Introduction – what is gestational diabetes?

Moderate to severe maternal hyperglycaemia in pregnancy has unique diabetes-related risks in that there are potential long-term consequences for two individuals rather than just one: the mother and her unborn baby. Gestational diabetes (GDM) has been defined as any degree of glucose intolerance with onset or first recognition during pregnancy⁽¹⁾, to differentiate it from pre-diagnosed type 1 or type 2 diabetes or maturity-onset diabetes of the young (MODY) in women that get pregnant. This broad definition of GDM therefore includes women whose glucose intolerance develops during pregnancy and those that had pre-existing diabetes which had not been diagnosed before pregnancy. The distinction here is important as, unlike most unborn babies of women who develop glucose intolerance in pregnancy, those of women with pre-existing diabetes can be exposed to hyperglycaemia in the first two trimesters of pregnancy resulting in an increased risk of a range of both isolated and multiple cardiovascular and other abnormalities (including central nervous system and musculoskeletal defects)⁽Reference Corrigan, Brazil and McAuliffe^2, Reference Correa, Gilboa and Besser³⁾. To try and clarify the situation, the Consensus Panel of the International Association of Diabetes and Pregnancy Study Groups (IADPSG) recently recommended that high-risk women found to have diabetes at their initial prenatal visit should be diagnosed as having overt diabetes rather than GDM⁽⁴⁾. To diagnose GDM at a later visit it was recommended that one or more of the following plasma glucose thresholds should be equalled or exceeded during a 75 g oral glucose tolerance test: 5·1 mmol/l (fasting), 10·0 mmol/l (1 h post-load) and 8·5 (2 h post-load) mmol/l⁽⁴⁾. One of the long-term risks for the mother with GDM is the development of type 2 diabetes later in life⁽Reference Bellamy, Casas and Hingorani⁵⁾, but in a minority of women with GDM the glucose intolerance does not disappear post-partum⁽Reference Buchanan, Xiang and Kjos⁶⁾. Whether this type of diabetes should be considered gestational or type 2 from its onset is unclear as: (i) if the new IADPSG recommendations are not implemented undiagnosed type 2 diabetes may have been present in these women before pregnancy; (ii) type 2 diabetes and diabetes that develops during pregnancy have a number of shared risk factors and are hypothesised by some to be the same condition⁽Reference Lauenborg, Grarup and Damm^7, Reference Robitaille and Grant⁸⁾; and (iii) the continuing glucose intolerance may be autoimmune related and more like type 1 diabetes than type 2⁽Reference Lapolla, Dalfrá and Fedele⁹⁾. Such uncertainties over its diagnosis and lack of agreement over which screening protocols or diagnostic thresholds should be used make GDM prevalence estimates difficult, but it is generally considered to be somewhere between 1 and 14 % of all pregnancies⁽¹⁾ depending on the population in question. What is clearer, however, is that in line with increased prevalences of particularly type 2 diabetes, the incidence of GDM is rising wherever obesity is becoming more prevalent⁽Reference Hunt and Schuller¹⁰⁾.

GDM has long been known to raise the risk of macrosomia in the offspring, with the high glucose levels thought to cross the placenta and stimulate fetal insulin secretion which then acts as a growth factor⁽Reference Pedersen¹¹⁾. Macrosomia brings its own difficulties such as increased risks of shoulder dystocia, brachial plexus injuries and clavicular fractures in natural deliveries leading to a higher requirement for birth by Caesarean section⁽Reference Gilmartin, Ural and Repke¹²⁾. Other short-term risks associated with GDM in the mother are pregnancy-induced hypertension and pre-eclampsia, urinary tract infections, pyelonephritis and polyhydramosis (which itself leads to increased risk of abruption placentae). There is also increased risk of stillbirth and congenital abnormalities⁽Reference Kapoor, Sankaran and Hyer¹³⁾. Short-term risks for the baby include neonatal hypoglycaemia (caused by the excess insulin produced initially in response to the maternal hyperglycaemia, once the baby has been born and that drive has been removed), hyperbilirubinaemia, hypocalcaemia, respiratory distress syndrome, and polycythaemia⁽Reference Gilmartin, Ural and Repke¹²⁾. Having been diagnosed with GDM, as already stated, the mother is subsequently at increased risk of developing type 2 diabetes⁽Reference Bellamy, Casas and Hingorani^5, Reference Buchanan, Xiang and Kjos⁶⁾, with the prospectively studied Coronary Artery Risk Development in Young Adults (CARDIA) cohort showing that this risk is independent from preconception glucose tolerance and obesity or a family history of diabetes⁽Reference Gunderson, Lewis and Tsai¹⁴⁾. As well as long-term risks for herself, in her offspring there is increased risk of childhood obesity⁽Reference Hillier, Pedula and Schmidt^15, Reference Dabelea, Mayer-Davis and Lamichhane¹⁶⁾, and type 2 diabetes and hyperlipidaemia in adolescence and beyond⁽Reference Malcolm, Lawson and Gaboury^17–Reference Pettitt, Lawrence and Beyer²¹⁾. Where the baby is female, exposure to maternal hyperglycaemia in utero increases their own risk of subsequently developing GDM in their own pregnancies⁽Reference Claesson, Aberg and Marsál²²⁾. This metabolic programming by in utero exposure to hyperglycaemia therefore is a transgenerational effect that may contribute to the expected huge increase in prevalence of type 2 diabetes worldwide⁽Reference Wild, Roglic and Green²³⁾, especially given the increasing prevalence of obesity.

Risk factors for gestational diabetes

Like all other major forms of diabetes, GDM results from inadequate insulin secretion for the degree of insulin resistance. As has already been stated, the risk factors for GDM (Table 1) share similarities with those for type 2 diabetes. In fact, the relatively high risk that women who develop diabetes in pregnancy have for subsequently developing type 2 diabetes suggests that certain forms of these conditions have common precedents, the physiological insulin resistance of pregnancy manifesting the disease state somewhat earlier than would otherwise occur. This insulin resistance is likely to be caused by placental hormones and/or proteins, such as placental growth hormone, cortisol, human placental lactogen⁽Reference Gilmartin, Ural and Repke¹²⁾ or TNF-α⁽Reference Barbour, McCurdy and Hernandez²⁴⁾, given that for the majority of women with GDM the glucose intolerance resolves post-partum⁽Reference Buchanan, Xiang and Kjos⁶⁾. Risk factors for GDM must therefore either contribute directly to this insulin resistance and/or relative insulin deficiency, or they must be associated or correlated with other factors that do. The traditional, and most cited, risk factors for GDM are high maternal age, weight and parity (which are often correlated), a family history of type 2 diabetes and the previous birth of a macrosomic baby⁽Reference Ben-Haroush, Yogev and Hod²⁵⁾. Of the more recently described risk factors, high or low maternal birth weights⁽Reference Innes, Byers and Marshall²⁶⁾ are important, given the previously described transgenerational effects. Other potential risk factors that have been variably associated with higher maternal glucose concentrations in the third trimester of pregnancy and which therefore may alter GDM risk include multiple pregnancy (for a review, see Norwitz et al. ⁽Reference Norwitz, Edusa and Park²⁷⁾) and short stature⁽Reference Moses and Mackay²⁸⁾.

Table 1 Risk factors for gestational diabetes (GDM)

Having briefly highlighted what GDM is, and what its risk factors are, I now want to focus the remainder of the present review on recent advances in two areas that have developed rapidly, the genetics of GDM and its treatment. Of the current options available to manage GDM, all women will require dietary intervention (and probably exercise) whilst some will require additional pharmacological therapy. Pinpointing genetic risk factors for GDM will help identify mechanisms underlying its pathophysiology and potentially may reveal new preventative strategies and even therapeutic targets. Ultimately, increased knowledge about the genetics and treatment of GDM will help prevent complications in both the mother and child. Readers wanting a review of other established aspects of the condition are referred to other excellent up-to-date reviews of the subject⁽Reference Buchanan, Xiang and Kjos^6, Reference Gilmartin, Ural and Repke^12, Reference Ben-Haroush, Yogev and Hod^25, Reference Cheng and Caughey^29–Reference Hod, Jovanovic and Di Renzo³¹⁾.

Genetics of gestational diabetes

The cause of familial aggregation of GDM with a first-degree relative who has or has previously had GDM or another type of diabetes is likely to have both genetic and (non-genetic) environmental components, especially given that in females both low and high birth weights⁽Reference Innes, Byers and Marshall²⁶⁾ are associated with the future development of GDM in their own pregnancies. This suggests that a pregnant woman with poorly controlled, pre-existing type 1 diabetes is at increased risk of giving birth to a macrosomic baby who, if female, is subsequently at increased risk of developing GDM and/or type 2 diabetes⁽Reference Sobngwi, Boudou and Mauvais-Jarvis³²⁾ in her own pregnancies and beyond. As well as such metabolic programming effects, genetic variation also plays its part in regulating size at birth⁽Reference Dunger, Petry and Ong³³⁾ and therefore risk of GDM in women with low or high birth weights.

The collection of large DNA cohorts, combined with improvements in DNA technologies, has driven rapid increases in knowledge about the genetics of all major forms of diabetes in recent years. For type 2 diabetes, the most common form, studies of large DNA cohorts that have been assessed by whole-genome association have allowed the elucidation of genetic markers of risk in or near genes that would have been extremely unlikely to have been considered using a candidate approach with an a priori hypothesis. So whereas 5 years ago there were only two markers that were robustly associated with type 2 diabetes, gained through linkage and/or candidate genetic association studies (the PPARγ and K channel, inwardly rectifying, subfamily J, member 11 variants)⁽Reference Frayling³⁴⁾, the list now stands at more than twenty-two loci⁽Reference Weedon, McCarthy and Hitman^35–Reference Yasuda, Miyake and Horikawa⁴⁰⁾ (Table 2). Subsequent to these studies at least ten of these loci (KCNJ11, TCF7L2, CDKAL1, KCNQ1, CDKN2A/CDKN2B, HHEX/IDE, IGF2BP2, SLC30A8, TCF2, FTO) have now been associated with GDM risk⁽Reference Lauenborg, Grarup and Damm^7, Reference Shaat, Ekelund and Lernmark^41–Reference Shin, Lae Park and Shin⁴⁶⁾, which again is not surprising given the common precedents of certain forms of these two types of diabetes and the potential that some of the cases in these studies actually had undiagnosed type 2 diabetes before conceiving. A number of other markers, most of which have also been less robustly associated with type 2 diabetes in certain populations, have also been associated with GDM risk. However, findings for GDM are often based on relatively small sample sizes (relative to sizes used to discover new markers of type 2 diabetes risk⁽Reference Weedon, McCarthy and Hitman^35–Reference Zeggini, Scott and Saxena³⁸⁾). These findings are often not confirmed in other populations and cannot be considered robust. Nevertheless, polymorphic markers at or near the following genes may contribute to the polygenic risk for GDM: insulin variable number of tandem repeats⁽Reference Litou, Anastasiou and Thalassinou⁴⁷⁾; insulin receptor substrate 1⁽Reference Fallucca, Dalfra and Sciullo⁴⁸⁾; β3-adrenergic receptor⁽Reference Festa, Krugluger and Shnawa⁴⁹⁾; mannose-binding lectin⁽Reference Megia, Gallart and Fernandez-Real⁵⁰⁾; calpain 10⁽Reference Leipold, Knofler and Gruber⁵¹⁾; plasminogen activator inhibitor 1⁽Reference Leipold, Knoefler and Gruber⁵²⁾; insulin receptor⁽Reference Ober, Xiang and Thisted⁵³⁾; sulfonylurea receptor 1⁽Reference Rissanen, Markkanen and Karkkainen⁵⁴⁾; tRNA Leu mitochondrial⁽Reference Chen, Liao and Roy⁵⁵⁾; glucokinase⁽Reference Shaat, Karlsson and Lernmark⁵⁶⁾; hepatocyte nuclear factor 1α⁽Reference Shaat, Karlsson and Lernmark⁵⁶⁾. Like for types 1 and 2 diabetes⁽Reference Weedon, McCarthy and Hitman^35, Reference Lango and Palmer^57, Reference van Hoek, Dehghan and Witteman⁵⁸⁾, the overall genetic risk for GDM is highly likely to be made up from the sum of relatively small contributions from a number of different genes⁽Reference Lauenborg, Grarup and Damm⁷⁾ – perhaps different genes in different populations depending on population prevalences of the various risk alleles.

Table 2 Genes that either contain or are near polymorphic markers that are associated with type 2 diabetes⁽Reference Weedon, McCarthy and Hitman^35–Reference Yasuda, Miyake and Horikawa⁴⁰⁾

dbSNP, Single Nucleotide Polymorphism Database.

Given that GDM in pregnant women tends to reveal a genetic predisposition to other types of diabetes, it is not surprising that most commonly the form in question is type 2 diabetes, especially if other risk factors such as obesity are also present. However, studies of familial clustering of diabetes show an increased prevalence of type 1 diabetes in offspring of mothers with GDM⁽Reference Dörner, Plagemann and Reinagel⁵⁹⁾. This suggests that GDM may also be caused by genetic variation that predisposes a woman to autoimmune type 1 diabetes or late autoimmune diabetes of adulthood⁽Reference Lapolla, Dalfrá and Fedele⁹⁾. Indeed, about 10 % of women with GDM may have an autoimmune form of this condition⁽Reference Lapolla, Dalfrá and Fedele⁹⁾. In general, studies of human leucocyte antigen (HLA) markers in relation to autoimmune GDM have proved inconsistent due to small sample sizes and ethnically mixed study groups⁽Reference Lapolla, Dalfrá and Fedele⁹⁾, with some studies showing no linkage or association⁽Reference Bell, Barger and Go^60–Reference Shaat, Ekelund and Lernmark⁶³⁾. However, others have shown positive relationships with markers such as HLA-DR3 or HLA-DR4 in islet cell antibody-positive women with GDM⁽Reference Rubinstein, Walker and Krassner⁶⁴⁾, or indeed any women with GDM⁽Reference Freinkel, Metzger and Phelps^65, Reference Ferber, Keller and Albert⁶⁶⁾, HLA-Cw7⁽Reference Lapolla, Betterle and Sanzari⁶⁷⁾ and HLA-DR3-DQ2, DR4-DQ8 and MHC class I chain-related gene A (MICA) 5·0/5·1 in autoantibody-positive women with GDM⁽Reference Törn, Gupta and Sanjeevi⁶⁸⁾ and HLA-DR7 dQ2, DR9-DQ9, DR14-DQ5, MICA5·0⁽Reference Törn, Gupta and Sanjeevi⁶⁸⁾ and DQB1*0602⁽Reference Papadopoulou, Lynch and Shaat⁶⁹⁾ in women with GDM who were not autoantibody positive.

Not surprisingly, given the link between reduced size at birth and increased subsequent risk of developing type 2 diabetes⁽Reference Hales, Barker and Clark⁷⁰⁾, some of the type 2 diabetes genetic risk loci have also recently been shown to be associated with low birth weight⁽Reference Freathy, Bennett and Ring⁷¹⁾. In one study, participants with risk alleles for the CDKAL1 and HHEX-IDE loci were born on average 80 g lighter than those participants without the risk alleles⁽Reference Freathy, Bennett and Ring⁷¹⁾. Given that these two loci are also associated with the development of GDM⁽Reference Lauenborg, Grarup and Damm⁷⁾, there is a clear link between the genetic risk of GDM and alterations in fetal growth. Following on from an earlier report by Haig⁽Reference Haig⁷²⁾, we recently proposed that as well as the mother's genes contributing to her risk of developing GDM in pregnancy, polymorphic variation in fetal growth genes could also contribute to risk of GDM in the mother⁽Reference Petry, Ong and Dunger⁷³⁾. The basis for this relies on the kinship theory of pregnancy⁽Reference Haig and Westoby⁷⁴⁾ (sometimes called the conflict theory) which suggests that genes inherited from the father will tend to try and boost fetal growth, whilst those inherited from the mother will try and limit or restrict it. Mitochondrial genes, which are exclusively inherited from the mother, at least when not affected by paternal leakage, heteroplasmy or recombination⁽Reference White, Wolff and Pierson⁷⁵⁾, and imprinted genes⁽Reference Reik, Constância and Fowden⁷⁶⁾, where the copy inherited from one of the parents is inactivated depending on both the gene in question and the developmental stage of the offspring, are ideally suited to mediate these alterations in growth through altering the availability and transfer of nutrients to the fetus. There are a number of novel studies in human subjects indirectly linking genetic variation in the fetus with changes in maternal glucose concentrations in pregnancy. First, a large observational study stratifying pregnancies according to the sex of the offspring found an increased incidence of GDM in women carrying boys rather than girls⁽Reference Sheiner, Levy and Katz⁷⁷⁾, possibly resulting from a higher dietary energy intake in pregnant women carrying boys⁽Reference Tamimi, Lagiou and Mucci⁷⁸⁾. Second, another large observational study found higher maternal glucose concentrations in women carrying twins than in those carrying only one baby⁽Reference Schwartz, Daoud and Zazula⁷⁹⁾. In a retrospective study of women carrying offspring with Beckwith–Wiedemann syndrome there was a trend for an increased risk of the women developing GDM compared with when the same women carried non-affected siblings⁽Reference Wangler, Chang and Moley⁸⁰⁾. In our own studies of a common variant in the imprinted, maternally expressed H19 gene, when transmitted to the baby the variant was associated with maternal glucose levels in pregnancy⁽Reference Petry, Ong and Barratt⁸¹⁾.

To develop the concept that variation in fetal growth genes is able to alter maternal risk of GDM we recently assessed the maternal glucose tolerance of phenotypically wild-type mice carrying offspring with their H19 genes disrupted⁽Reference Petry, Evans and Wingate⁸²⁾, common variation in this gene being associated with variation in size at birth in humans⁽Reference Petry, Ong and Barratt⁸¹⁾. These mouse offspring have a 13 kb region knocked out which included the entire H19 gene and 10 kb of its 5′-flanking region including its Igf2 control element⁽Reference Leighton, Ingram and Eggenschwiler⁸³⁾. This causes them to have a 30 % increase in birth weight⁽Reference Leighton, Ingram and Eggenschwiler^83, Reference Chiao, Fisher and Crisponi⁸⁴⁾. On the first day of pregnancy there was no difference in the glucose tolerances of those pregnant mice carrying H19 knockout offspring from those carrying only wild-type offspring. However, by day 16 of the 21 d pregnancy, in the third trimester about the time when GDM becomes more prevalent in humans⁽Reference Seshiah, Balaji and Balaji⁸⁵⁾, the areas under the curves of intra-peritoneal glucose tolerance tests performed in phenotypically wild-type mice carrying H19 knockout offspring was 28 % higher than those from wild-type mice carrying only wild-type offspring. Whilst the reason for this could be the removal of a functional H19 gene which normally acts to repress Igf2 expression⁽Reference Haig⁸⁶⁾, it could also be that the removal of the Igf2 control element effectively doubles Igf2 expression in the growing fetuses and placentas⁽Reference Leighton, Ingram and Eggenschwiler⁸³⁾ (how this might influence maternal glucose concentrations is shown in Fig. 1). Whilst further mechanistic studies are ongoing, these results are proof of principle that altering the fetal gene is able to alter maternal glucose tolerance in pregnancy. The relevance of this to humans is difficult to test directly due the confounding effects of the mothers' own genes on their glucose tolerance in pregnancy⁽Reference Shaat and Groop^87, Reference Watanabe, Black and Xiang⁸⁸⁾ and the fact that the fetus inherits half of its genes from its mother so that it is therefore difficult to separate out which genes are having which effect⁽Reference Petry, Ong and Dunger⁷³⁾. Nevertheless, this can be partially overcome when testing associations of common polymorphic variation in paternally expressed imprinted genes, studies of which have already begun.

Fig. 1 Schematic representation of how the fetal genotype, in this case fetal mice that have the H19 gene and 10 kb 5′-flanking region disrupted, may cause an increase in maternal blood glucose concentrations so as to increase their potential glucose supply and help enhance their growth⁽Reference Petry, Ong and Dunger^73, Reference Petry, Evans and Wingate⁸²⁾. It is hypothesised that the increased Igf2 expression in these mice causes increased expression of various placental hormones (and other proteins) that are secreted into the maternal circulation and have metabolic effects that lead to the raising of maternal blood glucose concentrations.

In summary, progress in the study of the genetics of GDM is hampered by such factors as the heterogeneous causes and criteria for diagnosing the condition and its relative scarcity⁽Reference Lapolla, Dalfrá and Fedele⁹⁾. What is clear is that there is a polygenic rather than single gene risk for its development⁽Reference Lauenborg, Grarup and Damm⁷⁾. Not surprisingly, given that GDM can be split into non-autoimmune and autoimmune forms, genes associated or linked with GDM tend to be associated with type 2 diabetes for the non-autoimmune form or type 1 diabetes for the rarer autoimmune form. If larger GDM cohorts could be recruited, possibly by pooling existing data and sample sets, genome wide association followed by candidate gene studies would have greater statistical power to detect additional associations of genes with GDM. Such genes are likely to include some of those already associated with either type 1 or 2 diabetes (and possibly offspring birth weight). For a more complete set of genes associated with the risk of developing GDM it is possible that assessments of polymorphic variation in fetal growth-related genes may also be needed⁽Reference Petry, Ong and Dunger⁷³⁾.

Prevention and treatment of gestational diabetes

The Hyperglycemia and Adverse Pregnancy Outcome (HAPO) study, which investigated the glucose tolerances of over 23 000 women with diabetes-free pregnancies, recently showed a strong linear relationship between circulating maternal glucose concentrations in the third trimester of pregnancy and risk of offspring birth weight being over the ninetieth centile⁽Reference Metzger and Lowe⁸⁹⁾, partially explained by changes in fetal adiposity⁽⁹⁰⁾. Whilst before the publication of these results it was apparent that macrosomic babies were often born to mothers with the most severely impaired glucose tolerance in pregnancy, suggesting a link between increased fetal growth and high maternal glucose concentrations, it is now clear that there is a strong continuous association between maternal glucose tolerance and a number of different adverse pregnancy outcome events even in the sub-diabetes range. This suggests that even in the presence of unalterable GDM risk factors such as multiple genetic risk alleles, optimising treatments and therefore improving maternal glucose tolerance is beneficial. Indeed the importance of treatment was shown by a randomised controlled trial of 1000 women with GDM where lower rates of adverse pregnancy outcome events such as macrosomia, pre-eclampsia, admissions to neonatal intensive care units and perinatal complications were found in women who performed blood glucose monitoring, were given dietary advice and treatment if necessary, in comparison with women who received just routine care⁽Reference Crowther, Hiller and Moss⁹¹⁾. To reduce the risk of these complications there are three strategies used for the treatment of GDM: dietary modification, regulated exercise and pharmacological. Women with the severest form of the condition, which may become evident in the first trimester of pregnancy rather than the more common third trimester⁽Reference Seshiah, Balaji and Balaji⁸⁵⁾ and/or might be autoimmune mediated⁽Reference Lapolla, Dalfrá and Fedele⁹⁾, are likely to require all three forms of treatment. Most women though (up to 90 % in the UK⁽⁹²⁾) may be adequately treated using just the first two strategies. However it is managed, the Fifth International Workshop on Gestational Diabetes Mellitus recommended that current maternal capillary blood glucose targets should be: fasting below 5·3 mmol/l, 1 h after starting a meal below 7·8 mmol/l and 2 h after starting a meal below 6·7 mmol/l⁽Reference Metzger, Buchanan and Coustan⁹³⁾.

Conclusions and future prospects

Due to potential fetal programming and the ensuing transgenerational effects, the increases in the incidence of GDM may enhance the massive public health burden worldwide as ‘diabetes begets diabetes’⁽Reference Claesson, Aberg and Marsál^22, Reference Ma and Chan¹⁵⁶⁾. There is an urgent need, therefore, to reduce the effects of GDM in pregnancy and to do it in light of the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) study finding that maternal glucose concentrations in the third trimester of pregnancy, even in the sub-diabetes range, are linearly related to risk of adverse pregnancy outcomes rather than there being a particular maternal glucose threshold below which it is ‘safe’⁽Reference Metzger and Lowe⁸⁹⁾. Clearly, only some of the risk factors for GDM can be modified: the easiest of which may be limiting pre-pregnancy weight which in theory can be achieved by dietary, exercise or even pharmacological means.

Even allowing for difficulties caused by differences in screening protocols and diagnostic thresholds, there are several key questions that still need answering to optimise the treatment of GDM (Table 3). First, for the dietary treatment and even prevention of GDM it is important to gain more convincing proof that low-GI diets and exercise offer real benefits to the pregnant woman. The treatment of GDM by oral hypoglycaemic agents appears to be safe in the short term, but potential long-term effects on the offspring are unknown and will require long-term follow-up. For treatment of GDM by insulin, the safety and efficacy of the use of long-acting insulin analogues need to be established as they may help improve maternal glycaemia more effectively than is currently possible with conventional insulins. The efficacy and safety of the use of closed-loop technologies⁽Reference Chitayat, Jovanovic and Hod¹⁵⁷⁾ (‘the artificial pancreas’ consisting of a continuous glucose monitor, an insulin pump containing human insulin or a rapid-acting insulin analogue and a control algorithm linking the two) in pregnancy also needs to be ascertained. Whilst such systems have not been tested in pregnancy so far, early results from children and adolescents suggest that at present they appear to work well under basal conditions but they may be currently less able to adequately cope with high carbohydrate loads at meal times⁽Reference Weinzimer, Steil and Swan¹⁵⁸⁾. They may therefore be most effective in GDM when guidelines over the consumption of frequent small meals and snacks⁽Reference Abell^97–Reference Dornhorst and Frost⁹⁹⁾, rather than large meals, are followed. In conclusion, there remain a number of key questions that need answering before regimens for treating GDM can be considered optimal. Recent efforts to clarify the diagnosis of GDM⁽⁴⁾ should help with the recruitment of more uniform populations to studies seeking to address such issues, which in turn should reduce the heterogeneity of the results they produce and aid the drawing of more definitive conclusions.

Table 3 Key remaining questions to optimise the treatment of gestational diabetes (GDM)

GI, glycaemic index.