Hemoglobin A1c and Early Gestational Diabetes

Abstract

Background:

Screening for diabetes in early pregnancy is recommended for high-risk women, however, the optimal test for the diagnosis of early gestational diabetes mellitus (GDM) is unknown. Thus, the objective of this study was to evaluate hemoglobin A_1c (HbA_1c) as a diagnostic test for early GDM compared with two-step testing.

Materials and Methods:

Retrospective cohort of women with prior GDM or obesity who had HbA_1c and two-step testing <21 weeks' gestation. Early GDM was diagnosed by 1 hour, 50 g oral glucose challenge test (GCT) ≥135 mg/dL and ≥2 abnormal values on 3 hour, 100 g oral glucose tolerance test or GCT >200 mg/dL. The area under the receiver operating characteristic curve (AUC) evaluated HbA_1c for diagnosis of early GDM.

Results:

Of 243 women, 14 (5.8%) had early GDM by two-step testing. Median HbA_1c levels were higher among women with GDM versus those without GDM (5.8% vs. 5.3%, p < 0.001). The AUC for HbA_1c compared with two-step testing was 0.80 (95% CI 0.69–0.91). The optimal HbA_1c threshold was 5.6% (64% sensitivity, 84% specificity).

Conclusions:

HbA_1c is moderately predictive of early GDM compared with two-step testing, and a threshold lower than that used for diabetes diagnosis among nonpregnant adults is justified.

Introduction

Gestational diabetes mellitus (GDM) is one of the most common medical complications in pregnancy affecting as many as 15% of pregnant women in the United States.¹ Historically, GDM has been defined as hyperglycemia first recognized during pregnancy with screening performed in the third trimester. More recently, however, early pregnancy diagnosis of GDM has gained attention as untreated early hyperglycemia can be associated with adverse perinatal outcomes, including congenital anomalies, fetal growth abnormalities, preeclampsia, preterm birth, shoulder dystocia, and perinatal death.^2

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The American College of Obstetricians and Gynecologists (ACOG), American Diabetic Association (ADA), and the International Association of Diabetes and Pregnancy Study Groups (IADPSG) recommend early pregnancy diabetes screening among women at high risk for undiagnosed pregestational or gestational diabetes.^7

–10 However, the optimal test to screen for early GDM is not certain. The ADA and IADPSG allow the use of oral glucose tolerance testing, fasting or random blood glucose level, or hemoglobin A_1c (HbA_1c),^9,10 for early pregnancy diabetes screening. HbA_1c relies on nonenzymatic glycation of hemoglobin and estimates average blood glucose over ∼120 days. ACOG supports a two-step approach with a screening 1-hour 50 g oral glucose challenge test (GCT) followed by a diagnostic 3-hour 100 g oral glucose tolerance test (OGTT) if the screening GCT is positive.⁷ Due to lack of sensitivity of HbA_1c to detect early hyperglycemia, ACOG does not endorse its use as a stand-alone diagnostic test.⁷

HbA_1c as a test for diabetes mellitus among nonpregnant individuals is precise,¹¹ accurate,¹² easily obtainable through a single venipuncture, and conveniently performed regardless of symptoms of nausea/vomiting or a nonfasting state. These characteristics make HbA_1c an attractive alternative to two-step testing among nonpregnant individuals. Although universal HbA_1c screening in early pregnancy has been instituted at centers in Colorado,¹³ California,¹⁴ and Washington,¹⁵ it is unclear how the result should be interpreted, and if HbA_1c could be utilized as a diagnostic test for early GDM. Previous studies have shown significantly lower HbA_1c levels during early pregnancy compared with a nonpregnant state,^16,17 and pregnancy-specific thresholds for the detection of early GDM have not been established.^18,19 It remains to be defined whether HbA_1C in pregnancy can be used as a valid diagnostic test for early GDM.

We measured the predictive ability of HbA_1c to diagnose early GDM, defined as an abnormal two-step glucose testing <21 weeks' gestation among women at high risk for diabetes as part of an ongoing clinical quality initiative to improve early GDM screening.

Materials and Methods

This was a retrospective cohort study of high-risk women with singleton gestations who underwent both HbA_1c and two-step testing <21 weeks' gestation at the University of North Carolina at Chapel Hill from June 15, 2016 to July 15, 2017. During this time, we undertook a clinical quality initiative whereby obstetric providers were asked to perform HbA_1c in addition to routine two-step testing for GDM. This quality initiative was aimed at optimizing early identification of GDM among high-risk women. For this study, women were considered high risk if they had a history of GDM in a prior pregnancy or obesity, defined as body mass index (BMI) ≥30 kg/m² at <21 weeks' gestation. We excluded women with pregestational diabetes (defined as clinical diagnosis before pregnancy or HbA_1c ≥6.5% at <21 weeks' gestation), metformin use, anemia with an initial hematocrit <27 mg/dL, and homozygosity for hemoglobinopathy.

Electronic medical records were reviewed and demographic, medical, and obstetric characteristics were abstracted. HbA_1c and two-step oral glucose testing results were also collected from the medical record. Early GDM was defined as a positive 1-hour 50 g GCT ≥135 mg/dL followed by two or more abnormal values on a 3-hour 100 g OGTT based on Carpenter-Coustan criteria (fasting ≥95 mg/dL, 1-hour ≥180 mg/dL, 2-hour ≥155 mg/dL, and 3-hour ≥140 mg/dL) or GCT >200 mg/dL.²⁰

All HbA_1c and two-step oral glucose tests were performed by the University of North Carolina McLendon Laboratory, a hospital laboratory with Clinical Laboratory Improvement Amendments (CLIA), and National Glycohemoglobin Standardization Program (NGSP) certification. HbA_1c was measured using a VITROS 5600 Integrated System, VITROS Chemistry Products Calibrator 31, and the VITROS Chemistry Products HbA_1c Reagent Kit. The between-run coefficient of variation percentage (CV%) at a mean HbA_1c of 5.75% and 10.73% was 2.27% and 2.38%, respectively. The 5% acceptable limit was met. Serum glucose was also measured using the VITROS 5600 Integrated System. The between-run CV% at a mean serum glucose of 89.74 mg/dL and 298.63 mg/dL was 0.88% and 0.95%, respectively. The 2% acceptability criterion was met.

Demographic and obstetric characteristics were compared by early GDM status using chi-square and Wilcoxon rank sum tests. The area under the receiver operating characteristic (ROC) curve (AUC) was used to estimate the predictive ability of HbA_1c for diagnosing early GDM compared with two-step testing, and the Liu method was used to identify the HbA_1c threshold that maximized both sensitivity and specificity.²¹ Sensitivity, specificity, and diagnostic accuracy were also calculated for alternative HbA_1c thresholds. All statistical analyses were performed with STATA software (version 14.0; Stata Corporation, College Station, TX). The study was approved by the Institutional Review Board of the University of North Carolina at Chapel Hill and was conducted in accordance with Standards for Reporting of Diagnostic Accuracy (STARD) studies.

Results

From June 15, 2016 to July 15, 2017, 426 high-risk women with singleton gestations were identified for study inclusion (Fig. 1). The final sample included a total of 243 (57%) women. Six women were excluded because of metformin use and three were excluded for pregestational diabetes with HbA_1c ≥6.5%. An additional 174 (40.8%) were excluded because they did not complete both methods of early GDM screening; 51 women did not have a HbA_1c, 52 women did not have two-step oral glucose testing, 70 women were not screened for GDM before 21 weeks' gestation, and 1 woman had invalid two-step oral glucose testing results because she ate during the test. Compared with women included in this study, women who were excluded because they did not complete early GDM screening (n = 173) were less likely to be nulliparous (25.4% vs. 37.5%, p = 0.01) and had a lower median BMI (33.7 vs. 36.1 kg/m², p < 0.01). However, there were no differences in maternal age, race/ethnicity, insurance status, or screening indication between women who completed early GDM screening and those who did not and were excluded (Supplementary Data and Supplementary Table S1).

FIG. 1.

Flow diagram of study participants. GDM, gestational diabetes mellitus; HbA_1c, hemoglobin A_1c.

Among women included in this study, 77 (32%) women were non-Hispanic black, 89 (37%) were non-Hispanic white, 55 (23%) were Hispanic, and the remainder were of other race. Fourteen (5.8%) women were diagnosed with early GDM based on two-step testing. Women who had early GDM were more likely to have a history of GDM or a history of GDM and obesity, compared with women without early GDM (Table 1). They also had higher HbA_1c levels, higher 1-hour GCT results, and were tested at a later gestational age. Of the 13 women who were diagnosed with early GDM and reached viability, 10 (77%) required treatment with either an oral hypoglycemic medication or insulin during pregnancy. There were no significant differences in maternal age, parity, race/ethnicity, or insurance status between women who were diagnosed with early GDM and those who were not (Table 1).

Table 1.

Maternal Demographic and Obstetric Characteristics by Early Gestational Diabetes Mellitus

	Early GDM (n = 14)	No early GDM (n = 229)	p
Maternal age (years)	35.5 (28.1, 39.2)	30.8 (25.8, 34.8)	0.08
Nulliparous	5 (35.7)	86 (37.6)	0.89
Race/ethnicity			0.20
Non-Hispanic black	2 (14.3)	82 (35.8)
Non-Hispanic white	5 (35.7)	84 (36.7)
Hispanic	5 (35.7)	51 (22.3)
Other	2 (14.3)	12 (5.2)
Private insurance	7 (50.0)	116 (50.9)	0.95
Screening indication			0.03
Obesity^a only	10 (71.4)	208 (90.8)
History of GDM only	2 (14.3)	15 (6.6)
Obesity^a and history of GDM	2 (14.3)	6 (2.6)
Early pregnancy BMI (kg/m²)	37.0 (33.7, 42.0)	36.0 (32.6, 42.0)	0.74
HbA_1c (%)	5.8 (5.4, 5.8)	5.3 (5.1, 5.5)	<0.001
Gestational age at HbA_1c (weeks)	14.3 (11.1, 16.6)	10.1 (8.6, 13.1)	<0.01
One-hour GCT result (mg/dL)	176.5 (162, 204)	106 (92, 124)	<0.001
Gestational age at 1-hour GCT (weeks)	16.1 (14.3, 19.0)	13.7 (12.0, 16.7)	0.09

Data presented as median (interquartile range) or n (%).

Obesity was defined as early pregnancy BMI ≥30 kg/m².

BMI, body mass index; GCT, glucose challenge test; GDM, gestational diabetes mellitus; HbA_1c, hemoglobin A_1c.

With regard to the diagnostic characteristics of HbA_1c for early GDM compared with two-step testing, the AUC for the ROC curve was 0.80 (95% CI 0.69–0.91) (Fig. 2). The HbA_1c threshold that optimized both sensitivity and specificity was 5.6%. This HbA_1c cutoff of ≥5.6% for the diagnosis of early GDM had a sensitivity of 64% and a specificity of 84%. Table 2 demonstrates the tradeoffs between sensitivity and specificity at higher and lower HbA_1c thresholds. For example, at a higher HbA_1c threshold of ≥5.9%, the sensitivity of HbA_1c for the diagnosis of early GDM was only 21%, but specificity improved to 96%. On the other hand, at a lower HbA_1c threshold of ≥5.3%, the sensitivity was improved at 93%, but at the expense of specificity, which decreased to 44%.

FIG. 2.

ROC curve for HbA_1c as a diagnostic test for early gestational diabetes. ROC, receiver operating characteristic.

Table 2.

Test Characteristics of Hemoglobin A_1c as a Diagnostic Test for Early Gestational Diabetes

HbA_1c threshold (%)	Women with early GDM (n)	Women without early GDM (n)	Sensitivity (%)	Specificity (%)	Diagnostic accuracy (%)^a
≥4.6	14	229	100.0	0.0	5.8
≥4.7	14	227	100.0	0.9	6.6
≥4.8	14	223	100.0	2.6	8.2
≥4.9	14	213	100.0	7.0	12.4
≥5.0	14	209	100.0	8.7	14.0
≥5.1	14	186	100.0	18.8	23.5
≥5.2	14	152	100.0	33.6	37.5
≥5.3	13	129	92.9	43.7	46.5
≥5.4	11	97	78.6	57.6	58.9
≥5.5	10	70	71.4	69.4	69.6
≥5.6	9	48	64.3	79.0	78.2
≥5.7	9	37	64.3	83.8	82.7
≥5.8	7	20	50.0	91.3	88.9
≥5.9	3	10	21.4	95.6	91.4
≥6.0	2	9	14.3	96.0	91.4
≥6.1	2	7	14.3	98.7	92.2
≥6.2	2	3	14.3	99.1	93.8
≥6.3	2	2	14.3	99.6	94.2
≥6.4	2	1	0.0	100.0	94.7

Diagnostic accuracy represents the % of women correctly classified as early GDM.

Discussion

In this study of high-risk pregnant women <21 weeks' gestation in a single tertiary care institution, we found that HbA_1c was moderately predictive of early GDM as compared with the two-step approach to GDM testing. HbA_1c levels were significantly higher in women with early GDM compared with those without early GDM, and the HbA_1c threshold that optimized both sensitivity and specificity was 5.6%. These results suggest that HbA_1c may be an acceptable alternative to the two-step approach in early pregnancy.

Although there is no strong evidence that early GDM screening improves maternal and neonatal outcomes, the ACOG, ADA, and IADPSG all recommend early screening for high-risk women, and thus it is important to know what test to perform and how to interpret the result. Some centers are already performing universal HbA_1c testing at the initial prenatal visit, but only a few studies have examined the utility of early pregnancy HbA_1c for the detection of early GDM in high-risk women.^13,15 In a prior observational cohort study, HbA_1c was evaluated as an adjunct to two-step screening for early GDM.¹³ At the University of Colorado, HbA_1c is performed universally along with the initial prenatal laboratory panel and women with an intermediate HbA_1c of 5.9%–6.4% undergo confirmatory 3-hour OGTT. In this study, HbA_1c of ≥5.5% provided the optimal sensitivity and specificity for the diagnosis of GDM with a modest AUC of 0.73 (95% CI 0.68–0.76) and a sensitivity of 56%. Based on these test characteristics, the authors concluded that it could not be used to replace routine two-step testing. However, the predictive ability of HbA_1c was measured with respect to GDM diagnosed both early and in the 3rd trimester of pregnancy, and women with early HbA_1c <5.9% did not undergo early two-step testing. Thus, the previous study was not able to make any definitive conclusions about whether early HbA_1c can be used as an alternative to early two-step testing. In the current study, we found a similar HbA_1c threshold of 5.6% that optimized sensitivity and specificity for the diagnosis of early GDM. While no screening test will ever be able to provide 100% sensitivity and specificity, our findings are similar to that of a 1-hour 50 g screening cutoff of 140 mg/dL, which has a sensitivity of 77%–88% and a specificity of 69%–89% for the diagnosis of GDM in the third trimester of pregnancy.

At Kaiser Permanente Washington, universal HbA_1c was implemented in 2011 and women with early HbA_1c 5.7%–6.4% at <20 weeks' gestation are diagnosed with prediabetes rather than early GDM and are subsequently referred to a certified diabetes educator. In a retrospective cohort study of these women, prediabetes (early HbA_1c 5.7%–6.4%) was identified as a risk factor for GDM in the 3rd trimester of pregnancy with an adjusted risk ratio of 2.8 (95% CI 2.4–3.3).¹⁵ Although the authors were not able to compare these prediabetic HbA_1c levels to OGTT results in early pregnancy, their findings support our results that women with HbA_1c >5.6%–5.7% are at increased risk for glucose intolerance during pregnancy.

Our study has several strengths. Unlike prior studies, our cohort was racially and ethnically diverse, which is important given the higher prevalence and morbidity of diabetes among minority populations.²² Additionally, all women included in the cohort had both early HbA_1c and early two-step testing, which allowed us to evaluate HbA_1c as an alternative to the two-step approach for early GDM screening and diagnosis. All specimens were analyzed in a single CLIA- and NGSP-certified laboratory decreasing the variability among study results. Although 40% of eligible women did not complete early HbA_1c and/or two-step testing, which may have introduced selection bias, we were able to identify the similarities and differences between these women and those included in our study.

Our study is not without limitations. Provider practices and patient preferences may have influenced completion of early HbA_1c and two-step testing resulting in a final sample that was not representative of all high-risk women, and as this was a single-center study, our results may not be generalizable to all populations. Additionally, due to the nature of the testing strategy, diagnostic 3-hour OGTT were performed ∼4 weeks after HbA_1c collection. Given worsening insulin resistance with advancing gestation, this delay may have resulted in a higher frequency of early GDM diagnoses at lower HbA_1c levels. However, we believe that this possibility was minimized by limiting our analysis to testing at <21 weeks' gestation. Not all women chose to have screening with hemoglobin electrophoresis, and thus it is also possible that women with unidentified hemoglobinopathies were included in the cohort and had lower HbA_1c levels. Last, the relatively small sample size with only 14 women diagnosed with early GDM limited the precision of the sensitivity and specificity estimates and limited the power to evaluate for effect modification by baseline maternal characteristics. Despite these limitations, however, our study adds to the growing body of literature surrounding the potential role of HbA_1c for the diagnosis of early GDM in high-risk women.

Conclusions

In summary, we found that HbA_1c was moderately predictive of early GDM compared with two-step testing at <21 weeks' gestation. In this cohort, a HbA_1c threshold of 5.6% optimized sensitivity and specificity, whereas lower HbA_1c thresholds increased sensitivity and higher HbA_1c thresholds increased specificity. Although there is insufficient evidence to support replacing two-step testing with HbA_1c or switching from two-step testing to a one-step approach, future studies may provide the evidence needed to support using HbA_1c as an adjunct to two-step testing for high-risk women unwilling or unable to undergo early pregnancy GCT. Based on our results and previously published findings, we anticipate that a lower HbA_1c threshold compared with that used for diagnosis of diabetes among nonpregnant adults would be necessary to provide acceptable sensitivity as a test for early GDM. Until that time, it is reasonable to continue to follow ACOG recommendations for early pregnancy diabetes screening with the two-step approach.⁷

Footnotes

Author Disclosure Statement

No competing financial interests exist.

Funding Information

No funding was received for this article.

Supplementary Material

Supplementary Data

Supplementary Table S1

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Supplementary Material

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