Why is the postnatal growth of preterm infants important?
Fetal and newborn growth is an important predictor of an individual’s health, both in the short term and across the whole life course. Preterm birth is a leading public health problem worldwide; it is responsible for up to 30% of neonatal deaths, and indirectly responsible for a further 20%.1,2 Standards are essential tools for monitoring growth; they are used at the individual and community level to ensure timely and adequate nutritional intervention, referral, and treatment of individuals and populations.
What tools are currently used to measure preterm infant growth and what are their limitations?
Five strategies exist for monitoring the postnatal growth of preterm infants; each has considerable limitations:
(a) Estimation of fetal weight by ultrasound: This is not appropriate because estimated fetal weight is, by definition, an estimation with large measurement errors.3,4 These ‘intrauterine’ growth charts do not consider the physiological weight loss that occurs during the neonatal period. Furthermore, striving to match the growth of ‘healthy’ fetuses (an aim not substantiated by any data) may be a challenge especially for very preterm infants. Even if achievable, such a goal may be associated with adverse short and long-term consequences.5
(b) Birthweight for gestational age charts: Data to construct them are cross-sectional and obtained from a single measure taken immediately after birth (which is a summary measure of fetal growth). ‘Size-at-birth charts’ should not be used to monitor postnatal growth.
(c) Postnatal longitudinal growth charts for preterm infants: Considerable efforts have been made to document the actual postnatal growth of very low birthweight babies. Many of these charts cannot be considered to be suitable for clinical use.6 Most lack rigorous participant inclusion/exclusion criteria; adequate quality control measures; reliable ultrasound based estimation of gestational age; adequate duration of follow-up and description of feeding practices.
(d) Prescriptive growth standards for infants born at term: The WHO prescriptive standards are used globally for term infants. 7 However, when these charts are used for preterm infants, the growth measures often fall far below the lowest centiles because the postnatal growth of preterms is different from that of term infants.
(e) A combination of birthweight for gestational age charts and prescriptive growth standards for term babies: This combination has the same fundamental problems listed above for each of its components.
What is the difference between a reference and a standard for growth monitoring?
References, often based on data routinely collected with limited or no standardisation and quality control, describe how subjects have grown at a particular place and time. In contrast, prescriptive standards describe how subjects should grow under optimal conditions - in the case of preterm newborns, according to their clinical status and degree of maturation.8,9 This prescriptive strategy for monitoring the growth of humans has been recommended by WHO since 1995.10
Standards are universal and may be used across time; they are ideal tools for standardisation of research protocols, systematic reviews and meta-analyses and international comparisons of nutritional status. These characteristics are crucial in the 21st century given the extent of ancestral admixture, migration, global economic growth and refugee problems.11
Is a standard suitable to monitor the growth of a preterm infant?
YES. It has been reported that standards cannot be produced for preterm infants because preterm newborns are not “normal” or “healthy”. We believe that preterms are in an “immature” rather than pathological state i.e. the pathological component, which is organ specific, is related to gestational age and complications of immaturity. The INTERGROWTH-21st Preterm Postnatal Standards12 may be used for monitoring postnatal growth in preterm babies and complement the international standards for Crown-Rump Length in the first trimester of pregnancy,13 Fetal Growth,14 Newborn Size at Birth,15 Very Preterm Size at Birth16 and Child Growth for term infants.7 Thus, growth and development may be monitored from the first trimester of pregnancy until age 5 years, irrespective of location, ethnic origin, or timing of birth.
Are the INTERGROWTH-21st Preterm Postnatal Growth Standards applicable to all preterm infants?
YES. The INTERGROWTH-21st Preterm Postnatal Growth Standards 12 are particularly suitable for monitoring postnatal growth in preterm babies after 32 weeks’ postmenstrual age and may be used for the assessment of preterm infants until 64 weeks’ postmenstrual age (6 months “corrected” age), the time at which they overlap, without the need for any curve adjustment, with the WHO Child Growth Standards for term newborns.
The construction of charts for very preterm infants <32 weeks’ gestation is problematic because there is no definitive information on the nutritional needs of these tiny babies; it may be argued that, during these early postnatal weeks, monitoring of growth should be carried out only to track a growth trajectory rather than used as a screening tool for detecting growth restriction.
The INTERGROWTH-21st standards allow all preterms to benefit from a postnatal growth monitoring strategy that matches the WHO Child Growth Standards, and provides continuity of care from the special neonatal care unit to the outpatient clinic.
How did the INTERGROWTH-21st Project select preterm infants for the standards?
INTERGROWTH-21st has produced prospective, longitudinal, prescriptive, postnatal growth standards specifically constructed for preterm infants from 27 weeks’ gestation, born to healthy mothers with well-dated pregnancies and no evidence of intrauterine growth impairment assessed by serial ultrasound from <14 weeks’ gestation.12 This unique cohort of infants was followed up using rigorous, standardised methodology for the assessment of anthropometric measures, health, nutrition, motor- and neuro-development until 2 years of age.
How were the preterm infants enrolled in the INTERGROWTH-21st Project fed?
An evidence-based nutritional protocol derived from currently recommended guidelines (mostly for stable infants who were able to have enteral feeding) was implemented across the participating study sites. It was based on exclusive breastfeeding at the time of hospital discharge, ideally continued exclusively until 6 months of age. It proved to be feasible and well accepted by clinical staff and mothers.17
What statistical methodology was used to generate the Preterm Postnatal Growth Standards?
Is a sample size of 201 preterm infants enough to create reliable standards?
YES. In this study of a low to medium risk population in which women were recruited in the first trimester of pregnancy and received frequent antenatal care, few preterm infants were born despite the large sample size (4607 pregnant women) from which they were derived.12
There are additional issues to consider when judging the “small” sample size of this study: a) WHO recommends, as a general rule, a total sample of 200 subjects of each sex for studies of human growth from a longitudinal design;19 b) longitudinal studies are more precise than cross-sectional ones; it has been calculated, in studies on fetal growth, that a longitudinal design requires half the sample size of a cross-sectional study in order to estimate a given centile with the same precision,20 i.e. our 201 newborns, who contributed 1750 measures during the follow-up, have power equivalent to a sample of 3500 in a cross-sectional study; c) the strict standardised protocols, training of staff, equipment and quality control procedures reduced measurement error and the likelihood of biased estimates; d) the resulting curves do not have any unexpected behaviour at any gestational age that can be related to the small amount of data available. Although it is likely that a larger sample would increase variability, the centiles close to the median are not expected to change markedly; and e) plots of individual measurements with overlapping centile curves and comparisons of empirical and fitted centiles showed good agreement.
Hence, the INTERGROWTH-21st standards are robust for more than 90% of the preterm population and, for those born <32 weeks’ gestation, are also robust after a few weeks of postnatal life when the babies are in a more clinically stable condition and able to start some enteral feeding.
Can the preterm longitudinal standards be used from birth?
The first evaluation at birth should be done using the cross-sectional size at birth charts 15,16 (intergrowth21.tghn.org) because this value is a summary measure of fetal growth. The INTERGROWTH-21st preterm longitudinal standards may be used during hospital stay and after discharge up to 6 months post-term. Most very preterm infants experience weight loss after birth. This weight loss can be monitored using the INTERGROWTH-21st Preterm Postnatal Growth Standards. When the preterms start re-gaining weight, the corresponding weight centile may be assigned and used for future weight assessment. Length and head circumference may be fully monitored from birth.
Which standards should be used for the assessment of preterm infants older than 6 months?
The WHO Child Growth Standards for term infants 7 are the natural continuation of the INTERGROWTH-21st Postnatal Growth Standards and should be used to monitor the growth of preterm infants older than 6 months.
How different are the INTERGROWTH-21st standards from the old reference charts?
The results of our systematic review of the literature showed that the methodological quality of the previous longitudinal charts was fair to low, with most charts being affected by methodological weaknesses.6 The INTERGROWTH-21st PRETERM POSTNATAL GROWTH STANDARDS are the only available standards that have all the following characteristics:
1) Gestational age was accurately assessed by combining reliable LMP with early fetal ultrasound.
2) Anthropometric measurements were taken by trained staff using identical standardised instruments and techniques.
4) Fetal growth was monitored by serial ultrasound to exclude preterm cases with evidence of fetal growth restriction.
5) The follow-up period was extended to 8 months to avoid the so-called right-edge effect in constructing the growth standards.
6) We avoided using birthweight as a proxy for prematurity.
7) Well-described analytical, statistical, and reporting methods were used.
Do the INTERGROWTH-21st Preterm Postnatal Growth Standards change the current definition of “extra-uterine growth restriction”?
YES. The new Preterm Postnatal Growth Standards 12 completely change the perspective. They are no longer based on the assumption that the postnatal growth of preterm infants should mimic the intrauterine growth of fetuses of the same gestational age, but rather describe the actual growth of preterm infants monitored longitudinally after birth. The new centiles are different from the fetal 14 and the cross-sectional size at birth neonatal centiles 15 and suggest to us that preterm infants should not be forced to grow rapidly to mimic fetal growth.
The concept of iatrogenic “extrauterine growth restriction” will no longer apply; the truly complicated infants will be detected by their slow growth compared to their preterm, but healthy, peers.
What should be done to ensure that all infants grow well according to these standards?
Breastfeeding should be supported, protected, and promoted. As recommended for term infants by WHO, and also for preterms for the first 6 months, mothers need to be informed and empowered to practice exclusive breastfeeding. Good health care and nutritional practices 21 should be available and accessible to all infants.
How do I obtain copies of the new growth charts and/or calculate centiles and Z scores?
Centiles for weight, length and head circumference, with corresponding z-scores, are presented in paper, electronic and phone-friendly formats for the follow-up of preterm infants from hospital care to outpatient clinics and family care. (https://intergrowth21.tghn.org).
How can I be sure I am using the charts correctly?
Educational materials and e-learning modules for use of the charts and anthropometry are available at https://intergrowth21.tghn.org
- World Health Organisation. Make every mother and child count, 2005
- Barros FC, Papageorghiou AT, Victora CG, et al. The distribution of clinical phenotypes of preterm birth syndrome: implications for prevention. JAMA Pediatr 2015;169:220-9
- Colman A, Maharaj D, Hutton J, et al. Reliability of ultrasound estimation of fetal weight in term singleton pregnancies. NZ Med J 2006;119:U2146
- Dudley NJ. A systematic review of the ultrasound estimation of fetal weight. Obstet Gynecol 2005;25:80–9
- Belfort MB, Gillman MW, Buka SL, Casey PH, McCormick MC. Preterm infant linear growth and adiposity gain: trade-offs for later weight status and intelligence quotient. J Pediatr 2013;163:1564-69
- Giuliani F, L Cheikh Ismail, E Bertino, ZA Bhutta, EO Ohuma, I Rovelli, A Conde-Agudelo, J Villar and SH Kennedy. Monitoring postnatal growth of preterm infants: present and future. AJCN 2016 Feb;103(2):635S-47S
- de Onis M, Garza C, Onyango AW, et al. WHO Child Growth Standards. Acta Paediatr Suppl 2006; 450: 1–101
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- Villar J, Knight HE, de Onis M, et al. Conceptual issues related to the construction of prescriptive standards for the evaluation of postnatal growth of preterm infants. Arch Dis Child 2010;95:1034-8
- de Onis M, Habicht JP. Anthropometric reference data for international use: recommendations from a World Health Organization Expert Committee. Am J Clin Nutr 1996;64:650-8
- Villar J, Papageorghiou AT, Pang R, et al. Monitoring human growth and development: a continuum from the womb to the classroom. Am J Obstet Gynecol 2015;213:494-9
- Villar J, Giuliani F, Bhutta ZA, et al. Postnatal growth standards for preterm infants: the Preterm Postnatal Follow-up Study of the INTERGROWTH-21st Project. Lancet Glob Health 2015;3:e681-91
- Papageorghiou AT, Kennedy SH, Salomon LJ, et al. International standards for early fetal size and pregnancy dating based on ultrasound measurement of crown-rump length in the first trimester of pregnancy. Ultrasound Obstet Gynecol 2014; 44: 641–48
- Papageorghiou AT, Ohuma EO, Altman DG, et al. International standards for fetal growth based on serial ultrasound measurements: the Fetal Growth Longitudinal Study of the INTERGROWTH-21st Project. Lancet 2014; 384: 869–79
- Villar J, Cheikh Ismail L, Victora CG, et al. International standards for newborn weight, length, and head circumference by gestational age and sex: the Newborn Cross-Sectional Study of the INTERGROWTH-21st Project. Lancet 2014; 384: 857–68
- Villar J, Giuliani F, Fenton TR, Ohuma EO, Ismail LC, Kennedy SH; INTERGROWTH-21st Consortium. INTERGROWTH-21st very preterm size at birth reference charts. Lancet. 2016 Feb 27;387(10021):844-5
- Cheikh Ismail L, Giuliani F, Bhat BA, et al. Preterm feeding recommendations are achievable in large-scale research studies. BMC Nutr 2016;2:9-17
- Ohuma EO, Hoch L, Cosgrove C, et al. Managing data for the international, multicenter INTERGROWTH-21st Project. BJOG 2013;120 Suppl 2, 64-70
- de Onis M, Victora CG, Garza C, Frongillo EA, Cole TJ, for the WHO Working Group on the Growth Reference Protocol. A new international growth reference for young children. In: Dasgupta P, Hauspie R, eds. Perspectives in Human Growth, Development and Maturation. Dordrecht, The Netherlands: Kluwer Academic Publishers; 2001:45-53
- Royston P. Calculation of unconditional and conditional reference intervals for foetal size and growth from longitudinal measurements. Stat Med 1995;14:1417-36
- Bhutta ZA, Giuliani F, Haroon A, et al. Standardisation of neonatal clinical practice. BJOG 2013;120 Suppl 2, 56-63