Controversy grows over redefinition of gestational diabetes

To the Editor: Moynihan has recently suggested that gestational diabetes mellitus (GDM) is a “non-entity”1 and cited controversy regarding new diagnostic criteria, while McIntyre and Oats have defended the practice of screening
for GDM.2 Robust data associate hyperglycaemia with adverse pregnancy outcomes;3 and randomised controlled trial data show a beneficial effect of screening and treatment on perinatal outcomes.4

However, it is short-sighted to consider only the immediate outcome of a pregnancy. GDM has very significant long-term consequences for mothers and their offspring. Half of all women diagnosed with GDM will later develop type 2 diabetes,
and they also bear a substantially increased risk of future cardiovascular disease.5 Identification of GDM therefore provides an opportunity to intervene with a view to improving the long-term health of young women who are at risk. Furthermore, in-utero hyperglycaemia seems to cause fetal programming effects which increase the risk of type 2 diabetes in offspring — additive to the genetic transmission of diabetogenic traits from mother to child.

The newly proposed International Association of the Diabetes and Pregnancy Study Groups (IADSPG) diagnostic criteria for GDM continue to use the oral glucose tolerance test (GTT) but will identify a greater number of women with GDM based on an abnormal fasting, rather than post-load, blood glucose level (BGL). We recently undertook a retrospective review of the results of diagnostic GTTs performed in 10 801 pregnant women between 2008 and 2011
in Western Sydney (at Westmead Hospital, Nepean Hospital, Blacktown Hospital, Auburn Hospital, and Moaven and Partners Pathology
[a private pathology service provider]). Based on the older Australasian Diabetes in Pregnancy Society (ADIPS) criteria, 15.7% of results were diagnostic of GDM (4.0% elevated fasting BGL, 13.9% elevated 2-hour BGL, 2.2% both). If the same results are reclassified using IADSPG criteria, 14.6% are diagnostic of GDM (8.6% elevated fasting BGL, 9.2% elevated 2-hour BGL, 3.2% both).

We also reviewed the obstetric outcomes of 541 women who attended Blacktown Hospital and had BGLs diagnostic of GDM according
to either criteria. Women identified
by IADSPG criteria had more macrosomic infants (17.0% v 5.4%), low birthweight infants (11.0% v 6.4%) and babies admitted to the special care nursery (45.5% v 23.2%) compared with women identified using ADIPS cut-offs (all P < 0.05 by the Fisher exact test). In other words, the IADSPG criteria seem to be better at identifying women who will have poor obstetric outcomes. The number diagnosed was no higher in this analysis (although this might change if 1-hour BGL cut-offs were to be included, as proposed by the IADSPG).

We argue that GDM remains an important clinical entity, and that it is worth getting the diagnosis right.

Gestational diabetes needs to be managed

To the Editor: McIntyre and Oats promote the International Association of the Diabetes and Pregnancy Study Groups (IADPSG) criteria for gestational diabetes mellitus (GDM) as being well reasoned.1 Derived from observational data and mathematical modelling in an attempt to provide a worldwide definition and to improve outcomes, these criteria will significantly increase the number
of women diagnosed with GDM2 in health care systems that have limited resources. To help achieve cost savings, clinicians should be leaders in preventing interventions in circumstances where effectiveness
or harm is unknown.3

The Australian Carbohydrate Intolerance Study in Pregnant Women trial4 and a US study on treatment for mild GDM5 reported similar outcomes in reducing the frequency of large-for-gestational-age babies, pre-eclampsia and shoulder dystocia despite different entry criteria. The IADPSG proposes more stringent criteria than are used in either of these studies, but without knowledge of additional benefit
or harm.

The National Institutes of Health recently released draft guidelines
on the diagnosis of GDM that
reject IADPSG criteria,6 making a worldwide definition less likely. Many reasons for this decision have been considered, including the need for evidence that any new criteria should provide benefits that outweigh harm. Our colleagues at the National Institutes of Health seem to have a very good point. Surely it would be sensible to compare IADPSG criteria with established practice in Australia in a randomised controlled setting before redefining the management
of GDM.

Gestational diabetes needs to be managed

To the Editor: McIntyre and Oats1 suggest that Australian medical practitioners should adopt the new International Association of the Diabetes and Pregnancy Study Groups (IADPSG) diagnostic criteria for the management of gestational diabetes mellitus (GDM),2 mainly because of the findings of the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) study.3 If adopted, a significant number of women will be diagnosed with GDM if their only blood glucose level (BGL) abnormality is a fasting BGL of
5.1–5.4 mmol/L. The quoted studies do not provide outcome data to confirm benefit at these levels.4,5 In addition, women currently diagnosed with GDM on the basis of a 2-hour BGL of more than 8.0 mmol/L but below the new IADPSG level of 8.5 mmol/L2 will no longer meet the criteria. But outcome data show a benefit of management at these levels.4 Also, the US study on treatment for mild GDM used a 100 g oral glucose tolerance test (OGTT)5 with a 2-hour BGL cut-off that approximates 8.0 mmol/L on a 75 g OGTT.6 Thus the two quoted outcome studies demonstrate benefit of treatment at BGLs that will no longer be accepted for the diagnosis of GDM.

The authors imply that the new criteria will not increase resource demand. The main abnormality in
the quoted intervention studies was the postprandial BGLs, which are amenable to lifestyle change.4,5 The fasting BGL is less responsive, at least in the short term. It is likely that a significant number of women will require insulin based on these lower fasting BGLs. Consequently, a woman with a fasting BGL of 5.1 mmol/L will be diagnosed with GDM, and will potentially be treated with insulin
to achieve the recommended fasting BGL of 5.0 mmol/L or less.2 Will a 0.1 mmol/L reduction in fasting BGL confer any clinical benefit?

The current guidelines7 are supported by outcome data demonstrating benefit from intervention. The HAPO study is hypothesis generating.3 What is required is an outcome study that randomly assigns women whose
only abnormality on their OGTT is a fasting BGL of 5.1–5.4 mmol/L. Until that study is completed, the current guidelines should continue to be used.

Gestational diabetes needs to be managed

In reply: Taylor welcomes a strong evidence base for clinical practice, which is echoed by d’Emden and colleagues. However, their strong support for the current Australian diagnostic criteria for gestational diabetes mellitus (GDM) is surprising, given that these criteria are the product of an “Ad Hoc Working Party” report.1 This guideline, published in 1991, clearly acknowledged a lack
of strong evidence and advocated criteria that were based on best available rounded values for the 95th centile of venous plasma glucose (VPG) levels in the fasting state (5.5 mmol/L) and 2 hours after a 75 g glucose load (8.0 mmol/L) — values that had been published in an unreferenced overview of Australian and European data.1 It advocated future prospective studies, such
as those which form the basis of
the International Association of
the Diabetes and Pregnancy
Study Groups (IADPSG) recommendations.2 Contrary to d’Emden et al’s assertions, the 1991 fasting and 2-hour VPG level cut-offs are misaligned. Contemporary data from the 2120 Australian women in the Hyperglycemia and Adverse Pregnancy Outcome study, using the 75 g oral glucose tolerance test, show that 5.5 mmol/L lies at the 98th centile for fasting VPG level, while 8.0 mmol/L corresponds to the 91st centile for
2-hour VPG level (own unpublished data). A recent summary of ambulatory blood glucose monitoring in pregnancy suggested even tighter normative values, with the 97th centiles for fasting blood glucose level (BGL) (4.8 mmol/L) and 2-hour post-meal BGL (6.6 mmol/L) being lower than previous guesstimates.3

Further, the IADPSG diagnostic thresholds are based not on cohort percentiles but on associations with diabetic fetopathy and correspond to equivalent levels of glucose-related risk, after extensive corrections for potential confounders. Considering the randomised controlled trials, we note that although the Australian Carbohydrate Intolerance Study
in Pregnant Women permitted recruitment of women with markedly elevated fasting BGLs, there were few such women.4 By contrast, the US study on treatment for mild GDM considered a fasting VPG level of 5.3 mmol/L or higher as indicative
of GDM that definitely required treatment and women in this category were excluded from the trial.5 The mean fasting VPG level in both trials was 4.8 mmol/L, thus both included substantial numbers of women with fasting VPG levels in the range specified by IADPSG. Both trials specified fasting BGL targets for women receiving treatment (5.5 mmol/L4 and 5.3 mmol/L5) and treated actively to achieve both these and post-meal glucose targets. Active treatment in both trials reduced important complications related to fetal overgrowth and pre-eclampsia.

Given the congruence of epidemiological and randomised controlled trial data, we believe that
it is time for implementation, rather than further procrastination.

Improved iodine status in Tasmanian schoolchildren after fortification of bread: a recipe for national success

Iodine is an essential micronutrient required for thyroid hormone synthesis. Inadequate dietary iodine intake is associated with a spectrum of diseases termed iodine deficiency disorders. The most serious and overt consequences are neurocognitive disorders and endemic goitre.1 Urinary iodine excretion is a marker of recent dietary iodine intake and is typically used to monitor population iodine sufficiency. Population iodine status is considered optimal when median urinary iodine concentration (UIC) is between 100 µg/L and 199 µg/L, with no more than 20% of samples having UIC under 50 µg/L.1

Concern about the emergence of widespread mild iodine deficiency in Australia and New Zealand led to mandatory iodine fortification of yeast-leavened bread in 2009.2 Tasmania has a well documented history of endemic iodine deficiency, with iodine supplementation strategies implemented since the 1950s.3 The use of iodophors as sanitising agents in the dairy industry was thought to have provided protection; however, urinary iodine surveys of Tasmanian school children in 1998 and 2000 showed a recurrence of iodine deficiency.4

In October 2001, the Tasmanian Government introduced a state-based voluntary iodine fortification program as an interim measure to reduce the recurrence of iodine deficiency. This program resulted in a modest but significant improvement in population iodine status.5 The Tasmanian voluntary fortification experience provided valuable information for the development of the Australia and New Zealand mandatory iodine fortification program.

In this article, we describe the results of the 2011 urinary iodine survey of Tasmanian schoolchildren and compare these results to surveys conducted before fortification and during a period of voluntary fortification.

Methods

A cross-sectional urinary iodine survey of Tasmanian schoolchildren was conducted in 2011. Survey methods were comparable to those used during the period of voluntary fortification, as described elsewhere.5

A one-stage cluster sampling method was used to randomly select school classes that included fourth-grade students from all government, Catholic and independent schools in Tasmania (such classes may include children in third, fourth, fifth and sixth grade, as composite class structures are popular in Tasmania). A total of 52 classes (from 49 schools) were invited to participate. This included 42 classes that had been randomly selected for the final survey conducted during the period of voluntary fortification and an additional 10 classes randomly selected in 2011 to boost sample size. In total, 37 classes (from 35 schools) agreed to take part, representing a class participation rate of 71%. Of the 880 children in participating classes, 356 (40%) returned positive consent and 320 (36%) provided a urine sample for analysis. These participation rates are comparable with the rates reported from previous surveys.5

Spot urine samples were collected at home, returned to school and transported by a private pathology provider to a laboratory where they were frozen and stored. Batch analyses were completed by the Institute of Clinical Pathology and Medical Research, Westmead Hospital. UIC was measured using the ammonium persulfate digestion method based on the Sandell–Kolthoff reaction.6

UIC data from children of comparable age from prefortification surveys and from participants in the surveys from the voluntary fortification period were used for comparison with the data from this survey.

Data were analysed using Stata version 11 (StataCorp). Median UIC, interquartile range and the proportion of samples with UIC under 50 µg/L were calculated for each survey. To facilitate comparisons between medians and the proportion of UIC results under 50 µg/L across intervention periods (prefortification, voluntary fortification and mandatory fortification), data were combined from the two prefortification surveys (1998 and 2000) and from the four surveys conducted during the period of voluntary fortification (2003, 2004, 2005 and 2007). Differences in median UIC across intervention periods were compared using Kruskal–Wallis χ2 (corrected for ties) with post-hoc Wilcoxon rank-sum test.

Ethics approval was obtained from the Tasmanian Health and Medical Human Research Ethics Committee and the Department of Education Tasmania. Parent or carer consent was obtained for all participating children.

Results

Of the 320 students participating in the 2011 survey, 158 (49%) were boys, 153 (48%) were girls and nine (3%) were of unknown sex. Participants were aged 8–13 years, with 83% aged 9–10 years. The median UIC in 2011 was 129 µg/L, and 3.4% of samples had a UIC under 50 µg/L.

The median UIC in 2011 was significantly higher than during the period of voluntary fortification (129 µg/L v 108 µg/L; P < 0.001), which in turn was significantly higher than the median UIC from the prefortification period (73 µg/L; P < 0.001) (Box 1). There was a reduction in the proportion of UIC results under 50 µg/L after voluntary fortification compared with prefortification, from 17.7% to 9.6% (P < 0.001), and a further reduction to 3.4% after mandatory fortification (P = 0.001) (Box 2). Box 3 shows the progressive improvement in median UIC results from Tasmanian urinary iodine surveys of schoolchildren over the iodine fortification intervention periods (prefortification, voluntary fortification and mandatory fortification).

Discussion

Our findings show a progressive improvement in the iodine status of Tasmanian schoolchildren over the iodine fortification intervention periods (from prefortification to voluntary fortification and mandatory fortification). This study also shows the specific benefit of a mandatory versus a voluntary approach to iodine supplementation.

Population iodine status is routinely assessed by measuring UIC, whereas determining the appropriate level of fortification in food relies on estimates of dietary intakes. The relationship between dietary iodine intake and UIC is usually linear — an increase in dietary intake results in a comparable increase in urinary excretion.7 The 56 µg/L increase in median UIC from prefortification to mandatory fortification is consistent with the predicted 52 µg/d increase in the mean dietary iodine intake for children aged 9–13 years, estimated by dietary modelling before the introduction of mandatory iodine fortification.8

This is the first study to specifically evaluate the adequacy of iodine nutrition in an Australian population after the introduction of mandatory iodine fortification of bread in 2009. The results are of significance to the Australian population more broadly, as the magnitude of effect of mandatory supplementation on the national population is likely to be similar to that observed in Tasmania.

In the 2004 National Iodine Nutrition Study, a survey of schoolchildren found that Western Australia had the highest median UIC of all Australian jurisdictions, at 142.5 µg/L.9 Extrapolating the magnitude of increase in UIC from our surveys to that observed in WA would result in a UIC just under 200 µg/L (56 µg/L + 142 µg/L), which is at the upper level of the optimal range.1

To facilitate comparisons, the sampling method used in our 2011 survey was modelled on the method used in the surveys conducted during the period of voluntary fortification.5 Classes that included fourth-grade children were originally chosen as the sampling frame to be consistent with World Health Organization guidelines for assessing population iodine status.1 Staff from the Department of Education Tasmania advised that this age group would be sufficiently independent to provide a urine sample, while minimising self-consciousness likely in older children. It is yet to be seen whether the observed impact of mandatory fortification is representative of other population groups, such as adults. Published surveys of prefortification UIC of Melbourne adults offer a useful baseline for this purpose.10 The Australian Health Survey 2011–2013 is measuring UIC in adults and children across Australia, and we anticipate this will provide further evidence of the iodine status in the Australian population.

Comparisons with prefortification surveys should be interpreted with the knowledge that there were subtle differences in sampling methods. A two-stage stratified sampling procedure was adopted in the prefortification period (1998–2000), where schools and then students from within schools were randomly selected. Subsequent surveys used a one-stage cluster sampling method with classes that included fourth-grade students as the sampling frame. These sampling differences are not considered significant and have been discussed elsewhere.5 Any sample bias associated with factors such as socioeconomic status or geographic location is unlikely to affect the results, as an association between UIC and these factors has not been found previously.4

Although the 2011 results are consistent with iodine repletion in the general population, they cannot be generalised to high-risk subgroups such as pregnant and breastfeeding women, whose daily iodine requirements increase by about 40%.11 Prior research in Tasmania has shown persistent iodine deficiency in pregnancy despite the introduction of voluntary iodine fortification.12 Recent evidence suggests that while mandatory iodine fortification may have benefited breastfeeding women, only those consuming iodine-containing supplements had a median UIC in the adequate range.13 Future studies of iodine nutrition should specifically assess the adequacy in these groups. Similarly, ongoing awareness of the recommendation that pregnant and lactating women take 150 µg of supplemental iodine per day should not be overlooked, particularly in those parts of Australia where marginal iodine deficiency has been previously reported.14,15

Changes to the iodine content of food supply (such as the level of iodine in milk or the level of salt in bread) or shifts in dietary choice (such as a preference for staples other than bread) could jeopardise iodine status in the future.3,16 The value of ongoing vigilance in monitoring population iodine status has been highlighted by previous authors.12,17,18 In addition, monitoring iodine levels in the food supply will be required to inform future adjustments to the mandatory iodine fortification program.

1 Urinary iodine concentration (UIC) of Tasmanian schoolchildren by year and intervention period

Intervention period

Year (n)

Median UIC (95% CI)

IQR

Proportion of samples with UIC < 50 µg/L (95% CI)

Prefortification*

1998 (124)

75 µg/L (72–80 µg/L)

60–96 µg/L

16.9% (10.3%–23.6%)

2000 (91)

72 µg/L (67–84 µg/L)

54–103 µg/L

18.7% (10.6%–26.7%)

Voluntary fortification*

2003 (347)

105 µg/L (98–111 µg/L)

72–147 µg/L

10.1% (6.9%–13.3%)

2004 (430)

109 µg/L (103–115 µg/L)

74–159 µg/L

10.0% (7.2%–12.8%)

2005 (401)

105 µg/L (98–118 µg/L)

72–155 µg/L

10.5% (7.5%–13.5%)

2007 (304)

111 µg/L (99–125 µg/L)

75–167 µg/L

7.2% (4.3%–10.1%)

Mandatory fortification

2011 (320)

129 µg/L (118–139 µg/L)

95–179µg/L

3.4% (1.4%–5.4%)

IQR = interquartile range. * Based on 1998–2005 surveys.5

2 Comparison of urinary iodine concentration (UIC) of Tasmanian schoolchildren across intervention periods

Fortification intervention period (n)

Median UIC (95% CI)

Difference from prefortification period

P* compared with results from prefortification period

P* compared with results from
voluntary
fortification period

Proportion of
samples with UIC < 50 µg/L
(95% CI)

Odds ratio (P)†
compared with results from
prefortification period

Odds ratio (P)†
compared with results from voluntary
fortification period

Prefortification (215)

73 µg/L (70–79 µg/L)

—

17.7% (12.6%–23.8%)

—

Voluntary fortification (1482)

108 µg/L (102–111 µg/L)

+ 35 µg/L

< 0.001

—

9.6% (8.1%–11.1%)

0.49 (< 0.001)

Mandatory fortification (320)

129 µg/L (118–139 µg/L)

+ 56 µg/L

< 0.001

3.4% (1.4%–5.4%)

0.17 (< 0.001)

0.34 (0.001)

* Difference in medians compared using Kruskal–Wallis χ2 (corrected for ties) with post-hoc Wilcoxon rank-sum test. † Difference in proportion of samples with UIC < 50 µg/L estimated by logistic regression.

3 Median urinary iodine concentration (UIC) of Tasmanian schoolchildren from 1998 to 2011