One-step or 2-step testing for gestational diabetes: which is better?

In the United States, the common approach to detecting gestational diabetes mellitus is the 2-step protocol recommended by the American College of Obstetricians and Gynecologists. A 50 g, 1-hour glucose challenge at 24 to 28 weeks' gestation is followed by a 100 g, 3-hour oral glucose tolerance test when a screening test threshold is exceeded. Notably, 2 or more elevated values diagnose gestational diabetes mellitus. The 2-step screening test is administered without regard to the time of the last meal, providing convenience by eliminating the requirement for fasting. However, depending upon the cutoff used and population risk factors, approximately 15% to 20% of screened women require the 100 g, 3-hour oral glucose tolerance test. The International Association of Diabetes and Pregnancy Study Groups recommends a protocol of no screening test but rather a diagnostic 75 g, 2-hour oral glucose tolerance test. One or more values above threshold diagnose gestational diabetes mellitus. The 1-step approach requires that women be fasting for the test but does not require a second visit and lasts 2 hours rather than 3. Primarily because of needing only a single elevated value, the 1-step approach identifies 18% to 20% of pregnant women as having gestational diabetes mellitus, 2 to 3 times the rate with the 2-step procedure, but lower than the current United States prediabetes rate of 24% in reproductive aged women. The resources needed for the increase in gestational diabetes mellitus are parallel to the resources needed for the increased prediabetes and diabetes in the nonpregnant population. A recent randomized controlled trial sought to assess the relative population benefits of the above 2 approaches to gestational diabetes mellitus screening and diagnosis. The investigators concluded that there was no significant difference between the 2-step screening protocol and 1-step diagnostic testing protocol in their impact on population adverse short-term pregnancy outcomes. An accompanying editorial concluded that perinatal benefits of the 1-step approach to diagnosing gestational diabetes mellitus "appear to be insufficient to justify the associated patient and healthcare costs of broadening the diagnosis." We raise several concerns about this conclusion. The investigators posited that a 20% improvement in adverse outcomes among the entire pregnancy cohort would be necessary to demonstrate an advantage to the 1-step approach and estimated the sample size based on that presumption, which we believe to be unlikely given the number of cases that would be identified. In addition, 27% of the women randomized to the 1-step protocol underwent 2-step testing; 6% of the study cohort had no testing at all. A subset of women assigned to 2-step testing did not meet the criteria for gestational diabetes mellitus but were treated as such because of elevated fasting plasma glucose levels, presumably contributing to the reduction in adverse outcomes but not to the number of gestational diabetes mellitus identified, increasing the apparent efficacy of the 2-step approach. No consideration was given to long-term benefits for mothers and offspring. All these factors may have contributed to obscuring the benefits of 1-step testing; most importantly, the study was not powered to identify what we understand to be the likely impact of 1-step testing on population health.

Research Gaps in Gestational Diabetes Mellitus: Executive Summary of a National Institute of Diabetes and Digestive and Kidney Diseases Workshop.

The National Institute of Diabetes and Digestive and Kidney Diseases convened a workshop on research gaps in gestational diabetes mellitus (GDM) with a focus on 1) early pregnancy diagnosis and treatment and 2) pharmacologic treatment strategies. This article summarizes the proceedings of the workshop. In early pregnancy, the appropriate diagnostic criteria for the diagnosis of GDM remain poorly defined, and an effect of early diagnosis and treatment on the risk of adverse outcomes has not been demonstrated. Despite many small randomized controlled trials of glucose-lowering medication treatment in GDM, our understanding of medication management of GDM is incomplete as evidenced by discrepancies among professional society treatment guidelines. The comparative effectiveness of insulin, metformin, and glyburide remains uncertain, particularly with respect to long-term outcomes. Additional topics in need of further research identified by workshop participants included phenotypic heterogeneity in GDM and novel and individualized treatment approaches. Further research on these topics is likely to improve our understanding of the pathophysiology and treatment of GDM to improve both short- and long-term outcomes for mothers and their children.

Stillbirth, Inflammatory Markers, and Obesity: Results from the Stillbirth Collaborative Research Network.

BACKGROUND: Obesity is associated with increased risk of stillbirth, although the mechanisms are unknown. Obesity is also associated with inflammation. Serum ferritin, C-reactive protein, white blood cell count, and histologic chorioamnionitis are all markers of inflammation. OBJECTIVE: This article determines if inflammatory markers are associated with stillbirth and body mass index (BMI). Additionally, we determined whether inflammatory markers help to explain the known relationship between obesity and stillbirth. STUDY DESIGN: White blood cell count was assessed at admission to labor and delivery, maternal serum for assessment of various biomarkers was collected after study enrollment, and histologic chorioamnionitis was based on placental histology. These markers were compared for stillbirths and live births overall and within categories of BMI using analysis of variance on logarithmic-transformed markers and logistic regression for dichotomous variables. The impact of inflammatory markers on the association of BMI categories with stillbirth status was assessed using crude and adjusted odds ratios (COR and AOR, respectively) from logistic regression models. The interaction of inflammatory markers and BMI categories on stillbirth status was also assessed through logistic regression. Additional logistic regression models were used to determine if the association of maternal serum ferritin with stillbirth is different for preterm versus term births. Analyses were weighted for the overall population from which this sample was derived. RESULTS: A total of 497 women with singleton stillbirths and 1,414 women with live births were studied with prepregnancy BMI (kg/m2) categorized as normal (18.5-24.9), overweight (25.0-29.9), or obese (30.0 + ). Overweight (COR, 1.48; 95% confidence interval [CI]: 1.14-1.94) and obese women (COR, 1.60; 95% CI: 1.23-2.08) were more likely than normal weight women to experience stillbirth. Serum ferritin levels were higher (geometric mean: 37.4 ng/mL vs. 23.3, p < 0.0001) and C-reactive protein levels lower (geometric mean: 2.9 mg/dL vs. 3.3, p = 0.0279), among women with stillbirth compared with live birth. Elevated white blood cell count (15.0 uL × 103 or greater) was associated with stillbirth (21.2% SB vs. 10.0% live birth, p < 0.0001). Histologic chorioamnionitis was more common (33.2% vs. 15.7%, p < 0.0001) among women with stillbirth compared with those with live birth. Serum ferritin, C-reactive protein, and chorioamnionitis had little impact on the ORs associating stillbirth with overweight or obesity. Adjustment for elevated white blood cell count did not meaningfully change the OR for stillbirth in overweight versus normal weight women. However, the stillbirth OR for obese versus normal BMI changed by more than 10% when adjusting for histologic chorioamnionitis (AOR, 1.38; 95% CI: 1.02-1.88), indicating confounding. BMI by inflammatory marker interaction terms were not significant. The association of serum ferritin levels with stillbirth was stronger among preterm births (p = 0.0066). CONCLUSION: Maternal serum ferritin levels, elevated white blood cell count, and histologic chorioamnionitis were positively and C-reactive protein levels negatively associated with stillbirth. Elevated BMIs, both overweight and obese, were associated with stillbirth when compared with women with normal BMI. None of the inflammatory markers fully accounted for the relationship between obesity and stillbirth. The association of maternal serum ferritin with stillbirth was stronger in preterm than term stillbirths.

Insulin Delivery Method and Admission for Glycemic Control in Pregnant Women with Type 1 Diabetes Mellitus.

OBJECTIVE: To determine if there was a difference in glycemic control admissions or perinatal outcomes in women with type 1 diabetes mellitus (DM) treated with multiple daily injections (MDIs) versus continuous subcutaneous insulin infusion (CSII). MATERIALS AND METHODS: This was a retrospective cohort study of women with type 1 DM with a singleton gestation who delivered between 2006 and 2014 at a tertiary hospital and received care at a dedicated DM clinic. Women who used MDI were compared with those who used CSII. The primary outcome was glycemic control admission during pregnancy. Secondary outcomes included adverse perinatal outcomes. RESULTS: There were a total of 156 women; 107 treated with MDI and 49 with CSII. Women treated with MDI had higher rates of glycemic control admissions versus those treated with CSII (68.2 vs. 30.6%, p < 0.001). Adjusting for age, ethnicity, public insurer, duration of DM, first recorded hemoglobin A1c (HbA1c), and DM comorbidities, the likelihood of admission remained higher in women on MDI versus CSII (AOR 5.9 [1.7-20.6]). Women treated with MDI had higher rates of postprandial hypoglycemia. Other perinatal outcomes were similar between the groups. CONCLUSION: Women with type 1 DM treated with MDI were more likely to have glycemic control admissions and postprandial hypoglycemia than those treated with CSII.

Prenatal Care Adherence and Neonatal Intensive Care Unit Admission or Stillbirth among Women with Gestational and Preexisting Diabetes Mellitus.

OBJECTIVE: To determine if there was an association between prenatal care adherence and neonatal intensive care unit (NICU) admission or stillbirth, and adverse perinatal outcomes in women with preexisting diabetes mellitus (DM) and gestational DM (GDM). MATERIALS AND METHODS: This is a retrospective cohort study among women with DM and GDM at a Diabetes in Pregnancy Program at an academic institution between 2006 and 2014. Adherence with prenatal care was the percentage of prenatal appointments attended divided by those scheduled. Adherence was divided into quartiles, with the first quartile defined as lower adherence and compared with the other quartiles. RESULTS: There were 443 women with DM and 499 with GDM. Neonates of women with DM and lower adherence had higher rates of NICU admission or stillbirth (55 vs. 39%; p = 0.003). A multivariable logistic regression showed that the lower adherence group had higher likelihood of NICU admission (adjusted odds ratio: 1.61 [1.03-2.5]; p = 0.035). Those with lower adherence had worse glycemic monitoring and more hospitalizations. Among those with GDM, most outcomes were similar between groups including NICU admission or stillbirth. CONCLUSION: Women with DM with lower adherence had higher rates of NICU admission and worse glycemic control. Most outcomes among women with GDM with lower adherence were similar.

The association of stillbirth with depressive symptoms 6-36 months post-delivery.

BACKGROUND: Stillbirths (≥ 20 weeks' gestation), which account for about 1 in 200 US pregnancies, may grieve parents deeply. Unresolved grief may lead to persistent depression. METHODS: We compared depressive symptoms in 2009 (6-36 months after index delivery) among consenting women in the Stillbirth Collaborative Research Network's population-based case-control study conducted 2006-08 (n = 275 who delivered a stillbirth and n = 522 who delivered a healthy livebirth (excluding livebirths < 37 weeks, infants who had been admitted to a neonatal intensive care unit or who died). Women scoring > 12 on the Edinburgh Depression Scale were classified as currently depressed. Crude (cOR) and adjusted (aOR) odds ratios and 95% confidence intervals [CI] were computed from univariate and multivariable logistic models, with weighting for study design and differential consent. Marginal structural models examined potential selection bias due to low follow-up. RESULTS: Current depression was more likely in women with stillbirth (14.8%) vs. healthy livebirth (8.3%, cOR 1.90 [95% CI 1.20, 3.02]). However, after control for history of depression and factors associated with both depression and stillbirth, the stillbirth association was no longer significant (aOR 1.35 [95% CI 0.79, 2.30]). Conversely, for the 76% of women with no history of depression, a significant association remained after adjustment for confounders (aOR 1.98 [95% CI 1.02, 3.82]). CONCLUSIONS: Improved screening for depression and referral may be needed for women's health care. Research should focus on defining optimal methods for support of women suffering stillbirth so as to lower the risk of subsequent depression.

Prediction of abnormal postpartum glucose tolerance testing in mild gestational diabetes mellitus.

OBJECTIVE: To describe the liikelihood of women with gestational diabetes mellitus (GDM)--who are at increased risk for developing overt diabetes--undergoing postpartum testing, and the patient characteristics associated with abnormal postpartum glucose tolerance testing (GTT) in mild GDM. STUDY DESIGN: This was a retrospective chart review that included mild GDM patients, defined as those with fasting plasma glucose levels < 95 mg/dL on a 3-hour 100-g oral glucose tolerance test (OGTT). Patients who underwent postpartum testing were assessed and predictive factors for abnormal results evaluated. RESULTS: Mild GDM was diagnosed in 414 (39.6%) women, 201 (48.6%) of whom completed a postpartum 2-hour 75-g OGTT. Abnormal testing was seen in 69 (34.3%), with diabetes in 6 (3%); those with abnormal testing had been diagnosed with GDM at an earlier gestational age, had higher 1-hour 50-g OGTT values, and were also more likely to require pharmacologic therapy. Combining several variables produced a predictive model with positive and negative predictive values of 50% and 84%, respectively. CONCLUSION: Antenatal factors (alone or in combination) do not allow for prediction of abnormal postpartum OGTT results in mild GDM patients. Patients with mild GDM are at a slightly decreased postpartum risk of developing diabetes and prediabetes as compared to other patients with GDM.

Diagnosis of gestational diabetes.

Abstract Previous approaches to diagnosing gestational diabetes mellitus (GDM) have included 50 g, 75 g and 100 g glucose challenges, lasting 1-3 hours, with 1 or 2 elevations required. Thresholds were validated by their predictive value for subsequent diabetes, or were the same thresholds used in non-pregnant individuals. None were based on their prediction of adverse pregnancy outcomes. Diagnostic paradigms vary throughout the world, making comparisons impossible and severely limiting communication among investigators. The Hyperglycemia and Adverse Pregnancy Outcome (HAPO) study collected outcome data on > 23,000 pregnancies recruited prospectively in nine countries after a blinded 75 g, 2-hour oral glucose tolerance test (OGTT) at 24-28 weeks gestation. Primary outcomes (LGA, PCS, neonatal hypoglycemia, high cord C-peptide), and most secondary outcomes (e.g. preeclampsia, preterm birth, shoulder dystocia and birth injury), were significantly, directly and continuously related to each of the three plasma glucose measurements. The International Association of Diabetes in Pregnancy Study Groups (IADPSG) developed recommendations for the use of a 75 g, 2-h OGTT, ≥ 1 elevation diagnosing GDM, with thresholds: fasting plasma glucose ≥ 5.1 mmol/L (92 mg/dL) , 1 h ≥ 10 mmol/L (180 mg/dL) and 2 h ≥ 8.5 mmol/L (153 mg/dL). These have generated wide discussion and are currently being considered throughout the world. They are pregnancy outcome-based; the 75 g glucose load will bring consistency to GTTs; universal adoption will lead to consistency of diagnostic criteria worldwide; studies of treatment at similarly mild levels of glycemia have demonstrated improvement in outcomes; use of a single abnormal value will obviate the confusion arising when one elevated value is encountered. The primary argument against the recommendations is that prevalence of GDM will rise to 16-18 %, increasing health care costs. Balanced against this is the world-wide epidemic of obesity, prediabetes and diabetes.

Counterpoint: Establishing consensus in the diagnosis of GDM following the HAPO study.

The International Association of Diabetes in Pregnancy Study Groups (IADPSG) recommended a new protocol of 1-step testing with a 75 g oral glucose tolerance test for gestational diabetes in 2010. Since that time, these recommendations have been carefully scrutinized and accepted by a variety of organizations, but challenged or rejected by others. In the current review, we present more details regarding the background to the development of the IADPSG recommendations and seek to place them in context with the available epidemiologic and randomized controlled trial data. In this "counterpoint," we also provide specific rebuttal for errors of fact and disputed contentions provided by Long and Cundy in their 2013 article in Current Diabetes Reports.

Impact of an intensive follow-up program on the postpartum glucose tolerance testing rate.

OBJECTIVE: Gestational diabetes mellitus (GDM) is a strong risk factor for the development of diabetes. We assessed the impact of a 1-year intensive follow-up demonstration program, using direct nurse and outreach worker case management, aimed at increasing compliance with postpartum oral glucose tolerance testing (OGTT). STUDY DESIGN: During the year of implementation, a nurse or bilingual outreach worker contacted patients to encourage attendance at their scheduled postpartum 2-h 75-g OGTT and assisted in overcoming obstacles to testing. All patients with GDM seen in our specialty clinic the previous year served as a control group for comparison. RESULTS: One hundred eighty-one patients treated during the year prior to implementation were compared to the 207 in the demonstration program. Baseline characteristics were similar in both groups. After the program's implementation, postpartum OGTT adherence increased from 43.1 to 59.4 % (p < 0.01, hazard ratio 1.59; 95 % confidence interval 1.20-2.12). Had the program been in place the previous year, we calculated that 12 additional cases of diabetes or prediabetes would have been detected, increasing the total number from 33 to 45 such cases. CONCLUSION: Implementation of direct nurse and outreach worker case management leads to a modest, but important increase in adherence to postpartum OGTT testing.

Placental findings in singleton stillbirths.

OBJECTIVE: To compare placental lesions for stillbirth cases and live birth controls in a population-based study. METHODS: Pathologic examinations were performed on placentas from singleton pregnancies using a standard protocol. Data were analyzed overall and within gestational age groups at delivery. RESULTS: Placentas from 518 stillbirths and 1,200 live births were studied. Single umbilical artery was present in 7.7% of stillbirths and 1.7% of live births, velamentous cord insertion was present in 5% of stillbirths and 1.1% of live births, diffuse terminal villous immaturity was present in 10.3% of stillbirths and 2.3% of live births, inflammation (eg, acute chorioamnionitis of placental membranes) was present in 30.4% of stillbirths and 12% of live births, vascular degenerative changes in chorionic plate were present in 55.7% of stillbirths and 0.5% of live births, retroplacental hematoma was present in 23.8% of stillbirths and 4.2% of live births, intraparenchymal thrombi was present in 19.7% of stillbirths and 13.3% of live births, parenchymal infarction was present in 10.9% of stillbirths and 4.4% of live births, fibrin deposition was present in 9.2% of stillbirths and 1.5% of live births, fetal vascular thrombi was present in 23% of stillbirths and 7% of live births, avascular villi was present in 7.6% of stillbirths and 2.0% of live births, and hydrops was present in 6.4% of stillbirths and 1.0% of live births. Among stillbirths, inflammation and retroplacental hematoma were more common in placentas from early deliveries, whereas thrombotic lesions were more common in later gestation. Inflammatory lesions were especially common in early live births. CONCLUSIONS: Placental lesions were highly associated with stillbirth compared with live births. All lesions associated with stillbirth were found in live births but often with variations by gestational age at delivery. Knowledge of lesion prevalence within gestational age groups in both stillbirths and live birth controls contributes to an understanding of the association between placental abnormality and stillbirth. LEVEL OF EVIDENCE: II.

Can hemoglobin A1c in early pregnancy predict adverse pregnancy outcomes in diabetic patients?

OBJECTIVE: To examine the association of elevated early pregnancy hemoglobin A1c (HbA1c) levels with adverse pregnancy outcomes in women with preexisting diabetes mellitus. STUDY DESIGN: Retrospective cohort study of 330 women with preexisting diabetes enrolled in a Diabetes in Pregnancy Program at an academic institution between 2003 and 2011 who had an early HbA1c determination. The frequencies of composite maternal adverse pregnancy outcomes (birth at<37 weeks, preeclampsia, and medically indicated birth <39 weeks), and composite fetal adverse pregnancy outcomes [shoulder dystocia, Apgar scores<7 at 5 minutes, small for gestational age (SGA), large for gestational age (LGA), and stillbirth] were compared between HbA1c categories (<6.5, 6.5-7.4, 7.5-8.4 and ≥ 8.5%). RESULTS: There was no statistically significant difference between composite adverse maternal pregnancy outcomes and composite adverse fetal pregnancy outcomes as well as other individual outcomes between different HbA1c categories. Of the vaginally delivered women in our cohort, the 37 patients with HbA1c levels of ≥ 8.5% had a significantly higher frequency of fetal shoulder dystocia than the 62 with HbA1c levels of < 8.5% (24.2 vs. 1.6%, P = 0.002). Neonates of patients with HbA1c ≥ 8.5% were more likely to have low five minute Apgar scores than neonates of patients with HbA1c < 8.5%, but this was of borderline statistical significance (7.4% vs. 0.5%, P = 0.05). CONCLUSION: In patients with preexisting diabetes mellitus, HbA1c levels of ≥ 8.5% during early pregnancy are not useful in predicting most adverse outcomes, although there may be an increased risk for shoulder dystocia.