known to show considerable variation in nutritional content. Donor human milk, the next best option of milk for preterm infants if mother’s own milk (MOM) is unavailable, is usually term milk or donated by mothers who are into many months of lactation. Thus, standard fortification may not be sufficient to meet the energy and protein needs of preterm babies because of the variability in mother’s milk contents itself.24,31,32

    6. Small for gestation (SGA): In preterm infants, particularly those who are also small-for-gestation, associated comorbidities may mandate frequent adjustments in feeding volumes. These babies, when cannot be given larger volumes of feeds, struggle with the similar concerns of inadequate protein and energy supply through routine fortification.33

    7. Multiple prematurity-related morbidities affecting growth during postnatal period: Prematurity is an important risk factor for EUGR, growth faltering, high morbidities, and poor neurodevelopmental outcomes.14 Duration of hospital stay and ventilator support, bronchopulmonary dysplasia, patent ductus arteriosus, and NEC are independent risk factors for EUGR.23

    8. Postnatal growth failure in preterm and intrauterine growth retardation (IUGR) infants: Healthy fetuses who deliver at term do not encounter interruptions in nutritional supply, depletion of nutritional stores, deprivation of growth factors provided by mother and placenta, or increased energy consumption at the gestational ages that preterm infants have to experience ex utero.34 Premature infants typically show considerable weight loss during the early neonatal period as feedings are still being established and due to multisystem illnesses mentioned above. However, even after achieving clinical stability, many do not achieve growth statistics similar to those of fetuses in utero, at least in terms of weight.29,35 Similarly, many infants who were born Small for gestation (SGA) in terms of weight, length, and head circumference do not respond to nutritional interventions and continue to show EUGR. Some may even show worsening Z-scores from birth to discharge. More comprehensive measurements of total body composition are needed, at least in infants who are no longer on multiorgan system support. We are currently engaged in these measurements and should be able to report some data soon.

  2. Non-modifiable risk factors for EUGR

    1. Epigenetic pathways and EUGR: EUGR is presumed to activate several reprogramming mechanisms. Various factors, both nutritional and environmental, regulate gene expression through epigenetic modifications36–38 that might be responsible for intrauterine and extra-uterine growth. Tozzi et al.39 reported that EUGR for weight and head circumference is associated with reduced intake of lipids and proteins in early days of life with hypermethylation of the IC1 (imprinting center 1) gene. Some authors emphasized that poor nutrition during the early part of life could be associated with epigenetic mechanism and underlined the relationship of decreased protein intake with DNA methylation.40,41 In another study, Gong et al. highlighted the association of low maternal protein intake in animal models with IC1 methylation.42 Once established, these epigenetic changes are difficult to reverse. Further research is needed to understand the value of these markers in EUGR for prognostication and as markers of response to potential therapeutic measures.

    2. Plasma metabolome alterations and EUGR: Dudzik et al.43 showed lower plasma levels of both essential and non-essential amino acids (especially branched chain amino acid) and several phospholipids (glycerophospholipids and sphingolipids) in EUGR preterm infants and also found further decline as per severity of EUGR (moderate >severe), which was irrespective of total parenteral and enteral nutrition in first week of life. Various bile acid metabolites were also found to be increased in severe EUGR infants, which could be hypothesized with the association of liver injury and growth failure. Further larger studies are required to understand the pathways of growth failure in preterm infants and their long-term effects on developmental outcomes. These biomarkers may facilitate early identification of growth failure and help evaluate clinical/nutritional interventions.

    3. EUGR and genomic imprinting: Molecular alterations in parentally imprinted genes lead to various human imprinting disorders, which are associated with effects on intrauterine and postnatal growth. This knowledge of human imprinting disorders can be extrapolated to understand the complex regulation and interaction of genomic next-generation sequencing, transcriptomics, as well as methylomics in postnatal growth of preterm infants.44

BEST WAYS TO PREVENT EUGR (Fig. 2)

Prevention of EUGR in preterm neonates is one of the biggest challenges to neonatologists. Lack of standardized and evidence-based nutritional practices in a neonatal unit are the most common and modifiable risk factors responsible for EUGR.15,20,21 The prerequisite in achieving optimal extra-uterine growth is the early identification of growth failure, timely intervention, and prevention. Although there are no evidence-based guidelines available, practice standardization and its consistent application can be done.45,46 Various ways that can improve nutritional status of preterm infant and hence decrease the frequency of postnatal growth failure are as follows:

  1. Multidisciplinary nutrition support team: A team comprising neonatologists, nutritionists, lactation consultants, and dedicated nursing staff can strive to provide a consistent, individualized nutritional support to all neonates admitted in the nursery and provide a higher growth rate during NICU admission.26,46 The support team can take the responsibility of regular nutrition specific rounds, growth chart plotting, and early identification of growth failure in preterm infants, which is an important milestone to prevent EUGR. Hence, it is advisable to have this support team observe and follow-up these babies during the hospital stay and after discharge for a sufficiently long period.

  2. Standardized feeding guidelines: Variation in the feeding practices guidelines in preterm infants is considered as one of the major determinants of postnatal growth failure.47 It is recommended that every unit must have and strictly adhere to the standardized feeding guidelines to avoid discrepancies between the neonatologist and patient-to-patient variability. This approach helps in48–50

    1. Immediate parenteral nutrition after preterm birth

    2. Initiating feeding and guide to advance them

    3. Rapid (or faster) achievement of full enteral nutrition

    4. Manage feeding intolerance

    5. Procedure and timing to introduce fortified human milk feedings

    6. Reduction in the duration of parenteral nutrition

    7. Rapid regaining of birth weight

    8. Improved anthropometrics at 36 weeks’ postmenstrual age (PMA).

Fig. 2: Ways to prevent EUGR (Extra-uterine Growth Restriction) related to inadequate caloric intake

Standardized feeding guidelines have been associated with lesser rates of NEC and late-onset sepsis, which are the two most important factors for growth failure in preterm infants.51,52

  1. Meeting early nutrition targets

    1. Early aggressive parenteral nutrition: Immaturity of the gut in very preterm babies impedes enteral nutrition in adequate amounts during initial days. Early, aggressive parenteral nutrition not only minimizes the initial weight loss, cumulative protein, and calorie deficit during the acute, sensitive phase but also helps in improving the long-term growth and neurodevelopmental outcomes.53,54 It is suggested to start amino acid in higher doses of 2–3 g/kg/day immediately after preterm birth.55,56 along with lipids in dose of 1–2 g/kg/day in early hours of life57 and subsequently increase the doses as recommended.

    2. Minimal enteral nutrition: Minimal amounts of human milk (minimal enteral nutrition/trophic feeds) ranging from 10 to 20 mL/kg, starting as early as possible, must be a part of the standard feeding guideline. It is proven that early vs late (<48 hour vs >72 hour) initiation of enteral feeds significantly decreases the time required to reach full feeds, lesser time to regain birth weight, and shorter duration of total parenteral nutrition (TPN).58

    3. Early aggressive enteral nutrition: In first 2 weeks of life, the EUGR group was given lesser enteral nutrition than non-EUGR group, which was correlated with healthy metabolomics profile (both amino acid and lipid profile) at the time of discharge in non-EUGR group.43

    4. Supporting breastfeeding and ensuring exclusive human milk: Evidence-based, locally acceptable and relevant strategies to focus on exclusive MOM feeds should be made in every unit like antenatal and postnatal counseling, providing lactation support and educating mother for milk expression,59,60 early and frequent pumping of milk,61 role of Kangaroo mother care (KMC) and non-nutritive sucking (NNS),62 and nursing education should be reemphasized.63 Donor human milk (DHM) should be considered as the second best choice in the absence of MOM, as there is sufficient evidence in literature that DHM decreases the risk of NEC, chronic lung disease, retinopathy of prematurity and other prematurity-related morbidities, either used alone or along with MOM, when compared with formula feeds, which indirectly affects the postnatal growth outcomes.64–66

    5. Targeted and adjustable fortification: Mother’s milk alone is considered insufficient to meet the higher energy demands of preterm infants and hence, needs multicomponent fortification. It significantly helps in better weight gain, length, and head circumference,67 safe in terms of feed intolerance and gastric emptying.68 However, at the same time, standard multicomponent fortification may not be sufficient for adequate growth of these small premature babies.

    6. Individualized fortification, which is a customized way of fortification guided by the growth and metabolic response of the baby, must be the focus of therapy.69 This includes target fortification, adjustable fortification, and super-fortification.70 However, none of these are considered ideal fortification, requiring further studies to formulize and draw optimal fortification strategies.

    7. Avoiding frequent disruption of feeds: Altered gastric aspirates and increase in the abdominal girth are the most common causes for frequent disruption of feeds. It has been proven on various occasions that evaluations of gastric residuals delay the feeding process and can even damage the gastric mucosa.71,72 Increase in abdominal circumference during prematurity is also variable and normal.73 Therefore, frequent abdominal girth monitoring and checking gastric aspirates before every feed is not recommended.

CONCLUSIONS

Extra-uterine growth retardation should not be defined only on the basis of one-time weight assessment at 36–40 weeks or at discharge but all the three anthropometric parameters—weight, length, and head circumference—should be used together as an assessment tool for overall postnatal growth of preterm infants. Refinement in defining EUGR will not only help in appropriate growth assessments but also aid timely assessment of true growth faltering and interventions to deal with it. Lack of uniformity and inconsistency in nutritional practices are the most common causes. Nutritional assessment should be done on at least weekly basis during the NICU stay so that EUGR can be diagnosed and addressed timely. A lot of research is required to understand the deviation in body compositions of these preterm infants, which affects the postnatal growth than just to optimize and establish the recommended nutrition intakes.

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