Scientific Evidence for Different Options for GDM Screening and Management: Controversies and Review of the Literature

Background. Gestational diabetes (GDM) affects up to 7% of pregnant women and is associated with several maternal and perinatal morbidities. International organizations suggest several different recommendations regarding how to screen and to manage GDM. Objective. We aimed to analyze the most important and employed guidelines about screening and management of GDM and we investigated existing related literature. Results. We found several different criteria for screening for GDM, for monitoring GDM, and for starting pharmacological therapy. When using IADPSG criteria, GDM rate increased, perinatal outcomes improved, and screening became cost-effective. Compared to no treatment, treatment of women meeting criteria for GDM by IADPSG criteria but not by other less strict criteria has limited evidence for an effect on adverse pregnancy outcomes.


Introduction
Gestational diabetes (GDM) can be broadly defined as glucose intolerance during pregnancy that affects women without previous diagnosis of diabetes or unknown state. The incidence is about 7% worldwide and this rate has been growing during the last decades and is estimated to increase in the future. The most important risk factors are maternal overweight and obesity, age greater than or equal to 35 years at delivery, hypertension, metabolic syndrome, nonwhite ethnicity, family history of diabetes mellitus, prior unexplained stillbirth, prior infant with congenital anomaly (if not screened during that pregnancy), prior macrosomic infant, history of gestational diabetes, chronic use of steroids, glycosuria, and known impaired glucose metabolism [1].
The importance of GDM is linked to the consequences of pregnancy and also after pregnancy to both mother and newborn. Hyperglycemia in the mother causes abnormal metabolism while in the fetus it causes hyperinsulinemia and its consequences, and incidence of complications is inversely proportional to glucose control. Macrosomia, polyhydramnios, operative delivery, shoulder dystocia, birth injury, perinatal mortality, hypertensive disorders and preeclampsia, congenital malformations (OR: 1.2-1.4), and risk of cesarean delivery are higher in women with GDM; in the long term, women with GDM have a higher risk of developing type 2 diabetes mellitus and cardiovascular diseases; long-term sequelae for offspring are obesity and metabolic syndrome. Approximately 50% of women identified as having GDM will develop frank diabetes within 10 years [2].
To prevent or decrease the risk of GDM, weight loss before pregnancy and cardiovascular exercise could be useful. In fact, aerobic exercise for 35-90 minutes 3-4 times per week during pregnancy is associated with a significantly higher incidence of vaginal delivery and a significantly lower incidence of cesarean delivery, with a significantly lower 2 BioMed Research International incidence of gestational diabetes mellitus and hypertensive disorders [3]. Prompt diagnosis and management are important to reduce worse pregnancy outcomes.
Nonetheless, screening, management, and follow-up of GDM are controversial on international organizations recommendations.

Screening Controversies
The aim of screening is to identify asymptomatic pregnant women at high risk of developing GDM. Screening appears to be cost-effective for prevention of obstetrical adverse outcomes and long-term consequences of GDM [4].
Regarding the effect of screening [1] on obstetrical outcomes, there are many controversies: (i) Selective Screening. Only women with risk factor for GDM are offered to be screened, that is, age > 25 years; ethnic origin Hispanic, African, Native American, South or East Asian, or Pacific Islander; BMI > 25; previous personal or family history of impaired glucose tolerance; or history of adverse obstetric outcomes associated with GDM.
(ii) Universal Screening. All women are subjected to screening; in developed countries where overweight and obesity are widespread health problems, this could be the best choice to avoid undiagnosed GDM.
Universal screening is the most commonly adopted method in the USA, while in other countries such as Italy the selective approach is preferred [5].
(b) When identifying the population, it is essential to decide the right time to screen.
Women with risk factors and high suspicion of undiagnosed type 2 DM (i.e., obesity, metabolic syndrome) should be screened before pregnancy or at the first prenatal visit (early screening). About 5-10% of women with risk factors have early GDM, and these represent 40% of all women with GDM.
In the absence of early screening or for women negative to early screen, universal screening should be performed at 24 to 28 weeks.
(c) Now we discuss how to screen. Screening for GDM is somewhat controversial and can be performed either with a One-Step or with a Two-Step approach.
(i) One-Step Approach. GDM screening is performed as an oral 75 g glucose load followed by glucose blood measurement 1 and 2 hours later. A positive result is defined as one value higher than target values. This approach is based on HAPO study [6] and is suggested by IADPSG [7], WHO [8], FIGO [5], and ADA [9]. In fact, HAPO study in 2008 demonstrated a direct correlation between maternal glucose levels and increased birth weight and neonatal hyperinsulinemia.
(ii) Two-Step Approach. GDM is performed as a 50 g onehour oral glucose load (glucose challenge test, GCT), given to nonfasting women, with a venous glucose measurement one hour later. A positive result is defined as a blood glucose value higher than 130, 135, or 140 mg/dL; the most common value used is 135 mg/dL (ACOG) [4]. Positive screening test is followed by a diagnostic test as an oral glucose tolerance test (GTT) that consists of a beverage with 100 g of glucose, with venous glucose measurement at fasting and after 1, 2, and 3 hours. A positive result is defined as 2 values higher than target values.
(d) Recommendations of international organizations are not standardized. Table 1 shows the different populations and times to screen and the thresholds used by the most important international organizations worldwide, updated to the latest recommendations [4,5,[8][9][10][11][12].
We found a large number of studies in international literature comparing One-Step and Two-Step test and different glucose thresholds. When evaluating the best screening method, clinically significant improvements in maternal and neonatal outcomes were analyzed. Two are the most significant studies: (1) Australian Carbohydrate Intolerance Study in Pregnant Women (ACHOIS) Trial Group: the aim was to determine whether treatment of GDM reduced the risk of perinatal complications.
(2) National Institute of Child Health and Human Development (NICHD) Maternal-Fetal Medicine Units (MFMU) Network Study: the intent was to determine whether treatment of women with mild GDM reduces perinatal and obstetrical complications.
Both trials agree with the rule of IADPSG criteria adoption on reducing fetal birth weight over the 90th percentile and the risk of developing maternal preeclampsia.
Furthermore, to compare the One-Step test to the Two-Step test, several possible study designs have been evaluated in the literature. We can summarize the literature in five groups.
(1) RCTs in which women underwent both the One-Step and the Two-Step tests and the women positive for the One- Step but negative for the Two-Step test were randomized to treatment of GDM versus no treatment: the only such RCT is by Weiss et al. [12], who unfortunately do not report outcomes specific to this group of women.
(2) RCTs of treatment versus no treatment of GDM, focusing on women positive for the One-Step but negative for the Two-Step test: we found 6 RCTs comparing insulin or glyburide to placebo or routine care, and all of them used a Two-Step approach with different glucose thresholds ( Table 2) [13][14][15][16][17][18]. In this group, ACHOIS trial by Crowther    [21] One-Step (2 h, 75 g) Two- Step (50 g, 1 h; 100 g, 3 h) 4.3% versus 0.0% Maternal and neonatal outcomes and neonatal outcomes have been analyzed only in 2 studies. Sevket et al. 's RCT reveals that GDM-negative women by IADPSG had better perinatal outcomes than GCT-negative women and GCT-positive women with a negative OGTT; Scifres et al. 's RCT concludes that rates of macrosomia, cesarean delivery, and pregnancy-induced hypertension were also similar between groups.
Interestingly, Meltzer et al. 's RCT analyzed costs of the One-Step compared to the Two-Step test: while the Two-Step test involved the lowest costs, the One-Step test recognized higher GDM rate. The authors' conclusion was in favor of the Two-Step test because the universal glucose screen with 50 g glucose load is an inexpensive, easy-to-administer tool for GDM screening, especially with the use of a lower diagnostic cut-off.
(4) Prospective non-RCTs or retrospective studies comparing incidence of GDM and/or outcomes between the One-Step and Two-Step methods: we found 9 retrospective studies comparing the One-Step approach with IADPSG criteria and Two-Step approach with ACOG criteria (Table 4) [22][23][24][25][26][27][28][29][30]. Regarding GDM rate, the incidence is higher for women undergoing the One-Step test in all the studies analyzing this issue. Only two studies concluded that IADPSG One-Step approach is useful to avoid worse pregnancy outcomes, in particular LGA and macrosomia [22,27], while five studies did not find statistically significant differences between the two approaches on outcomes [23][24][25][26]28].
(5) Prospective non-RCTs or retrospective studies reporting outcomes of women meeting criteria for GDM based on the One-Step test but not on the Two-Step test: we found 8 retrospective cohort studies (Tables 5 and 6) [31][32][33][34][35][36][37][38], but no study evaluated whether treatment of women meeting criteria for GDM by IADPSG criteria (One-Step test) but not by other less strict criteria has an effect on adverse pregnancy outcomes compared to no treatment. When analyzing outcomes, macrosomia was more common in women positive on 75 g IADPSG criteria but negative on CDA criteria and positive on 75 g IADPSG criteria but negative on NICE criteria.

Conclusion
Despite continuing controversy regarding whether the One- Step test or the Two-Step test should be used for GDM screening, we identified very limited evidence regarding whether treatment of women meeting criteria for GDM by IADPSG criteria (One-Step test) but not by other less strict criteria has an effect on adverse pregnancy outcomes compared to no treatment. Moreover, in none of the included studies was the study group with milder disease treated for GDM (positive for IADPSG criteria, but negative for less stringent criteria). We also found a large variety of different criteria (IADPSG, WHO, NICE, CDA, and C&C) for screening for GDM used in the literature. Therefore, it is not surprising that societies such as IADPSG, WHO, and FIGO recommend the One- Step approach (assuming that identification of women with milder GDM might have benefits for them and their babies), while others such as ACOG still recommend the Two-Step approach for screening.
Only well designed RCTs comparing the One-Step versus the Two-Step approach including huge populations could answer this question.

Management Controversies
The aim of management is to reduce the risk of adverse outcomes for the mother and the fetus. Several studies demonstrated that treatment can be effective in reducing adverse outcomes in GDM patients.
Regarding the effect of management on obstetrical outcomes, there are many variables that can play a role; these include (i) criteria to start therapy after diet alone: once GDM has been diagnosed, patients start nonpharmacological therapy, that is, well balanced diet based on BMI and physical exercise, but it is unclear how long this evaluation period should last before deciding to start pharmacological treatment; a recent systematic review found inconclusive evidence for the threshold value to start medical therapy [4]; (ii) type of initial therapy: insulin and oral hypoglycemic agents are equally effective and can be used as firstline therapy [5]; (iii) dose and frequency of initial therapy: therapy should start at the lower effective dose and then increase based on glucose monitoring; (iv) frequency of glucose monitoring: when patients start therapy, either diet or pharmacological therapy is important to establish whether glycemic control has been reached; while patients in pharmacological therapy should perform glycemic checks at least four times daily (fasting and after 1 or 2 hours from three main meals: breakfast, lunch, and dinner), there is uncertainty for women in nonpharmacological therapy [5]; (v) target glucose values: RCTs to identify ideal glycemic targets have not been performed, but ADA and ACOG recommend a threshold of 140 mg/dL at 1 hour postprandially or 120 mg/dL at 2 hours postprandially as glycemic targets to reduce the risk of macrosomia [5,9]; (vi) criteria for pharmacologic therapy dose adjustment: when choosing between tight versus very tight glycemic control, we have to consider risk of hypoglycemia, effects of non-well-controlled GDM, and women compliance; (vii) criteria for adding or switching pharmacologic therapy; (viii) fetal monitoring; (ix) time to delivery: women with GDM with good glycemic control and no other complications can be managed expectantly, while if GDM is not well controlled with therapy, induction of delivery could be considered [5].
We analyzed the literature to figure out which management is the best to follow. When evaluating RCTs [16,17,[39][40][41][42][43][44][45][46][47][48][49][50][51] which included criteria for starting pharmacologic therapy in women with GDM, the most common frequency for glucose monitoring was four times per day (i.e., when fasting and after each main meal). The effect of therapy on GDM was assessed using fasting of 90 (or 95) mg/dL and 2 hours of 120 mg/dL as blood glucose target values. Importantly, we found several different criteria for starting pharmacologic therapy after a period of diet alone, with the majority using very tight criteria of either 1 or 2 values in oneor two-week period higher than the target values, of which half used only 1 value and half used 2 values, while any RCT used less tight criteria (i.e., >50% glucose values higher than target values) (Table 7) [16,17,[39][40][41][42][43][44][45][46][47][48][49][50][51]. Finally, when analyzing international organizations guidelines on management of GDM, while there is consensus about glycemic targets, we found different opinions about therapy, monitoring, and time of delivery (Table 8). Moreover, there is limited information regarding other important criteria about dose and frequency of therapy, dose adjustment, and adding or switching pharmacologic therapy.
Moreover, the application of the IADPSG was associated with an increase in GDM prevalence up to 3.5-fold, as well as significant improvements in pregnancy outcomes (gestational hypertension, prematurity, CD, number of LGA and SGA, and 1-minute Apgar scores <7), and was cost-effective. This could be presumably by permitting the treatment of a greater number of women at risk for pregnancy complications [22].

Conclusion
There are many unsolved questions concerning GDM management. Analyzing the literature in detail, we found different criteria for screening for GDM, for monitoring GDM, and for starting pharmacological therapy. The hope is to reach universally approved and shared recommendations to improve health care and reduce costs and adverse outcomes for women with GDM and their babies.   Education for lifestyle change (exercise and diet) 1 value higher in 1 week F: fasting; GA: gestational age; IBW: ideal body weight; BW: body weight; BMI: body mass index. A Fasting and 1 hour after each main meal: breakfast, lunch, and dinner. B Fasting, before lunch and dinner, 2 hours after main meals, breakfast, lunch, and dinner, and at bedtime. C Fasting, preprandial before lunch and dinner, 1 and 2 hours after each main meal: breakfast, lunch, and dinner. D Fasting, preprandial before lunch and dinner, 1 hour after each main meal: breakfast, lunch, and dinner. E Fasting and 2 hours after each main meal: breakfast, lunch, and dinner.