New Pregnancy Criteria Sift Out MODY from Gestational Diabetes

July 08, 2015

Identifying women who might have maturity-onset diabetes of the young (MODY) is feasible during pregnancy using new pregnancy-specific screening criteria, at least in white patients, say Australian researchers.

MODY is most commonly caused by one of three genetic mutations and accounts for about 1% to 2% of all diabetes cases but is often misdiagnosed as either type 1 or type 2 diabetes, resulting in overtreatment or unnecessary therapy. Fasting glucose is high from birth (typically 5.5 to 8 mmol/L), but there are few symptoms and it may first be detected in pregnancy.

Currently, more than 80% of MODY cases are undiagnosed — performing universal testing for MODY in women with gestational diabetes is not practical because of the financial cost of the genetic tests needed to confirm the diagnosis, explain Victoria L Rudland, PhD, of the University of Sydney, Australia, and colleagues, in their paper published online June 24 in Diabetes Care.

But identifying it is key, they stress. "It is a form of diabetes with a low risk of complications and does not require treatment outside of pregnancy. It is important to differentiate MODY from gestational diabetes as management and outcomes differ," Dr Rudland and colleagues explained to Medscape Medical News in an email.

"In particular, the intensive glycemic control commonly employed in gestational diabetes may adversely affect the fetus of a pregnant woman with MODY," they explain.

Adopting the new pregnancy screening criteria, they were able to more than halve the need for expensive genetic testing, at least among white women. "But our study suggests the new screening criteria may perform less well in other ethnicities," they observe. "Further studies to develop ethnic-specific pregnancy screening criteria are indicated."

They say their findings "should change care and serve to highlight this form of diabetes to clinicians globally." Given that about 1% of women with gestational diabetes have MODY "and that this knowledge is important for their management, consideration of this diagnosis should be mentioned in gestational diabetes management guidelines for primary care, endocrinology, and obstetric care," they urge.

BMI May Become Less Useful for Screening as Obesity Rises

The proposed new pregnancy screening criteria are a fasting blood glucose of >5.5 mmol/L at antenatal testing but prepregnancy body mass index (BMI) of <25 mg/kg2 to identify pregnant women for further referral for genetic testing.

MODY most commonly arises from one of three heterozygous gene mutations — glucokinase (GCK)-MODY, hepatocyte nuclear factor 1 homeobox alpha ( HNF1A)-MODY, and hepatocyte nuclear factor 4 alpha (HNF4A)-MODY.

In this study, the Australian doctors looked for GCK-MODY.

They used a gestational diabetes database to identify 63 of 776 women who had a postpartum oral glucose tolerance test suggestive of GCK MODY. Of these 63, just under half, 31, agreed to undergo GCK testing. The accuracy of the new screening criteria and HbA1c were examined. The study group was ethnically diverse: 39% were Anglo-Celtic, 26% Southeast Asian, and 16% Indian.

Projected referrals were calculated by applying the new screening criteria to a larger gestational diabetes database of 4415 women.

Four of the 31 high-risk women (12.9%) were confirmed as having GCK-MODY. Assuming a similar prevalence among the remaining high-risk women who were unavailable for testing gives a prevalence of GCK-MODY of one in 100 cases of gestational diabetes, the researchers say.

The new screening criteria identified all Anglo-Celtic women with GCK-MODY but not the single Indian woman with it, as she did not satisfy the BMI criteria.

"While BMI has historically helped differentiate MODY from other types of diabetes, it may become less useful as background rates of obesity increase among all ethnicities," the doctors observe.

Hence, "we look forward to the advent of readily available, cheaper genetic tests," they told Medscape Medical News.

Unique Study Design Also Indicates Antepartum HbA1c Not Useful

The researchers highlight a major strength of their work is its unique design. "A difficulty in studying GCK-MODY is that, because of its low population prevalence, a prospective study would take several years to identify a sufficient number of women with GCK-MODY."

But their approach maximized the yield of GCK-MODY by preselecting from a gestational diabetes database women whose postpartum oral glucose tolerance test was highly suggestive of GCK-MODY based on well-substantiated selective screening criteria.

"Our detection rate…is consistent with another multiethnic gestational diabetes cohort and validates our approach," they explain.

This is also the first study to investigate antenatal HbA1c in GCK-MODY: no difference was seen in this measure of diabetes between the GCK-MODY and gestational-diabetes groups.

Therefore antepartum HbA1c "has limited value in differentiating GCK-MODY from standard gestational diabetes mellitus," they point out.

Dr Rudland and colleagues say that the application of these new pregnancy screening criteria would reduce referrals for genetic tests by 80% among white women. But they would refer substantially more Southeast Asian and Indian women despite a lower disease prevalence.

Diagnosis Affects Management

Expanding upon why it is important to detect GCK-MODY in pregnancy, Dr Rudland and colleagues explained that treatment of maternal hyperglycemia "depends on whether the fetus inherits the GCK mutation."

But it's not usually possible to tell if the fetus has inherited the mutation, so "unlike standard gestational diabetes, maternal hyperglycemia in pregnant women with GCK-MODY is not routinely treated," they observe. This is because, if the fetus does inherit the GCK mutation, it will usually have a normal birth weight in this case, and if maternal hyperglycemia is treated, it can potentially lead to a reduced birth weight.

"Instead, regular fetal growth assessments by ultrasonography are recommended to predict fetal genotype and guide maternal treatment," they explain.

And as children born to women with GCK-MODY theoretically have a 50% chance of inheriting the mutation, it is important to eventually assess the infant's genotype.

If misdiagnosed as type 1 diabetes or type 2 diabetes, these children may also receive unnecessary treatment and complications in screening and medical review, which again highlights the need to differentiate women with GCK-MODY from women with standard gestational diabetes, they conclude.

The authors report no relevant financial relationships.

Diabetes Care. Published online June 24, 2015.Abstract

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