We recorded graded monotonic associations of fasting and 2-hour post-load glucose level with LGA and high adiposity (as assessed by skinfold thickness) across most of the glucose distribution in both SA and WB women. The associations of glucose level with LGA appeared stronger in SA than WB women, but there was no statistical evidence of an interaction with ethnic origin. Applying the same method as the IADPSG to our data, we estimated fasting and post-load glucose thresholds for diagnosing GDM that are lower in SA women than in WB women. For WB women, our criteria included a fasting glucose threshold that was slightly higher, and a 2-hour glucose threshold that was markedly lower, than those recommended by IADPSG and WHO. Our results support a lower threshold for both fasting and 2-hour post-load glucose level for diagnosing GDM than is currently recommended by NICE in both WB and SA women. NICE supports higher fasting glucose thresholds to those proposed by the IADPSG and WHO in WB and SA women, but lower 2-hour post-load glucose thresholds. Using existing criteria, the prevalence of GDM in our cohort was about twice as high in SA than in WB women; when we applied the ethnic-specific criteria derived from our data, the prevalence was three times higher in SA women, and identified about 25% of SA women as having GDM.
Overall patterns of associations in our study, for both primary and secondary outcomes, were similar to
those seen in the HAPO study,6especially for fasting glucose levels.6Because of differences between ours
and the HAPO study6in the post-load glucose threshold used to exclude women from the study cohort,
our highest 2-hour post-load category (category 7) was similar to category 4 in the HAPO study.6As a result,
for some outcomes, the linear relationship seems to flatten at the upper end of the 2-hour post-load glucose categories.
TABLE 6 Prevalence of GDM in SA and WB women using different criteria (all values expressed in mmol/l)
Criteria
Criteria (all define GDM as the presence of having glucose levels at or above one or more of the following)
Prevalence in our study population: % (95% CI) Fasting glucose 1-hour post-load glucose 2-hour post-load glucose WB SA
Older, used in recent past
Exclusion in HAPO exclusiona 5.8 – 11.1 1.2 (0.9 to 1.5) 4.1 (3.6 to 4.7)
WHO (previous)b
7.0 – 7.8 4.7 (4.1 to 5.4) 10.4 (9.6 to 11.2)
WHO (previous, modifiedc 6.1 – 7.8 4.9 (4.3 to 5.6) 10.8 (10.0 to 11.7)
Recently proposed
NICEd 5.6 – 7.8 5.9 (5.2 to 6.6) 12.5 (11.7 to 13.4)
IADPSG/WHO (current)e
5.1 10.8 8.5 7.6 (6.8 to 8.5) 17.3 (16.3 to 18.3)
Our study
Same criteria for all womenf
5.3 – 7.5 8.7 (7.9 to 9.6) 17.4 (16.4 to 18.4)
For WB 5.4 – 7.5 8.3 (7.5 to 9.2) –
For SA 5.2 – 7.2 – 24.2 (23.1 to 25.3)
a Used in the HAPO study6
to exclude women with GDM. b Used by WHO up to 2013.
c Criteria used for all pregnant women in Bradford (and in other populations) at the time that women were recruited for the BiB study22
and used here to exclude those with GDM. d Criteria in current UK guidelines.41
e Criteria were developed using HAPO study6
data and were adopted by WHO in 2013. f Criteria developed in this study.
Compared with the IADPSG, who used data from the HAPO study,6we could not identify a 2-hour post-load
threshold: there was no threshold that reached an OR of 1.75 for BW of>90th percentile, and only SA
women reached a threshold for this OR for sum of skinfolds of>90th percentile. The IADPSG consensus
panel chose 1.75 to represent the lowest level of clinically important risk; a lower OR was not considered clinically important. GDM was diagnosed in our study using a lower 2-hour post-load glucose threshold than
in the HAPO study;6both studies excluded women with GDM as it would be unethical not to treat them.
If we had applied the same high 2-hour post-load glucose threshold as in the HAPO study6to diagnose GDM
and to exclude women from the main analysis, we would have been more likely to identify an OR of 1.75, because women with higher glucose concentrations and greater associated risk of the primary outcomes would have been included in our analyses. The 2-hour post-load glucose level used to exclude women with
GDM in the HAPO study6was much higher than that recommended by WHO, and also by other criteria
recommended at the time that the HAPO study6began, including the Australasian Diabetes in Pregnancy
Society criteria. Thus, the 2-hour post-load glucose threshold used to define GDM in the IADPSG and WHO
criteria is higher than that suggested by our study (seeTable 1). Because the diagnostic criteria for GDM in
our study meant that we excluded women from the main analyses with a much lower post-load glucose
threshold than was the case in the HAPO study,6we had difficulty identifying a glucose threshold that
reached an OR of 1.75 for sum of skinfolds of>90th percentile in WB women. Therefore, our GDM
diagnostic criteria for this group are mainly driven by results of the associations with LGA.
Consistent with other studies,42–45we have shown that using any criteria the prevalence of GDM is greater
in SA women than in WB women. When we used the same criteria for both ethnic groups, the criteria derived from our study resulted in a higher prevalence of GDM than the NICE criteria for both WB women and SA women, but broadly similar prevalences for both groups to those found with the IADPSG/WHO criteria. When we used ethnic group-specific criteria, the prevalences for WB women remained higher than the NICE criteria, but were similar to IADPSG/WHO criteria, whereas those for SA women became higher for both of these other two criteria. Our study cohort is large and well characterised. The broad consistency of
our findings with the results of the HAPO study,6and the fact that our results were unchanged when we
limited the analyses in SAs to those of Pakistani origin, suggests that the results might be generalisable to all white Europeans and SAs. Some participants had missing data for some variables, but the distribution of recorded variables and those from the pooled multiple imputed data sets were similar, as were the association results. We did not collect data for 1-hour post-load glucose concentrations, which were
measured in the HAPO study,6and a 1-hour post-load glucose threshold is included in IADPSG/WHO criteria
for GDM. Although the HAPO study6found linear associations of 1-hour post-load glucose levels with
adverse perinatal outcomes, none of the randomised trials that have shown the effect of treatments on adverse perinatal outcomes had used this to define GDM. Furthermore, it is unclear how many additional women in different populations are identified by this additional glucose measurement. Thus, the benefit of this additional measurement remains somewhat unclear. We do not have data for cord blood C-peptide concentrations or neonatal hypoglycaemia. High cord blood C-peptide concentrations were one of the criteria used by the IADPSG in the development of their diagnostic criteria; this additional information might have affected our results. However, the similar prevalences of GDM in WB women using the IADPSG/WHO criteria or our study criteria suggest that including these data would not have markedly changed our results.
Concerns have been raised about the increased prevalence of GDM and hence the cost to health services if
the IADPSG criteria are used worldwide in place of the previously widely used 1999 WHO criteria.25,46,47
Until the late 1990s, the main aim of diagnosing GDM was to identify women at risk of subsequent type 2
diabetes.48By contrast, the outcomes used to develop the IADPSG criteria, which we also used, were
chosen to identify offspring at risk of future high adiposity and cardiometabolic risk.48Although there is
evidence that GDM causes greater adiposity in offspring in later life,48,49there is still debate about the
validity of that evidence.50Thus, the extent to which the IADPSG or our criteria will accurately predict future
adverse offspring health remains to be established. Conversely, in view of the graded association of maternal glucose concentrations with adverse perinatal outcomes, lowering the thresholds used to diagnose GDM would identify more pregnancies at risk of these outcomes. Because effective, safe, and cheap treatments are available for GDM (e.g. lifestyle advice, metformin and insulin) that reduce glucose
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level across its distribution and help prevent adverse perinatal outcomes,51,52applying the IADPSG/WHO
2013 or our criteria in place of the WHO 1999 criteria, and also in place of the recently suggested NICE criteria, might improve perinatal outcomes. Because the NICE 2015 criteria recommend higher thresholds of fasting and post-load glucose levels than the IADPSG/WHO or our newly defined criteria, their use will
identify fewer women who are at increased risk of adverse outcomes.53
To conclude, our data support the use of lower fasting and post-load glucose thresholds in SA women than in WB women. They also suggest that compared with our criteria or those of the IADPSG/WHO, the criteria recommended by NICE might underestimate the prevalence of GDM, especially in SA women. The use of
our ethnic-specific thresholds for diagnosing GDM in SA women, and of either our–or the IASPSG/WHO–
criteria for white European women might reduce the occurrence of adverse perinatal outcomes, in particular LGA, as more at-risk women would be treated. However, the effect of applying any of the recently
proposed criteria on later life adiposity and associated cardiometabolic health in offspring are unknown and require further investigation. Furthermore the effectiveness of identifying and treating women with GDM at different cost-effectiveness thresholds, together with the use of varying glucose level thresholds, is also
unclear. Our comprehensive analysis detailed inChapter 7of this report examines this area and provides
Chapter 3
Associations of gestational fasting and
post-load glucose levels in women without existing or
gestational diabetes with perinatal and longer-term
outcomes: a systematic review
Introduction
This chapter presents a systematic review and meta-analyses to determine the association between graded increases in glucose level and risk of perinatal and longer-term outcomes. A version of this chapter has
been published in Farraret al.54This is an Open Access article distributed in accordance with the terms
of the Creative Commons Attribution (CC BY 3.0) license, which permits others to distribute, remix, adapt and build upon this work, for commercial use, provided the original work is properly cited. See: http://creativecommons.org/licenses/by/3.0/.
Previous systematic reviews
To our knowledge, this is the first comprehensive systematic review and meta-analyses examining the association of gestational glucose level with risk of perinatal and longer-term outcomes. We have previously
undertaken a review as part of a master’s degree dissertation.55In that dissertation, a systematic search
was undertaken to identify studies that investigated the association between gestational glucose levels [measured using the OGTT or oral glucose challenge test (OGCT)] and adverse outcomes. The findings of that review suggested strong associations between fasting glucose categories and both LGA and macrosomia and these associations were weaker for 2-hour post-load glucose categories. However, that review included only studies that had been published up to March 2013, and we are aware of additional studies since then. Furthermore, there was no attempt to explore sources of heterogeneity between studies.
The aim in this study was to expand and update the previous search and analyses in order to determine associations between fasting and post-load glucose levels, and both perinatal and longer-term maternal and offspring outcomes. This section is reported in accordance with PRISMA (Preferred Reporting Items for
Systematic Reviews and Meta-Analyses) guidelines.56