This study demonstrates that GROW and INTERGROWTH growth standards perform comparably in type 1 diabetes pregnancy and are both able to identify infants at increased risk of perinatal complications. LGA defined according to GROW centiles (> 90th and/or > 97.7th centile) showed stronger associations with preterm delivery, neonatal hypoglycaemia, hyperbilirubinaemia and NICU admission.
WHO standards were also able to predict outcomes, but do not incorporate gestational age at delivery, fail to adequately describe size at birth in preterm infants. For term infants, the WHO criteria gave a true birth centile, but for preterm infants, the WHO criteria gave a low centile, which reflected their prematurity, not their comparative size at birth. This measure of prematurity means that the WHO criteria were still able to predict outcomes, despite giving an unreliable birth centile, which demonstrates the importance of preterm delivery in relation to multiple neonatal complications. However, the inability to reliably attribute a birth weight centile is a substantial limitation in pregnancies of women with T1D, where rates of preterm delivery are high (40% in this study; 46% in clinical data 5).
As only a small proportion of the antenatal population has T1D diabetes, CONCEPTT represents one of the largest randomised trials with detailed data on perinatal outcomes, making it useful to assess fetal growth, maternal glycaemia and infant risk. Customised (GROW) centiles were reported for CONCEPTT, but the effect of the intervention was also seen using INTERGROWTH standards. Although accelerated fetal growth is common in T1D pregnancies, the rates of LGA in the CONCEPTT infants were higher than expected (66% in CONCEPTT compared to ~ 46% in a UK population using similar methodology 5). The reasons for this are unclear, particularly as the CONCEPTT population had better glycaemic control compared to the UK clinical population 5.
A central aspect to the controversy about GROW and INTERGROWTH centiles involves the perceived importance of maternal factors to the growth of the infant, and ethnicity in particular. A limitation of the CONCEPTT trial is that while it international, 86% of women recruited were of European / Mediterranean origin, which reduced the opportunity to look in depth at growth standard performance in different ethnicities. A further issue is that women who choose to participate in studies are often affluent, well-nourished and educated, and may not represent mothers with different socioeconomic circumstances. Although we have identified that infants < 25th centile displayed a trend to be at highest risk of multiple complications, very few infants fall into this category which makes detailed assessment of SGA in diabetic pregnancy very challenging.
The potential value of accurate growth standards is enormous, as identifying LGA or SGA infants offers the opportunity to treat perinatal complications. However, controversy surrounding the performance of different growth standards has been a barrier to improving care. Proponents of the GROW customised approach believe that incorporating maternal variables results in a more accurate representation of size at birth 10 16. Conversely, proponents of the INTERGROWTH-21st study state that variables such as ethnicity make little difference to size at birth, in a well –nourished population with access to adequate antenatal care13. A major focus for growth standards has been on the identification of infants who are SGA with a view to reducing stillbirth rates10.
In this study, standard-deviation-based criteria for the diagnosis of LGA have been assessed. Although a birth weight z score > 1 is considered consistent with LGA, this definition is different to standard centile-based definitions (> 90th centile)17. Different approaches to the LGA diagnosis contribute to difficulty in comparing populations internationally 18–20.
In this population, the standard definition of SGA identified few infants (1.3–1.8% both with GROW and INTERGROWTH standards). Although SGA is uncommon in type 1 diabetes pregnancy, it is likely than infants born < 10th centile do not represent all those with growth restriction. A better understanding of the causes and early identification of growth restriction in diabetic pregnancy should be a research priority. Larger data sets that examine the risks of this group are required, due to the small numbers in this category examined here.
A fundamental aim of antenatal care in T1D pregnancies involves careful control of maternal factors (e.g. glycaemia) to normalise fetal growth. GROW standards showed stronger associations with neonatal complications but this standard requires additional data to calculate, which may make it less feasible to guide routine care decisions. Significant odds ratios for INTERGROWTH standards were associated with Caesarean delivery, neonatal hypoglycaemia, NICU admission and the composite outcome in the > 97.7th centile group. GROW identified fewer infants as LGA compared to INTERGROWTH standards.
WHO growth standards performed poorly here, as there was no adjustment made for infants born preterm. This limitation highlights this system may miss infants at risk, especially those born preterm12. Fewer infants identified as LGA using the WHO standards compared to GROW and INTERGROWTH, but those identified were undeniably at high risk of complications. Therefore LGA infants not born near term using WHO standards are at risk of not being identified, giving fewer opportunities for intervention preventing complications.
GROW and INTERGROWTH approach preterm growth differently. GROW centiles are based upon the Hadlock formula for certain gestational ages, suggesting that the growth of preterm and term infants should be exactly the same at any timepoint 21. The INTERGROWTH standards do not make this assumption but are based on the size of preterm infants at birth. Although this approach seems more scientifically justifiable, as growth abnormalities may contribute to preterm birth, the INTERGROWTH standards were based upon data from real preterm babies, a relatively rare clinical occurrence in a healthy population, there were fewer infants in the very preterm categories which may introduce more uncertainty (details at https://www.intergrowth21.org.uk/protocol.aspx?lang=1 accessed 11/09/2018) 22. More studies in very preterm infants are needed to identify which growth standard might perform best in this group 23.
Despite maternal diabetes being a risk factor of perinatal morbidity, there has been relatively little assessment of different growth standards in this population. Kase and colleagues reported that customised centiles identified more infants as SGA/LGA compared to population centiles in diabetic pregnancies24. Narchi and Skinner had similar findings but concluded there was no evidence of a difference in mortality or morbidity between the infants identified by customised vs population growth standards25. The current study adds to the literature by highlighting differences between the common growth standards.