This study demonstrates that GROW and INTERGROWTH growth standards perform comparably in type 1 diabetes pregnancies, giving similar median birthweight centiles and comparable rates of LGA and SGA neonates. Furthermore, both GROW and INTERGROWTH defined LGA identified neonates at increased risk of complications. LGA defined according to GROW (>90th and/or >97.7th centile) showed stronger associations with preterm delivery, neonatal hypoglycaemia, hyperbilirubinaemia and NICU admission. In smaller infants, SGA defined according to INTERGROWTH criteria showed slightly stronger associations with outcomes. However, using any thresholds studied, weight related measures alone were not strong predictors of suboptimal perinatal outcomes (Table 3).
WHO standards do not incorporate gestational age at delivery, and thus fail to adequately describe size at birth in preterm infants. For term infants, the WHO criteria gave a true birthweight 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, which demonstrates the importance of preterm delivery in relation to multiple neonatal complications. However, the inability to reliably attribute a birthweight centile is a substantial limitation in type 1 diabetes pregnancies, where rates of preterm delivery are as high as 40%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. Proponents of GROW customised centiles believe that incorporating maternal variables results in a more accurate representation of size at birth 10 19. Conversely, proponents of the INTERGROWTH-21st standards claim that variables such as ethnicity make little difference to size at birth, in well-nourished populations with access to adequate antenatal care13. 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 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.
A major focus for growth standards has been on the identification of infants who are SGA with a view to reducing stillbirth rates10. Although we have identified that infants <25th centile displayed a trend to be at highest risk of multiple complications, very few infants fell into this category which made detailed assessment of SGA outcomes challenging. Although SGA is uncommon in type 1 diabetes pregnancy, it is plausible that infants born <10th centile do not represent all those with growth restriction.
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)20. Different approaches to the LGA diagnosis contribute to difficulty in comparing populations internationally 21-23.
A fundamental aim of antenatal care in T1D pregnancies involves careful control of maternal glycaemia to normalise fetal growth. This study shows that growth –related measures alone are not strong predictors of suboptimal perinatal outcomes. For example, a birthweight >90th centile on GROW and INTERGROWTH criteria could identify neonatal hypoglycaemia, NICU admission and respiratory distress with 71-77% sensitivity, but the specificity for these outcomes was around 32-42%.
These data are consistent with other work which highlights the challenges of accurate prediction of neonatal outcomes in T1D pregnancy. For example, Yamamoto and colleagues demonstrated that LGA was the only significant predictor for neonatal hypoglycaemia on adjusted logistic regression analysis (odds ratio 2.51, 95% CI 1.10-5.70)24. However, 36% of infants with neonatal hypoglycaemia were appropriate for gestational age, resulting in similar levels of sensitivity and specificity seen in the current report.
As only a small proportion of the general maternity population has type 1 diabetes, CONCEPTT represents one of the larger randomised trials with detailed data on perinatal outcomes, making it useful to assess fetal growth, and infant birthweight outcomes. 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 ~50% 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.
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 diabetes pregnancies25. 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 standards26. The current study adds to the literature by highlighting differences between the common growth standards in a generalisable population of pregnant women with type 1 diabetes. We had no women with optimal glucose control (defined as HbA1c<48 mmol/mol) in early pregnancy as these women were excluded from the CONCEPTT trial. However, population based studies confirm that only 15% of women with T1D achieve a first trimester HbA1c level <6.5% (48mmol/mol5) and thus the data presented here is representative for the vast majority of women. Future studies should evaluate growth standards and definitions of LGA and SGA in larger cohorts of women with diabetes, including among women with target HbA1c levels. Better understanding of the causes and early identification of growth restriction in diabetes pregnancy should be a research priority.