Abstract
Gestational diabetes mellitus (GDM) is becoming a more common diagnosis due to increasing risk factors related to obesity, sedentary behavior, and pregnancy with type 2 diabetes. GDM is currently defined as diabetes diagnosed during the second trimester. Controversy surrounds GDM screening and diagnosing due to changes in the diagnostic criteria guidelines; such as testing low-risk pregnant women and using the one-step method versus two-step method.
This review provides an insight into the new diagnostic criteria, and the controversy that surrounds it. In addition, it provides various approaches to the diagnosis of GDM, recommendations of various organizations, and the comparison of the first-step method versus the second-step method to diagnose GDM. The screening and diagnostic methods are both outlined, and the maternal and fetal complications associated with GDM.
Introduction
Gestational diabetes mellitus (GDM) is a medical condition often diagnosed during pregnancy that causes both maternal and fetal complications.1 GDM is screened during the second trimester between 24 to 28 weeks’ gestation. The test of choice consists of a two-step approach; the first step is the screening and the second step is diagnostic. The first step starts with a nonfasting 1-hour 50-gram oral glucose tolerance test (OGTT). The second step is a confirmatory fasting 3-hour 100-gram OGTT for confirmation. Prompt recognition of GDM is beneficial to the physician and the patient to establish an early treatment plan preventing further development and reducing maternal and fetal complications.2
Early identification of GDM improves the well-being of the mother and child during and after pregnancy. Therefore, OGTT diagnostic testing should be offered to all pregnant women regardless of high or low-risk factors.3 The test of choice according to American College of Obstetricians and Gynecologists (ACOG) guidelines to diagnose GDM is the two-step method, however, there are other testing methods. An example of another method includes the World Health Organization (WHO) one step method which consists of a 2-hour 75-gram OGTT, where the threshold values are the same when comparing a pregnant and a non-pregnant woman.3 This raises the question, which method is superior for early identification of gestational diabetes during the second trimester.
To decide which diagnostic method is superior, the background of GDM needs to be further studied, to include, high and low-risk factors that predispose women to develop GDM. In addition, a further review into how these risks factors affect the results of the one-step method and two-step method to diagnose GDM. This analysis should include systematic reviews and meta-analysis that compares the methodology and the end results of both methods.
Background
GDM is defined as a glucose intolerance that will be diagnosed during a patient’s first pregnancy.2 It is a condition that involves high levels of glucose in the blood.1 A well-known risk factor that predisposes the patient to develop gestational diabetes is pre-pregnancy obesity. Obesity is a multifactorial disease with multiple adverse metabolic disorders.5 Obesity occurs in 27.2% of women between the ages of 18-44 years old.5 Additional risk factors include ethnicity with a high prevalence of diabetes, prenatal exposures, socioeconomic status, dietary patterns 5 and sedentary behaviors during pregnancy.9
Fetal complications due to GDM include, but are not limited to, fetal hyperglycemia, newborn hypoglycemia, risk of developing respiratory distress syndrome in a premature infant, and fetal macrosomia that increases the risk of shoulder dystocia during vaginal delivery.2 Fetal macrosomia is a term used to describe a fetus that is large for gestational age (LGA).5 Macrosomia is related to the fetal insulin that promotes excessive growth which is a disproportionate growth leading to excessive amounts of subcutaneous fat and broad shoulders increasing the risk of shoulder dystocia.2 Overgrowth of the fetus occurs due to two factors, the elevated levels of nutrients that are delivered to the fetus and the hyperglycemic state of the mother.5 The organ responsible for nutrition transport to the fetus is the placenta. GDM alters the anatomy of the placenta by increasing its size and its functionality affecting the nutritional transport delivery system.5
Maternal complications due to GDM include hyperglycemia, increased risk of pregnancy-induced hypertension, preeclampsia, and consideration of a primary cesarean section.4 Maternal hyperglycemia leads to fetal hyperglycemia due to glucose crossing the placenta. The fetus in response to the physiological change, increases glucose concentration by increasing the production and release of insulin. Fetal hyperinsulinemia it is also known as diabetic fetopathy and is the cause of most fetal complications.2 GDM can also cause long-term complications in developing children including obesity, glucose intolerance, and metabolic syndrome. In addition, it can also cause postpartum complications with the mother, increasing the risk or development of type 2 diabetes mellitus.4
During pregnancy, the body undergoes several physiological and metabolic modifications to support the growth of the fetus throughout the pregnancy.5 The physiological change of interest is the adaptation of maternal insulin sensitivity during the term of pregnancy.5 Insulin is the primary hormone that drives glucose into the cells to control its levels in the blood. During pregnancy, the body becomes resistant to insulin, thus allowing glucose levels to increase in the blood in order to support fetal nutrition.1 The physiological response of the body is to increase insulin secretion to maintain normal glucose levels; therefore, causing the pregnancy to enter an insulin resistant state.5
GDM is tested and diagnosed at 24 to 28 gestational weeks.1 The American College of Obstetricians and Gynecologists (ACOG) provides the guidelines for screening and diagnostic criteria for GDM. ACOG recommends testing all pregnant women using the screening 1-hour 50-gram non fasting OGTT regardless of risk factors while acknowledging that pregnant women with low risk factors may not attain any benefit.8 Low risk factors indicators for GDM include women 25 years of age or younger, women not part of an ethnic group that is considered to have a high prevalence of diabetes, not overweight, no past medical history of abnormal glucose tolerance, no adverse pregnancy outcomes, and no family history of diabetes in a first-degree relative.2 Prior studies involving the 1 hour 50-gram OGTT have reported data indicating that the time of day (TD) or the last time a meal was consumed and the fasting duration (FD) influenced the glucose levels, therefore, affecting the glucose results during gestational OGTT.7
In comparison with ACOG guidelines, the International Association of Diabetes and Pregnancy Study Groups (IADPSG) recommends to test either all pregnant women or only women with high risk factors during the first prenatal appointment instead of testing at 24-28 gestational weeks.2 The American Diabetes Association (ADA) suggest only pregnant women with high risk factors should be tested. Both IADPSG and ADA recommends using the one-step method consisting of a 2-hour 75-gram OGTT.8 Results are based by using the same thresholds as nonpregnant individuals to diagnose GDM where a value greater than or equal to 200 mg/dL is a diagnosis for diabetes.2 The two-step method starts with the screening step, nonfasting 1 hour 50-gram OGTT, if the results equal 130 mg/dL or 140 mg/dL, then the screening test is followed by a confirmatory test, fasting 3-hour 100-gram OGTT. GDM is diagnosed if the confirmatory test equals: fasting >95 mg/dL, 1-hour > 180 mg/dL, 2-hour >155 mg/dL and the 3-hour >140 mg/dL.2
Methodology
A complete review was performed by using several sources to include randomized controlled trials, cohort study, and systematic reviews gathered from the Texas Tech Health Science Center library. Evidence and statistics were collected using ACOG, AccessObGyn, PubMed, UpToDate, EMB reviews, and MedlinePlus. The main topics and alternate terms were gestational diabetes 2 involvement in labor dystocia, Pregnancy-induced hypertension development due to gestational diabetes and diabetes mellitus oral testing. The largest result was provided by PubMed with 10383 articles and the least by MedlinePlus with 109 articles. The inclusion and exclusion key terms were used to further narrow down the article count, in addition, full text, 10-year publication date, humans and clinical trials were added, which reduced the article number to 150. The inclusion key terms included: Gestational diabetes, diabetes developed in pregnancy, female, English, 13 and older. The exclusion data included: Pregnancy with type 2 diabetes, comorbidities in pregnancy and diabetic females and pregnancy. Once the filters were applied it made it more attainable to review the literature.
The first article is a review providing an understanding of the early to the current development of GDM screening and diagnostic guidelines.2 This article was selected because it provides a background information to diagnose and screen GDM and how the guidelines were developed. The main study was in 1964 in where pregnant women between the first and second trimester were tested using the 3-hour 100-gram OGTT.2 The data obtained was compared to women that were tested periodically in the nonpregnant state to compare results of glucose readings.2 Various screening and diagnostic methods are compared with one another providing an outline of current recommendations and the controversies that surround them.
The second article was selected because in addition to risk factors, and comorbidities this study introduces how the time of the day (TD) or fasting duration (FD) may influence the glucose levels results of the screening portion of the two-step method. Very few studies have examined the effects of the time of day or fasting duration using the 1 hour 50-gram OGTT screening portion of the two-step method when screening for GDM.7
The third article is a cohort study that compares the one-step method versus the two-step method for screening and diagnosing of gestational diabetes. This article was selected because it compares both methods providing percentages of what method is more accurate to diagnose GDM. In addition, the article takes risk factors, pregnancy outcomes and incidence of GDM to obtain results.
1. Coustan D. Gestational Diabetes Mellitus. Clinical chemistry. 2013; 59(9): 1310-1321. DOI: 10.1373/clinchem.2013.203331
2. Wang P, Lu MC, Yu CW, Yan YH. Influence of the Time of Day and Fasting Duration on Glucose Level following a 1-Hour, 50-Gram Glucose Challenge Test in Pregnant Women. PLoS ONE. 2014; volume 9(11): e112526. doi: 10.1371/journal.pone.0112526
3. Elham H, Mohsen J, Ashraf A. Incidence, risk factors, and pregnancy outcomes of gestational diabetes mellitus using one-step versus two-step diagnostic approaches: A population-based cohort study in Isfahan, Iran. Diabetes Research and Clinical Practice. 2018; volume 140: 288-204 https://doi.org/10.1016/j.diabres.2018.04.014
Review of evidence
The first study is a review article by Coustan D. R., Gestational Diabetes Mellitus 2; this article provides information about different methods and approaches to diagnose gestational diabetes, including controversies and current recommendations.2 In addition, he reviews the obstetric medical management of GDM, both during labor and post-partum, time and mode of delivery and the implications of gestational diabetes for both the mother and the fetus.
Gestational diabetes was first observed back in 1882 by J. Matthews Duncan. In the 1950s W.U. P Jackson observed in the 1950s that women with gestational diabetes had a higher probability of undergoing fetal macrosomia and stillbirth. The term gestational diabetes was finally adopted in 1957, and at that time the method used to diagnose diabetes consisted of 3 hour 100-gram OGTT. Following these observations and definitions of gestational diabetes, the question that pregnancy perhaps altered the OGTT results was raised. The O’Sullivan and Mahan study was performed in 1964 and reported the results of 752 pregnant women between the second and third trimester using the 3 hour 100-gram OGTT to diagnose gestational diabetes and with the results obtained they noted that perhaps OGTT was affected by the state of pregnancy. The standard deviation cut-offs were 1, 2, and 3 standard deviations for each of the 4 values. Thus, a second data set of 3-hour OGTT was performed with 1013 women previously pregnant; however, the OGTT was performed in the non-pregnant state and the diagnostic criteria included two abnormal glucose values instead of one abnormal value. This was applied to avoid dependence on a single test result to be used as a diagnostic result.
The studies mentioned above revealed that the use of the 2 standard deviations above the mean values resulted in a similar percentage of 1.99 % of prevalence of gestational diabetes in comparison to the prevalence of diabetes in nonpregnant women. This study also revealed that 22.6% of individuals formerly diagnosed with gestational diabetes mellitus would develop diabetes within the following 8 years. The original O’Sullivan and Mahan values derived from the original study were as followed: fasting 90 mg/dL (5.00 mmol/L), 1 hour 165 mg/dL (9.16 mmol/L), 2-hour 143 mg/dL (7.94 mmol/L), 3-hour 127 mg/dL (7.05 mmol/L). These were raw rounded numbers widespread in the 1970’s. The values were based on venous blood and to analyze the values the Somogyi Nelson technique was used. The laboratories switched to plasma/ serum measurements versus the venous whole blood sampling, thus why original values were adjusted. The National Diabetes Group (NDDG) proposed different thresholds taking into account the difference between whole blood glucose and plasma glucose. Two sets of thresholds were proposed, both derived from the O’Sullivan and Mahan criteria and referred to as NDDG and Carpenter and Coustan (C&C). NDDG modification plasma values are: fasting 105 mg/dL (5.83 mmol/L), 1 hour 190 mg/dL (10.55 mmol/L), 2-hour 165 mg/dL (9.16 mmol/L), 3-hour 145 mg/dL (8.05mmol/L). The C&C modification plasma values are: fasting 95 mg/dL (5.27 mmol/L), 1 hour 180 mg/dL (9.99 mmol/L), 2-hour 155 mg/dL (8.60 mmol/L), 3-hour 140 mg/dL (7.77mmol/L). Both NDDG and C&C criteria were compared by using the original O’Sullivan methodology and they were 95% confidence limits of the original values mentioned above. The 2 sets of criteria are accepted by American College of Obstetricians and Gynecologists (ACOG) and the American Diabetes Association (ADA) and are still being used as a current alternative recommendation. However, in 2011 a new diagnostic criterion was incorporated into the ADA recommendations.
The O’Sullivan criteria thresholds were derived and validated specifically on the ability to predict the development of diabetes in the mother, however, it was preferable to obtain evidence-based criteria based on adverse pregnancy outcomes. Additionally, other diagnostic tests were being used including the World Health Organization (WHO) criteria based on the one-step method, 2 hour 75-gram OGTT in which the same thresholds are held for pregnant and nonpregnant women. The non-pregnant criteria values are as follow: fasting 126 mg/dL (6.99 mmol/L) and 2 hours 140 –199 mg/dL (8.27–11.05 mmol/L). The diagnostic values for diabetes include a fasting value of 126 mg/dL or a 2-hour value of 200 mg/dL (11.1 mmol/L). Due to the variation of diagnostic studies being used the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) study was designed.
The HAPO study was intended to evaluate the relationship of plasma glucose concentrations of the 2 hour 75-gram OGTT in relation to the different primary (macrosomia, primary cesarean sections, neonatal hypoglycemia and cord-blood serum C peptide) and secondary (preeclampsia, neonatal body fat, admission to the neonatal intensive care unit (NICU), and preterm birth) pregnancy outcomes with the idea to provide evidence-based data based on various adverse pregnancy outcomes.
The HAPO study performed blinded OGTT to over 23,000 pregnant women between the late second and early third trimester in 14 different centers involving 9 different countries. The study was based on the association between the primary and secondary pregnancy outcomes and the relationship with each of the OGTT values using the two-step method. Although the HAPO study did not address the direct relationship between the fasting and the 2-hour value with adverse pregnancy outcome, according to Coustan D2 various studies reported an association with adverse pregnancy outcomes. The HAPO results showed a direct association between each of the OGTT values performed at 24 –32 weeks’ gestation. This direct relationship supports the theory that maternal hyperglycemia leads to fetal hyperinsulinemia, therefore, increasing fetal fat deposition leading to macrosomia. This theory is also known as the Pedersen hypothesis.
The data was presented to the International Association of Diabetes in Pregnancy Study Groups (IADPSG) to provide recommendations in combination with the HAPO study. The identification and diagnosis of GDM was 16.1% of pregnant women with an increase of 18% due to pregnant women that were excluded due to prior high glucose values. The IADPSG recommendations suggest testing women with risk factors or all the pregnant women during the first prenatal visit versus late second trimester. The ADA recommends testing women only with risk factors. Both organizations recommend the one-step method. The IADPSG has been endorsed by ADA, but not yet endorsed by ACOG. ACOG endorses the two-step method universal screening to all pregnant women during the late second trimester regardless of high or low-risk factor.
The second article by Wang P, Lu M-C, Yu C-W, Yan Y-H. Influence of the Time of Day and Fasting Duration on Glucose Level following a 1-Hour, 50-Gram Glucose Challenge Test in Pregnant Women7. The study was aimed to investigate how fasting duration (FD) and the time of day (TD) affected the results of the OGTT, to include morning, afternoon, and/or night testing. A hospital-based study was conducted using a 1000 bed teaching hospital in Taiwan. The period of the study was between March through October of 2011. The pregnant patients underwent a 50-gram OGTT at 24–28 weeks of gestation. The patient exclusion data included a history of gestational diabetes mellitus, pre-pregnancy diabetes mellitus, and multifetal pregnancies. TD measurement was defined by the time of the blood drawn and subtracting one hour. The glucose levels were measured using venous plasma applying the glucose oxidase method. Further data was obtained by questionnaires and interviews providing basic data for each patient including maternal age, the number of pregnancies, pre-pregnancy weight, reported weight gain during gestational state, and the FD. The FD was defined as the time passed from the patient’s last meal.
All the patients were divided into 9 groups and assigned as the TD and FD groups. TD was between 9 AM–12 PM in the morning, 12 PM –5 PM in the afternoon and 5 PM –10 PM at night. The FD was the time passed from the patient’s last meal prior to the OGTT at 1-hour, 1 to 2- hour, and 2-hour. To analyze the distribution of the known patient’s risk factors, the chi-square test was used to analyze glucose levels in each group. The risk factors included age, nulliparity, pre-pregnancy body mass index and weight gained during pregnancy. The definition of weight gain was the “percentage of gestational weight gain = [(weight at the time of the 50-gram GCT 2 pre-pregnancy weight)/pre-pregnancy weight] x 100”7. The percentage of gestational weight gain was then categorized into four groups in 10% increments.
Originally published 15.10.2019