Gestational DiabetesMellitus: PrimumNon Nocere

M aturity-onset diabetes of theyoung (MODY) encompasses acollection of distinct forms of di-

abetes, which are inherited in an autosomal-dominant mode from the maternal orpaternal side of the family or occasion-ally occur as a de novo mutation. All thegenes involved affect either b-cell sensingor insulin secretion (1). The clinical pre-sentations of MODY are heterogeneous,reflecting the different gene mutationsinvolved, and the glucose dysregulationobserved ranges from a relatively inno-cent rise in the fasting glucose to frankdiabetes with neurological involvement(2,3).

An exact MODY prevalence withinthe general diabetes population hasproven difficult to assess because ofunderrecognition and lack of routinelyavailable and affordable diagnostic tools.A further confounder is that the reportedregional prevalence of specific MODYmutations varies considerably (4). Con-servative estimates suggest that between0.14–1.8% of all cases of diabetes couldbe attributable to MODY (4). It is to beexpected that among women screenedfor gestational diabetes mellitus (GDM)the prevalence of MODY will be higher,reflecting both the proportionatelylower prevalence of type 2 diabetes inwomen of this age group and the prob-ability that those with undiagnosedMODY will screen positive (5). Fromthe few population studies reported,mutations in the hepatocyte nuclear fac-tor 1 a (HNF1a) gene (MODY 3) and glu-cokinase (GCK) gene (MODY 2) accountfor the majority of cases (6).

MODY 2 is characterized by its highpenetrance, early onset, and lifelong fast-ing hyperglycemia. It is due to mutationsin the pancreatic GCK gene, which actsas the b-cell glucose sensor, setting theglucose threshold at which amplifica-tion of insulin secretion occurs (7). InMODY 2, this is set at 18–45 mg/dL (1.0–2.5 mmol/L), higher than for unaffectedadults (7). Glucose tolerance can remainstable over many years, provided that in-sulin sensitivity also remains stable (8).Although MODY 2 is associated withlifelong fasting hyperglycemia that may

progressively increase with age, long-term diabetes complications are uncom-mon (9,10).

MODY 2 does, however, have clinicalimplications in pregnancy when there isdiscordance between the maternal andfetal genotype; statistically this occurs in50% of all pregnancies in which themother or father carries the MODY mu-tation. When the mother is affected butnot the fetus, maternal hyperglycemiacauses fetal hyperinsulinemia and in-creased birth weight (11). By contrast,when the fetus carries the paternalMODY 2 gene, the levels of maternalglycemia are insufficient to stimulate ade-quate fetal insulin to sustain optimalgrowth, and birth weight is approxi-mately 500 g lower than for an unaf-fected sibling (11). When both themother and fetus share the MODY 2mu-tation, birth weight is normal, providingthe mother’s hyperglycemia is not treated,as the glucose threshold to trigger insulinsecretion is similar in the mother andfetus, and fetal insulin levels remain nor-mal. If, however, a mother with MODY 2has her hyperglycemia treated in preg-nancy and the fetus also carries the GCKmutation, birth weight can be severelycompromised (12). On the basis of theseobservations, it has been recommendedto treat hyperglycemia in the motherswith MODY 2 only when there is ultra-sound evidence of accelerated fetalgrowth (5).

Maternal hyperglycemia at levels ob-served in women with MODY 2 has inobservational and randomized trials beenassociated with adverse pregnancy out-comes (13,14). These studies have pro-vided the evidence for the InternationalAssociation of the Diabetes and Preg-nancy Study Groups (IADPSG) guidelineson the diagnosis of GDM (15). In theIADPSG guidelines, a fasting glucosevalue of $92 mg/dL (5.1 mmol/L) isconsidered diagnostic for GDM. As thisfasting value is set lower than other com-monly used diagnostic criteria, if adopted,more women with GDM would be diag-nosed (16). In addition, the lower fastingvalue by IADPSG criteria would label all

pregnant women with previously undiag-nosed MODY 2 as having GDM.

If, in keeping with the IADPSG di-agnostic criteria, a fasting glucose levelbelow 92 mg/dL (5.1 mmol/L) was alsoadopted as a management target in GDM,this would be difficult to achieve in womenwith MODY 2 treated with diet alone, andwould inevitably necessitate insulin ther-apy. More importantly these more strin-gent fasting glucose targets would bedetrimental to fetal growth in half of allpregnancies (12).

The article by Chakera et al. (17) inthis issue of Diabetes Care providesproof of concept that prior knowledgeof the fetal genotype can help predictfetal susceptibility to maternal hyper-glycemia and can therefore favorablyinfluence treatment in women withMODY 2. The article describes two preg-nancies in women withMODY 2 in whomglycemic management was tailored onthe basis of fetal genotyping, performedfollowing chorionic villus samplingundertaken for other indications. In bothpregnancies, the fetuses had inherited thematernalGCKmutation andwere thereforeprotected from the levels of maternal hy-perglycemia they were exposed to. Bothwomen would have warranted active glyce-mic management by current guidelines(18). Despite significantmaternal hypergly-cemia and no treatment, both infants wereborn at term with normal birth weights.

There are increasing numbers ofmaternal genes being identified that in-fluence fasting blood glucose and fetalgrowth (19). Our knowledge in this fieldwill expand with further subanalyses ofmaternal and fetal genes from the largeHyperglycemia and Adverse PregnancyOutcome (HAPO) cohort for which de-tailed biochemical, anthropometric, andgenetic data have been collected (19). Inthe absence of this knowledge and theability to detect fetal genotype noninva-sively during pregnancy, it must be ac-knowledged that universally appliedtreatment guidelines will not be appro-priate for a minority of women withGDM. However as 15–20% of today’santenatal population has GDM usingthe IADPSG criteria, this minority will

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still represent a sizable number of preg-nancies (16).

Identifying and managing pregnan-cies appropriately when either the moth-er or the father carries the MODY2 generequires a higher level of clinical suspicionamong family physicians, diabetologists,and obstetricians and greater access to thenecessary diagnostic tools. Until there areadvances in the noninvasive genotyping offetal DNA, for example using cell free fetalDNA, genotyping the fetus will requireopportunistic use of CVS if undertakenfor alternative indications.

The optimal treatment during preg-nancy of women with other monogenicforms of diabetes has not been wellevaluated. Permanent neonatal diabetesis believed to affect approximately 1 in200,000 births; however, the conditionis often misdiagnosed as type 1 diabetes.A variety of genes have been implicatedincluding activating mutations in thegene encoding the Kir6.2 subunit ofthe b-cell ATP-sensitive K channel(KCNJ11) (20). Good glycemic controlwith a lower risk of hypoglycemia canbe achieved in patients with the Kir6.2mutations using treatment with sulfo-nylureas rather than insulin (21). How-ever, the safety of sulfonylurea use inpregnancy has not been clearly estab-lished, and though some evidence ex-ists on the use of glyburide, the safetyof other agents such as gliclazide is un-known (22).

Gathering together sufficient num-bers of women with permanent neonataldiabetes in pregnancy to establish theoptimal therapy will depend on observa-tional data from those few specializedcenters that look after these women.Because of the general paucity of data, thetwo case reports by Gaal et al. (23) ofwomen with KCNJ11 mutations treatedexclusively during pregnancy with the sul-fonylurea glicazide, is a small but helpfulcontribution, which when added to otheranecdotal reports (24) will begin toestablish a knowledge base from whichguidelines can be formed. However, untilsafety data on the use of gliclazide inpregnancy is established, its use cannotbe routinely advocated in these circum-stances.

The reports from Chakera et al. andGaal et al. both highlight that treating allwomen with hyperglycemia in pregnancyusing generic evidenced-based algorithmicguidelines may not necessarily be in thebest interests of all mothers and theirbabies.

SHIVANI MISRA, MRCP1

ANNE DORNHORST, FRCP2

From the 1Department of Metabolic Medicine, Im-perial Healthcare NHS Trust, London, U.K.; andthe 2Department of Medicine, Imperial CollegeHealthcare NHS Trust, London, U.K.

Corresponding author: Shivani Misra, s.misra@imperial.ac.uk.

DOI: 10.2337/dc12-0689© 2012 by the American Diabetes Association.

Readers may use this article as long as the work isproperly cited, the use is educational and not forprofit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ fordetails.

Acknowledgments—Nopotential conflicts ofinterest relevant to this article were re-ported.

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